Sad state of progesterone research on bone

Role of progesterone on bone health in post menopause years

During premenopause years when estrogen is regularly secreted (menstruation cannot occur without estrogen), the level of progesterone hold the key to maintaining bone health, as reviewed earlier. Therefore, it is reasonable to assume that to be the case in post menopause hormone supplementation as well. However, when you read through the so far accumulated hormone supplementation research, you might come away with an impression that the effects of progesterone, real or fake, on bone are negligible or secondary at best to the bone spearing effects of estrogen (Long-term effects of progestins on bone quality and fractures. Jos H H Thijssen 2007 for a review). Although, many animal studies suggest otherwise as shown below 

• Effects of progesterone on postovariectomy bone loss in aged rats. E I Barengolts, H F Gajardo, T J Rosol, J J D'Anza, M Pena, J Botsis, S C Kukreja, 1990
• Progesterone-mediated stimulation of osteoprogenitor proliferation and differentiation in cell populations derived from adult or fetal rat bone tissue depends on the serum component of the culture media. Y Ishida, C G Bellows, I Tertinegg, J N Heersche, 1997
• Progesterone stimulates proliferation and differentiation of osteoprogenitor cells in bone cell populations derived from adult female but not from adult male rats. Y Ishida, J N Heersche, 1997 
• Effects of progestins on the metabolism of cancellous bone in aged oophorectomized rats. Y Yamamoto, T Kurabayashi, Y Tojo, T Yahata, A Honda, M Tomita, K Tanaka, 1998
• Effects of progesterone and 18-methyl levonorgestrel on osteoblastic cells. Min Liang, Er-Yuan Liao, Xin Xu, Xiang-Hang Luo, Xin-Hua Xiao, 2003
• Stimulatory effects of estrogen and progesterone on proliferation and differentiation of normal human osteoblast-like cells in vitro. B A Scheven, C A Damen, N J Hamilton, H J Verhaar, S A Duursma, 1992 
• Steroid hormone receptor expression and action in bone. R Bland, 2000 for a review

Due to the unfortunate history of HRT dominated by progesterone mimicking drugs and high dose oral progesterone, studies that illustrate proper use of progesterone are rare. One pioneering study by John R. Lee ("Osteoporosis Reversal: The Role of Progesterone," by John R. Lee, (International Clinical Nutrition Review 1990, see also What Your Doctor May Not Tell You About Menopause, by John R. Lee, M.D. with Virginia Hopkins, 1996, Warner Books.) used transdermal progesterone 20~40mg/day for 21 days/month. Only 40% of his patients used estrogen (oral estradiol 0.3mg or premarin 0.65mg, or vaginal estrogen) corresponding to the need to control menopausal symptoms. The age of patients ranged from 38 to 83 and BMD at lumbar spine ranged 0.5~1.3 g/cm² at the start. The most interesting aspect of this study is the increase of BMD (roughly 2~23% or 0.03~0.16g/cm² gain) proportional to the severity of the bone erosion regardless of age for both estrogen and non-estrogen users. This is a highly desirable outcome since you do not want BMD build-up in people who already have healthy BMD. That would be an indication of old bone accumulation rather than new bone formation.

When you compare Lee's data with BMD gain typically seen with antiresorptive agents (estrogen or bisphosphonates such as Fosamx) compiled by Claudie Berger et. al. 2008 (Change in bone mineral density as a function of age in women and men and association with the use of antiresorptive agents) there is a large (10 fold) difference in the magnitude of gain. With antiresorptive agents the gain ranges -0.04 ~ 0.01g/cm² , while the gains were 0.03~0.16g/cm² in Lee's.

Another attempt to demonstrate the efficacy of real estrogen + real progesterone supplementation on bones of early postmenopausal women with osteopenia (average BMD around 0.9g/cm²), used transdermal estradiol (increasing and decreasing doses of 25~75 microg/day) and oral progesterone (cyclic 50 mg/daily for 6 days and, subsequently, 100 mg daily for the next 6 days) imitating rise and fall of estrogen and progesterone throughout the therapeutic cycle. When compared to an oral estrogen + fake progesterone (1 mg estradiol valerate [358.39 g/mol] + 2 mg estriol [288.39 g/mol] + 0.25 mg levonorgestrel [312.466 g/ mol]), a slight advantage of combined bio-identical hormone therapy was observed in BMD gains. However, the bone building osteoblasts activity marker used (osteocalcin) did not show any increase, while bone collagen synthesis marker (carboxyterminal propeptide of type I procollagen) showed clear decrease over the 1 year trial period, indicating collagen that keeps bone from getting brittle was decreasing although BMD was increasing (see Bone Quality Is Just as Important as Density).

• Influence of modified transdermal hormone replacement therapy on the concentrations of hormones, growth factors, and bone mineral density in women with osteopenia. Stania?aw Stanosz, et. al. 2009

Compared to 17~18% BDM gain in 3 years (about 6% per year) seen in Lee's patients starting with BMD comparable to Stanosz's study, Stanosz's patients gained 3.8% in one year. There is no way to tell if this reflects a significant difference in the efficacy of the HRT protocols used, and if it does, if it is due to the effects of additional nutrition and exercise used by Lee's patients. However, one thing for sure is the detrimental effects of progesterone mimicking drugs and progesterone overdose that have been used by most HRT studies including the above Stanosz, et. al. study (see Hormone overdose: How can you tell?).

Fake progesterone with glucocorticoid activity

If anyone says progesterone is bad for your bone, they are talking about fake progesterone that has glucocorticoid activity. Real progesterone can bind to glucocorticoid receptors, but does not act like cortisol (Synthetic progestins used in HRT have different glucocorticoid agonist properties. Dominique Koubovec, Katharina Ronacher, Elisabeth Stubsrud, Ann Louw, Janet Patricia Hapgood 2005). Instead, it blocks excessive cortisol action (Steroid hormone receptor expression and action in bone. R Bland 2000 for a review). 

• After 6 months of conjugated oestrogen (Premarin) plus medroxyprogesterone (MPA) or conjugated oestrogen plus norethisterone (NET) treatments, serum osteocalcin level (bone formation marker) decreased by 29.4% and 23.5%, respectively, with the decrease in MPA being significantly greater than that in NET (Effect of progestins with different glucocorticoid activity on bone metabolism., Yoichiro Ishida, Takatomo Mine, Toshihiko Taguchi 2007).  
• Megestrol acetate also has glucocorticoid activity and causes bone erosion (Osteoporosis associated with megestrol acetate., Robert A Wermers, Daniel L Hurley, Ann E Kearns 2004). Just like MPA, it is also known to cause blood clots Megestrol acetate therapy in geriatric patients: case reviews and associated deep vein thrombosis. Leisa L Marshall, 2003
• Binding specificity of medroxyprogesterone acetate and proligestone for the progesterone and glucocorticoid receptor in the dog. P J Selman, J Wolfswinkel, J A Mol, 1996
• 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

Progesterone, cortisol, and vascular constriction

Real progesterone can block cortisol receptors to block excessive cortisol activity. Furthermore, vascular constriction is dependent on Ca+ (Vascular responses of ophthalmic arteries to exogenous and endogenous norepinephrine. H Ohkubo, S Chiba 1989), and progesterone, as a fast acting Ca+ blocker, can reduce excessive blood vessel constriction.

Even Medroxyprogesterone acetate (provera), a progesterone mimicking drug with significant cortisol activity, was demonstrated to reduce Glucocorticoid-induced osteoporosis in men. Effective therapy of glucocorticoid-induced osteoporosis with medroxyprogesterone acetate. E O Grecu, A Weinshelbaum, R Simmons, 1990.

Problematic Progesterone studies

Most studies (including the now infamous Women's Health Initiative clinical trials) have used progesterone mimicking drugs (some with high cortisol activity) instead of real progesterone. Those that used real progesterone are flawed with overdose (see the overdose section below), in addition to design limitations and the lack of critical information or analysis such as correlation among menopausal symptom, cortisol, initial BMD levels, and BMD gains, making it difficult to interpret. 

• The effects of progestins on bone density and bone metabolism in postmenopausal women: a randomized controlled trial. James H Liu, Ken N Muse, 2005,
• Influence of modified transdermal hormone replacement therapy on the concentrations of hormones, growth factors, and bone mineral density in women with osteopenia. Stania?aw Stanosz, et. al. 2009), 
• Soymilk or progesterone for prevention of bone loss--a 2 year randomized, placebo-controlled trial. Eva Lydeking-Olsen, Jens-Erik Beck-Jensen, Kenneth D R Setchell, Trine Holm-Jensen, 2004 

Problem of hormone overdose

More is not better when it comes to hormones, supplemented or your own. (see also Hormone overdose: How can you tell?)

Progesterone overdose   

• More than normal concentrations of progesterone suppresses osteoblast differentiation by up to 80% (Progesterone and bone: a closer link than previously realized. V Seifert-Klauss, M Schmidmayr, E Hobmaier, T Wimmer, 2012). 
• High dose of oral progesterone (100mg oral is enough to demonstrate this effect) is converted to deoxy-corticosterone (a potent mineralocorticoid) (Oral progesterone and estrogen/progestogen therapy. Effects of natural and synthetic hormones on subfractions of HDL cholesterol and liver proteins. U B Ottosson 1984), which can induce calcium excretion in kidney, and vascular calcification (Mineralocorticoid Receptor Activation Promotes Vascular Cell Calcification. Iris Z Jaffe, Yin Tintut, Brenna G Newfell, Linda L Demer, Michael E Mendelsohn 2007), although progesterone itself and its other metabolites can inhibit mineralocorticoid receptor (Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor. M Quinkler, B Meyer, C Bumke-Vogt, C Grossmann, U Gruber, W Oelkers, S Diederich, V Bahr, 2002). Therefore, research with high dose oral progesterone (such as shown below) may have serious side effects to some women that may wipe out any positive effects progesterone may have on bone.
• Effect of micronized progesterone on bone turnover in postmenopausal women on estrogen replacement therapy. G Azizi, A Hansen, K M Prestwood 2003, (400mg/day!!)
• Lack of effect of short-term micronized progesterone on bone turnover in postmenopausal women. Z Ikram, L Dulipsingh, K M Prestwood 1999 (200mg/day)  
• Sublingual administration of micronized estradiol and progesterone, with and without micronized testosterone: effect on biochemical markers of bone metabolism and bone mineral density. B E Miller, M J De Souza, K Slade, A A Luciano, 2000: estradiol (0.5 mg)+ micronized progesterone (100 mg)

Estrogen overdose and cortisol

Also, let's not forget that when you add progesterone to estrogen, the effects of estrogen increases many fold because progesterone increases estrogen receptors, and extremely high level of estrogen can intensify stress reaction and cortisol.  (see also Hormone overdose: How can you tell?)

• 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;
• Estrogen potentiates adrenocortical responses to stress in female rats. Helmer Feitosa Figueiredo, Yvonne M Ulrich-Lai, Dennis C Choi, James P Herman, 2006;
• Effect of neonatal ovariectomy and estradiol treatment on corticosterone release in response to stress in the adult female rat. Cheryl M McCormick, 2011).

In terms of clinical experiment, therefore, you cannot just compare estrogen supplementation against estrogen + progesterone supplementation without reducing estrogen dosage in estrogen + progesterone group, especially when estrogen dosage is far more than necessary to control menopausal symptoms to begin with (e.g. 2mg is 40 times more than what's needed, which is 0.05mg). 

• What goes on behind closed doors: physiological versus pharmacological steroid hormone actions. S Stoney Simons Jr, 2008

The notion that estrogen dominance, the consequence of Ovulatory Disturbances, is detrimental to bone health is an old news. Actually, it can do a lot more harm than weakening bone. It was pointed out by Ray Peat and John R. Lee decades ago. The logical approach to this problem is progesterone supplementation using low dose transdermal form, and its effectiveness has also been known (see Estrogen dominance: it's not just a theory and Safe Use of Hormones: the Hard Evidence). If you are wondering why there aren't very many researchers following up Ray Peat and John R. Lee's work, I suggest you read Natural Hormones: Why doctors are clueless? and The Hormone War is Heating Up.

 

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 <<You are here
   
8. Bone Quality Is Just as Important as Density
9. How to Maintain Bone Health