8/03/2008

DHEA for Menopause

Updated Dec. 2013
by Etsuko Ueda
According a 2011 Clinical review: DHEA replacement for postmenopausal women. by Davis SR, Panjari M, Stanczyk FZ, Dehydroepiandrosterone (DHEA) and/or its sulfate, DHEAS is a hormone secreted in large amount by adrenal gland, and in addition, brain produces its own DHEA and DHEAS (together, DHEA/S from here on), so do the ovary and testis, and even some peripheral tissues. DHEA and DHEAS convert to each other and to other androgens (including testosterone) and then to estrogens (estrone and estradiol) in various tissues according to the enzymes available locally.
The amount of DHEA/S found in blood circulation decreases dramatically with age as shown in the graph below, although the levels of other adrenal cortex hormones (cortisol=glucocorticoid and aldosterone=mineralcorticoid) do not change much with aging. Actually, menopausal symptoms such as hot flushes elevate cortisol level (see Pituitary hormones during the menopausal hot flash. D R Meldrum, et. al. 1999). DHEA/S is also produced in brain along with other neurosteroid/sex hormones, and when measured in cerebrospinal fluid, DHEA/S does not go down with age (Changes with aging of steroidal levels in the cerebrospinal fluid of women. K Murakami, et. al. 1999), which may be an indication of its importance in brain.
Figure From Regulation of the adrenal androgen biosynthesis. Rainey WE, Nakamura Y. 2008
Because of this age related sharp decline, the decline of DHEA has been thought to drive aging process, and various studies have been conducted to examine its role in aging related declines and diseases (DHEA deficiency syndrome: a new term for old age? J P Hinson and P W Raven 1999). However, the individual differences are so large that individual DHEA/S level cannot be used as a marker of aging.
According to a 2003 review, Dehydroepiandrosterone - is the fountain of youth drying out? (Celec P, Stárka L), when DHEA is measured alone in relation to degenerative disease processes such as cancer, cardiovascular diseases, insulin resistance, diabetes, osteoporosis, etc., the association is not always clear. However, when cortisol is taken into account, the cortisol/DHEA ratio seems more closely associated with the degenerative disease processes, indicating the destructive power of cortisol and protective role of DHEA against it.
Despite its promising profile, DHEA research is not as advanced as you would imagine. According to Celec and Stárka "There are two important reasons for this scientific delay of the general information about DHEA functions:
1)    DHEA is an endogenous metabolite that cannot be patented so that pharmaceutical companies are not interested in supporting research in this field.
2)    DHEA can be described as a "human molecule" because other investigated species have much lower concentrations. Especially the classical rodent laboratory animals are not suitable for experiments with DHEA. Moreover, even non-human primates produce only about 10 % of the "human amounts" of DHEA.
The conclusion they reached from studies available at the time was that a lower DHEA seems to be associated with a poorer health and increased health risks, but a lack of adrenal DHEA/S is not critical (a loss of DHEA from adrenal cortex does not lead to any particular diseases including cardiovascular and immunological diseases), except, DHEA supplementation is known to dramatically improve connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis (The connective tissue diseases and the overall influence of gender. R G Lahita, 1996).
While Celec and Stárka were rather cautious about the use of DHEA supplementation, a group of Canadian researchers at Laval University (F Labrie. et. al.) has been more enthusiastic about DHEA supplementation. They have been focusing on the metabolic conversion of DHEA, coining a term "Intracrinology" as opposed to Endocrinology. Their enthusiasm is based on their understanding that "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." and the synthesis of active steroids takes place "in peripheral target tissues where the action is exerted in the same cells where synthesis takes place" and "they are released from these target cells only after being inactivated" (DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. 2001). This understanding has lead them to:
1.     The development of combined androgen blockade which uses a pure antiandrogen added to chemical or surgical castration to block simultaneously the androgens of both testicular and adrenal origin at the start of treatment of prostate cancer. Similarly, the use of aromatase inhibitors or antiestrogen to block estrogen in breast cancer (Intracrinology: role of the family of 17 beta-hydroxysteroid dehydrogenases in human physiology and disease., F Labrie. et. al. 2000).
2.     The realization that the active hormone levels measured by blood test does not reflect the tissue levels. To measure how much DHEA is converted to active estrogens and androgens in the tissues, blood levels of their metabolites have to be measured. (Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology. Labrie F, et. al. 1997).
Note: It is not accurate to say that the androgens and estrogens converted from DHEA do not show up in blood circulation. This conclusion was drown from their 14 day trial, replicating a 28 day trial (The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J F Mortola, et. al. 1990) where only testosterone was detected to rise in serum (its peak was reached within a week or two). However, trials longer than 3 months show serum increase of estrogens and DHT as well as testosterone ( Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids. Alessandro D Genazzani, et. al. 2003).
3.     The promotion of DHEA for hormone replacement therapy: By running 12 month transdermal DHEA supplementation study with post menopause women, they have demonstrated that it stimulates bone formation and vaginal maturation, increases skin oil secretion, and decreases insulin resistance and menopausal symptoms, all without stimulating uterine lining buildup (Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women. Labrie F, et. al. 1997), clear indications of conversion of DHEA to androgens (skin oil secretion) and estrogens (vaginal maturation) and more, without systemic impact (no uterine lining buildup).
Advantage of adding DHEA to transdermal estradiol + progesterone therapy
Together with other researchers' studies and their own, Labrie's group has pointed out the advantage of DHEA alone or adding DHEA to standard ERT (estrogen replacement therapy) or HRT (estrogen + fake progesterone) (Is dehydroepiandrosterone a hormone? by F Labrie, et. al. 2005). However, their assertion of "When used as replacement therapy, DHEA is free of the potential risk of breast and uterine cancer" is not warranted and inconsistent with their claim made in #1. So long as DHEA turns into estrogens inside certain cells, only way to safeguard against breast cancer or any other estrogen driven cancer as well as blood clots and cardiovascular diseases is to counterbalance it with progesterone (see Safe Use of Hormones: the Hard Evidence and Menopause: Cardiovascular Health). Like wise, their assertion that "almost all present therapies are limited to a reduction of bone loss" and that DHEA is a rare exception is simply not true. That can only be true when you ignore the proper low dose transdermal estradiol + progesterone supplementation regimen (see Bone: Sad State of Progesterone Research and Hormone overdose: How can you tell?). Most of all, DHEA alone may not be enough to take care of the menopausal symptoms for most people, especially during the menopausal transition. It can take 2 to 3 months for its full effects to take place, in any case, particularly for the estrogen level, hot flushes, and the reduction of cortisol level (Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. M Stomati, et. at. 2000).
One of the interesting studies about the role of DHEA/androgens for menopausal women comes from Androgens and estrogens in relation to hot flushes during the menopausal transition. (Øverlie et al. 2002). They concluded "high levels of testosterone and DHEA-S seemed to protect against vasomotor symptoms. Our most important finding was, that among women who achieved hot flushes at the first assessment postmenopause, the high androgen level was a significant predictor of recovery from hot flushes at the last assessment, 1 year later." Also from Japan, Effect of Korean red ginseng on psychological functions in patients with severe climacteric syndromes. (T Tode, et. al., 1999) reported that DHEA-S levels in postmenopausal women with menopausal syndrome were about a half of those without menopausal syndrome (By the way, Red ginseng did not restore the DHEA level, but cortisol and cortisol/DHEA ratio decreased significantly).
Interestingly, SWAN (Study of Women’s Health Across the Nation, a longitudinal study of menopause) researchers have found out that most women have some ability to increase DHEA secretion when ovaries stop secreting hormones at menopause.
    Androstenediol complements estrogenic bioactivity during the menopausal transition. Lasley BL, Chen J, Stanczyk FZ, El Khoudary SR, Gee NA, Crawford S, McConnell DS. Menopause. 2012
    Circulating dehydroepiandrosterone sulfate levels in women who underwent bilateral salpingo-oophorectomy during the menopausal transition. Lasley BL, Crawford SL, Laughlin GA, Santoro N, McConnell DS, Crandall C, Greendale GA, Polotsky AJ, Vuga M. Menopause. 2011
    Circulating dehydroepiandrosterone sulfate concentrations during the menopausal transition. Crawford S, Santoro N, Laughlin GA, Sowers MF, McConnell D, Sutton-Tyrrell K, Weiss G, Vuga M, Randolph J, Lasley B. J Clin Endocrinol Metab. 2009
    The relationship of circulating dehydroepiandrosterone, testosterone, and estradiol to stages of the menopausal transition and ethnicity. Lasley BL, Santoro N, Randolf JF, Gold EB, Crawford S, Weiss G, McConnell DS, Sowers MF. J Clin Endocrinol Metab. 2002
This is consistent with the observations that DHEA/S increases during a period of distress (Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH. Front Neuroendocrinol. 2009), and the late perimenopause and early post menopause are the periods when menopausal symptoms are most severe.
Most of us are not that lucky to have strong enough adrenal to cope with menopausal transition without menopausal symptoms. Nearly 90% of women experience menopausal symptoms (Bresilda Sierra, et.al. 2005). They start about 2 years before the final menstrual period, and last 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, while you are wondering if the menses would ever come back) 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).
So for most of us, it is safe to assume that we have some degree of adrenal insufficiency by the age we start to have menopausal symptoms, and it may be wise to supplement DHEA. DHEA supplementation studies clearly indicate its positive effects on menopausal symptom reduction (Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women. Labrie F, et. al. 199; Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids. Genazzani, et. al. 2003), although it may not be adequate in most cases (Clinical review: DHEA replacement for postmenopausal women. Davis SR, Panjari M, Stanczyk FZ. 2011). When that is not enough, you can always add an ultra low dose of transdermal estradiol. The worst thing you can do is to let the menopausal symptoms linger. It will increase stress hormones that ravage your bones (see Bone: Destructive Power of Stress Hormones).
Caution: Either way, you need to supplement progesterone (real, natural, bio-identical progesterone in cream form) preferably as soon as a sign of transition or decline appears (at around 35 years of age for many people) before starting any other hormone to avoid estrogen dominance related risks (see Estrogen dominance: it's not just a theory and Safe Use of Hormones: the Hard Evidence).
As a treatment for menopausal symptoms, estradiol+progesterone is a clear winner over DHEA alone. However, there are areas of benefits that DHEA may further enhance or add to the benefits of estradiol+progesterone therapy. Although we do not know the full impact of DHEA decline with aging or adrenal insufficiency, the Mother nature gave it to us for a reason and it is better to have an adequate level of DHEA, I believe. At least, for post menopausal women, it boosts androgens which neither estradiol nor progesterone can. Since stimulation of skin oil secretion requires androgens, this is important for people who tend to have dry skin. For some people, it may also improve libido beyond estradiol+progesterone can.
Caution: Because of this effect on skin oil secretion, DHEA can cause skin/hair problems when overdosed. Therefore, my guideline for DHEA dosage is: if you start to have oily hair/skull or pimples, it is too much. For most people, 5 to 10mg/day (oral or transdermal) may be a safe and effective level.
One-year therapy with 10mg/day DHEA alone or in combination with HRT in postmenopausal women: Effects on hormonal milieu.(Nicola Pluchino, et. al. 2008) seems to agree. The good news is that a long term use of DHEA strengthens the adrenal gland's capacity to produce DHEA in response to adrenocorticotropic hormone (ACTH).
More difficult to evaluate is the supplemented DHEA's impact on brain. Since brain can produce its own DHEA/S, it  may be difficult to determine how much impact a long term low dose DHEA may have on brain of a healthy person. Nonetheless, according to Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). (Maninger, et. al. 2009), the major biological actions of DHEA/S in brain involve neuroprotection, neurite growth, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion, as well as anti-oxidant, anti-inflammatory and anti-glucocorticoid (cortisol) effects, and "Beneficial treatment effects are more likely to be seen in medically or neuropsychiatrically ill patients than in healthy individuals."

Personally, the first time I tried DHEA (30mg/day), I tried it because someone told me it might help me with my menopausal symptoms after I stopped estrogen. After 1 month, I did not feel any effect and discontinued. The second time, I tried it in addition to estradiol patch + progesterone cream without knowing what to expect, except that it might improve overall hormonal milieu. After about 3 months of 30mg/day DHEA, I noticed my hair getting oily, and started to see pimples near my hairline (androgen effect). I also noticed my vaginal wall felt more "alive" (estrogen + androgen effect ?). I could go back to sleep more often after waking up too early. I am not sure why, but may have something to do with reduced cortisol. The link between time of awakening and the level of morning cortisol has been reported by Association between time ofawakening and diurnal cortisol secretory activity. (Edwards S, Evans P, Hucklebridge F, Clow A. 2001), The diurnal patterns of the adrenal steroids cortisol and dehydroepiandrosterone (DHEA) in relation to awakening. (Hucklebridge F1, Hussain T, Evans P, Clow A. 2005) . Perhaps the easing of early wakening problem is an indication of reduced cortisol through a mechanism different from that of estradiol + progesterone.

7/26/2008

Hormones: Dos and Don'ts

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. 
  1. 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. 
  2. 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.  
  3. 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
[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
[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
[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.