A guide to bioidentical hormone replacement.

 

Women's Health Initiative Results:

"Given the Women’s Health Initiative Results, Should I stop my HRT? The answer depends on the type of HRT you are taking!"

 

On July 9, 2002, the Journal of the American Medical Association (JAMA) reported in an early release that the Women’s Health Initiative (WHI) study has been halted because after 5 years the safety monitoring board has detected that the risks of what they refer to as ‘hormone replacement therapy” appears to outweigh the benefits. Specifically, they determined in this randomized, placebo-controlled trial of 16,000 women that those taking the therapy had a small increase in invasive breast cancer, strokes, and heart attacks that out weighed the benefit of the small decrease in colorectal cancer and hip fractures.

 

This release has precipitated a media blitz featuring headlines like that in The New York Times, “Hormone Replacement Study Is a Shock to the Medical System,” and commentaries from experts like Wulf Utian, MD, a leading menopause authority calling it a “The biggest bombshell that ever hit in my 30-something years in the menopause area.”

 

These results do not come as a surprise to us at PhysioAge Medical Group. Furthermore, we do not think that this data in any way suggests that women taking transdermal estradiol cream and natural micronized progesterone (transdermal or oral) should discontinue their therapy. We believe this for the following reasons.

 

  1. While the study is rigorous and we accept its data, the conclusion propagated by the media is not applicable to ‘hormone replacement therapy’ (HRT) in general; rather its conclusion should be limited to HRT employing oral conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), the drugs known by the brand names Premarin and Provera. It is this drug combination alone that has now been proven to have an unfavorable risk to benefit ratio.
  2. We are not surprised that this combination has not shown the full benefit expected based on previous epidemiologic studies of estrogen replacement. A number of smaller studies have demonstrated the adverse effects of Provera on the cardiovascular system. For example, in animal studies, Provera has been shown to lessen the inhibitory effect of estrogen on coronary artery atherosclerosis development [1] and to nullify the preventative effect of estrogen in an animal model of angina. [2] . Similar results have also been shown in women [3] .
  3. This negative effect of Provera on the vascular system in combination with the known increase in clotting factors that oral estrogen replacement causes, are likely the cause of the increased blood clots, strokes, and heart attacks that occurred despite the substantial evidence that estrogen benefits the cardiovascular system [4-9] . Although the Premarin alone arm of the trial was not stopped for adverse effects on the cardiovascular system, we will not be surprised if that arm is found to have less benefit than expected as well because of this increase in clotting factors. It may be that this arm just does not have the added insult of the Provera to make the increased risk evident at this time.
  4. Similarly, the small increase in breast cancer risk is not surprising either. A recent study [10] compared the effect of continuous oral Premarin and Provera, oral estradiol alone, and transdermal estradiol alone on breast density by mammogram. The three treatments caused an increase in density of 40%, 6%, and 2% respectively, and it has been suggested by many studies that greater breast density by mammography confers an increased risk of breast cancer. The small increase with transdermal estradiol alone and large increase with oral Premarin and Provera indicate the differential effect of these regimens on breast tissue and potentially breast cancer risk.
  5. Evidence for the safety of progesterone comes from pregnancy. The level of natural progesterone is highest in pregnant women. Women who have multiple pregnancies that go to term are at considerably lower risk for breast cancer than women who are never pregnant. This suggests that exposure to continuous moderate levels of progesterone in the bioidentical HRT we practice does not increase the risk of breast cancer.
  6. There are many other reasons for taking natural, transdermal estrogen replacement therapy with micronized progesterone that were not addressed in this study. In addition to the documented decrease in colon cancer and fractures, here is just fraction of other evidence:

 

    • There is epidemiologic data that the age of onset of Alzheimer’s Disease is significantly delayed and even prevent in users of ERT [11-13] . This bolstered by biological evidence of estradiol’s effect on the maintenance of neurons in the part of the brain important for forming memories [14-18] .
    • Even in non-demented women, women who have used ERT perform better on tests of memory than those who never have used ERT [19].
    • Perimenopausal women with depressive symptoms treated with transdermal estradiol have a 68% remission rate compared with 20% for placebo [20].
    • Long-term ERT may reduce cataract formation by 30 to 60% [21].
    • Transdermal estradiol ERT has been shown to increase the collagen content of skin potentially forestalling skin aging [22] .

     

In conclusion, we agree that this study has established that women taking continuous combined HRT with oral Premarin and Provera should discontinue therapy because the albeit small risks outweigh the benefits of the therapy. We do not, however, believe that this study has at all reduced the importance of replacing a woman’s loss of estrogen during the perimenopause and beyond. Simply put, there is a better way. The available clinical, animal, and laboratory data all point to the benefits—without the risks mentioned above—of transdermal estradiol replacement with micronized progesterone, if a woman has not had a hysterectomy, to protect her heart, bones, brain, mood, skin, and eyes.

 

  1. Adams, M.R., et al., Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol, 1997. 17(1): p. 217-21.
  2. Williams, J.K., et al., Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol, 1994. 24(7): p. 1757-61.
  3. Rosano, G.M., et al., Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol, 2000. 36(7): p. 2154-9.
  4. Alpaslan, M., et al., Short-term estrogen administration ameliorates dobutamine-induced myocardial ischemia in postmenopausal women with coronary artery disease. J Am Coll Cardiol, 1997. 30(6): p. 1466-71.
  5. Pines, A., et al., The acute effects of sublingual 17beta-estradiol on the cardiovascular system. Maturitas, 1999. 33(1): p. 81-5.
  6. Lee, T.M., S.F. Su, and C.H. Tsai, Oestrogen attenuates coronary vasoconstriction after angioplasty: role of endothelin-1. Eur J Clin Invest, 2002. 32(3): p. 141-7.
  7. Albertsson, P.A., H. Emanuelsson, and I. Milsom, Beneficial effect of treatment with transdermal estradiol-17-beta on exercise-induced angina and ST segment depression in syndrome X. Int J Cardiol, 1996. 54(1): p. 13-20.
  8. Chester, A.H., et al., Oestrogen relaxes human epicardial coronary arteries through non-endothelium-dependent mechanisms. Coron Artery Dis, 1995. 6(5): p. 417-22.
  9. Rosano, G.M., et al., Short-term anti-ischemic effect of 17beta-estradiol in postmenopausal women with coronary artery disease. Circulation, 1997. 96(9): p. 2837-41.
  10. Lundstrom, E., et al., Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transdermal and low-potency estrogen regimens. Climacteric, 2001. 4(1): p. 42-8.
  11. Yaffe, K., et al., Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. Jama, 1998. 279(9): p. 688-95.
  12. Henderson, V.W., Estrogen, cognition, and a woman's risk of Alzheimer's disease. Am J Med, 1997. 103(3A): p. 11S-18S.
  13. Tang, M.X., et al., Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet, 1996. 348(9025): p. 429-32.
  14. Woolley, C.S., H.J. Wenzel, and P.A. Schwartzkroin, Estradiol increases the frequency of multiple synapse boutons in the hippocampal CA1 region of the adult female rat. J Comp Neurol, 1996. 373(1): p. 108-17.
  15. Woolley, C.S. and P.A. Schwartzkroin, Hormonal effects on the brain. Epilepsia, 1998. 39 Suppl 8: p. S2-8.
  16. Woolley, C.S., Effects of estrogen in the CNS. Curr Opin Neurobiol, 1999. 9(3): p. 349-54.
  17. Woolley, C.S., Effects of oestradiol on hippocampal circuitry. Novartis Found Symp, 2000. 230: p. 173-80; discussion 181-7.
  18. Woolley, C.S. and B.S. McEwen, Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol, 1993. 336(2): p. 293-306.
  19. Maki, P., A. Zonderman, and S. Resnick, Enhanced verbal memory in nondemented elderly women receiving hormone-replacement therapy. Am J Psychiatry, 2001. 158(2): p. 227-33.
  20. Soares, C.N., et al., Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry, 2001. 58(6): p. 529-34.
  21. Worzala, K., et al., Postmenopausal estrogen use, type of menopause, and lens opacities: the Framingham studies. Arch Intern Med, 2001. 161(11): p. 1448-54.
  22. Brincat, M., et al., Skin collagen changes in post-menopausal women receiving oestradiol. Maturitas, 1987. 9(1): p. 1-5.

Joseph M. Raffaele, MD