Hormone Research Review

Menopausal Symptoms And Cardiovascular Health

2011-10-27T22:45:00.016-05:00

by Etsuko Ueda, October 2011

Effects of Menopause on Cardiovascular Health

Epidemiological data indicates that the incidence of cardiovascular diseases is greater in men aged 30~50 yr compared with women of similar age. Among women, the incidence of cardiovascular diseases is greater in postmenopausal compared with premenopausal women, and the advantage women had over men before menopause largely diminishes in postmenopause years.

Menopause and risk of cardiovascular disease: the Framingham study. W B Kannel, M C Hjortland, P M McNamara, T Gordon 1976

Age at menopause as a risk factor for cardiovascular mortality. Y T van der Schouw, Y van der Graaf, E W Steyerberg, J C Eijkemans, J D Banga 1996

Population-based study of age at menopause and ultrasound assessed carotid atherosclerosis: The Tromso Study. O Joakimsen, K H Bonaa, E Stensland-Bugge, B K Jacobsen 2000

Sex differences and the effects of sex hormones on hemostasis and vascular reactivity. D W Schwertz, S Penckofer 2001

The unavoidable implication is that the ovarian hormones (estradiol and progesterone) somehow protect women against cardiovascular diseases. Many experiments have been conducted on women and men as well as animals, and there is no doubt that the ovarian hormones exert profound effects on cardiovascular functions.

The ovarian hormones affect blood supply through blood vessel dilation, contraction, and permeability by directly acting upon the layers of the blood vessel walls as well as through autonomic nerve system (for a review of underlying mechanism, see Gender, sex hormones, and vascular tone., Julia M. Orshal and Raouf A. Khalil, 2004).

Amongst, the most studied seems what is known as endothelium dependent flow-mediated dilation, a mechanism of the inside vessel walls to sense the blood flow increase and adjust the vessel size accordingly. Nitric oxide is considered to be the main mediator of blood vessel dilation (to relax vascular smooth muscles), and ovarian hormones can facilitate the endothelium's production of Nitric Oxide (For a review, see Hormonal modulation of endothelial NO production. Sue P Duckles, Virginia M Miller 2010).

The amount of blood supplied to a certain part of body is constantly changing reflecting the changes in conditions and needs. When there is a heat build-up in the body, surface blood flow increases to radiate the heat. When eating, blood supply to the digestive system increases to activate digestive function. When engaging in mental activity, blood flow to the brain is increased. When a certain group of muscles are used, blood flow to those muscles increases, and so forth.

Part of it is controlled by the autonomic nerve system neurotransmitter acetylcholine and co-transmitters such as calcitonin gene-related peptide (CGRP), part of it is controlled by flow-mediated dilation, and both of which are dependent on the endothelium's ability to produce NO and other blood vessel dilating substances as opposed to the contracting substances such as endothelin.

If the vascular smooth muscles do not relax and expand when there is more blood flow to the area, the blood flow speed, resistance, and pressure increase, which causes more ware and tare to the heart and the vessels, meanwhile the blood supply itself is reduced, depriving the cells of necessary oxygen and nutrients. In other words, endothelium dependent dilation is an important indicator of blood supply and cardiovascular health and risk in general. (for an overview, see Endothelial Dysfunction and Coronary Artery Disease, Paulo R. A. Caramori, Alcides J. Zago 1997).

The endothelium dependent flow-mediated dilation is not a measure of stiffness, although stiffness can reduce endothelium dependent flow-mediated dilation (Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium., Xinqi Peng, Saptarsi Haldar, Shailesh Deshpande, Kaikobad Irani, David A Kass, 2003). In general, the strength of endothelium dependent dilation is evaluated relative to endothelium independent dilation, which can be induced by administering NO producing substances such as nitroglycerin, glyceryl trinitrate or sodium nitroprusside, and is thought to be equally affected by stiffness as endothelium dependent dilation.

The endothelium dependent flow-mediated dilation is a reflection of how much endothelium is stimulated by the shear stress generated by the blood flow increase (Wall Shear Stress - an Important Determinant of Endothelial Cell Function and Structure - in the Arterial System in vivo. Discrepancies with Theory., Robert S Reneman, Theo Arts, Arnold P G Hoeks, 2006). In other words, the ability to expand the blood vessel diameter is a reflection of the endothelium's ability to sense and react to the shear stress with NO production, which in turn relaxes the vascular smooth muscle.

The endothelium dependent flow-mediated dilation is a well established phenomena that can be used in clinical evaluation as a sign of "the fundamental and very early step in the development of atherosclerosis" ([Regulation and dysfunction of endothelium-dependent vasomotricity. What can be applied to clinical practice?], J M Halimi, Y Lebranchu 2003).

It is also well established that low estrogen + progesterone state (post menopause or early follicular phase in normal menstrual cycle) reduces endothelium dependent flow-mediated dilation, and a higher estrogen + progesterone state (supplementation or late follicular to mid luteal phase) increases endothelium dependent dilation.

Young reproductive age women show an overwhelming pattern of increased systemic vascular reactivity (measured by flow-mediated dilation) and reduced blood pressure during the late follicular phase right before ovulation, corresponding to the estradiol and NO levels. It is reflected on both central (aortic) and peripheral blood pressures, which were lowest during late follicular phase (Central, peripheral and resistance arterial reactivity: fluctuates during the phases of the menstrual cycle. Eric J Adkisson, et. al. 2010).

In addition to the expansion of blood vessel diameter, the effects can be shown at its underlying bio-chemical levels, as amount of NO production, number of estrogen receptors, and amount of the proteins involved in the NO production (Vascular Endothelial Estrogen Receptor {alpha} is Modulated by Estrogen Status and Related to Endothelial Function and eNOS in Healthy Women. Kathleen M Gavin, Douglas R Seals, Annemarie E Silver, Kerrie L Moreau 2009). During a normal menstrual cycle, they observed that the estradiol level changed more than 2 time and progesterone level more than 5 times from the early follicular low hormone phase (2-6 d after onset of menses) to early luteal high hormone phase (24-48h after positive ovulation test). Corresponding to this change, the number of estrogen receptors in endothelium were 30% less in low hormone phase compared to high hormone phase.

Endothelium dependent dilation and menopause

Since menopause is a result of ovarian hormone decline, there is little surprise that compared to young reproductive age women, postmenopausal women show reduced endothelial dependent dilation (Comparison of forearm endothelial function between premenopausal and postmenopausal women with or without hypercholesterolemia. Mitsuhiro Sanada,et. al. 2003). During the early postmenopause years (48 to 63 yrs olds were tested) estradiol level is comparable to low estradiol phase of normal menstrual cycle and so is the number of estrogen receptors. The progesterone level is much lower than that of early follicular, and the flow-mediated dilation can be even lower (by about 30%) than the early to mid follicular phase (2-8 d after onset of menses) (Vascular Endothelial Estrogen Receptor {alpha} is Modulated by Estrogen Status and Related to Endothelial Function and eNOS in Healthy Women. Kathleen M Gavin, Douglas R Seals, Annemarie E Silver, Kerrie L Moreau 2009).

Compared to young reproductive age women, men of similar age show lower endothelium dependent flow-mediated dilation comparable to that of low estrogen + progesterone phase of women (Modulation of Endothelium-Dependent Flow-Mediated Dilatation of the Brachial Artery by Sex and Menstrual Cycle, Masayoshi Hashimoto, et. al. 1995). Postmenopausal women without hormone therapy show endothelium dependent flow-mediated dilation as low as that of age matched men. (Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels., K K Koh, J W Son, J Y Ahn, S K Lee, H Y Hwang, D S Kim, D K Jin, T H Ahn, E K Shin 2001). These observations correspond well to the epidemiological findings that the cardiovascular health advantage the reproductive age women have over men largely diminishes with menopause.

Another key factor that is under hormonal influence and has impact on cardiovascular health is the sympathetic nerve activity. There too women have advantage over men, and the advantage does not seem to completely disappear after menopause even in women with hypertension, although menopausal symptoms are associated to hyperactive sympathetic nerve activity and underactive para sympathetic nerve activity.

The effect of gender on the sympathetic nerve hyperactivity of essential hypertension. A J Hogarth, A F Mackintosh, D A S G Mary 2006

Sympathetic nerve hyperactivity of essential hypertension is lower in postmenopausal women than men. A J Hogarth, J Burns, A F Mackintosh, D A S G Mary, 2008

Caffeine and Blood Pressure Response: Sex, Age, and Hormonal Status. Noha H Farag, et. Al. 2010

After surgical menopause, endothelial function rapidly declines: 1 week after ovariectomy, significant decreases of flow-mediated dilatation were observed (Rapid changes of flow-mediated dilatation after surgical menopause. Masahide Ohmichi, et. al. 2003).

The deterioration reaches maximum in 12 weeks in rats (measured by dilation response to ACh) (Long-term effects of ovariectomy and estrogen replacement treatment on endothelial function in mature rats., Farzad Moien-Afshari, Emma Kenyon, Jonathan C Choy, Bruno Battistini, Bruce M McManus, Ismail Laher, 2003). 12 weeks sounds consistent with my personal experience. I started to notice the unmistakable signs of menopausal symptoms in full swing about 3 months after stopping estrogen.

Note: Hormonal status is by no means the only thing that affect endothelial function. The release of NO by the endothelial cell can be up-regulated by estrogens, exercise, dietary factors, etc., and down-regulated by oxidative stress, smoking, oxidized low-density lipoproteins, etc (for a review, see Endothelial Dysfunction and Vascular Disease., Paul M Vanhoutte, Hiroaki Shimokawa H, Eva H C Tang, Michel Feletou, 2009).

Since the menopausal symptoms such as hot flashes are also related to the drop in ovarian hormones, you would expect a substantial correlation between menopausal symptoms and cardiovascular health.

As expected, the severity of hot flash is associated with a reduced endothelium dependent flow-mediated dilation early in menopause. However, its expected consequence such as atherosclerosis (measured as carotid intima-media thickness), does not seem to develop until later in menopause (Endothelial Function, But Not Carotid Intima-Media Thickness, Is Affected Early in Menopause and Is Associated with Severity of Hot Flushes., Aris Bechlioulis, et. al. 2010).

Interestingly, the menopausal symptoms seem to be the one affected by the factors influencing the cardiovascular health. Not the other way round. In other words, the severity of menopausal symptoms seems to be another manifestation of cardiovascular health. A significant correlation between the severity of menopausal symptoms and factors known to increase cardiovascular disease risk such as stress, smoking, and less physically active was observed in a large multi-racial/ethnic sample of 16,065 women aged 40-55 years in the U.S. (Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age., E B Gold, B Sternfeld, J L Kelsey, C Brown, C Mouton, N Reame, L Salamone, R Stellato 2000).

In Sweden, a large population-based sample of 5523 women, aged 46 to 57 years was studied. Hot flash and night sweats were analyzed against common cardiovascular health indicators such as cholesterol, BMI, and blood pressures. A small but significant correlation emerged (Menopausal Complaints Are Associated With Cardiovascular Risk Factors., Gerrie-Cor M Gast., et. al. 2008).

Taken together, these observations suggest that the severity of menopausal symptoms such as hot flashes reflect much more than the hormonal decline.

According to a review by Gambacciani and Pepe, 2009 (Vasomotor symptoms and cardiovascular risk. ) Menopausal hot flushes correlate with lower level of plasma antioxidant activity, an increased cardiovascular reactivity to stressful situations, elevated cholesterol, higher sympathetic nerve activity, impaired flow-mediated dilation, hypertension and a higher risk of aortic calcification. All the available findings indicate that hot flushes can be seen as a marker for underlying vascular changes among mid-life, otherwise healthy, menopausal women.

When you examine the people who have succumbed to cardiovascular illnesses, impairment of endothelium dependent dilation seems always present. Impaired endothelium-dependent dilation was observed both at the coronary and peripheral circulation in post-menopausal women with angina and normal coronary angiograms (Acute and mid-term combined hormone replacement therapy improves endothelial function in post-menopausal women with angina and angiographically normal coronary arteries. M Sitges, et al. 2001). Elderly ischemic stroke patients (58.3% male, median age 73 years) show impaired endothelial dependent dilation corresponding with the severity and poor outcome (Brachial arterial flow mediated dilation in acute ischemic stroke., D Santos-Garcia, M Blanco, J Serena, S Arias, M Millan, M Rodriguez-Yanez, R Leira, A Davalos, J Castillo, 2009). Menopausal women with hypertension show reduced endothelium dependent flow-mediated dilation (Effect of estrogen replacement therapy on endothelial function in peripheral resistance arteries in normotensive and hypertensive postmenopausal women. Y Higashi, et.al. 2001). Conversely, people with reduced endothelium dependent flow-mediated dilation are likely to progress to the next stage of the disease process such as hypertension (Flow-mediated vasodilation and the risk of developing hypertension in healthy postmenopausal women. Rosario Rossi, 2004).

Effects of hormone therapy

It is well established that menopausal hormone therapy improves endothelial dependent dilation.

Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. E H Lieberman, et. at.,1994, (oral estradiol at a dose of 1 mg/d or 2 mg/d)

Hormone replacement therapy is associated with improved arterial physiology in healthy post-menopausal women. J A McCrohon, et. al. 1996. (premenopause, postmenopause 2+yrs users of standard ET or HRT, postmenopause never users : 9.6, 6.2, 4.4%)

Effects of transdermal and oral estrogen supplementation on endothelial function, inflammation and cellular redox state. H Kawano, et al. 2003 (The flow-mediated endothelium-dependent dilation of the brachial artery increased for both. However, serum levels of thioredoxin (a marker of the cytoprotective antioxidant system) decreased for both, and high-sensitivity C-reactive protein (hs-CRP) incresed for oral Premarin. 12 weeks, No progesterone.)

Hormone replacement effects on endothelial function measured in the forearm resistance artery in normocholesterolemic and hypercholesterolemic postmenopausal women. Mitsuhiro Sanada, et. al. 2002, (conjugated equine estrogen (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) daily for 6 months)

Blood pressure control and hormone replacement therapy in postmenopausal women at risk for coronary heart disease. James A McCubbin, Suzanne G Helfer, Fred S Switzer 3rd, Thomas M Price 2002

Hormone therapy's relation to atherosclerosis has been observed as expected. As you get older, the effects of no hormone therapy become more pronounced.

Arterial intima-media thickness: site-specific associations with HRT and habitual exercise., Kerrie L Moreau, Anthony J Donato, Douglas R Seals, Frank A Dinenno, Sharon D Blackett, Greta L Hoetzer, Christopher A Desouza, Hirofumi Tanaka 2002

The effect of hormone therapy is almost immediate (within 24 hours, if not instant).

Acute and mid-term combined hormone replacement therapy improves endothelial function in post-menopausal women with angina and angiographically normal coronary arteries. M Sitges, et al. 2001 (Impaired endothelium-dependent vasodilation exists both at the coronary and peripheral circulation in post-menopausal women with angina and normal coronary angiograms. Flow-mediated dilation improves in these women after short (24 h) and mid-term (6 weeks) therapy with 50microg transdermal oestradiol irrespective of concomitant medroxyprogesterone use. An abnormal coronary artery response to acetylcholine was observed in all women as well as impaired brachial flow-mediated dilation. Brachial flow-mediated dilation significantly increased after 24 h of 100 microg/day oestradiol treatment, clear trend for blood clot in 6 weeks)

Menopausal hormone therapy can restore the endothelium dependent flow-mediated dilation and cardiovascular health advantage. It has been confirmed by many researchers with various types of estrogen, progesterone, or the combination of the two. However, it is very important to note that all studies that used anything other than transdermal estradiol + natural progesterone (=bioidentical to human's) and bothered to look at various cardiovascular health indicators, observed diminished endothelium dependent dilation effects or unwanted side effects such as higher blood coagulation and inflammation factors, and blood clot risk (for a review, see Safe Use of Hormones: the Hard Evidence). Amongst, the Women's Health Initiative (WHI) clinical trial results may be still fresh in many people's mind (for a review of WHI studies, see Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Jacques E. Rossouw, et. al. 2009).

According to Sitruk-Ware's review, progesterone substitute drugs, such as medroxyprogesterone acetate (Provera, Amen, Cycrin), and norethindrone acetate (Aygestin, Norlutate), exert a partial detrimental effect on the beneficial actions of estrogens with regard to lipid changes, atheroma development, or vasomotion. (Progestins and cardiovascular risk markers., R Sitruk-Ware, 2000, Different cardiovascular effects of progestins according to structure and activity., A Nath, R Sitruk-Ware, 2008, )

When patients who suffered ischemic colitis were examined, none were using natural progesterone. They were using conjugated estrogens (Premarine), conjugated estrogens plus medroxyprogesterone acetate, 17beta-estradiol plus norethisterone, or estradiol valerate plus norgestrel, all of which turned out to be the cause of the rare ischemic colitis (Ischemic colitis in postmenopausal women taking hormone replacement therapy., S Zervoudis, T Grammatopoulos, G Iatrakis, G Katsoras, C Tsionis, I Diakakis, C Calpaktsoglou, S Zafiriou 2008).

Another example is a long term estrogen therapy without progesterone. Despite the fact that estrogen is well known for its facilitative effect on endothelium dependent dilation and NO production, the long term 17beta-estradiol 1mg daily proved to be not very beneficial for NO level. (Long-term effect of estrogen replacement on plasma nitric oxide levels: results from the estrogen in the prevention of atherosclerosis trial (EPAT)., Juliana Hwang, Wendy J Mack, Min Xiang, Alex Sevanian, Roger A Lobo, Howard N Hodis 2005)

Along with the endothelium dependent flow-mediated dilation, cardiovascular advantages of menopausal hormone therapy (and the high hormone phase of monthly cycle) was observed also on:

Reduced Vascular inflammation (Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels., K K Koh, J W Son, J Y Ahn, S K Lee, H Y Hwang, D S Kim, D K Jin, T H Ahn, E K Shin 2001)

Carotid arterial compliance (ability to expand) Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women. Kerrie L Moreau, et. Al. 2003),

Arterial intima-media thickness (atherosclerosis) (Arterial intima-media thickness: site-specific associations with HRT and habitual exercise. Kerrie L Moreau,et. al. 2002)

Vascular endothelial cell oxidative stress is reduced along with endothelium-dependent dilation improvement (Direct Evidence of Endothelial Oxidative Stress With Aging in Humans. Relation to Impaired Endothelium-Dependent Dilation and Upregulation of Nuclear Factor {kappa}B. Anthony J Donato, et. Al. 2007).

During the menstrual cycle, flow-mediated vasodilation changes along with the estrogen and progesterone levels and so does the frequency of the ischemic episodes, which is more frequent during low estrogen/progesterone phase, as you would expect.
Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina. H Kawano, T Motoyama, M Ohgushi, K Kugiyama, H Ogawa, H Yasue, 2001,

Increasing NO by other means such as by nitrite supplementation also have positive effects on cardiovascular system (yes, Viagra, Levitra, or Cialis will work also), in terms of endothelium-dependent dilation, artery stiffness, antioxidant effect, and anti-inflammation.

Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging., Amy L Sindler, Bradley S Fleenor, John W Calvert, Kurt D Marshall, Melanie L Zigler, David J Lefer, Douglas R Seals, 2011

Clinical Translation of Nitrite Therapy for Cardiovascular Diseases., John W Calvert, David J Lefer, 2009

Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk., Giuseppe M C Rosano, Antonio Aversa, Cristiana Vitale, Andrea Fabbri, Massimo Fini, Giovanni Spera 2005

Since the increased antioxidant activity is part of NO benefits on cardiovascular health, and that part of benefits may be obtained by supplementing antioxidant such as alpha-lipoic acid. It was shown to reduce vascular oxidative stress and inflammation, at least in rats.

Vascular oxidative stress and inflammation increase with age: ameliorating effects of alpha-lipoic acid supplementation., Lixin Li, Anthony Smith, Tory M Hagen, Balz Frei, 2010

Cardiovascular Protective Role Of Progesterone

Many researchers seems to be satisfied by simply demonstrating estrogen's effects on cardiovascular health and treating progesterone as a nuisance that can be potentially detrimental, but has to be tolerated to protect uterus from cancer. Is estrogen alone enough to protect your cardiovascular health? Not really. Actually, it can be detrimental to cardiovascular health in terms of blood clot risk and heart attach risk, even with the safest transdermal estradiol. The progesterone's preventative role against coronary artery spasm induced heart attaches has been known for a long time (The mechanism of coronary artery spasm: roles of oxygen, prostaglandins, sex hormones and smoking., M Karmazyn, M S Manku, D F Horrobin 1979), and its role as a fast acting calcium blocker is well established as reviewed below.

This is particularly important since heart attaches due to coronary artery spasm is said to be a major cause of death in postmenopausal women. It is deadlier than the coronary artery blockade by atherosclerotic plaques and more frequent than cancer death in postmenopause years. Yet progesterone's role is not getting much attention from medical community. Coronary Artery Spasm: A 2009 Update -- Stern and Bayes de Luna or any of its critics (e.g. Letter by Morikawa et al Regarding Article, ''Coronary Artery Spasm: A 2009 Update) does not even mention progesterone therapy as a potential treatment. Apparently, not much became of 1997 article Coronary artery spasm: a hypothesis on prevention by progesterone (I Kanda, M Endo 1997), although progesterone's effects and the underlying mechanism have been know for some time as can be seen in the following articles.

Vascular Effects of Progesterone : Role of Cellular Calcium Regulation. Mario Barbagallo, Ligia J. Dominguez, Giuseppe Licata, Jie Shan, Li Bing, Edward Karpinski, Peter K. T. Pang, Lawrence M. Resnick 2001

The effect of progesterone on spontaneous and agonist-evoked contractions of the rat aorta and portal vein. M S Mukerji, H L Leathard, H Huddart 2000

Prompt effect of progesterone on the adrenergic response of smooth muscles. S Morishita 1986

Nongenomic vasodilator action of progesterone on primate coronary arteries. Richard D Minshall, Dusan Pavcnik, David L Browne, Kent Hermsmeyer 2002

Ca2+ release mechanism of primate drug-induced coronary vasospasm. K Miyagawa, J Vidgoff, K Hermsmeyer 1997

When you read progesterone research, the important thing to note is the fact that some researchers have been calling progesterone substitute drugs such as medroxyprogesterone acetate (Provera, Amen, Cycrin), and norethindrone acetate (Aygestin, Norlutate), "progesterone" instead of identifying the actual drug used. Consequently, the field of progesterone research has been contaminated and many researchers as well as doctors have come to believe that progesterone may be detrimental to cardiovascular health, as well as a cancer risk. Both are totally false.

One such example is Progesterone abolishes estrogen and/or atorvastatin endothelium dependent vasodilatory effects.(Andre Arpad Faludi, Jose Mendes Aldrighi, Marcelo Chiara Bertolami, Mohamed H Saleh, Renata Alves Silva, Yara Nakamura, Isabela R O Pereira, Dulcineia Saes Parra Abdalla, Jose Antonio Franchini Ramires, Jose Eduardo M R Sousa 2004). Although what they actually used was norethisterone acetate, they are calling it "Progesterone" in the title of the paper.

Similarly, Effects of exercise training on bone remodeling, insulin-like growth factors, and bone mineral density in postmenopausal women with and without hormone replacement therapy. L A Milliken, et. al., 2003 , states "Any physician prescribed HRT regimen ... estrogen plus progesterone taken orally". There are many hormone combinations that match this description, and it is impossible to know if they used bio-identical or non bio-identical estrogen and progesterone based on this description (judging from the results and given the standard medical practice at the time, "progesterone" was most likely non bio-identical substitute drugs).

The reason why it is important to distinguish the real progesterone from its substitutes is that estrogen + progesterone substitutes does become a risk factor in many ways including but not limited to coronary artery spasm and atherosclerosis.

In monkeys, the increased risk of coronary vasospasm can be demonstrated within 4 weeks of Medroxyprogesterone (Aka Provera in the U.S. used in the WHI clinical study and most widely prescribed in the U.S. until 2002) therapy. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. K Miyagawa, J Rosch, F Stanczyk, K Hermsmeyer 1997.

Medroxyprogesterone acetate interferes with the endothelial control (attenuation) of vascular tone (contraction). Chronic treatment with progesterone but not medroxyprogesterone acetate restores the endothelial control of vascular tone in the mesenteric artery of ovariectomized rats., Thierry Chataigneau, Murielle Zerr, Marta Chataigneau, Freanderic Hudlett, Carole Hirn, Fanny Pernot, Valeric Barbara Schini-Kerth 2004

The difference can be seen at molecular level. Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells., Tommaso Simoncini, Paolo Mannella, Letizia Fornari, Antonella Caruso, Monica Y Willis, Silvia Garibaldi, Chiara Baldacci, Andrea R Genazzani. 2004

Another reason why medroxyprogesterone is so harmful for cardiovascular system is that it makes the vascular wall sticky and promotes inflamation, plaque build up, and atherosclerosis, while progesterone inhibits adhesion molecule, and platelet aggregation. The consequence is higher blood clot risk which was clearly seen in WHI clinical trials and French E3N Cohort study series (see Safe Use of Hormones: the Hard Evidence). Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells. M Otsuki, H Saito, X Xu, S Sumitani, H Kouhara, T Kishimoto, S Kasayama 2001

Progesterone and 17 beta-estradiol acutely stimulate nitric oxide synthase activity in rat aorta and inhibit platelet aggregation. J Selles, N Polini, C Alvarez, V Massheimer 2001

Unlike estrogen, progesterone given alone does not adversely affect vascular function in postmenopausal women. Progesterone does not influence vascular function in postmenopausal women. Suzy Y Honisett, Ben Pang, Lily Stojanovska, Krishnankutty Sudhir, Paul A Komesaroff 2003

Unlike some progesterone substitute drugs such as medroxyprogesterone acetate (Provera, Amen, Cycrin), norethindrone acetate (Aygestin, Norlutate) that interfere with estrogen's endothelium based effects, natural progesterone at physiological dose does not interfere with NO dependent dilation. Preserved forearm endothelial responses with acute exposure to progesterone: A randomized cross-over trial of 17-beta estradiol, progesterone, and 17-beta estradiol with progesterone in healthy menopausal women., K J Mather, E G Norman, J C Prior, T G Elliott, 2000

Moreover, progesterone can induce NO production also. Rapid effect of progesterone on the contraction of rat aorta in-vitro., Meili Zhang, G J Wang, Christina G Benishin, Peter K T Pang. 2003

~~here is something funny about the data~~)

Female sex hormones have been implicated in the cardioprotection of premenopausal women. However, the cardiovascular actions of these hormones and the effects of their natural fluctuations during the menstrual cycle are not fully understood. We studied changes in vascular function during the menstrual cycle in 15 healthy premenopausal women. Four noninvasive procedures were performed during the early follicular (EF), late follicular (LF), early luteal (EL), and late luteal (LL) phases: flow-mediated dilatation (FMD) of the brachial artery during reactive hyperemia, laser Doppler velocimetry (LDV) with direct current iontophoresis of acetylcholine (ACh) and nitroprusside, whole body arterial compliance (WBAC), and pulse wave velocity. Hormone levels were consistent with predicted cycle phase and showed that all subjects ovulated during the cycle studied. FMD, LDV with ACh, and WBAC varied cyclically, with significant increases from the F to LF phase, sharp falls in the EL phase, and significant recoveries in the LL phase. These changes were most marked for FMD [EF, 8.8 +/- 0.6%(mean +/- SEM); LF, 10.0 +/- 0.7; EL, 4.2 +/- 0.6; LL, 8.6 +/- 0.9] and the LDV response to ACh (EF, 2.7 +/- 0.2 V/min; LF, 3.3 +/- 0.4; EL, 1.8 +/- 0.3; LL, 2.7 +/- 0.4). WBAC changed similarly (EF, 0.58 +/- 0.08 arbitrary units; LF, 0.84 +/- 0.06; EL, 0.65 +/- 0.05; LL, 0.68 +/- 0.06). Sodium nitroprusside-induced vasodilatation decreased significantly from EF to EL, with no other significant difference, and pulse wave velocity did not vary significantly over the four time points. Conductance and resistance artery endothelial reactivity and smooth muscle sensitivity to nitric oxide and arterial compliance are modulated significantly in response to the changing hormonal patterns of the menstrual cycle. These findings emphasize the importance of menstrual phase in the interpretation of data on endothelial function and may provide insights into the mechanisms underlying sex differences in cardiovascular risk and other disease processes in premenopausal women.

Estradiol's benefitial effect on endothelium-dependent dilatation is a well established phenomena, however, the relation between endothelium-dependent dilatation and coronary artery spasm is not clear.

Flow-mediated, endothelium-dependent dilatation of the brachial arteries is impaired in patients with coronary spastic angina. T Motoyama, H Kawano, K Kugiyama, K Okumura, M Ohgushi, M Yoshimura, O Hirashima, H Yasue 1997

Caucasian patients suffering from coronary vasospastic angina have an intact peripheral endothelium-dependent vasoreactivity. Ali Yilmaz, Matthias Vohringer, Anastasios Athanasiadis, Peter Ong, Rimma Merher, Dieter Ratge, Cornelius Knabbe, Udo Sechtem 2008

In fact, the detrimental effect of estrogen alone hormone therapy is not limited to blood clot risk. A heart rate variability study with estrogen alone therapy observed reduced heart rate variability, which is an indicator of coronary artery spasm risk.

Postmenopausal estrogen therapy modulates nocturnal nonlinear heart rate dynamics. Irina Virtanen, Eeva Ekholm, Paivi Polo-Kantola, Heikki Hiekkanen, Heikki Huikuri 2008

Progesterone induces endothelium-independent relaxation rather than the endothelium-dependent relaxation estrogen facilitates. It can manifest as attenuation of arterial contraction, which is consistent with its role in prevention of vascular spasm.

Progesterone induces endothelium-independent relaxation of rabbit coronary artery in vitro. C W Jiang, P M Sarrel, D C Lindsay, P A Poole-Wilson, P Collins 1992

Properties of a progesterone-induced relaxation in human placental arteries and veins. H A Omar, R Ramirez, M Gibson 1995

Progesterone and modulation of endothelium-dependent responses in canine coronary arteries. V M Miller, P M Vanhoutte 1991

It is obvious that progesterone and estrogen have different roles in vascular function, and are not designed to function alone. The detrimental effect of the imbalance will show up one way or the other.

Differential effects of progesterone and 17beta-estradiol on the Ca(2+) entry induced by thapsigargin and endothelin-1 in in situ endothelial cells., J Y Toshima, K Hirano, J Nishimura, H Nakano, H Kanaide, 2000

Another point to note is that lower doses of both estrogen and progesterone were found more beneficial to endothelium functions, which cautions against any study results that used higher doses and did not examine the differential effects of dosage levels.

Different role of endothelium/nitric oxide in 17beta-estradiol- and progesterone-induced relaxation in rat arteries. H Y Chan, X Yao, S Y Tsang, F L Chan, C W Lau, Y Huang 200

Summary

To the extent estrogen and progesterone influence the endothelium-dependent flow meditated dilation, autonomic nerve system reactivity, atherosclerosis, and vascular spasm, all of which are implicated as cardiovascular health and risk indicators, estrogen and progesterone are deeply involved in cardiovascular health throughout the women's adult life. Young healthy women show endothelium-dependent flow meditated dilation fluctuate coinciding with the menstrual cycle. All measures of cardiovascular health (Blood pressure, endothelium-dependent flow meditated dilation, peak blood flow, plasma NO) are most favorable in high estrogen + progesterone phase. Premenopause women with ischemic cardiovascular risk tend to have more problem when both estrogen and progesterone are low.

Unlike menstrual cycle where the low hormone phase lasts only a week, menopause put women in the lower than low hormone phase indefinitely. The cardiovascular health advantage the pre-menopausal women have over men largely diminishes with menopause. Menopausal hot flushes can be seen as a marker for underlying vascular changes among mid-life, otherwise healthy, menopausal women. Hormone therapy in a form of transdermal estradiol + natural progesterone effectively reduces the cardiovascular health risk of ovarian hormone deficiency without adverse side effects.

It is tragic that the large scale HRT clinical trials conducted as part of Women's Health Initiative in the U.S. used a wrong form of HRT and totally obscured the safe and effective use of real estrogen and progesterone (both in low dose transdermal) and both doctors and the general public are left scared and confused. For reviews, see Hormones: Dos and Don'ts, and Safe Use of Hormones: the Hard Evidence.

Safe Use of Hormones: the Hard Evidence

2011-08-21T21:56:00.004-05:00

by Etsuko Ueda, August 2011

"Is it safe? " is the big question on many people's mind when it comes to hormone supplementation today. I believe that question has been settled. In What Your Doctor May Not Tell You About Breast Cancer, estrogen is aptly called as "angel of life and angel of death". It's angel of life because it promotes cell growth and proliferation, the most noticeable for women being the monthly cycle of uterine lining buildup in preparation for pregnancy. It is angel of death because when it is not under progesterone's control, it can run amuck, creating and aiding the generation and growth of cancerous cells, blood clots, and coronary vascular spasm to list just a few. Don't confuse this protective role of progesterone with the destructive nature of progesterone substitutes (aka progestine or progestogen, there are several), which has been clearly demonstrated by WHI Clinical Trials in the U.S. and other studies that used progesterone substitutes.

It is very important to note that the only large scale long term study that compared real progesterone with progesterone substitutes so far is the French E3N cohort study series. They produced three reports so far, and all of them (breast cancer risk, blood clot risk, asthma onset risk) show a combination of transdermal estradiol + real progesterone is as safe as not using any hormone, while any other estrogen + progesterone substitute combination or estrogen only therapy shows increased risks.

The E3N studies show estrogen + progesterone is safer than estrogen alone supplementation. The same thing happens with your own hormones when progesterone and estrogen goes out of balance . This is known as estrogen dominance, and it is the primary reason why so many women develop various health problems during the decade leading up to menopause (see Estrogen dominance: it's not just a theory).

Actually, it is not just estrogen, but other hormones (DHEA, androstenedione, testosterone: probably because they easily convert to estrogen in various tissues) can become health hazard also, when progesterone is low. It was demonstrated with breast cancer, both for premenopause women and for postmenopausal women.

It isn't just breast cancer, blood clot, and asthma onset, that progesterone is known to protect you from. In his 1993 edition of "Progesterone in Orthomolecular Medicine", Ray Peat, a biologist listed a wide range of progesterone's protective role from embryo to old age, based on his studies and others' available back then:

Prevents acute poisoning of many kinds
Reduces the incidence of birth defects
Reduces the incidence of cancer of uterus, breast, and kidney
Reduces the incidence of epilepsy, habitual miscarriages, auto-immune diseases
Regulates heart and vascular smooth muscle, prevent spasm
Neutralize excessive estrogen and cortisol
Improve metabolic efficiency
Resolve hypoxia
Reduces edema
normalize fluid pressure in bursitis, glaucoma, swollen cartilage, etc.
Influence the brain development and intelligence of the baby
Promote magnesium uptake and blocks calcium uptake (this has a profound implication in blood clotting, blood sugar stability, diuretic kidney function, histamine release control, phagocytosis and other immune functions, Glucagon, insulin, vascular spasm, vascular tone, nerve stabilization (against over excitation, seizure, epilepsy, sleep apnea) , and protection against toxic or excitotoxic cell death)

Today, there are endless variety of thousands of studies that back up Ray Peat's conclusion, demonstrating how bio-identical natural hormones protect women's health or men's. Below are only a small fraction of the studies out there on the protective role of hormones in the field of neuroscience alone. Although the public is still kept in dark, the evidence is overwhelming. Only the clinical studies designed to show it in women are few and far between. Of course, those lucky enough to have learned of transdermal natural progesterone (sold as skin cream in the U.S.) aren't waiting for their doctors to catch up.

The wasted large scale clinical trials

The WHI Clinical Trials was supposed to give us enough data to answer many questions surrounding menopausal hormone therapy. Instead, they exposed an entire generation of menopausal women to dangerous drugs, scared and confused consumers and doctors alike, and sent researchers chasing dead-end false leads. All because it used a wrong form of hormone therapy (Premarin + Provera), the adverse effects of which have been known for quite some time, and yet, the pharmaceutical industry and medical establishment have chosen to ignore, if not hide (see The Hormone War is Heating Up).

The only safe and effective form of HRT is transdermal Estradiol+ real Progesterone continuous Regimens as the E3N Cohort Studies above and others have clearly shown. However, even when real estrogen and progesterone is used, it is not uncommon to see studies (or prescriptions for that matter) that use more than 10 times of the optimal ranges (around 0.03 ~ 0.05mg of estradiol + 10 ~ 20 mg of progesterone per day, both transdermal. See Hormones: Dos and Don'ts) .

In the French E3N cohort study, the natural progesterone used was primarily oral (paired with 0.05mg transdermal estradiol, 100mg per day progesterone in capsule has been the most common form of natural progesterone prescription). The studies so far has not reported any adverse health hazard associated with natural oral progesterone use, however, there are many people who cannot tolerate 100mg per day oral progesterone, including myself, because of dizziness or tiredness it induces (progesterone and its metabolites act as tranquilizer through GABAa receptors, and given a large enough dose, induce dizziness and tiredness, while the same mechanism prevents over excitation of neurons and make your brain feel calm in optimal dose).

Metabolic and hormonal parameters in post-menopausal women 10 years after transdermal oestradiol treatment, alone or combined to micronized oral progesterone. Jose L Cuadros, et. al., 2011
Prostanoids and catecholamines after oral administration of natural progesterone. J Tapanainen, A Kauppila, T Metsa-Ketela, H Vapaatalo 1989
Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Gerhard, et. al. 1998 (two 0.1-mg patches of Estraderm, natural progesterone as a vaginal cream, 300mg)

Therefore, many of the existing study results with oral progesterone are of only a limited use from a practical point of view.

The responsibility of the people who design large scale studies with serious implications

Perhaps the people most disturbed by the WHI results were estrogen researchers themselves. Estrogen looked so promising as the ultimate fountain of youth. At least that was what they were trying to sell. From my vantage point, there is no excuse for not knowing the detrimental effects of the particular estrogen (Premarin) and fake progesterone (Provera=medroxyprogesterone acetate) used in the studies before hand. There has been enough research indicating the risks, even before the clinical trial was launched in 1991 (actual recruitment 1993-1998). They knew the danger as early as 1961 (see Estrogens, progestogens and thrombosis, F . R. Rosendaal, at. al. 2003). By 1967 a study was conducted (Records Unit and Research Advisory Service of the Royal College of General Practitioners. Oral contraception and thromboembolic disease. J R Coll General Pract 1967;). Medroxyprogesterone acetate (the progesterone substitute used in the WHI clinical trials) has been used as contraceptive for many years with a long list of adverse side effects. By 1984 the superiority of bio-identical (natural) progesterone was demonstrated (Oral progesterone and estrogen/progestogen therapy. Effects of natural and synthetic hormones on subfractions of HDL cholesterol and liver proteins. U B Ottosson 1984).

Large scale long term clinical studies: Are they really necessary to determine the effects?

Risks and benefits can be evaluated much earlier, long before the actual diagnosable symptoms appear as clinical end points. In other words, you don't have to wait to see if people get sick to see the effects of the treatments. There are various indicators and markers that can tell what biological processes are activated or suppressed that are critical to the disease development. For example, bone breakdown and formation processes can be monitored by their chemical byproducts for osteoporosis development and reversal. So are blood clots and plaque formation risks in a form of reactive C-protein, fibrinogens, cholesterols, etc. Infrared camera breast exam can detect abnormal pattern of blood vessel development long before the cancerous lumps. It is about time to rethink the barbaric practice of clinical trials that is designed to see if a certain treatment would cure the illness or end up killing the patients.

Menopausal Symptoms And Underlying Mechanism

2011-08-21T21:18:00.012-05:00

by Etsuko Ueda, August 2011

Connecting the dots

Over the course of history, women have tried a variety methods to deal with menopausal symptoms without knowing the exact cause. Today we know they are caused by the withdrawal of ovarian hormones progesterone and estradiol. Ever since chemists have figured out how to make hormones, bio-identical to human's or otherwise, many experiments have been conducted to find the best approach, and women and their doctors have been presented with a wide array of choices. Whatever the choice, it eventually reaches to a point where some form of estrogen supplementation becomes highly desirable and nothing else seems quite satisfactory, pointing to a unique and important role estrogen plays in women's body. As I reviewed in Menopausal symptoms: What are we complaining?, the most common, salient and easy to recognize features of menopausal symptoms associated with estrogen withdrawal are:

Brain strain sensation (foggy brain), along with difficulty in concentrating
Hot flash (vasomotor symptoms)
Feeling of stress, anxiety, irritable, sweating
Low energy, easily fatigued
Similarities with other withdrawal symptoms (Benzodiazepine, morphine, etc.)
Urogenital / Vaginal atrophy

In my search to figure out the underlying biological mechanism, I could find many studies connecting hormones, neural functions, and hot flashes / vasomotor functions. But I could not find studies on foggy brain or difficulty in concentrating, as I reported else where. It turns out that estrogen's role in cognitive functions including the ability to concentrate has been studied in terms of its role in maintaining the cholinergic system activities. The neurons and synapses in cholinergic system use acetylcholine to transmit the signals, and they are found in such areas as hippocampus, basal prefrontal cortex, and in many areas of neo cortex. The parasympathetic system neurons are also cholinergic, and together with the sympathetic system (partly cholinergic), they form the autonomic nerve system. It is called cholinergic because the neurotransmitter acetylcholine (ACh) is made from choline (one of B vitamins).

Estrogen, Underactive Cholinergic System, And Difficulty In Concentrating

Estrogen (through Estrogen Receptor alpha=ERalpha) enhances the cholinergic neurons' response to ACh signals through a mechanism involving a protein called CREB (Cyclic adenosine monophosphate Response Element-Binding) protein, which is known for its involvement in the development of habituation, habit formation and addictions also.
Estrogen induces estrogen receptor alpha-dependent cAMP response element-binding protein phosphorylation via mitogen activated protein kinase pathway in basal forebrain cholinergic neurons in vivo. Eva M Szego, Klaudia Barabas, Julia Balog, Nora Szilagyi, Kenneth S Korach, Gabor Juhasz, Istvan M Abraham, 2006

Wiki: Substance dependence:

Estrogen (through ERbeta) is involved in the regulation of G-protein Signaling 9-2 (RGS9-2) protein, which can reduce the neural response to various stimulants. Estrogen reduces RGS9-2 to make the neurons more responsive. RGS9-2 is also involved in addictions.
Evidence for the involvement of ERbeta and RGS9-2 in 17-beta estradiol enhancement of amphetamine-induced place preference behavior. , Jill L Silverman, James I Koenig

Estrogen is also involved in ACh release itself.
Regulation of cortical acetylcholine release: insights from in vivo microdialysis studies. Jim R Fadel , 2010

The cholinergic neurons have a special membrane-bound, G-protein coupled estrogen receptor (GPR30) that enables estrogen to facilitate the neuron's acetylcholine release.
GPR30 co-localizes with cholinergic neurons in the basal forebrain and enhances potassium-stimulated acetylcholine release in the hippocampus. , R Hammond, D Nelson, R B Gibbs

ACh release is part of the neuronal correlates of sustained visual attention.
Increases in cortical acetylcholine release during sustained attention performance in rats. A M Himmelheber, M Sarter, J P Bruno., 2000

The effects of manipulations of attentional demand on cortical acetylcholine release. A M Himmelheber, M Sarter, J P Bruno, 2001
Modes and models of forebrain cholinergic neuromodulation of cognition. Michael E Hasselmo, Martin Sarter 2011

Estrogen has strong effects on the cholinergic system, while progesterone's role in the cholinergic system is limited to enhancement of the estrogen effects, possibly through the general effect of progesterone to increase the number of estrogen receptors.
Ovarian hormones differentially influence immunoreactivity for dopamine beta- hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys., M F Kritzer, S G Kohama 1999.

Estrogen increases parasympathetic activity through NMDA receptors and reduces sympathetic nerve activities through GABAa receptors.

Estrogen-induced autonomic effects are mediated by NMDA and GABAA receptors in the parabrachial nucleus. Tarek M Saleh, Barry J Connell, 2003

Although, estrogen seems to have opposite effect on sympathetic nerve activities though GABAa receptors through insular cortex. (Sympathoexcitatory effects of estrogen in the insular cortex are mediated by GABA. Tarek M Saleh, Barry J Connell, Alastair E Cribb 2005)

An underactive parasympathetic system (cholinergic) allows the sympathetic system (adrenergic) to become overactive, when estrogen is lacking. (Estrogen blocks the cardiovascular and autonomic changes following vagal stimulation in ovariectomized rats. T M Saleh, M C Saleh, B J Connell 2001),

The overactive sympathetic system can manifest as increased feeling of tension/stress, anxiety, sweating, hot flashes, and chill or "hard to get warm" condition, and estrogen effectively remedies all of them.
The underactive parasympathetic system can manifest as commonly seen menopausal complaints of dry eyes, dry mouth, less sexual arousal, weaker digestion, etc., since the parasympathetic system controls the glandular system.
This fits well with the observations that anything that can elevate the parasympathetic activity or that can reduce sympathetic activity can ease menopausal symptoms. These benefits can derive from various relaxation techniques such as paced deep breathing, massage, acupressure, and acupuncture, to drugs including Clonidine and others (Pathophysiology and Treatment of Menopausal Hot Flashes. Robert R. Freedman, 2005).

These characteristics of the cholinergic neurons make it a perfect candidate to explain the underlying neural mechanism of the menopausal symptoms, not only the difficulty in concentrating but also the hot flash and other related menopausal symptoms. The picture emerging from these studies is: Estrogen deprived/addicted brain struggles with an underactive cholinergic/parasympathetic system and overactive sympathetic (adrenergic) activity. It is our common knowledge that when we are upset, anxious, nervous, or fearful - when sympathetic autonomic activity level is high - our performance (cognitive or otherwise) suffers compared to when we are cool, calm, and collected - when cholinergic/parasympathetic neural activity is strong. Menopausal estrogen withdrawal puts the brain in an even more disadvantaged state, and the brain strain sensation or the foggy brain sensation may be the brain's plea for help. Strangely, though, researchers studying cholinergic system and its role in cognitive functions in relation to menopause do not seem interested in menopausal symptoms.

The link between menopausal symptoms and cognitive impairment

According to some research, nearly 90% of women experience menopausal symptoms (Bresilda Sierra, et.al. 2005). They start about 2 years before the final menstrual period, and lasts for many years. Nearly 50% of all women reported vasomotor symptoms 4 years after their final menstrual period, and 10% of all women reported symptoms as far as 12 years after final menstrual period, 1 year following the final menstrual period (late perimenopause) seems the most difficult time in terms of bothersome symptoms (Revisiting the Duration of Vasomotor Symptoms of Menopause: A Meta-Analysis. Mary Politi, Mark Schleinitz, Nananda Col 2008).

Longitudinal studies from The Study Of Women's Health Across The Nation (SWAN) project also reported that cognitive complaints were most prevalent during the menopause transition period (late perimenopause), and some aspects of cognitive functions they have tested (namely tasks involving processing speed and verbal memory) were affected during the transition period, and a weak correlation with depressive and anxiety symptoms was seen in the data collected. Interestingly however, cognitive test scores recovered after the transition period (postmenopause) without hormone therapy. (Effects of the menopause transition and hormone use on cognitive performance in midlife women., G A Greendale,et. al., 2009, Menopause-associated symptoms and cognitive performance: results from the study of women's health across the nation., Gail A Greendale et. al.,2010).

Consistent with the SWAN finding, a monkey study (Executive function and attention are preserved in older surgically menopausal monkeys receiving estrogen or estrogen plus progesterone. Mary Lou Voytko, Rhonda Murray, Casey J Higgs 2009) also reported that the effect of hormone withdrawal was no longer detectable after 6 month: Executive function deficits were evident within 3 months after ovariectomy, but no longer detectable by 6 months after surgery.

A British study (Cognitive function across the life course and the menopausal transition in a British birth cohort. Helen Kok, et. al., 2006 ), on the other hand, found progressive decline of performance on search speed and concentration tasks over the course of menopause transition and beyond (pre-, peri-, and postmenopause). Unlike the SWAN studies, postmenopausal women showed the lowest scores on those cognitive tasks.

Since hot flash is a big part of menopausal symptoms, you would expect some kind of correlation between the hot flash severity and the cognitive deficit, if menopausal cognitive impairment should have anything to do with the severity of menopausal symptom. It was only when the number of hot flashes were measured objectively, a significant correlation with "delayed verbal memory" performance emerged (Objective hot flashes are negatively related to verbal memory performance in midlife women. Pauline Maki, et. al., 2008).

The discrepancies seen among these studies probably are due to the sensitivity of the tasks and measures used. Less sensitive measures can demonstrate the menopause effect only when the symptoms are overwhelmingly strong, and more subtle impairments would go undetected.

Menopause and Cognitive Decline

Decline of mental capacity in old age is everyone's concern, and menopausal hormone withdrawal and supplementation has been investigated in that context. The initial effects of menopausal hormone withdrawal seem transient and reversible by hormone supplementation, although there is a possibility that the severity of the symptoms may be a reflection of the damage already done (Glucocorticoids and the ageing hippocampus. C Hibberd, J L Yau, J R Seckl, 2000, Impact of the Hypothalamic-pituitary-adrenal/gonadal Axes on Trajectory of Age-Related Cognitive Decline. Cheryl D Conrad, Heather A Bimonte-Nelson, 2011, Longitudinal Analysis of the Association Between Vasomotor Symptoms and Race/Ethnicity Across the Menopausal Transition: Study of Women’s Health Across the Nation. Ellen B. Gold, et. al. 2006).

It's been also suggested that after a long term estrogen/progesterone deprivation, suffering through all those symptoms, structural changes or damage may set in through various mechanisms, and it may not be reversible (A cross-sectional study of hormone treatment and hippocampal volume in postmenopausal women: evidence for a limited window of opportunity. Kirk I Erickson, et. al. 2010). The degenerative changes in the brain can be examined through a variety of methods: psychological tests to measure cognitive performance, or by using brain imaging, inspection of actual brain tissues, or chemical analysis to assess the integrity of brain structure and activity patterns. Most current research measures the physical integrity of the brain in terms of the white or gray matter volume, the neural fiber density in certain areas or overall, the number of neurons of certain category, the metabolic tracer densities, or the blood flow volume.

The Women's Health Initiative (WHI) studies showed a higher risk of dementias for women receiving estrogen in a form of 0.625 mg/day conjugated equine estrogens (Premarin) with or without 2.5 mg/day medroxyprogesterone acetate (Provera) as progesterone substitute (it's chemical structure is not identical to real human progesterone). The detrimental effect of those hormone drugs on blood clot risk has been known and WHI studies could not escape from it.

The WHI follow-up analysis indicated that those hormone drugs were particularly detrimental to women who had a sign of cognitive decline or of high blood pressure at the start of the study (Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study. S M Resnick, et. al., 2009; Relationship of hypertension, blood pressure, and blood pressure control with white matter abnormalities in the women's health initiative memory study (WHIMS)-MRI trial., Lewis H Kuller, et. al., 2010). Abnormal white matter lesion volumes were also associated with the hormone drugs used in the WHI study (Relationship of hypertension, blood pressure, and blood pressure control with white matter abnormalities in the women's health initiative memory study (WHIMS)-MRI trial., Lewis H Kuller, et. al., 2010). That is exactly what can be expected from the blood clot risks both drugs have been know for (see Hormone: Does and Don'ts).

The French E3N Cohort study on blood clot risk (Postmenopausal Hormone Therapy and Risk of Idiopathic Venous Thromboembolism. Results From the E3N Cohort Study.), on the other hand, indicated transdermal natural estradiol 0.05 mg + natural progesterone were as safe as not using hormone supplementation at all, while all other types and forms of estrogen alone or estrogen + progesterone substitute increased blood clot risk. The blood clot risk can also be demonstrated in healthy women as increased thrombin generation long before any clinical health problem develops (Increased thrombin generation among postmenopausal women using hormone therapy: importance of the route of estrogen administration and progestogens. Pierre-Yves Scarabin,et. al., 2011).

There is no doubt that removing menopause symptoms using hormones improves mental functioning and quality of life in general even when a wrong form of hormone supplementation is used. That is usually the reason many women start hormone therapy and stay on it. It is also clear that wrong forms of hormone supplementation can raise various health risks in the long run for sure as WHI clinical trials and their follow up studies, French E3N studies, and others have demonstrated. Moreover, if you look at individual cases rather than the statistical results, the harms can sometimes manifest immediately since blood clot incidences can occur within a matter of weeks and cancers can grow within a few months.

What is not clear is whether the right form of hormone therapy can slow down mental decline or reduce the dementia risk that seems an inevitable part of aging. One study (Early menopausal hormone use influences brain regions used for visual working memory. Alison Berent-Spillson, et. al., 2010) compared those who never used hormones to those currently using or who used in the past for at least for 10 years continuously. The study found the hormone use advantageous. The measures used were a visual memory task performance and the related brain activity measured by functional MRI (visual memory task involves a core function of cholinergic system). Interestingly, the past users tested after 1 to 3 years since stopping hormones maintained the advantage compared to never users, but not as much as the current users. The abstract did not indicate if any of the past users or never users were still suffering menopausal symptoms, although it is well known that stopping estrogen will bring back the symptoms in most cases (Vasomotor symptoms usually reappear after cessation of postmenopausal hormone therapy: a Swedish population-based study., Lotta Lindh-Astrand, et. al. Menopause. 2009), and menopausal symptoms can last more than 12 years for some women.

Also, this study examined post menopausal women who used a wrong form of hormones (Premarin with or without Provera), but it avoided the health risk issues by eliminating everyone sick or otherwise not healthy at the time of testing. It also excluded plant hormone (soy food?) users. All these exclusions can introduce some unknown biases. The study also did not describe or track any other symptoms of menopause their subjects may or may not have suffered. The results of the study may have been different if they looked into only those (current, past and never users) who did not have any significant menopausal complaints or symptoms. There are so many things that can make this study difficult to interpret, but it is the only functional MRI study done on menopausal hormone therapy so far.

Epidemiological surveys on Alzheimer's disease (AD) in old age also indicated the advantage of menopausal hormone supplementation that seems to increase with the duration of HRT use. Women who used HRT 10 years or more had AD risk comparable to that of men, and shorter duration was associated with higher risk (Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. Peter P Zandi, et. al., 2002). Unfortunately, because the HRT used was the wrong form of hormones (Premarin with or without Provera), it makes the interpretation rather difficult. How can you make sense out of this data against the WHI clinical trial data that ended up with higher incidences of dementias with longer use? It may simply be indicating that longer the HRT duration the more weaker and vulnerable have passed away, and only those resilient have survived?

Animal studies have observed a lasting advantage of estrogen-only therapy in ovariectomized rats which persisted at least up to 7 months. (Transient Estradiol Exposure during Middle Age in Ovariectomized Rats Exerts Lasting Effects on Cognitive Function and the Hippocampus. Shaefali P Rodgers, Johannes Bohacek, Jill M Daniel, 2010).

So far, animal studies as well as human studies indicate that the physical structure of the brain, such as size, number of neurons, or fiber density, either overall or in some critical areas are better preserved when hormones are supplemented, except for a long term use of the wrong forms of hormones by vulnerable women (Effects of hormone therapy on brain morphology of healthy postmenopausal women: a Voxel-based morphometry study. Marina Boccardi et. al. 2006; Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes. Ramon Casanova, et. al., 2011 ).

However, what kind of advantage a structural preservation would give in terms of mental functioning is not at all clear. Some researchers seem to suggest that cognitive deficits associated with menopausal symptoms are precursors to the later decline and dementias. This however is not certain. The brain shrinks as part of the normal aging process. However, the pattern of brain shrinkage seen in people with early sign of dementia is abnormal compared to that of normal aging brains (Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. I Driscoll, C Davatzikos, et. al., 2009). Dementia is also associated with abnormal lesion volume (Relationship of hypertension, blood pressure, and blood pressure control with white matter abnormalities in the women's health initiative memory study (WHIMS)-MRI trial., Lewis H Kuller, et. al., 2010).

Critical window of opportunity?

Researchers have been trying to find whether there is a critical window of opportunity: meaning that if you miss that window (may be a few years after the last menstruation), the hormone is no longer effective in bringing back normal functioning. Worse, hormone deprivation may initiate the degenerative process.

In rats, when initiated after 5 months of ovarian hormone deprivation, estradiol only therapy no longer improves learning. Its effect on uterus was also reduced (Estradiol replacement enhances working memory in middle-aged rats when initiated immediately after ovariectomy, but not after a long-term period of ovarian hormone deprivation. Jill M Daniel, et. al., 2005, The ability of oestradiol administration to regulate protein levels of oestrogen receptor alpha in the hippocampus and prefrontal cortex of middle-aged rats is altered following long-term ovarian hormone deprivation. Johannes Bohacek, Jill M Daniel 2009). I wonder why they did not add progesterone. Since progesterone will increase estrogen receptors, the result can be different.
In monkeys, some structural changes can be seen in just 2 years of hormone deprivation (Effects of two years of estrogen loss or replacement on nucleus basalis cholinergic neurons and cholinergic fibers to the dorsolateral prefrontal and inferior parietal cortex of monkeys. Gregory Paul Tinkler, Joseph Raphael Tobin, Mary Lou Voytko, 2005).
In humans, compared to young women and postmenopausal estrogen therapy users, never-users had significantly lower gray matter concentration bilaterally in orbitofrontal cortices and cerebellum, right inferior frontal and precentral cortices, and left paracentral cortex (Effects of estrogen therapy on age-related differences in gray matter concentration. D Robertson, M Craig, T van Amelsvoort, E Daly, C Moore, A Simmons, M Whitehead, R Morris, D Murphy 2009).
Also, consistent with a critical period hypothesis, shorter intervals between menopause and the initiation of hormone treatment were associated with larger hippocampal volumes. Nonetheless, it did not seem to translate into spatial memory performance differences (A cross-sectional study of hormone treatment and hippocampal volume in postmenopausal women: evidence for a limited window of opportunity. Kirk I Erickson, Michelle W Voss, Ruchika S Prakash, Laura Chaddock, Arthur F Kramer 2010).

Do these studies prove there is a critical window of opportunity? Not so fast. For the cholinergic system to benefit from estrogen, it has to have estrogen receptors (Viral Vector-mediated Delivery of Estrogen Receptor-alpha to the Hippocampus Improves Spatial Learning in Estrogen Receptor-alpha Knockout Mice. Thomas C Foster, et. al., 2008). Since progesterone regulates estrogen receptor expression, it is rather peculiar to see research after research that used estrogen only therapy to examine the critical period hypothesis. The exclusive focus on estrogen in so many studies is misguided. The importance and advantage of proper use of progesterone is shown in various studies:

Many women find complete relief from menopausal symptoms with progesterone only therapy (Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Leonetti, et. al., 2003).
Progesterone-only therapy can enhance learning and memory of aged mice (Progesterone enhances learning and memory of aged wildtype and progestin receptor knockout mice. Cheryl A Frye, Alicia A Walf 2010).
An increase of estrogen receptors alone is sufficient to bring back cognitive functions in ovariectomized mice without adding estrogen (see above Foster, et. al., 2008).
Estrogen therapy may not be effective when cholinergic function is not supported (Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons. R B Gibbs, et. al. 2011).

In other words, to prove the critical period hypothesis, we need to see studies with the right form of estrogen + progesterone therapies.

There is also evidence that hormone therapy can be effective even after a long period of hormone deprivation. It has been demonstrated that initiation of progesterone therapy can have effects on bone mineral density long after menopause, even over 80 years of age (Osteoporosis reversal with transdermal progesterone., John R. Lee 1990, see also What Your Doctor May Not Tell You About Menopause, by John R. Lee, M.D. with Virginia Hopkins, 1996). I personally witnessed old women's hair started to grow back when progesterone therapy was initiated for the first time in their 80's.

Cholinergic system is not the only thing hormones protect

The cholinergic system has been the main focus of the studies in menopausal cognitive decline. The cognitive tasks that demonstrated the effects of hormones are often characterized as attention processes, executive functions, processing speed, learning, working memory, etc. For example, various versions of cued multiple choice task have been used to assess sustained visual attention, which has emerged as one of the core functions of cholinergic system, especially at hippocampus. The cue is presented only for a brief period in a way if you are not paying attention, you would miss it.

While others may experience it as memory problem in some other context, the cognitive impairment I have experienced can be best characterized as difficulty in concentrating, and it was particularly noticeable when working on computer screens. Some people may experience it as tired eyes. Maintaining the visual attention on a specific aspect of the display to accomplish the task at hand, without losing the place or the train of thought was very tiring, and I was constantly fighting the urge to close my eyes to rest or catch my attention drifting, and quickly became exhausted. These characteristics fits well to the notion of impaired "sustained visual attention" arising from the underactive cholinergic system. Similarly, a study that examined middle-aged computer terminal operators found that the work-related physical discomfort scores (mainly eyes, but arm, neck, shoulder, hip were also involved) correlate with menopausal symptom scores (Sumika Yoshimura 2007), indicating that the menopausal symptoms may be the underling cause of the discomfort and difficulties.

I have not examined all the cognitive tasks used in the studies to demonstrate hormone effects, but my impression is that they are tasks that require attention, concentration, or conscious effort, which has higher energy requirements compared to simply accessing established memories and skills, or drifting into daydreaming.

It is tempting to say the deficit is mainly in cholinergic system, but it may only be a part of the story. The high energy demand aspect of the affected cognitive functions points to the role of hormones in neural energy production (Progesterone and Estrogen Regulate Oxidative Metabolism in Brain Mitochondria. Ronald W Irwin, 2008), and there is no reason to think it only affects cholinergic system.

Since the cholinergic system is an essential part of normal mental functioning, some form of abnormality in the cholinergic system is always present in dementia brains. That, however, does not necessarily indicate the impairment is cholinergic specific or originated from cholinergic system, either.

For the prevention of old age dementias, I would count on the protective roles of hormones that have much broader implications on the brain health. For example:

Cardiovascular health (especially blood pressure, vascular spasm, and blood clot).
Anti-inflammation (Sex steroids control neuroinflammatory processes in the brain: relevance for acute ischemia and degenerative demyelination. Markus Kipp, et. al., 2011).
Mitochondrial health (Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid. Jia Yao, et. al., 2011, Progesterone and Estrogen Regulate Oxidative Metabolism in Brain Mitochondria. Irwin, et. al., 2008).
The ability to cope with blood glucose fluctuations (Menopausal hot flash frequency changes in response to experimental manipulation of blood glucose. Sharon L Dormire, Nancy King Reame 2003).

To settle the issue

The questions to be answered are:

Does every menopausal women benefit from hormone supplementation in terms of cognitive aging and the health in general if they use the right form of hormone therapy (bio-identical transdermal estradiol 0.03~0.05 mg/day + bio-identical transdermal progesterone 10~20 mg/day, continuous regimen)?
Can you protect your brain and the rest of the body for that matter, by maintaining hormonal balance all though the adult life, supplementing bio-identical transdermal progesterone when the need arises? And does it reduce the severity of menopausal symptoms?

The answers should be "yes", "yes", and "yes". The idea originates from the conclusion Ray Peat, Ph.D and late John R. Lee, M.D. reached decades ago based on the research available back then. Their recommendations have been followed by many doctors and women around the world with positive results. Today, there are endless variety of research that demonstrate how bio-identical natural hormones protect women's health or men's. Below are only a small fraction of the studies out there on the neuroprotective role of hormones alone. The evidence is overwhelming. Only lacking are actual studies that are designed to answer these specific questions in humans.

The WHI clinical trials was supposed to give us enough data to answer many questions surrounding menopausal hormone therapy. Instead, they exposed an entire generation of menopausal women to dangerous drugs, scared and confused consumers and doctors alike, and sent researchers chasing dead-end false leads, all because it used wrong forms of hormone therapy. It's a shame that it happened in the face of the fact that Premarin and Provera or Prempro have been known for a long list of serious side effects, which the pharmaceutical industry and medical establishment have chosen to ignore, if not hide (see The Hormone War is Heating Up).

Caution for overdose

It should also be noted that, although estrogen plays an important role in the cholinergic system and many other parts of human body, estrogen is an excitetoxin, so without progesterone's protection, estrogen can make the brain more vulnerable to stress. Estrogen can harm the brain when overdosed, and it can amplify stress hormone responses to psychosocial stress, as indicated in the following studies.

Overdose of progesterone, on the other hand, in animal experiments as well as in human can pose a different kind of problem due to progesterone and its metabolites' GABAa mediated sedative effects (Pharmacology of endogenous neuroactive steroids., Doodipala Samba Reddy, 2003). You cannot expect any heavily sedated animal (or human for that matter) to perform well on a cognitive task. Researchers who experiment with various dosage levels often find lower doses more effective. (Effects of estrogen and progesterone treatment on rat hippocampal NMDA receptors: relationship to Morris water maze performance. El-Bakri NK, et. al. 2004, Different role of endothelium/nitric oxide in 17beta-estradiol- and progesterone-induced relaxation in rat arteries. H Y Chan, et. al., 2001).

Note: Premarin + Provera (used in the WHI clinical trials and most commonly prescribed in the US) has been known for low compliance, and many people do not like the way it feels and soon discontinue. Recent studies provided a clue. Provera (a progesterone substitute) shuts down important neural activities (Impact of progestins on estradiol potentiation of the glutamate calcium response. Jon Nilsen, Roberta Diaz Brinton 2002). Consistent with its negative impact on the neural activities, Premarin + Provera (or simply referred as HT or HRT) was observed to worsen some aspects of verbal memory while reducing hot flashes (Effects of botanicals and combined hormone therapy on cognition in postmenopausal women. Pauline Maki, 2009, Effects of the menopause transition and hormone use on cognitive performance in midlife women., G A Greendale,et. al., 2009).

Hormones' benefits for other areas of body, such as cardiovascular system, bones, urogenital tissues, etc. are much more straight forward, as I will review next.

Menopausal symptoms: What are we complaining?

2010-09-14T00:34:00.030-05:00

by Etsuko Ueda, September 2010

Part I: The most troublesome and most overlooked menopausal symptom

Hot flush is almost synonymous with menopause in the US. According to some research, more than 80% of menopause age women experience it. If you have not actually experienced it, you would wonder what the big deal is. Feeling too warm and getting a little sweaty may be inconvenient in some situations, but it cannot be really that bad. True, if that's all there is. Many non menopausal people experience something similar when they have a bowl of hot soup, for example. But, in most cases that's not all. Actually, hot flushes may not be the dominant, or most troublesome symptom for many people. There are several troublesome aspects to menopausal symptoms with or without hot flushes, which a person may not want to attract too much attention to, due to a fear that she/he may be treated like a nut case, or due to a lack of words that adequately describe it.

My journey

The first hot flushes came when I was on a hormone blocker in my mid 40's in a failed attempt to stop uterine fibroid. It came as a wave of warmth that ran through my body more or less at a regular interval and did not bother me at all, which promptly went away right after the total hysterectomy when my doctor gave me an estradiol patch (0.05mg/day). From there on, I've never had hot flushes or any other so called menopausal symptoms until I started to experiment to quit estrogen, which was a big mistake. "Vasomotor symptoms usually reappear after cessation of postmenopausal hormone therapy: a Swedish population-based study." (Lotta Lindh-Åstrand, et. al. Menopause. 2009), although "Postmenopausal women without previous or current vasomotor symptoms do not flush after abruptly abandoning estrogen replacement therapy." (M Hammar, et. al., Maturitas. 1999),

Experimenting with estrogen

When I first discovered natural progesterone and learned that my health was deteriorating due to estrogen dominance and progesterone deficiency, I learned many women can do just fine with progesterone alone (less likely if your ovaries are gone, I came to realize later). I called late Dr. John Lee right after I read his book, What Your Doctor May Not Tell You About Menopause (to ask about Japanese translation rights, but it was already in translation). He kindly took my call and gave me some advice to reduce estrogen slowly 3 months at a time, meaning reduce by half each 3 months to see if I can get used to it. But in my eagerness, I thought I was able to quit in 3 months. First, I took short breaks from estrogen and made the breaks gradually longer. After about 3 months of that, when 1 week break did not cause any problem, I stopped estrogen and continued with the 20 to 30 mg/day of progesterone in cream form which I started 3 months earlier. It looks like I had 1 to 2 months worth reserve of stored estrogen in my body at that point, and after that I started to notice unmistakable symptoms.

Looking back, the first sign was a "burned out / I am pushing too hard" reaction. I was getting nervous and sweaty (the oily kind) and felt as if I was pushing too hard in a normal room temperature doing regular work. There was a reason to think I could be actually exhausted. So I did not give it much thought at the time. Although I could not remember the last time I had had that kind of reaction to that level of stress, it did not happen repeatedly after I took a good rest.

Then came a strange "brain strain sensation" that felt like something was gripping and squeezing my brain, which was straining to function freely, but could not. Whatever it was, I had this constant sickly sensation in my head, that interfered with my concentration. More strangely, it was there all day during the day time, but promptly lifted at around 5:00 p.m. (indicating some relation to circadian rhythm of brain metabolism, cortisol or... Does anyone out there have any clue?). I had never experienced anything like that before in my life, and it was far more troublesome than the occasional hot flashes, the weird sensation of pulsation right above my naval, the prickling "electric" sensation of the skin/nerve that felt much like the sensation you would have when alarmed or shocked, the racing heart, or even the early wakening sleep problem. Another thing that scared me was my bones, which seemed bruising too easily. One time I drove for about 45 minutes without quite realizing my tail bone was hitting a crease of a bunched up thick jacket. By the time I noticed the pain the damage was done, and it took months for the pain in my tail bone to go away.

Non estrogen remedies

I eventually resumed estrogen and almost all of the troublesome symptoms went away, including the brain strain sensation and its associated symptom of hard to concentrate. Below is a list of some remedies I tried while I stayed off estrogen. Keep in mind I was on bio-identical progesterone cream all that time.

Taking licorice root extract significantly reduced "brain strain sensation" almost immediately, but did not eliminate it completely.
I increased fermented soy products in my diet (3 servings a week at least), which took the edge off my hot flushes, and increased the virginal discharge. But it was not quite satisfactory. Especially in the morning, I woke up after 4 to 5 hours of sleep and laying down feeling tired and trying to go back to sleep tossing and turning, while my heart rate stayed elevated and breathing shallow, getting too warm to the point I had to kick off the cover until I felt too cold.
I also tried adrenal hormone called DHEA (30mg/day oral) soon after I started have the symptoms, but it did not seems to make any difference and I discontinued after one month (I did not know it would take 3 months to kick in). Several years later long after I resumed estrogen, I decided to try it again, thinking it may improve my overall hormone profile, and decided to stay on it regardless. After about 3 months, however, I noticed some changes. The most noticeable changes were oilier hair and skin, virginal discharge, and libido. My sleep problem seemed also improved. I was still waking up after 4 to 5 hours, but going back to sleep was getting easier. Since then I reduced DHEA to 30mg every other day, which reduced all the changes proportionally.

How Everyday Language Shapes the Recognition of Menopausal Symptoms

When I decided to look into the "Brain Strain sensation", I could not remember the common expression for it, although I have read a fair number of books and articles on menopause. No problem, I thought, I can look up Internet and any list of menopausal symptoms would list some version of it for sure. Well, it was not that simple. The associated symptoms, such as difficulty in concentrating and fatigue are commonly mentioned, but the head/brain sensation itself is not. That was until I looked up The Greene Climacteric Scale, which has been commonly used in menopause research (http://www.menopausematters.co.uk/greenscore.php). It includes among other things "Pressure or tightness in head or body" and "Difficulty in concentrating". However, unlike hot flushes, I've not found any study focusing on this symptom.

I also combed through some forum discussions by menopausal women as well as some non-conventional healthcare information websites. There I have found, "heavy and congested head", "contracting squeezing scalp, temples and forehead". I have also found "weird head pressure" and more broadly "funny head feeling". More commonly used are "foggy brain" and "brain fog", but it is not clear whether everyone is using it to mean the specific head sensation, just the difficulty in concentrating, or both. In any case, there are many websites that offer nutritional, hormonal, and life style remedies for "brain fog", menopausal or otherwise. Even a major news media (ABC news) picked up "brain fog" in "Menopause: Hormones Can Help Memory and Lift Brain Fog " to explain the cognitive aspects. However, the writer seems totally oblivious to the brain strain sensation aspect of it.

Japanese words for menopausal symptoms

My native language is Japanese, but no word was popping up in my head that exactly fits the sensation I was experiencing, either. A general expression for such sickly feeling in Japanese can be すっきりしない, which is similar to the English expression of "not refreshed" feeling, an expression one might also use when constipated (which can also happen with too low estradiol). But I did not feel it was accurately describing the sickly sensation I was experiencing in my head. Then I remembered the expression my mother often used in her menopause years to describe some sickly head sensation; モンモン(MON-MON). At that time I was at an impression that it was associated with high blood pressure she had, but looking back, it was most likely menopause related.

MON-MON (which I took to mean uncomfortable sickly head sensation with some kind of temperature build-up) is an onomatopoetic word, a class of words (similar to twinkle, sizzle, buzz, etc.) the Japanese language allows endless variations to capture otherwise difficult to describe sounds, moods, motions, sensations, etc.

I also combed Internet in Japanese. In the conventional western medicine community in Japan, the cluster of menopausal symptoms are referred to as不定愁訴. It roughly translates as non-specific or unidentifiable complaints, by which they mean a cluster of complaints that indicate generalized sickly feelings that have no corresponding measurable or detectable abnormality according to the standard western medical textbook. This label is by no means confined to menopausal complaints, and used widely to any such complaint often considered to be a result of dysfunctional autonomic nerve system, if not psycho-somatic. (I can almost hear the echo of "It's all in her head".)

They have also developed several lists of such menopausal complaints based on commonly used English menopause scales (e.g. The Greene Climacteric Scale, Kupperman Index, etc.), adapted specifically to the complaints seen among the Japanese women (so they claim). The length ranges from 10 to 21 items, however, I could not find anything that suggests the "brain strain sensation" nor the difficulty in concentrating, only a reference to "heavy head" paired with headache. Interestingly, however, some of them include tired eyes, which is similar to brain strain sensation, only you feel it mainly in the back of your eyes. Also included is stiff neck and shoulders, which can be similar or related to brain strain sensation, only you feel it mainly in shoulders close to neck, and back of the neck, while brain strain is mainly in front and sides of your head. Interestingly, both "tired eyes" and "stiff shoulders" have well established words in Japanese (眼精疲労and肩こり), while the brain strain sensation does not. According to a survey of Japanese women aged 49.5+/-3.0 (Factor analysis of climacteric symptoms in Japan, MK Melby, 2005 Maturitas), three most prevalent symptoms were shoulder stiffness, memory loss (I assume it is memorization capacity loss. Something must have been lost in translation), and stress.

More traditional and/or non-conventional healthcare websites and personal blogs in Japan portray a slightly different picture as do the English counter parts. They often mention some pressure like sensation around the head as well as some sickly head feelings they call MOYA-MOYA (an onomatopoetic expression of foggy: To me, it sounds like milder version of the brain strain sensation).

Then I came across a list of symptoms used to check andropause (the male version of menopause) status used at a Urology clinic of the St. Marianna University School of Medicine in Japan. Interestingly, it includes this MOYA-MOYA head (21.1% responded Yes) as well as heavy head (20.1%), along with difficulty in concentrating (44%) and low energy (43.8%). Is it more prevalent among men? Or does it matter more to men? Or the target population of the clinic uses brain more?

Another interesting aspect of the above list of andropause symptoms, when compared to those of menopause, is the absence of "Depression", which is included in every list of women's menopause symptoms I have seen. It is also frequently mentioned in andropause symptom lists, for that matter. Instead, it includes sleep problem (37.6%), anxiety (30.9%), lower sexual vitality (21.6%), irritable (19.6%), sweaty (18%), impotence (18%). Apparently, the researchers and doctors at the St. Marianna University School of Medicine have determined the head sensations were more relevant symptoms than depressive mood in identifying testosterone deficiency. Does it reflect the real difference between Japanese men and women in terms of the actual symptoms? Probably not. Their list of andropause symptoms looks more relevant to what I have experienced than any menopause symptom list I have seen so far.

Does anyone know what's really going on?

The more I dug the more murky it became. I had no idea menopausal symptoms were surrounded by this much "fog". Apparently, there is an increasing awareness that many menopausal symptom surveys had been poorly prepared to capture the real picture, partly because they did not have adequate input from the women themselves. In other words, researchers often don't bother to ask the women if the questionnaires contain all the relevant symptoms. See "A feminist Approach to Research on Menopausal Symptom Experience." Eun-Ok Im, Fam Community Health 2007 about how a study can fail to capture the real picture.

The difficulty is understandable. Even if you are free of all the preconceptions and prejudices, you need to separate reproductive hormone specific aging from general aging, for one. There is an increasing evidence that sleep problem may not be menopause specific (in my case, estradiol and progesterone did resolved most of the problems except the sleep problem). For a review, see Hot flashes: behavioral treatments, mechanisms, and relation to sleep (Robert R. Freedman, The American Journal of Medicine 2005). You also need to separate primary symptoms from secondary symptoms. Anxiety, depression and irritability may be secondary to a constant discomfort, or related to coincidental life events such as awareness of aging, changes in their social roles and relationships, etc. (Lynnette Sievert, et. al., Symptom groupings at midlife: cross-cultural variation and association with job, home, and life change. Menopause. 2007). Then there is a problem of accurately recognizing and describing the symptom. There may not be a well establish words for some of the symptoms and/or it may not be socially acceptable complaints and suppressed.

A good example of the language effect was demonstrated by surveys of hot flushes among Japanese women. For English speaking populations, hot flush is a well recognized symptom. However, researchers who used translated menopause symptom questionnaires to survey Japanese women found lower occurrences of hot flushes, and learned that there is no specific word for hot flushes in Japanese vocabulary. (How Japanese Women Talk about Hot Flushes: Implications for Menopause Research. Jan Morgan Zeserson, Medical Anthropology Quarterly, New Series, 2001). Moreover, hot flush prevalence varied depending on which one of the common expressions of body heat sensation was used; (Vasomotor symptom prevalence and language of menopause in Japan. Melby, MK, 2005, Menopause ).

In conclusion

1. Any description of menopause/andropause symptoms that does not include some version of this brain strain sensation along with the difficulty to concentrate is probably created by people who have not really experienced or understood the full range of hormone related menopausal symptoms.
In a low socio-economic Ecuadorian population (385 women, mean age of 47.6 +/- 5.5 years), the most frequently and intensive presenting symptoms of the 21 symptoms composing the Greene Climacteric Scale were: difficulty in concentrating (87%), feeling unhappy or distressed (82%), headaches (83.9%), and hot flashes (82%) (Bresilda Sierra, et.al. 2005, Maturitas)

2. We need to be very careful when we talk about depression in relation to menopause. There is depression and then there is depression.

A) Recent studies show depression decreases in post menopause years (Freeman E.W, et. al. 2004, Arch Gen Psychiatry, P E Bebbington, et. at. Psychol Med. 1998). So do Irritability and mood swings in correlation with the drop of hormone levels. (Freeman E.W, et. al. 2008, Obstetrics and gynecology). This is a sharp contrast to the perimenopausal period when depression increases (Clayton AH, Ninan PT, 2010. Prim Care Companion J Clin Psychiatry), as well as anxiety (Juan Enrique M Blümel, at. al. 2004, Maturitas)
A study in England has found that "only vasomotor and atrophic symptoms vary with menopausal status. Other somatic and psychological symptoms experienced by middle-aged women cannot be regarded as part of the same 'menopausal syndrome'." (M Porter, et. al. 1996, British journal of obstetrics and gynaecology)
Although the physical symptoms are uncomfortable, worrisome, debilitating, and they definitely make anyone feel miserable, and in that sense they are depressing, but it should not be confused with clinical mood depression (namely, sadness, crying spells, constant negative thoughts).

B) Physiological depression on the other hand, can result from low hormones (estrogen, progesterone, testosterone, DHEA, Vitamin D (sunlight), etc.), as well as from a chronic lack of sleep and insulin resistance. I would include Loss of vigor and libido, Feeling tired or lacking in energy, Slow digestion, Slow mental processes, Difficulty in concentrating, Muscle weakness, etc. into this category.

3. We need to be very careful when trying to understand conditions that is hard to describe and there are no well established labels, not to mention objective measures. Unlike hot flashes in which temperature, hart rate, sweating, and various blood hormone levels can be objectively monitored, moods, feelings, and sensations are subjective. In absence of the objective measures, there is a plenty of room for misunderstanding, distortion, and dismissal. Simple wordings in a questioner can be misunderstood or inadequate in representing individual's subjective experiences. "Pressure or tightness in head or body" may not sound close enough to brain strain sensation or foggy brain, for example. If it is translated into, let's say Japanese in a certain way, Japanese women may not relate it to stiff neck and shoulders nor to head pressures and MOYA-MOYA head.

4. Researchers should listen to their subjects more carefully. We know what we are talking about. When we say it is difficulty in concentrating, that's what it is, which was clearly indicated in recent studies "Subjective cognitive complaints at menopause associated with declines in performance of verbal memory and attentional processes." (M Schaafsma, et. al. Climacteric. 2009), and [Cognitive function in menopausal women evaluated with the Mini-Mental State Examination and Word-List Memory Test] (Rita de Cássia Leite Fernandes, et. al., Cad Saude Publica. 2009).

The Hormone War is Heating Up

2009-10-08T13:16:00.023-05:00

The other day, I had my radio on. It was airing Betraying Nature (by David Suzuki). I was doing something else at the time, but there was one segment that caught my attention. "Deny, dismiss, delay. It's the same general strategy used by the tobacco industry and others to obfuscate issues and keep the public confused. And it's worked." I said to myself that's exactly what's been going on with the bio-identical vs fake hormone debate. Then he said "First, deny the problem exists. Fund plenty of paid experts to overwhelm the media and make them provide balance by getting those skeptics or deniers into every story." That's pretty much confirmed my suspicions. The Oprah Show included some of those denier doctors (Dr. Wulf Utian, executive director of the North American Menopausal Society and Dr. Lauren Streicher, an assistant professor of obstetrics and gynecology at Northwestern University and a practicing ob-gyn at Chicago's Northwestern Memorial Hospital) and the blatantly unscientific and illogical statement from FDA officials saying that they don't recognize a thing called "bio-identical" hormone. The Oprah bashing writer of the Newsweek magazine is also a well known friend of pharmaceutical industry. All these people have financial connections to the pharmaceutical industry and acting as their mouth piece, according to Jeffery Dach MD blog. That is in the mass media, but the same thing has been going on in the professional medical journals also.

When I reviewed the history of natural progesterone cream research, there were clear indications of the deniers' influences. They produced one FAILED study, and have been using it as the proof that natural progesterone cream is no good (see Med J Aust. 2005 Mar 7;182:237-239 Transdermal progesterone creams for postmenopausal women: more hype than hope? by Barry Wren). From a purely scientific point of view, one failed study does not prove anything. It simply means they failed. There can be a million reasons an experiment can fail. There might have been some mishandling of the materials, data, instruments; the preparations might have been inferior, etc. for example. When it fails, it does not prove there is no effect, unless it is replicated many times by other researchers. Of course, there are studies that successfully demonstrated the efficacy of natural progesterone cream, and in the presence of those successful studies, a failed study is just that, a failed study. (See a review by George R. Gillson, MD, PhD, David T. Zava, PhD, A Perspective on HRT for Women: Picking Up the Pieces After the Women's Health Initiative Trial - Part 2)

The next stage is to dismiss; "When the scales begin to tip and the tactic starts to fail, then switch to dismiss. Accept that the problem exists but insist either that nothing can be done about it or..."

Well, even after the WHI's PremPro clinical trials have shown clear health hazards of the fake hormones in 2002, they are still trying to deny the problem by unscientific claims that Provera and Premarin (PremProm) are safe for early post menopausal women if used for less than 5 years. If you are persuaded by such arguments, you have a serious science IQ deficiency. It took 5 years to reach the preset statistical hazard ratio, but there were people who became sick in less than one year, and they developed more severe symptoms than non user cancer victims. "...the WHI study found that, among 10,000 women taking estrogen plus progestin for one year, there will be 8 more cases of breast cancer among the hormone users than if they had not taken the therapy"is what the researchers said. So, it is only as safe as Russian roulette, I would say. The lethal effects did not disappear even when the age (years since the onset of menopause) was taken into consideration in the reanalysis. Scientifically, it was a total waste of time and tax pair's money to even contemplate any possibility of favorable results from these fake hormones, who's contributions to the disease processes are known at molecular level (see a review by Holtorf, el al. 2009). I hope the recent outcome of the Wyeth breast cancer lawsuit will make doctors think twice before prescribing them. It is a shear madness that Wyeth, the pharmaceutical company of PremPro is still allowed to sell those fake hormones, which generated $1.1 billion in 2008. We, the general public is paying the bill as higher medical costs, reduced productivity, and disrupted lives the victims and the people around them ultimately suffer.

They are also shifting the gear to the next dismiss stage by saying there is nothing better, and the safety of bio-identical hormones are not proven (see the policy statements of American Medical Association, North American Menopause Society, American Endocrine Society, The American College of Obstetricians and Gynecologists (ACOG). "No Scientific Evidence Supporting Effectiveness or Safety of Compounded Bioidentical Hormone Therapy" is the exact words from ACOG NEWS RELEASE, which is "blatantly false" and qualifies as "scientific fraud". An increasing number of doctors are coming out to publicly accuse those medical associations they belong themselves. At the forefront of this battle are the doctors who have been treating both male and female patient with a wide variety of natural hormones based on decades worth of scientific and clinical studies. It is not just female hormones estrogen and progesterone, but male hormone testosterone, adrenal hormone cortisol, and thyroid hormone thyroxine all have this natural=bioidentical against fake=synthetic hormone issues. And it is about time the consumers as well as doctors were informed of the differences, the hazards of fake hormones, and how to use the real bioidentical-to-human's hormones (see Hormones: Dos and Don'ts)

According to David Suzuki, next stage is delay. Some has declared the bio-identical hormone debate is over. As far as the science is concerned, it's long been over, but that does not mean it will be embrace by everyone concerned right away. It's not just feet dragging and blindfolding that is going on. Those who have financial stakes in those fake hormones seem to be fighting it to the bitter end. The best defense is an offence. The battle seems to be escalating and the tactics getting dirtier.

Perhaps most of us did not have enough imagination to anticipate how dirty they would get. Although it was not the first time he was harassed by government regulators, this time the attacks against Jonathon Wright MD and his fellow holistic=natural=real medicine doctors were coordinated attacks (In Washington state, there are 15 doctors who belong to American College for Advancement in Medicine and 5 of them were persecuted by trumped up absurd charges). Now he is fighting back at various levels, counter attacking against the so called mainstream medicine doctors who control American Medical Associations and FDA and have been acting as big pharma's mouth piece, according to Jeffrey Dach MD BioIdentical Hormone Blog

Doctors aren't the only target. In October 2007 FTC also harassed Seven Online Sellers of progesterone cream, totally dismissing the pioneering study by Dr. Jone R. Lee (Lee, John R., M.D., "Osteoporosis Reversal: The Role of Progesterone," International Clinical Nutrition Review (1990), 10:384-391.). If they are truly serious about protecting consumers from false claims, they should go after Fosamax. Compounding pharmacies were also attacked. They had to fight against FDA's move to restrict doctors' access to natural hormones through compounding pharmacy, which was reversed (see Virginia Hopkins Health Watch and Patients, Doctors, Pharmacists Praise Bipartisan House Resolution On Compounded Hormones Containing Estriol).

As maddening and shameful as they are, these episodes will no doubt go down in the science and medical history footnotes, along with the Intelligent Design and the monkey trial, as the collateral damages of W. Bush's presidency and the Republican rule that turned America into a land of greed and voodoo science.
Late Dr. John R. Lee began his fight in late 1980's, long before the PremPro study was abruptly terminated in 2002. I was glad the study was terminated and shocked the world. Finally the truth is out, I thought. But I was naive. The very next year, when I read September 2003 position statement of The North American Menopause Society I realized what was going on; deny and dismiss. Today, 8 years later, not much has changed on the surface. Their position statements indicate they still think they can get away with it.

September 2003 position statement of The North American Menopause Society said:
"In the absence of clinical trial data from each estrogen and progestogen, the clinical trial results for one agent probably should be generalized to all agents within the same family, especially with regard to adverse effects." And they claimed that it is "the most up-to-date and scientifically based recommendations currently available on the clinical use of ET/EPT in peri- and postmenopause."

The AMA 2008 statement says:
"There is no credible evidence that bio-identical hormones are safer than traditional estrogen and progesterone products (Premarin and Provera)".

There have been too few real attacks against their blatant unscientific claims for so long. There are many people other than the doctors and the victims, namely scientists, politicians, and journalists who could have examined the issue and raised the public awareness. Where have they been? Why doesn't FDA have competent scientists? May be most of them are bought? What are the insurance companies doing? Both health and malpractice insurance companies should discourage doctors from prescribing the fake hormones and encourage the use of bio-identical hormones. Don't they have enough mathematicians and statisticians to see the implications? While the American doctors have been blindfolded, large scale safety studies have been carried out and published in other parts of the world, such as French E3N cohort study (see reviews listed below fore more). They can save a bundle if they did. Isn't that the promise of this free market system? Or are they colluding with the big phama too? If the 2002 PremPro results did not clearly tell them the party is over, may be 9,000 lawsuits will.

Some of the Websites I found helpful and inspiring:

Website of Late Dr. John R. Lee: is still open thanks to his wife.

Jeffrey Dach MD: His blog is my inspiration.

The Battle for BioIdentical Hormones by Jeffrey Dach MD (He can use some coaching on his presentation style, thought.)
Natural Medicine 101: How to Win the Medical Information War and Take Control of Your Health

Bioidentical Hormone Initiative: Their publicity campaign is awesome.

The Truth about Hormone Therapy in Wall Street Journal Opinion page
CNBC segment on male menopause treatments, and other numerous media appearances
The definitive review: The Bioidentical Hormone Debate: Are Bioidentical Hormones (Estradiol, Estriol, and Progesterone) Safer or More Efficacious than Commonly Used Synthetic Versions in Hormone Replacement Therapy?

Oprah show on Hormones: I don't quite understand their confusion about availability and the safety of bioidenticlal hormones, though. Just ask a few pharmacies about what is compounded, what is packaged, and what is over the counter.

Virginia Hopkins: The coauthor and editor of late Dr. John R. Lee's books and newsletters

David T. Zava, PhD: Expert on breast cancer and hormone tests. Coauthored:

What Your Doctor May Not Tell You About Breast Cancer, by John R. Lee, M.D. David Zava, Ph.D, and Virginia Hopkins, 2002 Warner Books.
George R. Gillson, MD, PhD, David T. Zava, PhD, A Perspective on HRT for Women: Picking Up the Pieces After the Women's Health Initiative Trial - Part 1 , International Journal of Pharmaceutical Compounding Vol. 7 No. 4 July/August 2003
George R. Gillson, MD, PhD, David T. Zava, PhD, A Perspective on HRT for Women: Picking Up the Pieces After the Women's Health Initiative Trial - Part 2, International Journal of Pharmaceutical Compounding Vol. 7 No. 5 September/October 2003

David Suzuki, PhD: As a biologist turned environmental activist / broadcaster, he would probably prefer to see a stronger voice against the use of fake hormones as contraceptives as well as HRT (along with the chemicals in personal care products, industrial, agricultural, and plastic wastes), which go into not only our sewer systems but also polluting the rivers and coastal waters deforming marine lives. 1/3 of smallmouth bass showed signs of Gender-Bending in a nation wise study.

PremproCounsel Legal Team

My hormone pages
(PDF version of this post)

DHEA for Menopause

2008-08-03T11:15:00.006-05:00

Dehydroepiandrosterone (DHEA) is a hormone precursor secreted in large amount by adrenal cortex, and converted to many steroid/sex hormones in various tissues. Like many other hormones, the amount of DHEA secreted decrease dramatically with age. Researchers in Italy have been gathering data on the effects of DHEA supplementation in menopausal women, which have shown profound implications. Personally, a puzzling menopause/stress related sleep disturbance I have suffered for many years is finally showing a sign of improvement after staying on DHEA + combination of tonic herbs for a several months (the symptom did not improve with Estradiol + Progesterone supplementation).

Here is one of the exciting articles on DHEA (Labrie et al. J Endocrinol. 2005 Nov ;187 (2):169-196)

"All the enzymes required to transform DHEA into androgens and/or estrogens are expressed in a cell-specific manner in a large series of peripheral target tissues, thus permitting all androgen-sensitive and estrogen-sensitive tissues to make locally and control the intracellular levels of sex steroids according to local needs. This new field of endocrinology has been called intracrinology. In women, after menopause, all estrogens and almost all androgens are made locally in peripheral tissues from DHEA which indirectly exerts effects, among others, on bone formation, adiposity, muscle, insulin and glucose metabolism, skin, libido and well-being. In men, where the secretion of androgens by the testicles continues for life, the contribution of DHEA to androgens has been best evaluated in the prostate where about 50% of androgens are made locally from DHEA. Such knowledge has led to the development of combined androgen blockade (CAB), a treatment which adds a pure anti-androgen to medical (GnRH agonist) or surgical castration in order to block the access of the androgens made locally to the androgen receptor. In fact, CAB has been the first treatment demonstrated to prolong life in advanced prostate cancer while recent data indicate that it can permit long-term control and probably cure in at least 90% of cases of localized prostate cancer. The new field of intracrinology or local formation of sex steroids from DHEA in target tissues has permitted major advances in the treatment of the two most frequent cancers, namely breast and prostate cancer, while its potential use as a physiological HRT could well provide a physiological balance of androgens and estrogens, thus offering exciting possibilities for women's health at menopause."
(to be continued)

Hormones: Dos and Don'ts

2008-07-25T17:56:00.011-05:00

As I explained in Natural Hormones: Why doctors are clueless? section, most doctors are still following the highly biased guidelines drug companies have laid out for them and clueless and confused when it comes to safe and effective use of natural hormones (see also what PremproCounsel Legal Team has found).

So, here is the dos and don'ts of menopause hormonal health management and the relevant research papers, in case your doctor is one of those confused and misinformed.

Important: Don't let your doctor overdose you.

Doctors are brain washed to think: most of oral natural progesterone or estrogen gets "digested", therefore it requires 10 times more than what you actually need.
Doctors are brain washed to think: natural progesterone or estrogen does not get absorbed much through skin, therefore it requires 10 times more than what you actually need.
Doctors are brain washed to think: your blood hormone level (98% inactive, 2 % active form of hormone) has to achieve the same level as normal reproductive age level by supplementing active form of hormone (micronized powder in gel cap or liquid in cream, oil, gel, patch, spray, etc.), and measuring inactive form of hormones. Although what really matters is the level of active form of hormones and the traditional blood test is not sensitive enough to keep track the active form of hormones.

One time I consulted a doctor who seemed better informed. When I asked him about oral progesterone, he prescribed me 100mg capsules. It made me so tired and lethargic I had to quit after 2 days.

Dos:

1. Use natural bio-identical hormones at lowest dose necessary in transdermal forms (skin cream*, patch, oil, spray, vaginal gel/cream/ring**). The higher the dosage the more bleeding and spotting will occur, not to mentions all the overdose side effects and hormonal imbalance risks. For many women with intact ovaries, 20mg/day progesterone cream without estrogen can completely eliminate hot flashes and other menopausal symptoms during the early post menopause years (see the table below). 0.025mg/day transdermal estradiol + progesterone is enough to control menopause symptoms for most women, 0.05mg/day transdermal estradiol + progesterone will take care the rest^{^[1]}. For protection of uterine lining (endometrium), as low as 10mg/day vaginal progesterone can protect uterus against estrogen stimulated proliferation, although individual differences exist. Keep in mind that maximum daily progesterone secretion during normal cycle is around 30mg.

*Caution: for the progesterone cream to be well absorbed and protected from oxidation, it has to be suspended in some protective delivery medium (e.g. liposome) or dissolved in protective oil such as vitamin E. Gritty and/or watery cream is not effective. High quality cream will resist oxidation up to 3 months after opening, but not much more. Also, the cream has to be rubbed in well to clean and soft part of skin free of mineral oil to ensure absorption.

**Caution: vaginal rings are know to cause tissue irritations and should be monitored closely.

2. Start progesterone supplementation with the first sign of menopause transition to prevent estrogen dominance. The progesterone level drops several years before menopause, while estrogen level stays normal or higher^{^[2]}. Even during the early post menopause years, the estrogen level stays high enough to stimulate endometrial proliferation^{^[3]}, therefore progesterone supplementation is needed to prevent estrogen dominance syndromes including uterine cancer.

3. Use continuous regimen (no estrogen only days). There is no need to induce bleeding to protect your uterus in post menopause years (D L Moyer et al. 1993^{^[4]}). Low dose progesterone (as low as 10 mg/day vaginal and 30 mg/day skin cream) is enough to protect uterus lining (endometrium) in the continuous regimen when combined with low to medium dose estradiol (see the table below). However, it is normal to see some spotting or bleeding at the beginning of continuous regimen. Continuous regimen is also important for protection against ovarian cancer^{^[5]}.

4. Get regular check-up. Although maintaining healthy hormonal balance the right way will reduce various health risks, it will not make you bullet proof.

Don'ts:

1. Use of unopposed estrogen is not justified even for women without uterus. Besides the well known uterine cancer risk, it raises risks of breast cancer^{^[6]}, ovarian cancer ^{^[7]} [8], stroke^{^[9]}, dementia[10] and a wide range of estrogen dominance syndromes. In other words, whenever you use estrogen, you need to use progesterone (bio-identical) along with it. Anybody who says otherwise is ignorant of the differences between the real and fake progesterone as well as the serious nature of estrogen dominance syndromes.

2. Use of fake hormones of any kind is not justified for any condition. They raise breast cancer risk^{^[11]}, blood clot risk^{^[12]}, bad cholesterols^{^[13]}, to mention just a few. How can you tell which one is real? If the active ingredients does not simply say "progesterone" or "estradiol" or "17-beta estradiol", stay away. Note also that all birth control drugs are fake hormones.

3. Use of oral hormone delivery (pills, capsules) is not justified for any condition. It negatively affects cholesterol^{^[14]}, cardio-vascular risk^{^[15]}, and metabolic risk factors^{^[16]}. It is less effective in controlling uterine lining^{^[17]}. It burdens liver and kidney[18], raises gallbladder disease risk[19]. Oral progesterone can cause fatigue, depressive mood, and PMS like symptoms due to the high standard dose (100 mg capsule is the lowest available) and high rate of metabolic conversions, especially when it is not in balance with estrogen level^{^[20]}. Progesterone and its metabolites are GABAa receptor activators (i.e. They act as tranquilizer). Given a large enough dose, it can induce drunkenness and slow down digestive as well as cognitive functions^{^[21]}.

4. Use of venous blood hormone tests for measuring hormone supplementation level is useless. It's been known that the plasma hormone levels and uterine lining status do not correlate (Trevoux, et al. 1986^{^[22]}, Sojo-Aranda et al. 1988^{^[23]}, ). The same applies when you try to see the effects of hormone supplementation (Ficicioglu et al. 2004^{^[24]}, Tavaniotou et al. 2000^{^[25]}, Friedler et al. 1999^{^[26]}). Measuring hormone levels in venous blood, be it plasma or red blood cells, free or bound, is like measuring oxygen in venous red blood cells and concluding the person is suffocating. Saliva or capillary blood spot test reflects what's delivered to the tissues much better. However, there is no need to use such indirect measures that go through a rapid change with each application^{^[27]} [28] [29]. When you need to know if the symptoms improved, you measure the symptoms. When you need to know if the uterus is protected, you check the uterus, and so forth.

Table 1. Continuous regimen studies with transdermal (non oral) natural progesterone on post menopausal women

Study	Size/duration	Estrogen	Progesterone	Results
Leonetti et al. 1999[30]	43 (47 placebo) women within 5 years of natural menopause, 1 year trial	no estrogens (daily multivitamins and 1200 mg of calcium)	quarter teaspoon of cream (containing 20 mg progesterone) to the skin daily or placebo	vasomotor symptom relief: 25 of 30 (83%), 5 of 26 (19%) with placebo, complete relief in 11 of 30. Most reached maximum relief after the first month. no bone loss or gain spotting: 8 women
Leonetti et al. 2003[31]	32 women time since menopause (7.1 ±6.2 years) 28 day trial	premarin (oral conjugated estrone) 0.625mg/day started 2 weeks before progesterone to stimulate endometrium	twice daily transdermal application of 0%, 1.5%(30mg /day), or 4.0%(80mg/day) P in 1000 mg cream, adjusted by body weight	The endometrial proliferation scores (EPS) Initial EPS=2 a Final EPS=0 for 30mg and 80mg group, no change for 0% (placebo) group 0=inactive, 1=scantly proliferative, 2= moderately proliferative, 3= proliferative, 4= highly proliferative. Spotting occurred in 3 during the washout estrogen-only period, 3 during the first 2 weeks of P treatment (2 in 0% group, 1 in 1.5% group) greater than 98% compliance
Arvind Vashisht et al. 2005[32]	41 (3 of 44 did not complete) 48 week trial	1 mg transdermal estradiol daily	40 mg transdermal natural progesterone cream daily	At 24 weeks, 48% remained entirely amenorrhoeic. At 48 weeks 35% had been entirely amenorrhoeic and 50% had either no bleeding or spotting alone. The number of bleeding episodes did not reduce with time. 32 % proliferative or hyperplastic.
Arvind Vashisht at al. 2005[33]	same as above	same as above	same as above	Women reported significant reductions in menopausal symptoms, as measured by the Green Climacteric Scale, after 24 and 48 weeks of combined treatment.
D de Ziegler et al. 2000[34]	67 women for 6 months	estrogens (not specified) most likely transdermal estradiol 0.05 mg	vaginal progesterone gel (Crinone 4%= (45 mg) twice weekly	54 (80.6%) of 67 amenorrhoeic throughout 6 months. No hyperplasia
Cicinelli, Ettore et al. 2002[35]	26 women, I year	transdermal estradiol 0.05 mg	vaginal progesterone gel (Crinone 4%= 45 mg) twice weekly	287/350 (82%) cycles were amenorrheic. endometrial atrophy in 24 (92.3%) cases and signs of decidualization in 2 cases.
Hamada et at. 2003[36]	20 women 16 weeks	vaginal ring estradiol 160 microg/day	4 month vaginal ring progesterone 10 or 20 mg/day.	Significant decreases in the incidence of hot flushes and night sweats as well as a striking improvement in mood scores as early as 2 weeks after insertion. Increased vaginal discharge within the first 6 weeks. Endometrium thickness of <3mm Vaginal bleeding was more frequently apparent among users of the 20mg ring, although bleeding and spotting were confined to the first 6 weeks.
Ben-Chetrit et al. 2005[37]	29 women ring kept 4 to 6 months 11 dropped out due to side effects	same as above	same as above	Reduced climacteric symptoms, prevented endometrial proliferation, and provided an acceptable bleeding pattern. Endometrial thickness increased in 6(20%).
Suvanto-Luukkonen et al. 1998[38]	15 women I year trial	percutaneous estradiol gel containing 1.5 mg estradiol daily	natural progesterone 100 mg daily vaginal	After 12 months of therapy, no significant change in endometrial thickness (2.5 mm -> 2.4mm), 5 had inactive or atrophic endometrium, 10 were proliferative. No hyperplasia.

Notes: Red indicates excessive dosage, oral form, or otherwise problematic, that should not be followed.

[1] H Gadomska, E Barcz, A Cyganek, Y Leocmach, H Chadha-Boreham, L Marianowski. Efficacy and tolerability of low-dose transdermal estrogen (Oesclim) in the treatment of menopausal symptoms. Curr Med Res Opin. 2002 ;18 (2):97-102,

[2] Santoro N, Brown JR, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. 1996;81(4):1495-1501.

[3] R Trevoux, J De Brux, M Castanier, K Nahoul, J P Soule, R Scholler. Endometrium and plasma hormone profile in the peri-menopause and post-menopause. Maturitas. 1986 Dec ;8 (4):309-26

[4] D L Moyer, B de Lignieres, P Driguez, J P Pez. Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes. Fertil Steril. 1993 May ;59 (5):992-7

[5] Tomas Riman, Paul W Dickman, Staffan Nilsson, Nestor Correia, Hans Nordlinder, Cecilia M Magnusson, Elisabete Weiderpass, Ingemar R Persson Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst. 2002 Apr 3;94 (7):497-504 1.

[6] Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Agnes Fournier, Franco Berrino, Francoise Clavel-Chapelon. Breast Cancer Res Treat. 2007 Feb 27.

[7] James V. Lacey Jr. et al., Menopausal Hormone Replacement Therapy and Risk of Ovarian Cancer, 288 JAMA 334 (2002).

[8] Karen Wernli, Polly Newcomb, John Hampton, Amy Trentham-Dietz, Kathleen Egan. Hormone therapy and ovarian cancer: incidence and survival. Cancer Causes Control. 2008 Feb 9

[9] Garnet L Anderson et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291 (14):1701-12

[10] Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH; Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2947-58.

[11] Agnes Fournier, Franco Berrino, Francoise Clavel-Chapelon. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2007 Feb 27

[12] J L Ambrus, I B Mink, N G Courey, K Niswander, R H Moore, C M Ambrus, M A Lillie. Progestational agents and blood coagulation. VII. Thromboembolic and other complications of oral contraceptive therapy in relationship to pretreatment levels of blood coagulation factors: summary report of a ten-year study. Am J Obstet Gynecol. 1976 Aug 15;125 (8):1057-62,

[13] U B Ottosson Oral progesterone and estrogen/progestogen therapy. Effects of natural and synthetic hormones on subfractions of HDL cholesterol and liver proteins. Acta Obstet Gynecol Scand Suppl. 1984 ;127 :1-37,

[14] M Erenus, B Karakoc, A Gurler Comparison of effects of continuous combined transdermal with oral estrogen and oral progestogen replacement therapies on serum lipoproteins and compliance. Climacteric. 2001 Sep ;4 (3):228-34

[15] Karine Lacut, Emmanuel Oger, Jean-Herve Abalain, Marie-Pierre Moineau, Dominique Mottier. Effects of oral and transdermal 17 beta-estradiol combined with progesterone on homocysteine metabolism in postmenopausal women: a randomised placebo-controlled trial. Atherosclerosis. 2004 May ;174 (1):173-80

[16] J C Stevenson, D Crook, I F Godsland, B Lees, M I Whitehead. Oral versus transdermal hormone replacement therapy. Int J Fertil Menopausal Stud. 1993 ;38 Suppl 1

[17] Tavaniotou et al. Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum Reprod Update. 2000, 6 (2):139-48

[18] K A Steingold, D W Matt, D DeZiegler, J E Sealey, M Fratkin, S Reznikov. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab. 1991 Aug ;73:275-80

[19] Bette Liu, Valerie Beral, Angela Balkwill, Jane Green, Sian Sweetland, Gillian Reeves. Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study. BMJ. 2008 ;337 :a386

[20] B de Lignieres, M Vincens. Differential effects of exogenous oestradiol and progesterone on mood in post-menopausal women: individual dose/effect relationship. Maturitas. 1982 Apr ;4 (1):67-72.

[21] E W Freeman, L Weinstock, K Rickels, S J Sondheimer, C Coutifaris. A placebo-controlled study of effects of oral progesterone on performance and mood. Br J Clin Pharmacol. 1992 Mar ;33:293-8

[22] R Trevoux, J De Brux, M Castanier, K Nahoul, J P Soule, R Scholler Endometrium and plasma hormone profile in the peri-menopause and post-menopause. Maturitas. 1986 Dec ;8 (4):309-26

[23] I Sojo-Aranda, R Alonso-Uriarte, M Gonzalez-Diddi, V Cortes-Gallegos. The biological expression of natural progesterone. J Steroid Biochem. 1988 Aug ;31 (2):219-22

[24] C Ficicioglu, B Gurbuz, S Tasdemir, S Yalti, H Canova. High local endometrial effect of vaginal progesterone gel. Gynecol Endocrinol. 2004 May ;18 (5):240-3

[25] Tavaniotou et al. Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum Reprod Update. 2000, 6 (2):139-48

[26] Friedler et al. Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotrophin-releasing hormone agonist: a comparative study between vaginal and oral administration. Hum Reprod. 1999 Aug ;14 (8):1944-8

[27] O'leary P.; Feddema P.; Chan K.; Taranto M.; Smith M.; Evans S. Salivary, but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre-and postmenopausal women. Clinical Endocrinology, Volume 53, Number 5, November 2000 , pp. 615-620(6)

Topical application of progesterone cream will show up in saliva within 30 to 60 min., and reaches high peak in 1 to 4 hours, then falls thereafter.

[28] E Cicinelli, S Sabatelli, D Petruzzi, S Stragapede, M Lapenna, G Balzano [Transvaginal absorption of an oleic solution of progesterone (Gestone) in fertile women] Minerva Ginecol. 1995 Mar ;47 (3):99-102

P in oil 100 mg, Blood P level peaked in 1 to 4 hours, was still higher than baseline after 24 hours.

[29] B Villanueva, R F Casper, S S Yen. Intravaginal administration of progesterone: enhanced absorption after estrogen treatment. Fertil Steril. 1981 Apr ;35 (4):433-7

The peak level can be 20 to 40 times baseline. After how much P given not mentioned in the abstract.

[30] H B Leonetti, S Longo, J N Anasti.Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol. 1999 Aug ;94 (2):225-8

This confirmed the common observation of those doctors who have been recommending progesterone skin cream for menopausal symptoms that 2 in 3 women in the US can manage menopause with progesterone only therapy.

[31] Leonetti H, Wilson KJ, Anasti JN. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Fertil Steril 2003; 79: 221-222.

Premarin 0.625mg was the most often prescribed estrogen in the US at the time, and they demonstrated natural progesterone cream can be combined effectively with it instead of Provera, which has been know for its multitude of side effects.

[32] Arvind Vashisht, Fred Wadsworth, Adam Carey, Beverley Carey, John Studd. Bleeding profiles and effects on the endometrium for women using a novel combination of transdermal oestradiol and natural progesterone cream as part of a continuous combined hormone replacement regime. BJOG. 2005 Oct ;112 (10):1402-6

I wonder why they used 1 mg /day transdermal estradiol, which is 40 times higher than what's needed. No wonder 40mg/day progesterone cream could not control endometrium adequately. Doctors at Chelsea and Westminster Hospital, London, UK are starting to realized that they cannot simply dismiss progesterone cream based on serum/plasma hormone level like they did in their 2000 study. However, they did not learn much about the right estradiol dosage since. Or was it their main aim to discourage the use of progesterone cream? Whatever the reason, I hope they are not routinely prescribing such a high amount of estradiol to their menopause patients.

[33] Arvind Vashisht, Fred Wadsworth, Adam Carey, Beverley Carey, John Studd. A study to look at hormonal absorption of progesterone cream used in conjunction with transdermal estrogen. Gynecol Endocrinol. 2005 Aug ;21 (2):101-5

[34] D de Ziegler, R Ferriani, L A Moraes, C Bulletti. Vaginal progesterone in menopause: Crinone 4% in cyclical and constant combined regimens. Hum Reprod. 2000 Jun ;15 Suppl 1 :149-58

[35] Cicinelli et al. Twice-weekly transdermal estradiol and vaginal progesterone as continuous combined hormone replacement therapy in postmenopausal women: A 1-year prospective study. American Journal of Obstetrics & Gynecology. 187(3):556-560, September 2002.

[36] A L Hamada, T Maruo, T Samoto, S Yoshida, H Nash, I M Spitz, E Johansson. Estradiol/progesterone-releasing vaginal rings for hormone replacement therapy in postmenopausal women. Gynecol Endocrinol. 2003 Jun ;17 (3):247-54

With the local effect of transdermal delivery, 10 mg/day progesterone is enough to control endometrium even with relatively high dose of estradiol used in this study. They also demonstrated that enough hormones reached brain to control menopausal symptoms and mood.

[37] Avraham Ben-Chetrit, Drorit Hochner-Celnikier, Tzina Lindenberg, David Zacut, Shlomo Shimonovitz, Hadassa Gelber, Irving M Spitz. Vaginal ring delivering estradiol and progesterone: a possible alternative to relieve climacteric symptoms. Isr Med Assoc J. 2005 May ;7 (5):302-6.

The vaginal ring was apparently abrasive and irritated the tissues, which caused 11 of 28 people to dropout. I wonder how they did in the Japanese arm of the study, which does not mention anything about it in the abstract. I wonder who would use vaginal rings if they know they can try progesterone skin cream to see if it work for them.

[38] E Suvanto-Luukkonen, H Malinen, H Sundstrom, J Penttinen, A Kauppila. Endometrial morphology during hormone replacement therapy with estradiol gel combined to levonorgestrel-releasing intrauterine device or natural progesterone. Acta Obstet Gynecol Scand. 1998 Aug ;77 (7):758-63

This study was done to demonstrate the superiority of levonorgestrel-releasing intrauterine device (LNG-IUD). The high doses reflect the attempt to achieve "normal" plasma level commonly believed necessary at the time. Too bad they did not create natural progesterone releasing device. Although, I cannot imagine inserting IUD in my uterus even if it is natural progesterone, much less a fake progesterone like levonorgestrel.

Natural Hormones: Why doctors are clueless?

2008-07-25T17:27:00.083-05:00

If you've never been exposed to this seemingly simple issue of how to maintain the hormonal balance and health, you are probably wondering why the controversy? In this day and age--with all the technologies to measure even the tiniest trace amount of hormones anywhere in the body, and drugs to block any hormone almost at will, plus manufacturing capabilities to produce hormones of any shape or form whether they exist in nature or not--you might think that all the experts would agree on the basic facts. But with billions of dollars for drug companies at stake, the quality of life (if not life and death) of billions of women and men get caught up in confusion.

When I was told "You should be using natural progesterone." by a nutritional supplement dealer, my response was "But, I don't have uterus and my doctor told me…". Before I could finish my sentence, she told me "You need to read this." and pulled out a printout of some summary information on the subject. I took it home, and as I started to read it, I realized what I was reading, if true, was a major medical blunder in modern medicine. You might even say it has a smell of conspiracy that makes "the Vast Right-Wing Conspiracy" on Bill and Hilary Clinton pale in comparison (see what PremproCounsel Legal Team has uncovered). That was 1998, many years before the Women's Health Initiative (WHI) clinical trial was terminated with shocking results in 2002.

In case you are not familiar, the clinical trial found that women treated with combined Premarin (estrogen from horse urine) and Provera (a fake progesterone) therapy experienced higher rates of breast cancer, stroke, heart attack, pulmonary embolism, and blood clots. (In 2003, Premarin-only arm of the same study was also stopped early with increased risks of stroke and dementia. Another study done by National Cancer Institute (NCI) found that long-term estrogen-only use significantly increased the risk of ovarian cancer.)

Actually it wasn't shocking to those in the know, including the drug companies. Most of those side effects have been known and listed on the warning labels, albeit not adequate. So, after spending millions of dollars of tax-payer's money and exposing tens of thousands of women to the hazardous substances, there was an eerie silence instead of swift action to ban the dangerous fake hormones along with the so called "standard HRT". Then the damage control began. They went back and "reanalyzed" the WHI clinical trial data and stepped up their campaign to tell doctors that it's OK to continue the "standard HRT". Their claim was that if you just look at the younger, healthier subjects, they were OK, and besides, there is nothing better anyway. Of course women aren't buying it (neither the French^[1], nor the Brazilians), but it's what the US doctors are told in their medical journals, in their professional society's position statement^{^[2]}, and fellow physician speakers, most of whom are paid by drug companies.

History

It all began when it became clear that real (natural bio-identical) hormones are not easily absorbed when taken orally because most of it gets "digested" (converted or metabolized to some other forms of hormones), and the drug companies opted to tinker with the hormones to make indigestible fake hormones rather than figuring out effective delivery methods of the real hormones. For one thing, there is more money in selling patentable artificial (fake) substances than in selling naturally occurring substances that are not patentable.

Of course, there are always ingenious people who see a need and figure out a way. If you need to avoid digestion, you use other routes--such as skin. Skin can absorb lots of things. Luckily, progesterone has been one of the safe hormones available without prescription in the US. So, progesterone skin cream and oil became available as over the counter supplements. It did not require any large scale studies to convince the consumers. All you need to do is to try it out yourself to see it work for you. It is inexpensive, easy to use, and safe. By the time late Dr. John R. Lee published his first book of the "What Your Doctor may Not Tell You About …." series in 1996, there were more than 30 companies manufacturing and selling progesterone cream he found suitable for supplementation.

Then, there surfaced a group of people--a propaganda machine, if you will--who started to publish articles in medical journals to discredit everything related to natural bio-identical hormones, especially the progesterone cream available over the counter or from compounding pharmacies^{^[3]}^{^[4]}^{^[5]}. First they thought they were on firm ground when progesterone cream failed to raise plasma progesterone level to a luteal (after ovulation) level and failed to induce bleeding with cyclic regimen. They were confident that was pretty good evidence to convince doctors that progesterone cream was no good. Then they found out that the world of menopause hormone therapy had shifted to continuous regimen and that low level progesterone had been demonstrated to be enough to protect uterine lining from hyper proliferating (the cause of uterine cancer) without inducing monthly bleeding (D L Moyer et al. 1993^{^[6]}).

They also found out that saliva or capillary blood hormone test will show a strong evidence of absorption. But, they were not deterred. They are still pushing the propaganda by discrediting saliva test itself by saying that saliva hormone levels do not correlate with plasma hormone levels^{^[7]}. No logic or data is presented in support. It is just an inconvenient fact that they want to ignore.

First, saliva test was used simply to show that a plenty of progesterone gets absorbed^{^[8]}. The timeline and the amount of hormones that show up in saliva after application is a separate issue. Besides, since when did the plasma hormone test become a reliable indicator of progesterone action in women's body? There are plenty of evidences to prove it is not (Trévoux, et al. 1986^{^[9]}, Sojo-Aranda et al. 1988^{^[10]}, Friedler et al. 1999^{^[11]}, Tavaniotou et al. 2000^{^[12]}, C Ficicioglu et al. 2004^{^[13]}). Yet they argue the lack of correlation with the plasma progesterone level discredit the saliva test (I can argue the exact opposite; The lack of correlation discredits the plasma hormone tests). By making these disingenuous baseless arguments, they are discrediting themselves.

Evidently, some of them became so disparate as to make up lies^{^[14]} about late Dr.John R. Lee who dedicated his retirement years to educate the world the importance of progesterone in women's health and how safe and easy it is to maintain hormonal balance and health using over the counter natural progesterone cream, while pointing out the danger of fake hormones used in birth control pills and conventional HRT. It is not hard to imagine, that very fact --easy, safe, inexpensive, and effective-- could be the exact reason why some in the drug industry and medical establishment try so hard to discredit its use. Over the counter natural progesterone cream can be a serious competition that can affect their bottom lines.

Transdermal application of steroid-sex hormones are not limited to natural progesterone cream and all steroid-sex hormones are of similar size and structure. Transdermal applications such as Cortisone (a fake cortisol) cream, estrogen and testosterone (both fake and real) in patch/cream/gel/oil form/spray, fake progesterone/estrogen patch for contraceptives, vaginal rings/gel/cream containing natural progesterone and estradiol have been FDA approved, and known well absorbed. So if they want to claim natural progesterone in cream form some how can not be absorbed and ineffective, they need to demonstrate the biological mechanism of why natural progesterone alone behaves differently. Anything short of that should be rejected.

When they realized there is no scientific basis to argue that progesterone cream cannot be absorbed, instead of calling to ban the fake hormones that have been proven dangerous, they started to argue there is no evidence that natural bio-identical hormones are safer than fake hormones that have been proven dangerous, and until some large scale experiments are conducted, you need to assume they are equally dangerous^[15] and need to control them the same way (meaning no over the counter products should be allowed). They are trying to convince doctors as well as FDA that access to nature hormones should be restricted. FDA's move to restrict doctors' access to natural hormones through compounding pharmacy was defeated thanks to those who staid vigilant^[16] ^[17].

Let's get it straight. We already have decades worth of research data on natural hormones. After all, they are exact bio-identical substances to what our body makes. That means every research that looked at endogenous hormone status of women from menarche to menopause and beyond is part of natural hormone research. It is disingenuous to pretend those research have no bearing on natural hormone supplementation.

The North American Menopause Society 2008 Position Statement^{^[18]}. speaks louder than anything else about who is controlling the information with whose interest in mind by their failure to differentiate the proven dangerous fake progesterone (progestins such as medroxyprogesterone acetate used in Provera and Prempro, norethindrone acetate, etc.) from natural progesterone (in 2004 Position Statement, they did not even bother to mention natural progesterone). Their bias becomes even clearer when you put it next to the 2004 position statement of Brazilian Society of Endocrinology and Metabolism that concluded "Whenever possible, one should use 17-beta estradiol, associated to natural progesterone" (both 17-beta estradiol and natural progesterone are the main hormones produced in ovaries).

The fact is the train has already left the station while doctors are all confused, misinformed, and disoriented by those disingenuous propaganda articles in the aftermath of the Prem-Pro WHI clinical trial fiasco. Millions of people have been using over the counter progesterone cream all over the world. If you are given a choice between a drug that is proven dangerous and a hormone your body used to make and thrived on, is there any doubt about which you chose? Unlike the fake hormone Prempro that some doctors are still routinely prescribing despite the fact it's been proven dangerous and notorious for its compliance problem (it makes you feel miserable and many will stop using it), the over the counter natural progesterone cream has many satisfied customers who continue to use it. By keeping doctors ignorant and misinformed, the medical community will further lose credibility they have already lost by the Prem-Pro clinical trial fiasco.

References

[1] Fournier, Franco Berrino, Françoise Clavel-Chapelon. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2007 Feb 27
This study compared different progestogens (natural progesterone and fake ones) in combination with transdermal estradiol) in long term post menopause hormone replacement therapy. Natural progesterone was the clear winner. Estrogen only (either oral Premarin or transdermal estradiol) turned our not safe against breast cancer either.

[2] Menopause. 2008 Jun 20; Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society.

They are making all sorts of excuses to encourage doctors to continue using HRT regimens the WHI studies proved dangerous. At the same time they discourage the use of other alternatives, especially natural bio identical hormones、claiming you need to assume they are just as dangerous as the fake ones.

[3] J Gen Intern Med. 2007 Jul ;22 (7):1030-1034 Bioidentical Hormones for Menopausal Hormone Therapy: Variation on a Theme. Adriane Fugh-Berman, Jenna Bythrow

A propaganda article to scare doctors away from natural bio-identical hormones. In one breath they say fake hormones are OK to use although they are proven dangerous. In another breath they attack natural hormones because the studies that proved its safety and efficacy is not perfect. Basically they are disregarding any and all evidences that does not agree with their desire to continue the status quo of using dangerous fake hormones.

[4] J Obstet Gynaecol. 2007 Oct ;27 (7):655-9 Transdermal natural progesterone cream for postmenopausal women: Inconsistent data and complex pharmacokinetics. M A A Elshafie, A A A Ewies

Another one of those propaganda articles to scare doctors away from natural progesterone cream. Which do you choose? Drugs proven dangerous or over the counter supplement products that have been used by millions of satisfied customers and plenty of studies to prove it is safe and effective? They are counting on doctors ignorance about hormone tests other than those using venous blood. They are telling the doctors it's too complex for them to understand and does not bother to explain. Or, they don't have any explanation?

[5]Med J Aust. 2005 Mar 7;182:237-239 Transdermal progesterone creams for postmenopausal women: more hype than hope? Barry Wren

Another one of those propaganda articles. He runs progesterone cream studies that fail to show positive results and claims that his failure to show positive result can discredit studies showing positive results. In the world of science, you cannot prove something does not exists. One demonstration of positive result is enough to prove it exist. When he found saliva test can detect progesterone at high level, he simply pushed it aside by saying "The level of progesterone detected in saliva was up to several hundred times greater than that measured in blood. This suggests that progesterone is probably concentrated and excreted by the salivary glands instead of filtering passively down a diffusion gradient from red blood cells to saliva." Here, he feels no need to dig deep into the underlining biological mechanism to solve the puzzles. He simply discredit the saliva test by disingenuous argument and baseless speculation, clinging on to his earlier argument that "slight/no increase in plasma progesterone" is proof enough that progesterone cream does not work.

The disingenuous nature of his arguments gets totally exposed when he makes up lies about late Dr. John Lee designed to give impression that everything he said about progesterone cream was to promote the progesterone cream he developed and sold. A total lie. Dr. Lee did not develop nor sell progesterone cream.

[6] D L Moyer, B de Lignieres, P Driguez, J P Pez. Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes.
Fertil Steril 1993 May ;59 (5):992-7

[7] John G Lewis. Steroid Analysis in Saliva: An overview. Clin Biochem Rev. 2006 Aug ;27 (3):139-46

Another one of those propaganda articles. He discredit saliva test by noting a lack of correlation between blood and saliva progesterone levels. He obviously believes that venous blood hormone level is the true indicator of how much hormone is available to various tissues in the body. This is another area doctors are not adequately trained and he thinks he can get away with his disingenuous baseless speculation.

[8] O'leary P.; Feddema P.; Chan K.; Taranto M.; Smith M.; Evans S. Salivary, but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre-and postmenopausal women. Clinical Endocrinology, Volume 53, Number 5, November 2000 , pp. 615-620(6)

[9] R Trévoux, J De Brux, M Castanier, K Nahoul, J P Soule, R Scholler. Endometrium and plasma hormone profile in the peri-menopause and post-menopause. Maturitas. 1986 Dec ;8 (4):309-26

[10] I Sojo-Aranda, R Alonso-Uriarte, M González-Diddi, V Cortés-Gallegos. The biological expression of natural progesterone. J Steroid Biochem. 1988 Aug ;31 (2):219-22

[11] Friedler et al. Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotrophin-releasing hormone agonist: a comparative study between vaginal and oral administration. Hum Reprod. 1999 Aug ;14 (8):1944-8

[12] Tavaniotou et al. Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum Reprod Update. 2000, 6 (2):139-48

[13] C Ficicioglu, B Gurbuz, S Tasdemir, S Yalti, H Canova. High local endometrial effect of vaginal progesterone gel. Gynecol Endocrinol. 2004 May ;18 (5):240-3

[14] Barry Wren Transdermal progesterone creams for postmenopausal women: more hype than hope? Med J Aust. 2005 Mar 7;182:237-239

[15] Adriane Fugh-Berman and Jenna Bythrow, Bioidentical Hormones for Menopausal Hormone Therapy: Variation on a Theme. JGIM 2007

[16] Virginia Hopkins Health Watch

[17] Patients, Doctors, Pharmacists Praise Bipartisan House Resolution On Compounded Hormones Containing Estriol

[18] Menopause. 2008 Jun 20; Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society.

PMS, Bloating, PCOS, OHSS, ART, and …

2008-05-26T15:35:00.015-05:00

If you know what PCOS and OHSS mean, you probably have been through ART. For those who are not familiar with these acronyms, PCOS is short for Polycystic Ovary Syndrome and OHSS is short for Ovarian Hyper Stimulation Syndrome, which goes hand in hand with PCOS in Assisted Reproductive Treatments (ART).

I don't mean to ridicule those who went through the ordeal, but both PCOS and OHSS are preventable and if you sought ART due to PCOS and ended up with OHSS, you did not get the best medical advice or treatments. Supplementation of real (bio-identical to human's) progesterone is known to prevent OHSS and it is part of the established guideline for prevention of OHSS (e.g. THE MANAGEMENT OF OVARIAN HYPERSTIMULATION SYNDROME by Royal College of Obstetricians and Gynaecologists, 2006).

In case you don't know what Ovarian Hyper Stimulation Syndrome is, it is a rare but potentially fatal complications that occurs when ovulation is induced by administering high doses of follicular stimulating hormone (FSH extracted from human urine or produce by recombinant technology) in combination with some other ovulation controling hormones. Its prominent feature is enlarged ovaries with multiple mature follicles producing extremely high level of estrogen. After ovulation, bloating develops with fluid rapidly accumulating in abdominal cavities, eventually spreading to other organs including lungs, while blood gets thicker and the resulting blood clots and organ failures can lead to fatality, if acute respiratory distress syndrome or diarrhea with electrolyte imbalance did not.

The significance of OHSS research in understanding PMS and pre-menopausal symptoms lies in the fact that it deals with the exact same hormonal pattern, only amplified many times over. Moreover, since it is dealing with life and death conditions, one can hope that any misconceptions and misinformation such as "progesterone causes edema" or "there is no difference between various progesterone like drugs and real progesterone" will be exposed and expelled. One might also argue that the misguided attribution of edema to progesterone delayed the identification of the real cause and effective treatment. Ujioka et al. 1997 is one such misguided study.

The most elegant and decisive study I came across is Louis Chukwuemeka Ajonuma, et. al. 2005. They have observed clear indications that estrogen promotes fluid shift and progesterone suppresses it. They also demonstrated the underlying mechanism mediated by cystic fibrosis transmembrane conductance regulator (CFTR), which is up-regulated by estrogen and down-regulated by progesterone. The reason it is called cystic fibrosis transmembrane conductance regulator is that certain mutation of CFTR is known to cause cystic fibrosis. The critcal involvement of CFTR was demonstrated by showing that OHSS does not occur in animals with such CFTR mutations, neither in normal animals with CFTR expression blocked.

CFTR is also known for its role in several pathological conditions, such as cholera-induced diarrhea, in which there are massive fluid fluxes across epithelial membranes.

Now, going back to PMS and pre menopausal symptoms, in which the high level of follicular stimulating hormone (FSH) induces enlarged ovaries and high level of estrogen WITHOUT corresponding high level of progesterone, it perfectly makes sense that bloating or edema is one of the main symptoms, and supplementation of real progesterone alleviate the symptoms. Actually, the effect of progesterone in reducing edema is so strong that it has been demonstrated to save brain injured patients if it is started within 6 hours (ideally within 2 hours) of the injury by a team of Emory Univerciy researchers.

Also the large individual differences in the manifestation of bloating in PMS and premenopausal symptoms is understandable, since CFTR has many variations (more than 1000 identified).

When we talk about PMS and premenopausal symptoms, we cannot avoid talking about all those negative mood swings, which is almost synonymous with PMS. In OHSS studies, they are too busy trying to save the mother and the pregnancy, everything else seems to take a backseat. So we have to look elsewhere for hormone related mood swings and their underlying mechanism. Perhaps the neuroscience may give us some clue.

By the way, if you are interested in clinical (human) OHSS studies, a review by Abbas Aflatoonian, M.D., Tahereh K. Bidgoli, M.D. Prevention is the ideal treatment of OHSS!!! 2005 is a good place to start.

References

Royal College of Obstetricians and Gynaecologists. THE MANAGEMENT OF OVARIAN HYPERSTIMULATION SYNDROME. Green-top Guideline No. 5, September 2006

Takeshi Ujioka, Kohei Matsuura, Tetsuro Kawano, and Hitoshi Okamura. Role of progesterone in capillary permeability in hyperstimulated rats. Human Reproduction vol.12 no.8 pp.1629?1634, 1997

Louis Chukwuemeka Ajonuma, Lai Ling Tsang, Gui Hong Zhang, Connie Hau Yan Wong, Miu Ching Lau, Lok Sze Ho, Dewi Kenneth Rowlands, Chen Xi Zhou, Chuen Pei Ng, Jie Chen, Peng Hui Xu, Jin Xia Zhu, Yiu Wa Chung, and Hsiao Chang Chan. Estrogen-Induced Abnormally High Cystic Fibrosis Transmembrane Conductance Regulator Expression Results in Ovarian Hyperstimulation Syndrome. Molecular Endocrinology 19(12):3038–3044

David W. Wright et al. ProTECT: A Randomized Clinical Trial of Progesterone for Acute Traumatic Brain Injury. Ann Emerg Med. 2007;49:391-402

Abbas Aflatoonian, M.D., Tahereh K. Bidgoli, M.D. Prevention is the ideal treatment of OHSS!!! Iranian Journal of Reproductive Medicine Vol.3. No.2 pp:51-61, 2005

Estrogen dominance: it's not just a theory

2008-05-20T23:52:00.030-05:00

To bring my knowledge on Reproductive Aging up-to-date to deal with my menopause and to benefit the people I give advise on the matter, I've decided to check recent journal articles on the subject. To me, Progesterone in Orthomolecular Medicine by Dr. Raymond Peat (PhD)[1] is the bible in this field. The version I have is copyrighted at 1993, about 20 years after he wrote his doctoral dissertation. Dr. John Lee (M.D.), the author of What Your Doctor May Not Tell You About ... book series[2] [3] [4], started with what Dr. Peat introduced to him. Dr. Lee first published his data on osteoporosis in 1990[5], so he must have met Dr. Peat at least several years before that.
The basic phenomena observed and established by Dr. Peat and Dr. Lee are:

Women's health issues are caused largely by "Estrogen dominance" where estrogen / progesterone balance is lost due to too much estrogen, too little progesterone or both.
Correcting this imbalance using bio-identical (as opposed to fake) progesterone and nutritional supplements will correct or prevent most of the problems such as PMS and pre and post menopausal discomfort and health crisis.

Their reasoning is sound, their observations well informed, and millions of women, including me, have been following their advice and finding it helpful. Yet, there are so much medical myth yet to be dispelled. Most doctors are not informed. As recent as May of 2008, one of my readers contacted me to consult what went wrong with her doctor prescribed natural progesterone supplementation regimen, that made her bleed every week with pulsed schedule and feel awful with overdose. To end all that myth, misunderstandings, and disinformation once and for all, I decided to review up-to-date data and clarify some nagging questions that needed to be answered.

First I looked for a solid proof that pre- and peri- menopause put women in "Estrogen dominance". That was not hard at all. There it was published in 1996 Journal of Clinical Endocrinology and Metabolism by Nanette Santoro, et al[6]. (New Jersey Medical School). That's more than 10 years ago. So, anything written since then about pre and peri menopause that does not take this study into consideration is probably not worth reading.

Now, if you have done some net search and visited the web sites backed by mainstream medical communities and U.S. government, you already KNOW, as your reproductive system gets older, your estrogen gradually decreases, and you probably have no clue what happens to your progesterone level, but it did not seem to matter. For PMS, some site told you it may be caused by progesterone because PMS only happens during the time progesterone is secreted. And if you dig a little deeper, you will find plenty of clinical and experimental studies that seem to back up their recommendations, but at a closer look reveal serious flaws of overdose (more on this later).

You also learned that the best treatment is birth control pills, be it PMS or pre- and peri- menopause symptoms, to boost estrogen, to regulate your periods with fake progesterone, and the contraception is the added bonus[7]. Of course, you have probably encountered plenty of Web sites like this one that warn you about those "mainstream" medical approaches.

An interesting article came out in 2007, written by Dr. Prior, an endocrinologist based on her own menopause transition experience and research that followed, as well as her fight to get a natural progesterone clinical trial approved (Walking the Talk: Doing Science with Perimenopausal Women and their Health Care Providers, Prior, et. al. 2007). Basically, she found out that the medical information she was taught as a physician was totally false and useless to deal with her own preimenopause and her patients', and the "authority" did not want any clinical trial that can change the statusquo of prescribing birth control pills for perimenopause problems.

Why the myth persists? And why are they perpetuating it ?(more on this later). Progesterone does not cause PMS, neither the low estrogen level causes the perimenopausal symptoms. It is estrogen dominance (often high estrogen and low progesterone) that causes them. All that miseries women go through during PMS and the years leading up to the end of reproductive years are not caused by the low estrogen level or the secretion of progesterone. Quite the opposite. Let's put to an end to all that myth and the ill informed medical practice of giving estrogen and fake progesterone to women with already elevated estrogen level and reduced progesterone level. For most women, the low estrogen level becomes an issue only shortly before her period stops all together.

The next question is what the Estrogen Dominance (high level of estrogen before ovulation and the high level of estrogen along with the low level of progesterone in the latter half of the cycle) does to a woman. By 1993, Dr. Peat already had pretty good idea about what, how, and why of Estrogen Dominance symptoms. Actually, by 1977 Katharina Dalton, a British doctor, has written The Premenstrual Syndrome and Progesterone Therapy[8] based on her success with natural progesterone. Dr. Peat lists about 30 manifestations of Estrogen Dominance in his Progesterone in Orthomolecular Medicine and explained the underling mechanism at molecular level. Has there been any follow up studies to confirm their finding and insights?

Search engines can find any topic you can think of. However, I would not hold my breath to find concerted effort in hormone related prevention or wellness research, or public campaigns to disseminate the correct information. It isn't happening even for a disease reaching epidemic proportions like diabetes. It seams that in modern medicine, the research tend to concentrate on diseases that are expensive to treat, with a focus on developing new patentable drugs and the cutting edge treatment methods, in other words, where serious money can be made. The exceptions might be those countries with socialized medicine (e.g. England, Canada and Scandinavians) or countries with limited resources (e.g India and China) that have a strong incentives to take "a stitch in time save nine" approach seriously.

One of the fields that seem to have a good accumulation of research is the assisted reproductive treatments that uses hormones to stimulate ovulation, which induces the exact hormonal imbalance as estrogen dominance[9]. It even has a name, Ovarian Hyper Stimulation Syndrome, OHSS for short. It is potentially a life threatening condition (didn't we know it!) with massive fluid shift similar to bloating only exponentially amplified. The established guideline for the prevention of OHSS is to give the women progesterone* after ovulation as luteal phase hormonal support. In fact, the effect of progesterone in reducing bloating/swelling is so strong that it has been demonstrated to save brain injured patients[10] [11].

Now, never mind about the fact that if she is given progesterone and some nutritional advice to restore the hormone balance, she probably can get pregnant on her own. That will be another topic.

* Should not be confused with all those fake progesterone doctors and drug companies and even your government have been heavily promoting as cure-all contraceptive/HRT to the detriment of women's health. The only substance qualified to be called "progesterone" is the real, natural, bio-identical progesterone. The use of fake progesterone for fertility treatment is totally unwarranted. They come with a long list of side effects both to the baby and to the mother, while real progesterone is safe and readily available (after all, it is identical to what your body makes). You need to make sure what you are getting is real progesterone, because an average doctor doesn't seem to know the difference.

(to be continued)

[1] Progesterone in Orthomolecular Medicine by Raymond Peat, PhD, available at Dr. Ray Peat's Web site.
Every time I read it, it impresses me how much was know in biology by mid 1970s, and infuriates me to see that even today, more than 30 years later most doctors are still clueless. And it is sickening to realize we still have to fight against FDA who is stepping up their campaign to scare off the consumers by questioning the efficacy and the safety of bio-identical hormones from compounding pharmacies and supplement companies, all the while the same substances that is packaged by big drug companies at ridiculously high doses are left unquestioned.

[2] What Your Doctor May Not Tell You About Breast Cancer, by John R. Lee, M.D. David Zava, Ph.D, and Virginia Hopkins, 2001 Cahners Business Information.
The co-author David Zava is a big name in breast cancer research and saliva hormone test field. If you want to know why estrogen and the chemicals that mimic estrogen cause cancers, and how progesterone protect you against it, all at molecular level, this is the book to read. You will find the effective prevention strategies self evident, calling early detection a prevention is a spin, and why the mammography is actually bad for your breast.

[3] What Your Doctor May Not Tell You About PreMenopause, by John R. Lee, M.D. Jesse Hanley, M.D., and Virginia Hopkins, 1999, Warner Books.

[4] What Your Doctor May Not Tell You About Menopause, by John R. Lee, M.D. with Virginia Hopkins, 1996, Warner Books.
This is the first of the series. The courage to go beyond what other doctors are doing and the intellectual integrity behind it, you will know when you read it. The unfortunate aspect of this book is that it gives you an impression that no one need to take estrogen for menopause, which is not quite true and he repeatedly corrected later.

[5] Lee, John R., M.D., "Osteoporosis Reversal: The Role of Progesterone," International Clinical Nutrition Review (1990), 10:384-391.
The first study to show Osteoporosis can be reversed. It is heard to believe that most of the well established journals did not take it serious enough to publish it. Today no one questions about the fact that you can increase your bone mass at any age, and that all three factors (nutrition, use of muscle, and hormone balance) can contribute to the reversal. You knew, didn't you?

[6] Santoro N, Brown JR, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. 1996;81(4):1495-1501.
They collected urine every morning for 6 month from women at various reproductive stages (5 to 6 women in each group) and measured the metabolites of estradiol and progesterone, as well as LH and FSH. Their clever method of analysis made the data clean and easy to understand. A land mark study that was expanded into much larger studies, the Study of Women?'s Health Across the Nation (SWAN) and the Daily Hormone Study (DHS). Any hormone study that does not take this study into consideration is not worth reading.

[7] Ismail Hassan, Khaled Mk Ismail, Shaughn O'brien PMS in the perimenopause. J Br Menopause Soc. 2004 Dec;10 (4):151-6 15667751
"The simplest approach may be to give oestradiol transdermally and to administer the progestogen by the intrauterine route using the levonorgestrel intrauterine system." is their conclusion. It is clear to them that estrogen alone can take care of the symptoms. But in case she wants to keep her uterus, levonorgestrel intrauterine system can prevent the uterine cancer and avoid PMS like symptoms Provera causes. It even works as contraceptive. Natural progesterone? not quite sure, but why bother? seems to be their attitude. The case is closed as far as they are concerned. That was exactly what was prescribed to me after my hysterectomy in 1985 and in a few years I found my health slowly deteriorating. They flush their knowledge of latest this or that, but no fundamental changes in their approach, which I assume reflecting the current state of the mainstream medicine. Anyhow, I cannot give a serious consideration to any perimenopause study that does not mention Santoro et al. 1996. Also to suggest progesterone/allopregnanolone causes depression is such a spin and disinformation.

[8] Katharina Dallton, The Premenstrual Syndrome and Progesterone Therapy., Year Book Medical Publishers, Inc., Chicago, 1977.
I have not read this book yet.

[9] Abbas Aflatoonian, M.D., Tahereh K. Bidgoli, M.D. Prevention is the ideal treatment of OHSS!!! Iranian Journal of Reproductive Medicine Vol.3. No.2 pp:51-61, 2005
A good review with good focus and good balance.

[10] Wright et al., ProTECT: A Randomized Clinical Trial of Progesterone for Acute Traumatic Brain Injury, Ann Emerg Med. 2007;49:391-402.

After 20 years of animal experiments, they finally had the opportunity to take it to the clinical trial. The astonishing success of this landmark study is changing the landscape of hormone research.

[11] Ann Emerg Med. 2007 Jun 21; : Does Progesterone Have Neuroprotective Properties? Donald G Stein, David W Wright, Arthur L Kellermann Brain Research Laboratory, Department of Emergency Medicine, School of Medicine (Stein, Wright).
According to Dr. Peat, progesterone protect a lot more than your brain. As the name suggests, it protects pregnancy, the fetus and the mother from ill effects of stress and toxic substances. But you don't have be pregnant or even woman to have the protective effects of progesterone. The brain injury patients they saved in ProTECT were all men.