Progesterone to fight Covit-19 pneumonia

It is clear that more men get sicker than women, and more men are dying from covit-19. "All across the United States, the coronavirus is killing more men than women, data show" is the title of a Washington Post article. The following graph shows the magnitude of the sex difference (some how it does not have the US data).


https://www.statista.com/chart/21345/coronavirus-deaths-by-gender/

We already know why men are more vulnerable. According to the 2016 study done by researchers at the Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America,
Progesterone-Based Therapy Protects Against Influenza by Promoting Lung Repair and Recovery in Females. (Olivia J Hall, et al).  It is progesterone that helps fight the pneumonia, and someone should give it a try to see if it works to reduce the death rate for men.

We have made the novel observation that administration of progesterone to female mice depleted of progesterone confers protection against both lethal and sublethal influenza A virus infection. In particular, progesterone reduces pulmonary inflammation, improves lung function, repairs the damaged lung epithelium, and promotes faster recovery following influenza A virus infection. Progesterone causes protection against severe outcome from influenza by inducing production of the epidermal growth factor, amphiregulin, by respiratory epithelial cells. This study provides insight into a novel mechanistic role of progesterone in the lungs...

I have seen death rate by age and death rate by sex, but not the death rate separated by sex for each age group. If hormones have anything to do with it, the death rate for older group should show similar death rate for men and women. Further more, older women on estradiol + progesterone (natural) may have better chance of surviving Covit-19 pneumonia compared to those who are not. By the same token, younger women with suppressed progesterone may not do well. I wounder anyone care to find out.

So, if you are not in a habit of using progesterone cream to maintain your hormonal balance, old or young, get some progesterone cream to protect yourself now!  You don't need prescription to buy it in the U.S.

If you have been using Hydroxychloroquine to cope with Lupus, and cannot get it now because they are trying it on the covit-19 cases, you can try Progesterone, many have been.

I think men can also benefit from it. it's not totally new territory for men. Progesterone + DHEA has been used by many men to cope with andropause. Since progesterone can prevent men's brain from swelling in acute brain injuries (ProTECT: A Randomized Clinical Trial of Progesterone for Acute Traumatic Brain Injury. David W. Wright et al., Ann Emerg Med. 2007)   it may also prevent men's lung from swelling in cytokine storm of viral infection. It has no adverse side effect. So, rub some progesterone cream on your skin everyday just in case. It will help you keep calm, too (its well know benefit, it has to be the real natural progesterone, though). But, don't overdose, or you may negate its effect.

If you want to get some perspectives, here is a review article:
Sex Hormones Regulate Innate Immune Cells and Promote Sex Differences in Respiratory Virus Infection

Hormone overdose: How can you tell?

By Etsuko Ueda

I often hear from post menopausal women who have been struggling trying to decide which is worse, doctor prescribed hormone regimen or menopausal symptoms. The bottom line is: If you do not feel well, something went wrong, and in most cases, it's hormone overdose. It can be estrogen overdose, progesterone overdose, or both (use of fake hormones is out of the question).

In June 2009, one person wrote me "I am 53 and have been using the Vivelle .025 patch for hot flashes and mood swings for around 5 months. Feel great, but then my doctor said I had to take the course of 12 days every 6 months of progesterone as I still have my uterus. So, I took only two days of the Prometrium 100 mg he prescribed and I got almost an allergic reaction to it, facial and eye swelling and redness and started bleeding and cramping on day two. I quit the prometrium after the second day and the bleeding lasted another full week. Also came with horrible headaches that wouldn't go away."

It is very unfortunate, although typical, that her doctor did not know progesterone cream (20~30mg a day) can be used along with estradiol (continuous regimen) to suppress uterine lining thickening (see Hormones: Dos and Don'ts).

Another person wrote me in November 2011 "I had a total hysterectomy about 5 years ago and have been fighting problems ever since. My doctor has prescribed estradiol pill 1mg and I felt like crying all the time, so I incorporated Progesterone cream and now I’ve gained about 8 lbs in 2 weeks and have anxiety every morning. Also weird dreams. My libido has been in the toilet for years now, my poor hubby."

Three months later, after having tried what I suggested, she wrote me saying "I have used your dosages of all 3 hormones and they are perfect for me. No more hot flashes, no crying all the time, And the libido has kicked in. I can't thank you enough for your email. I have been to 3 different doctors and not one has gotten it right, this is over a period of 4 years."

These cases illustrate some important points:

1. Most doctors are clueless or misinformed about hormone supplementation.
2. Even a ultra low dose of estradiol 0.025~0.050mg/day patch is effective against menopausal symptoms, but stimulates uterine lining thickening if progesterone is not used along with it.
3. High dose progesterone such as Prometrium 100 mg cause overdose problems (water retention, tired and sluggish), and many women cannot tolerate it. I tried it for 2 days and felt so terrible, that I threw it a way. Since Prometrium 100 mg is the most commonly prescribed natural progesterone and many do not feel well on it, many women end up exposing themselves to unnecessary hormone related health risks either by taking estrogen alone or by giving up on hormone supplementation all together.
4.  If you add progesterone to estrogen overdose, things can get worse, because progesterone increases estrogen sensitivity by increasing estrogen receptors. (That's why you need to start with progesterone first and then add estradiol at the lowest dose and see if you need to increase it or not.)

How can you tell when it's too much or not enough

Since today's medical science is not advanced enough to tell exactly how supplemented hormones get distributed and used in your body, there is no hormone test you can rely on to see your dose is not enough or too much. So how you feel is the best way to tell. For practical information, see Safe & Effective Natural HRT = progesterone cream + DHEA + low dose estradiol patch.

Not enough estrogen: Vaginal atrophy or dryness is the best way to tell if your estrogen level has been enough or not, because estrogen seems just about the only thing that matters. Progesterone can make estrogen work better, but no amount of progesterone can prevent it if estrogen level is not adequate, according to my experience. Commonly, people think hot flash is the sign of menopause = low estrogen, but hot flash can happen even when estrogen is secreted enough to trigger menstruation. Foggy brain is another sign, but it can be transient. Furthermore, there are other diseases and conditions that can trigger foggy brain, hot flashes and/or night sweat. Clinically, endothelium dependent flow-mediated dilation (on-demand blood supply) becomes weaker when estrogen is low, which has profound effects on your cardiovascular health which affects the rest of the body as well (see Menopausal Symptoms And Cardiovascular Health, Menopause and How estrogen helps bone health?)

Too much progesterone: As I pointed out in a case above, if you don't feel well (swelling and other water retention related symptoms, as well as feeling sleepy, sluggish, tired), that is a sure sign. Generally, you are safe in a range of 10~40mg /day transdermal. 100mg is too much.

1. The most important thing to remember about progesterone overdose is this: Progesterone is known to have biphasic action on water retention and cellular calcium/magnesium ion ratio. "Biphasic action" means that some of the beneficial effects will be lost and the opposite effects may appear when you take too much progesterone.
• Water retention and swelling is commonly reported by people who are subjected to progesterone overdose, while at a lower dose (10 to 40 mg/day) diuretic effect (facilitates urination, reduces intracellular water) has been reported. The diuretic effect is attributed to the progesterone's role in blocking mineralcorticoid, which gets lost if progesterone is lacking or overdosed resulting in water retention and swelling by increased deoxy-corticosterone, a potent mineralocorticoid, and 100mg oral dose is enough to demonstrate this effect. This water retention from a lack of progesterone or overdose is different from estrogen driven bloating which is most pronounced around abdomen, although, both can coexist.

Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands. R Rupprecht, J M Reul, B van Steensel, D Spengler, M Soder, B Berning, F Holsboer, K Damm, 1993

Serum levels of progesterone and some of its metabolites including deoxycorticosterone after oral and parenteral administration. U B Ottoson, K Carlstrom, J E Damber, B von Schoultz, 1984

• Promotion of intra-cellular magnesium level is well known property of progesterone, while estrogen promotes intra-cellular calcium. Together, these two hormones regulate cellular calcium/magnesium ion ratio. This is the reason progesterone can be used as a calcium blocker. However, when progesterone is overdosed, it seems to lose this effect. As a result, your cells may not get enough magnesium, calcium/magnesium ion ratio may shift in favor of calcium, and you may experience something similar to estrogen dominance, which can result in various harmful effects (Sex steroid hormones exert biphasic effects on cytosolic magnesium ions in cerebral vascular smooth muscle cells: possible relationships to migraine frequency in premenstrual syndromes and stroke incidence. W Li, T Zheng, B M Altura, B T Altura, 2001). Below are some of the harmful effects:
• The cellular activities and regeneration get amplified (uterine lining gets thicker, cancerous cells multiply faster)
• Your brain cells get more excitable at higher level, brain seizures can get triggered more easily, and get harder to calm down.
• Your blood vessels and intestines go into spasm more easily, triggering heart attacks and diarrheas.
• Magnesium has been effectively used for some form of epilepsy such as eclampsia as well as ADHD and PMS. Similarly, progesterone has been shown to reduce Catamenial epilepsy and PMS, however, progesterone overdose may reduce these benefits, although I have not seen any study designed to demonstrate it.

For more information on the beneficial effects of progesterone at a proper dosage, see PMS: The Underlying mechanism, and Safe Use of Hormones: the Hard Evidence.

Progesterone related water retention is different from estrogen driven bloating, which is mediated by cystic fibrosis transmembrane conductance regulator (CFTR) (Estrogen-Induced Abnormally High Cystic Fibrosis Transmembrane Conductance Regulator Expression Results in Ovarian Hyperstimulation Syndrome. Louis Chukwuemeka Ajonuma, et. al. 2005).

2. Progesterone and its metabolites Allopregnanolone work as GABAa mediated sedative and make you feel calm at a right dosage, but make you feel tired and sluggish, slowing down psychomotor, and digestive functions at a higher dosage. Again 100mg oral dose is enough to demonstrate this effect. (Administration of progesterone produces mild sedative-like effects in men and women. Anna H V Soderpalm, Sommer Lindsey, Robert H Purdy, Richard Hauger, Harriet de Wit, 2004; Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women. H de Wit, L Schmitt, R Purdy, R Hauger , 2001).

Not enough progesterone: Although its health consequence is serious (see Safe Use of Hormones: the Hard Evidence), our body does not seem to have a way to tell it reliably. One thing I notice when I am off progesterone is irritable bowel: fatigue and stress can trigger cramping and diarrhea too easily. Rubbing progesterone cream on abdomen can stop it almost immediately. Clinically, if you use estrogen without progesterone, your blood coagulation factors go up (your blood gets thicker and stickier, making blood clots to form easily), just like your intestines, your cardiovascular system goes into spasm more easily to trigger heart attacks (see Menopausal Symptoms And Cardiovascular Health), and your uterine lining gets thicker, which can lead to heavy bleeding, cramping, and uterine cancer. Please note that a menstruation with heavy bleeding and/or cramping is not normal at any age, and it may be a sign of low progesterone.

Skin and hair problems may also indicate not enough progesterone. In What your Doctor May Not Tell You About Menopause , John R. Lee pointed out skin problems such as acne, seborrhea, rosacea, psoriasis, and keratoses in middle age and beyond may be an indication of not enough progesterone. I personally witnessed keratoses (hard horn like growth) on a 80+ years old woman's leg disappear with progesterone cream applied directly on it. So did a polyp like growth on my neck. Hair loss may be also an indication of not enough progesterone. I personally witnessed white hair grow back on women over 80 years old with progesterone cream in 3 to 6 months.

To get the maximum benefit of progesterone, be sure to supplement magnesium about 300mg/day. Many of progesterone's biological effects are based on its ability to increase intracellular magnesium (see PMS: The Underlying mechanism).

Too much estrogen: Estrogen is a stimulant, not just to your brain but to your entire body and some people even call it excite-toxin. Your brain becomes more excitable (less controllable). It can amplify stress hormone responses to psychosocial stress, as indicated in the following studies. It can also cause bloating and other PMS like symptoms.

• The effects of sex and hormonal status on restraint-stress-induced working memory impairment. Rebecca Shansky, Katya Rubinow, Avis Brennan, Amy Arnsten 2006
• Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. C Kirschbaum, N Schommer, I Federenko, J Gaab, O Neumann, M Oellers, N Rohleder, A Untiedt, J Hanker, K M Pirke, D H Hellhammer 1996
• Impact of progestins on estradiol potentiation of the glutamate calcium response. Jon Nilsen, Roberta Diaz Brinton, 2002

Clinically, your new cell generation gets accelerated: uterine lining gets thicker, more cancerous cells gets generated, if there is not enough progesterone to control them (see What Your Doctor May Not Tell You About Breast Cancer, by John R. Lee, M.D. David Zava, Ph.D, and Virginia Hopkins, 2001).

Confusing symptoms of not enough estrogen and too much estrogen

Women who go through natural menopause transition experience symptoms associated with a volatile fluctuation of hormones: Period may skip for a few months at a time, then you may be surprised by a heavy bleeding, often progesterone is not secreted, estrogen can be extremely high or very low. Since low estrogen leads to under-active parasympathetic system and overactive sympathetic system, while too much estrogen (even with normal progesterone) can lead to hyperactive brain, both low and high estrogen may lead to similar neural instability, tension, and vulnerability to stresses.

The first thing to do during menopausal transition is to start progesterone to minimize the risk of estrogen dominance. However, starting progesterone when estrogen is very high can make the symptoms worse, since it elevates estrogen sensitivity. The logical solution is to start progesterone while estrogen is very low, that is shortly after the start of your period. However, when it is highly irregular, it may not be easy to tell when your estrogen level is low. In those cases, you might want to start progesterone very slow. Whichever the case, it may take 3 month or more to stabilize your hormones. When you start to have menopausal symptoms such as hot flashes and foggy brain, add ultra low dose of estradiol patch and/or DHEA to control the symptoms and to reduce the bone ravaging stress hormones.

Too much DHEA: As I reviewed in DHEA for Menopause, 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). Therefore, you may need to lower the dosage after a while. 


For more information, See:
Menopausal symptoms: What are we complaining?
Menopausal Symptoms And Cardiovascular Health
Menopause and What Really Happens to your Bones
Hormones: Dos and Don'ts
Safe Use of Hormones: the Hard Evidence
PMS: The Underlying mechanism

Important: You probably found this page because you had questions about hormones. I hope you have found the answer you have been looking for. If you are uncertain, please note the following:

Before you post your HRT questions, please try what I think safe and effective for at least 3 months: estradiol 0.025~0.050mg/day patch, with 20~40mg/day progesterone cream (about 1000mg progesterone in 2oz cream). You can also add DHEA 5~10mg /day.

That is the only recommendation you will get from me.

Bone Quality Is Just as Important as Density

by Etsuko Ueda

Bone Quality

Traditionally, the status of bone health has been measured by bone mineral density. However, the ineffectiveness of Fosamax in preventing bone fracture made it abundantly clear that there is more to bone strength than bone mineral density. It turned out that "bone quality" is just as important as BMD.

• The effect of antiresorptives on bone quality. Robert R Recker, Laura Armas 2011 
• Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. T Mashiba, C H Turner, T Hirano, M R Forwood, C C Johnston, D B Burr 2001 
• Severely suppressed bone turnover: a potential complication of alendronate therapy. Clarita V Odvina, Joseph E Zerwekh, D Sudhaker Rao, Naim Maalouf, Frank A Gottschalk, Charles Y C Pak 2005
• Mandibular necrosis in beagle dogs treated with bisphosphonates. Db Burr, Mr Allen 2009
• Microdamage accumulation in the monkey vertebra does not occur when bone turnover is suppressed by 50% or less with estrogen or raloxifene. Jiliang Li, Masahiko Sato, Chris Jerome, Charles H Turner, Zaifeng Fan, David B Burr 2005
• Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs. M Saito, S Mori, T Mashiba, S Komatsubara, K Marumo 2008

Hormones and bone quality

Here again hormones have significant role.

The figures below are taken from 3D imaging of bone structures for a 44 year old woman (A) and a 61 year old woman (B). The porosity is clearly seen in B compared to A. (Masako Ito, 2006)

The bone mineral density (BMD) commonly used to measure the strength of bone reflects the difference in porosity such as seen in the above examples. However, by volume, 50 % of bone is collagen (protein) which provides interlocked grid like structure (matrix) to hold the mineral contents together. If this collagen matrix is degraded and becomes brittle, the bone will become brittle like a chalk and easily snaps, and it will not be detected by BMD.

"Older people can have up to tenfold increased 10-year fracture risk in comparison with younger individuals with the same BMD... more than 50% of all fractures occur in women with osteopenia, as defined by a -2.5 < BMD T score ≤ -1; at-risk women in this group will not be detected by applying the World Health Organization BMD definition of osteoporosis." (Bone quality and osteoporosis therapy. Regina Matsunaga Martin, Pedro Henrique S Correa 2010).

The degradation of collagen and protein in general is a well known part of aging process that results in wrinkles, hardening of blood vessels, and hardening of all sorts of tissues including eyes, brain, kidney, liver, etc., and its mechanism is well known. The primary culprits are glucose (blood sugar) that causes sugar burn, and homocysteine, a potent source of free radicals that cause oxidative damages (Mitsuru Saito 2008 (Japanese)). They damage protein and produce hardened dysfunctional tissues. Bones and tendons become discolored and yellow-brownish. 

 Fractured Bone with degraded discolored collagen

Homocysteine (an intermediate metabolite of sulfur amino acid methionine, which is a building block and a metabolite of protein.) is well known for its toxicity owing to its byproducts such as superoxide and hydrogen peroxide (oxidative damage promoting free radicals) and association with the hardening of tissues. The reason diabetes causes so many health problems is because it greatly speeds up this process due to high blood sugar level, which in turn impairs kidney function that is critical for filtering and processing harmful homocysteine.

• Nonenzymatic cross-linking pentosidine increase in bone collagen and are associated with disorders of bone mineralization in dialysis patients. Jun Mitome, Hiroyasu Yamamoto, Mitsuru Saito, Keitaro Yokoyama, Keishi Marumo, Tatsuo Hosoya 2011

Furthermore, these damages start inflammation chain reactions, which in turn lead to all sorts of tissue damages and degradation and more oxidative damages. In case of collagen, this process allows glycation (sugar burn) to take over the part of the collagen tissue called cross-links and form advanced glycation end products as the tissue is newly generated. It prevents normal maturing and mineralization in case of bone tissues (Mitsuru Saito 2008 (Japanese)).

It should also be noted that any toxicity including low grade infections, inflammations, and some medications (including wrong hormone therapies) will increase free radicals and stress hormone cortisol. That alone is enough to cause some bone deterioration (and every part of your body for that matter).

• Short-term exposure to dioxin impairs bone tissue in male rats. P Monica Lind, Carolina Wejheden, Rebecca Lundberg, Pedro Alvarez-Lloret, Sanne A B Hermsen, Alejandro B Rodriguez-Navarro, Sune Larsson, Agneta Rannug 2009 
• The Effect of Rosiglitazone on Bone Quality in a Rat Model of Insulin Resistance and Osteoporosis. Laura D Sardone, Richard Renlund, Thomas L Willett, Ivan G Fantus, Marc D Grynpas 2011
• Cortical bone is more sensitive to alcohol dose effects than trabecular bone in the rat. Delphine B Maurel, Nathalie Boisseau, Claude-Laurent Benhamou, Christelle Jaffre 2011
• A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women. Jan Shifren, Sophie Desindes, Marilyn McIlwain, Gheorghe Doros, Norman Mazer 2007 
• Tibolone, transdermal estradiol or oral estrogen-progestin therapies: effects on circulating allopregnanolone, cortisol and dehydroepiandrosterone levels. N Pluchino, A D Genazzani, F Bernardi, E Casarosa, M Pieri, M Palumbo, G Picciarelli, M Gabbanini, M Luisi, A R Genazzani 2005
• The influence of the route of oestrogen administration on serum levels of cortisol-binding globulin and total cortisol. 2007 
• Effects of estrogen versus estrogen and progesterone on cortisol and interleukin-6. Kate M Edwards, Paul J Mills 2011 
• Effects of high dose oestrogen therapy on circulating inflammatory markers. R Wilson, A Spiers, J Ewan, P Johnson, C Jenkins, S Carr 2009

Biochemical markers of bone quality degradation

How much your body, including bones, is subjected to this type of degradation can be monitored by analyzing the levels of homocysteine and pentosidine (one of collagen glycation end products) in blood and urine. Also, the accumulation of advanced glycation end-products (AGEs) in skin tissues can be used as an indicator of bone collagen degradation.

The good news is that both blood sugar level and homocysteine level can be controlled by diet, exercise, nutritional supplements, and hormones. Even the vicious cycle of impaired kidney function and high homocysteine level can be controlled to some extent. Homocysteine metabolic pathways are well known: including the critical enzymes and cofactor vitamins (B6, B12, choline, and Folic acid). Also the conditions that increase homocysteine levels are well known; impaired kidney function, cortisol, low estrogen/progesterone levels, genetic defects of critical enzymes. In other words, the remedies to slow down the degradation process is well know.

One reason Fosamax (or bisphosphonate in general) cannot protect your bone despite the increased BMD is that it degrades collagen cross-linking.

• One study reported that just one year of continued use of bisphosphonates can increase the advanced glycation end products (pentosidine) by 34% to 58% (Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra. M Allen, E Gineyts, D Leeming, D Burr, P Delmas 2008) 
• Bone micromechanical properties are compromised during long-term alendronate therapy independently of mineralization. Y Bala, B Depalle, D Farlay, T Douillard, S Meille, H Follet, R Chapurlat, J Chevalier, G Boivin 2011.

Another reason Fosamax (or bisphosphonate in general) cannot protect your bone despite the increased BMD is that it suppresses bone turnover too much. Bone mineralization occurs in two stages: Primary mineralization occurs when the new collagen matrix begins to mineralize quickly up to 50% to 60% of the maximum mineralization value. The secondary mineralization proceeds slowly for a number of years to fill the rest. If the removal rate is too fast, the bone tissues will be removed before they are fully mineralized and half-way mineralized bone tissues will increase. If the removal is too slow, on the other hand, over mineralized old and brittle bone tissues increase. Therefore it is important to strike the balance. This balance can be achieved better by estrogen than bisphosphonate (Microdamage accumulation in the monkey vertebra does not occur when bone turnover is suppressed by 50% or less with estrogen or raloxifene. Jiliang Li, Masahiko Sato, Chris Jerome, Charles H Turner, Zaifeng Fan, David B Burr 2005).

For more on bone quality and collagen cross-links, see

• Nonenzymatic cross-linking pentosidine increase in bone collagen and are associated with disorders of bone mineralization in dialysis patients. Jun Mitome, Hiroyasu Yamamoto, Mitsuru Saito, Keitaro Yokoyama, Keishi Marumo, Tatsuo Hosoya 2011 (increase of pentosidine is associated with slow bone-formation rate/bone volume and mineral apposition rate) 
• Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. M Saito, K Marumo 2009
• Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation-induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. M Saito, K Fujii, S Soshi, T Tanaka 2006
• Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation-induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. M Saito, K Fujii, S Soshi, T Tanaka 2006 
• Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment. Masataka Shiraki, Tatsuhiko Kuroda, Yumiko Shiraki, Shiro Tanaka, Tsuyoshi Higuchi, Mitsuru Saito 2011 
• Comparison of effects of alfacalcidol and alendronate on mechanical properties and bone collagen cross-links of callus in the fracture repair rat model. Mitsuru Saito, Ayako Shiraishi, Masako Ito, Sadaoki Sakai, Naohiko Hayakawa, Masahiko Mihara, Keishi Marumo 2010 
• Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. Elizabeth Shane, David Burr, Peter R Ebeling, Bo Abrahamsen, Robert A Adler, Thomas D Brown, Angela M Cheung, Felicia Cosman, Jeffrey R Curtis, Richard Dell, David Dempster, Thomas A Einhorn, Harry K Genant, Piet Geusens, Klaus Klaushofer, Kenneth Koval, Joseph M Lane, Fergus McKiernan, Ross McKinney, Alvin Ng, Jeri Nieves, Regis O'Keefe, Socrates Papapoulos, Howe Tet Sen, Marjolein C H van der Meulen, Robert S Weinstein, Michael Whyte, 2010
• Enzymic and non-enzymic cross-linking mechanisms in relation to turnover of collagen: relevance to aging and exercise. N C Avery, A J Bailey, 2005 
• Skin advanced glycation end-product accumulation is negatively associated with calcaneal osteo-sono assessment index among non-diabetic adult Japanese men. H Momma, K Niu, Y Kobayashi, L Guan, M Sato, H Guo, M Chujo, A Otomo, C Yufei, H Tadaura, T Saito, T Mori, T Miyata, R Nagatomi, 2011
• Lower osteocalcin and osteopontin contents of the femoral head in hip fracture patients than osteoarthritis patients. S Tanaka, K Narusawa, H Onishi, M Miura, A Hijioka, Y Kanazawa, S Nishida, S Ikeda, T Nakamura, 2011
• Bone quality and osteoporosis therapy. Regina Matsunaga Martin, Pedro Henrique S Correa 2010
• [Evaluation of the influence of sex hormones on homocysteine concentration in pre- and postmenopausal women] Grazyna Bednarek-Tupikowska, Krzysztof Tupikowski, Anna Bohdanowicz-Pawlak, Bozena Bidzi?ska, Jadwiga Szymczak, Alicja Filus, Justyna Kuliczkowska, Andrzej Milewicz, 2005

Homocysteine and hormones

Effect of hormones on homocysteine level

Because of the well established associations among menopause, cardiovascular diseases, gender differences, and homocyteine level, the effects of hormones on homocysteine level have been explored long before homocysteine's effects on osteoporosis became apparent (Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment. Masataka Shiraki, Tatsuhiko Kuroda, Yumiko Shiraki, Shiro Tanaka, Tsuyoshi Higuchi, Mitsuru Saito, 2011). It has been well demonstrated that estrogen or estrogen + progesterone can reduce homocyteine level (Hormone replacement therapy and plasma homocysteine levels. W M van Baal, R G Smolders, M J van der Mooren, T Teerlink, P Kenemans, 1999) and testosterone can increase it (Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. E J Giltay, E K Hoogeveen, J M Elbers, L J Gooren, H Asscheman, C D Stehouwer, 1998).

With experimental animals, surgical menopause (ovary removal) is routinely used to induce high homocysteine level. On the other hand, the homocysteine metabolic pathways are well known and hormones do not seem involved. Although, the underlying mechanism does not seem clearly understood, it is safe to assume that the link between the sex hormones and homocysteine level is not at the downstream of methyonin - homocysteine metabolism. Rather, the link seems to be at the upstream, the rate of muscle breakdown/rebuilding. In other words, testosterone increases the rate of muscle breakdown/rebuilding and estrogen slows it down. While surgical menopause (ovary removal) will increase the breakdown by the increased cortisol due to the distress of surgical menopause in addition to the lowered estrogen.

• Hyperhomocysteinemia in patients with Cushing's syndrome. Massimo Terzolo, Barbara Allasino, Sandra Bosio, Elena Brusa, Fulvia Daffara, Massimo Ventura, Emiliano Aroasio, Gianna Sacchetto, Giuseppe Reimondo, Alberto Angeli, Clara Camaschella, 2004;.  
• Serum Homocysteine: Relationship with Circulating Levels of Cortisol and Ascorbate. Jose F Cascalheira, Monica C Parreira, Andreza N Viegas, Maria C Faria, Fernanda C Domingues, 2008.
• Cortisol levels and metabolic parameters in middle- and advancedage subjects: associations with age. K Terzidis, A Panoutsopoulos, A Mantzou, P Tourli, G Papageorgiou, K Saltiki, G Tsagalis, C Mara, M Alevizaki, 2011).
• The effect of tissue breakdown can be seen in the creatinine and albumin levels that show clear correlation with hormone related homocysteine level differences (Oral estradiol decreases plasma homocysteine, vitamin B6, and albumin in postmenopausal women but does not change the whole-body homocysteine remethylation and transmethylation flux. R G V Smolders, K de Meer, P Kenemans, C Jakobs, W Kulik, M J van der Mooren, 2005)

These effects of estrogen and testosterone were demonstrated with transsexual males and females also. A woman who starts to take a large dose of testosterone will see increased homocysteine level, while a man who starts to take estrogen will have a reduced homocysteine level (Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. E J Giltay, E K Hoogeveen, J M Elbers, L J Gooren, H Asscheman, C D Stehouwer, 1998).

Although the effect of sex hormones on homocysteine has been demonstrated, they explain only a small fraction of the total homocysteine level in general population, against the effects of base protein metabolism (Factors explaining the difference of total homocysteine between men and women in the European Investigation Into Cancer and Nutrition Potsdam study. J Dierkes, A Jeckel, A Ambrosch, S Westphal, C Luley, H Boeing, 2001), and among osteoporotic postmenopausal women, kidney function is the most dominant factor (Homocysteine levels and risk of hip fracture in postmenopausal women. Meryl S Leboff, Rupali Narweker, Andrea Lacroix, Lieling Wu, Rebecca Jackson, Jennifer Lee, Douglas C Bauer, Jane Cauley, Charles Kooperberg, Cora Lewis, Asha M Thomas, Steven Cummings, 2009).

• Estrogens as regulators of bone health in men. Liesbeth Vandenput, Claes Ohlsson, 2009 
• Estradiol prevents homocysteine-induced endothelial injury in male rats. Kamellia R Dimitrova, Kerry W DeGroot, Alfonso M Pacquing, Johan P Suyderhoud, Eugen A Pirovic, Thomas J Munro, Jacqueline A Wieneke, Adam K Myers, Young D Kim, 2002 
• The effect of supraphysiologic doses of testosterone on fasting total homocysteine levels in normal men. J M Zmuda, L L Bausserman, D Maceroni, P D Thompson, 1997 
• Homocysteine and cysteine: determinants of plasma levels in middle-aged and elderly subjects. L Brattstrom, A Lindgren, B Israelsson, A Andersson, B Hultberg. 1994

Here again, progesterone mimicking drug, Provera (medroxyprogesterone acetate) has been proven to be very detrimental. HRT with medroxyprogesterone acetate (MPA) does not reduce homocysteine (due to increased cortisol activities; MPA acts like cortisol also.), while BMD studies demonstrated positive effects as reviewed earlier. 

• Hormone replacement therapy does not affect plasma homocysteine in postmenopausal women with coronary artery disease. Free tissue factor pathway inhibitor antigen, a circulating anticoagulant, is related to plasma homocysteine. Ingrid Os, Audun Os, Per Morten Sandset, Silje Bolling, Ingebjorg Seljeflot, Srdjan Djurovic, Arne Westheim, 2002 
• The effect of estrogen replacement therapy on total plasma homocysteine in healthy postmenopausal women. P B Berger, R R Herrmann, D A Dumesic, 2000
• A randomized placebo-controlled study of the effect of transdermal vs. oral estradiol with or without gestodene on homocysteine levels. R G V Smolders, M J van der Mooren, T Teerlink, J M W M Merkus, M V A M Kroeks, H R Franke, C D A Stehouwer, P Kenemans, 2003 
• Binding of progestins to the glucocorticoid receptor. Correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes. K Kontula, T Paavonen, T Luukkainen, L C Andersson, 1983

Bone series articles:

1. Menopause and What Really Happens to your Bones
2. False Promise of Fosamax
3. Estrogen Paradox
   
4. Role of Progesterone in Bone Health
   
5. Stress Hormones Destroy Bones
6. Menopause and How estrogen helps bone health?
7. Sad State of Progesterone Research
8. Bone Quality Is Just as Important as Density  <<You are here
   
9. How to Maintain Bone Health

Stress Hormones Destroy Bones

by Etsuko Ueda

It isn't just estrogen and progesterone that go through changes. FSH and LH rise and so does the stress hormone cortisol, while most hormones, including human growth hormone, DHEA, insulin-like growth factors, inhibins, thyroid, etc. start to decline as early as mid 30's.

Amongst, the hormone well known for its destructive power on bone is a stress hormone cortisol, and it is well established that cortisol increases with age. 

• Aging and the adrenal cortex. S S Yen, G A Laughlin 1998,
• Effects of aging on adrenal function in the human: responsiveness and sensitivity of adrenal androgens and cortisol to adrenocorticotropin in premenopausal and postmenopausal women. Parker CR Jr, Slayden SM, Azziz R, Crabbe SL, Hines GA, Boots LR, Bae S. 2000 (maximally stimulated levels of DHEA after ACTH bolus were significantly lower in the older women than in younger women; those of androstenedione were similar in both age groups, and the maximally achieved levels of Cortisol were higher in the older women than in the younger women.)
• Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women. Jonathan Q Purnell, David D Brandon, Lorne M Isabelle, D Lynn Loriaux, Mary H Samuels. 2004 (24-h plasma free cortisol levels were increased with age in association with increased cortisol production rate)
• Changes with aging of steroidal levels in the cerebrospinal fluid of women. K Murakami, T Nakagawa, M Shozu, K Uchide, K Koike, M Inoue 1999

Catabolic effect of Cortisol

Cortisol, also known as glucocorticoid, is well known for it's catabolic (breakdown) effects on bones, muscles, and protein in general. This is one of catabolic hormones along with epinephrine and glucagon. 

• Acute response of human muscle protein to catabolic hormones. D C Gore, F Jahoor, R R Wolfe, D N Herndon, 1993
• Bone mineral density, prevalence of vertebral fractures and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian Multicenter Study. Iacopo Chiodini, et. al., 2009
• Cortisol secretion, bone health and bone loss: a cross-sectional and prospective study in normal non-osteoporotic women in the early postmenopausal period. Giangiacomo Osella, Massimo Ventura, Arianna Ardito, Barbara Allasino, Angela Termine, Laura Saba, Rosetta Vitetta, Massimo Terzolo, Alberto Angeli, 2012

Cortisol increases especially during the late perimenopause and early post menopause years when menstrual irregularities are greatest, and menopausal symptoms are most severe.

• Increased urinary cortisol levels during the menopause transition., Nancy F Woods, Molly C Carr, Eunice Y Tao, Heather J Taylor, Ellen S Mitchell, 2006
• Cortisol levels during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study. Nancy Woods, Ellen Mitchell, Kathleen Smith-Dijulio, 2009).

Cortisol is an important stress hormone that allows us to be alert and energetic to face life's challenges with less pain. But it comes with a price, and our body is not built to stay in that state days and weeks on end, much less months and years. Except for a lucky few (less than 10%), women go through a stressful menopausal symptoms during the late perimenopause and early post menopause years (Bresilda Sierra, et.al. 2005), which is accompanied by elevated cortisol, epinephrine, and norepinephrine levels (Pituitary hormones during the menopausal hot flash. D R Meldrum, J D Defazio, Y Erlik, J K Lu, A F Wolfsen, H E Carlson, J M Hershman, H L Judd, 1984. Biophysical and endocrine-metabolic changes during menopausal hot flashes: increase in plasma free fatty acid and norepinephrine levels. M Cignarelli, E Cicinelli, M Corso, M R Cospite, G Garruti, E Tafaro, R Giorgino, S Schonauer. 1989). That is, unless something is done about it (Here lies a dilemma of research on menopause. You have to find women who agree to do nothing about it, which may not be easy or ethical, and potential for biased sampling).

"Glucocorticoids (GCs) are used frequently in a variety of diseases because of their strong anti-inflammatory and immunosuppressive effects. However, corticosteroids have many metabolic side effects, such as insulin resistance, hypertension, glaucoma, and osteoporosis. GC-induced osteoporosis (GIOP) is one of the most devastating side effects because bone loss during long-term GC treatment is generally irreversible and because of its clinical manifestations (eg, vertebral and nonvertebral fractures)." (Advances in glucocorticoid-induced osteoporosis. Debby den Uyl, Irene E M Bultink, Willem F Lems, 2011).

The mechanism has been identified at molecular level: Glucocorticoid preserves osteoclasts (cells involved in bone resorption) while reducing and impairing osteoblasts and osteocytes (cells involed in bone formation and mineralization). In addition, it impairs bone metabolism via inhibition of calcium resorption in the gastrointestinal tract and inhibition of the kidney's ability to reabsorb calcium (Glucocorticoid-induced osteoporosis: pathophysiology and therapy. E. Canalis & G. Mazziotti & A. Giustina & J. P. Bilezikian, 2010).

• Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Charles A OBrien, Dan Jia, Lilian I Plotkin, Teresita Bellido, Cara C Powers, Scott A Stewart, Stavros C Manolagas, Robert S Weinstein, 2004
• Glucocorticoids suppress bone formation via the osteoclast. Hyun-Ju Kim, Haibo Zhao, Hideki Kitaura, Sandip Bhattacharyya, Judson A Brewer, Louis J Muglia, F Patrick Ross, Steven L Teitelbaum 2006
• Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Alexander Rauch, Sebastian Seitz, Ulrike Baschant, Arndt F Schilling, Anett Illing, Brenda Stride, Milen Kirilov, Vice Mandic, Andrea Takacz, Ruth Schmidt-Ullrich, Susanne Ostermay, Thorsten Schinke, Rainer Spanbroek, Mario M Zaiss, Peter E Angel, Ulf H Lerner, Jean-Pierre David, Holger M Reichardt, Michael Amling, Gunther Schutz, Jan P Tuckermann, 2010
  

Bone series articles:

1. Menopause and What Really Happens to your Bones
2. False Promise of Fosamax
3. Estrogen Paradox
   
4. Role of Progesterone in Bone Health
   
5. Stress Hormones Destroy Bones <<You are here
   
6. Menopause and How estrogen helps bone health?
7. Sad State of Progesterone Research
8. Menopause and Bone Quality
9. How to Maintain Bone Health