Menopause and How estrogen helps bone health?

by Etsuko Ueda

Estrogens have been widely used to slow down the bone erosion (Ultra low-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. Karen M Prestwood, et. al. 2003) in late perimenopause and post menopause years. The common notion is that the low estrogen level in perimenopause and menopause years somehow will speed up the old bone removal process leading to the bone erosion and osteoporosis, and taking estrogen and/or drugs such as bisphosphonate (Fosamax, etc.) will stop that. However, as I reviewed in Bone: Estrogen Paradox, this is a too simplistic notion.

During perimenopause years, for a year or two before the final menstrual period, there are occasional skipped periods with low estrogen/progesterone, and each can lasts 3 ~ 6 months, then during the later half of late perimenopause (1~2 years after the final period) no progesterone is secreted from ovaries and estrogen eventually settles at a lower level, and stays low there after. If it is just a matter of estrogen level, normal estrogen half the time is better than none, and bone erosion would not slow down in post menopause years. It seems that whatever estrogen supplementation does to slow down bone erosion in perimenopause and post menopause years, the same estrogen secreted in your body cannot stop bone erosion (or menopausal symptoms for that matter) despite its normal or sometimes higher than normal levels during late perimenopause, especially when estrogen is not accompanied by progesterone as reviewed in Role of Progesterone on Bone Health.

Whatever supplemented estrogen does to stop the bone erosion, its effect on bone must be something other than its direct effects on bone cells. Taken together,  I bet the severe menopausal symptoms have a lot to do with bone erosion during this period (I could not find any study that measured the severity of menopausal symptoms along with bone measures. However, cortisol has been measured in the context of menopausal transition bone studies). 

Estrogen and menopausal symptoms

One obvious link is its power to eliminate menopausal symptoms such as hot flashes, which is associated with high cortisol, epinephrine, and norepinephrine levels. As I reviewed in Menopausal Symptoms And Underlying Mechanism, estrogen can strengthen parasympathetic system to counteract hyperactive sympathetic system characteristic of menopausal symptoms, easing estrogen withdrawal symptoms.

• "estrogen supplementation in perimenopausal women selectively attenuates vasoconstrictor responses to norepinephrine and reduces total body norepinephrine spillover, which is an index of sympathetic neural activity." (Estrogen supplementation decreases norepinephrine-induced vasoconstriction and total body norepinephrine spillover in perimenopausal women. K Sudhir, M D Elser, G L Jennings, P A Komesaroff 1997)
• Menopause is also accompanied by stronger alpha-adrenergic peripheral vasoconstriction both at rest and during exercise. (Autonomic regulation of blood pressure in menopause. Wanpen Vongpatanasin 2009)

Estrogen + real progesterone can safely eliminate menopausal symptoms, and to that extent can reduce stress level, hence the stress hormone (cortisol, epinephrine, and norepinephrine) levels. Actually, most of menopausal symptoms can be eliminated by estrogen alone in most cases, but that is not safe as I reviewed in Safe Use of Hormones: the Hard Evidence. For some women progesterone alone therapy can also eliminate menopausal symptoms, and to that extent, progesterone can also reduce cortisol. (Actually progesterone can suppress cortisol activity directly, even a progesterone mimicking drug medroxyprogesterone acetate, can reduce Glucocorticoid-induced osteoporosis (Effective therapy of glucocorticoid-induced osteoporosis with medroxyprogesterone acetate. E O Grecu, A Weinshelbaum, R Simmons 1990).

Effect of Nitric Oxide (NO) on blood supply and bone health

Estrogen's ability to increase NO production seems an important mediating factor with its power to increase blood circulation.

• NO production was found critical in estrogen's stimulation of bone formation activity (Nitric oxide mediates 17beta-estradiol-stimulated human and rodent osteoblast proliferation and differentiation., M C O'Shaughnessy, J M Polak, F Afzal, M V Hukkanen, P Huang, I MacIntyre, L D Buttery, 2000) 
• Nitroglycerine (an NO donor) was found to be as effective as estrogen in preventing bone loss in women with surgical menopause, indicating it may be the estrogen's effects on NO production, in turn blood vessel dilation and NO's anti-oxidant activity that is critical in reducing bone erosion (Osteoporosis and cardiovascular disease: brittle bones and boned arteries, is there a link?, Samy I McFarlane, Ranganath Muniyappa, John J Shin, Gul Bahtiyar, James R Sowers, 2004, Nitric oxide: novel therapy for osteoporosis., Sunil J Wimalawansa, 2008, The nitrogen-containing bisphosphonate, zoledronic acid, increases mineralisation of human bone-derived cells in vitro., Beiqing Pan, Luen Bik To, Amanda N Farrugia, David M Findlay, Jonathan Green, Stan Gronthos, Andreas Evdokiou, Kevin Lynch, Gerald J Atkins, Andrew C W Zannettino, 2004). 
• "In ovariectomized rats, reduced nitric oxide release from the skeletal muscle caused by estrogen deficiency contributes to augmented sympathetic vasoconstriction during muscle contraction." Autonomic regulation of blood pressure in menopause. Wanpen Vongpatanasin 2009 
• Nitrate patch prevents steroid-related bone necrosis., Wolf Drescher, Rainer Beckmann, Richard Kasch, Melanie Pufe, Matthias Knobe, Nisreen Kweider, Joachim Hassenpflug, Markus Tingart, Thomas Pufe, Mahmed Kadyrov, 2011
•  DHEA, which is also known for its bone preserving effect, is also enhances NO synthesis (Effects of dehydroepiandrosterone replacement therapy on bone mineral density in older adults: a randomized, controlled trial. Jankowski CM, Gozansky WS, Schwartz RS, Dahl DJ, Kittelson JM, Scott SM, Van Pelt RE, Kohrt WM.J Clin Endocrinol Metab. 2006;  Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms.Simoncini T, Mannella P, Fornari L, Varone G, Caruso A, Genazzani AR.
  
  Endocrinology. 2003)

As I reviewed in Menopausal Symptoms And Cardiovascular Health, estrogen and progesterone exert profound effects on regulation of cardiovascular system and blood circulation. By facilitating the production of blood vessel dilating substance NO, estrogen indirectly helps blood supplies to where and when needed. If blood flow to bone marrow is compromised due to insufficient NO production or atherosclerosis, bone health can suffer. In fact, when magnetic resonance perfusion (blood supply) imaging became available to measure bone marrow perfusion, it was demonstrated that the reduction in blood supply closely mirrors the reduction in bone mineral density. This change is also accompanied by increased marrow fat area and decreased erythropoietic marrow area (new blood cell generating area). So, not only the blood supply is reduced, but also, new blood cell generation capacity is reduced.

• Compromised Bone Marrow Perfusion in Osteoporosis. James F Griffith, David Kw Yeung, Polly H Tsang, Kai C Choi, Timothy Cy Kwok, Anil T Ahuja, Kwok S Leung, Ping C Leung, 2008 
• Reduced bone perfusion in proximal femur of subjects with decreased bone mineral density preferentially affects the femoral neck. Yi-Xiang J Wang, James F Griffith, Anthony W L Kwok, Jason C S Leung, David K W Yeung, Anil T Ahuja, Ping Chung Leung, 2009 
• Reduced bone perfusion in osteoporosis: likely causes in an ovariectomy rat model. James F Griffith, Yi-Xiang J Wang, Hua Zhou, Wing Hang Kwong, Wing Tak Wong, Yan-Lin Sun, Yu Huang, David K W Yeung, Ling Qin, Anil T Ahuja, 2010 
• Bone mineral density and blood flow to the lower extremities: the study of osteoporotic fractures.  M T Vogt, J A Cauley, L H Kuller, M C Nevitt, 1997 
• Forearm endothelial function and bone mineral loss in postmenopausal women. Mitsuhiro Sanada, et. al. 2004

Moreover, poor oxygen supply can cause more blood mononuclear cells to turn into bone-eating osteoclasts.

• Hypoxia stimulates osteoclast formation from human peripheral blood. Jennifer C Utting, Adrienne M Flanagan, Andrea Brandao-Burch, Isabel R Orriss, Timothy R Arnett 2010

Estrogen and angiogenesis

Estrogen is well know for its facilitating effects on blood vessel generation (angiogenesis). Low estrogen can impair angiogenesis, resulting in poor blood supply by failing to maintain small blood vessels.

• Reduced local blood supply to the tibial metaphysis is associated with ovariectomy-induced osteoporosis in mice. Wen-Ge Ding, Zhao-Xiang Wei, Jin-Bo Liu 2011

Cortisol, norepinephrine and blood vessel constriction

Both cortisol and norepinephrine (sympathetic nerve activity) are known to constrict blood vessels while increasing heart rate. It is designed to increase blood flow to muscles to cope with fight or flight situation. However, chronic elevation of these hormones can lead to excess constriction and reduced blood supply even when resting. If blood supply is important in bone health, cortisol certainly can play a detrimental role in it in addition to other effects mentioned earlier. Chronic elevation of cortisol can increase vascular sensitivity to noradrenalin (norepinephrine) leading to a stronger vascular constriction, while reducing the parasympathetic cholinergic vasodilatation. Further more, cortisol can reduce blood flow by constricting blood vessels directly.

• "In congenital 11 beta-hydroxysteroid dehydrogenase deficiency intra-arterial infusion of cortisol caused vasoconstriction (20% reduction in blood flow in the infused arm) and accentuated the response to application of lower-body negative pressure, which stimulates sympathetically mediated vasoconstriction (35% reduction). However, intra-arterial infusion of cortisol had no effect in healthy subjects either with or without administration of liquorice. Carbenoxolone potentiated both noradrenaline induced forearm vasoconstriction (P < 0.01) and pressor response (P < 0.001). We conclude that 11 beta-hydroxysteroid dehydrogenase modulates the access of cortisol to vascular receptors and thereby influences vascular sensitivity to noradrenaline."Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man. B R Walker, A A Connacher, D J Webb, C R Edwards 1992
• "Cholinergic vasodilatation was impaired after cortisol administration, reaching statistical significance at 5 days " Cortisol inhibits cholinergic vasodilation in the human forearm. G J Mangos, B R Walker, J J Kelly, J A Lawson, D J Webb, J A Whitworth 2000
• Cortisol can reduce blood flow by constricting blood vessels directly: A Critical Role for Vascular Smooth Muscle in Acute Glucocorticoid-Induced Hypertension. Julie E Goodwin, Junhui Zhang, David S Geller 2008; Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension. Julie E Goodwin, Junhui Zhang, David Gonzalez, Sebastian Albinsson, David S Geller 2011; Glucocorticoid-induced hypertension. Julie E Goodwin, David S Geller 2011

High cortisol along with high norepinephrine and epinephrine (overactive sympathetic nerve system) and underactive parasympathetic nerve system that characterize menopausal symptoms (see Menopausal Symptoms And Underlying Mechanism) induces chronic blood vessel constriction (hypertension). It does not seem to matter how much estrogen is secreted at that point. All that matters is how sever the menopausal symptoms are. In other words, the studies so far reviewed seem to indicate that if you can avoid sever and prolonged menopausal symptoms, you can avoid severe bone erosion regardless of the estrogen level (estrone, a weaker form of estrogen, never gets completely depleted. Ovaries and adrenal glands continue to secrete estrone precursor hormones and body tissues convert them to estrone). Estradiol supplementation is particularly useful for bone preservation as ultralow dose of it can eliminate the menopausal symptoms, hence cortisol and norepinephrine.

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?  <<You are here
   
7. Sad State of Progesterone Research
8. Menopause and Bone Quality
9. How to Maintain Bone Health