16 August 2009

Post-menopausal estrogen therapy

Menopause is the eventual reduced production of sex hormones in women. Follicular cells in the ovaries appear to become exhausted by continual cycles of ovulation and atresia (1). The ovaries become less responsive to stimulation from gonadotropin—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—causing estrogens and progesterone levels to lower. The ovaries degenerate causing further diminished estrogen production until the hormone is only produced in limited amounts by other tissues (1).

The loss of estrogens production also reduces cardioprotective effects of this particular hormone. Estrogens, estradiol in particular, protects cardiovascular health because of its binding to estrogen receptors (ERs). ERs in absence of estrogen are associated with heat shock protein (HSP); estrogen binding promotes dissociation (2). Estrogen binding also changes gene transcription, altering levels and kinds of cellular proteins (2). The alterations directly affect myocardial, vascular smooth muscle and endothelial cells.

In vascular smooth muscle cells, estradiol has vasodilatory effects and functions in contractibility and growth. Its mechanisms may be related to effects on calcium channel currents, increases of Ca2+ and/or activation of K channels (2). In effect, estradiol leads to increased secretion of NO and cGMP production (2). These are thought to be estradiol’s primary antiatherogenic actions, although other mechanisms may exist such as promotion of endothelial cell regeneration and angiogenesis.

Because estrogen has been found to reduce risk of cardiovascular disease in postmenopausal women, future research on estrogen therapy is merited. Side risks involved, however, may be too serious for estrogen to be prescribed at this time.

Authors who analyzed Women’s Health Initiative (WHI) randomized trials from 1993-2004 on use of conjugated equine estrogens found that death from other hazards such as breast cancer did not favor use of estrogen therapy (3;4). Critics suggest that prescribers of estrogen therapy should have waited WHI results to have avoided cases of breast cancer (3). WHI trials, in fact, also found that hormone therapy, unfortunately, did little to reduce risk of coronary heart disease suggesting that more research is needed (5). The WHI data are related to both pre-menopause and post-menopause therapies with estrogen (4).

Reference List

1. Cohn RM, Roth KS. Biochemistry of Disease: Bridging Basic Science and Clinical Practice. Baltimore: Williams & Wilkins, 1996.
2. Skafar DF, Xu R, Morales J, Ram J, Sowers JR. Clinical review 91: Female sex hormones and cardiovascular disease in women. J Clin Endocrinol Metab 1997;82:3913-8. Available at: http://jcem.endojournals.org/cgi/content/full/82/12/3913
3. Postmenopausal hormone therapy and breast cancer. Prescrire Int 2009;18:66-7.
4. Prentice RL, Manson JE, Langer RD et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009;170:12-23.
5. Banks E, Canfell K. Invited Commentary: Hormone therapy risks and benefits--The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis. Am J Epidemiol 2009;170:24-8.

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