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 
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).
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). 
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. 

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   

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?)
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). 
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.

No comments:

Post a Comment

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.