Sep 24th, 2020

Greg Wolf, one of our esteemed Clinical Advisory Board members, shares his clinical experience about Heart Health and Physiologic Restoration in Menopause via his 3-part series.

A powerful study, which demonstrates these benefits discussed at the end of part 2, is the Danish Osteoporosis Prevention Study (DOPS). DOPS, like the WHI, was a prospective, randomized, double blind, controlled study involving 1006 women followed for 16 years. These women averaged only 7 months from the onset of menopause to the start of hormone replacement therapy versus the average of 12 years women were without hormones in the WHI. The women who were randomized to the treatment group in the DOPS were given HRT for 10 years. The hormones were then stopped, and the women were observed for 6 more years off the hormones, bringing the study length to 16 years. The DOPS used oral 17-beta-estradiol and the synthetic progestogen Norethindrone.

What DOPS found is that the women in the treatment group versus women in the placebo group, had a 43% decrease in all-cause mortality over the first 10 years of the study. Recall, the treatment group’s hormones were discontinued at the 10-year mark. Six years later, at the 16-year mark, the women who had been treated with HRT still had a 34% reduction in all-cause mortality.

The DOPS showed even bigger benefits when the outcomes for heart attack and heart failure were combined with mortality. This composite endpoint showed a 52% reduction for the treatment group versus the placebo group at 10 years, which was still a 49% reduction at the 16-year mark. (4)

Another study designed to test the hormone-timing hypothesis in relation to atherosclerosis progression in postmenopausal women was the “Early versus Late Intervention Trial with Estradiol” aka ELITE Trial, which was published in that most prestigious of all medical journals, The New England Journal of Medicine, in 2016. This study evaluated the lining of the carotid artery and measured the rate that the lining of the carotid artery thickened using the noninvasive and easily performed carotid ultrasound. The medical term to describe this thickening is Carotid Intima Media Thickness or CIMT.

CIMT has been shown to be a predictor of the presence, or not, of coronary artery disease, or, in other words, heart disease. Furthermore, the more thickening over any given period of time the more rapidly heart disease is developing. Any treatment that slows the progression of CIMT is, therefore, preventing heart disease from developing.

The ELITE trial showed that women who start estradiol replacement within 6 years of the onset menopause will slow the progression of CIMT and, therefore, slow the development of coronary artery disease. (5)

Meta-analyses have also considered the timing hypothesis with respect to the start of HRT in menopause. A meta-analysis is a study which combines the data from multiple studies into one big study.

One meta-analysis with an aggregate 39,000 women found a 32% reduction in heart disease if women started HRT within 10 years of the onset of menopause. The other meta-analysis aggregated 23,708 women and found a 38% decrease in all-cause mortality, again if HRT was started within 10 years of the onset of menopause. (6, 7)

What has been highlighted so far is that starting HRT soon after the onset of menopause meaningfully slows vascular aging in women thereby preventing both cardiovascular disease and mortality

However, studies also show that the oral route of estradiol delivery is problematic because it increases the tendency of women to develop blood clots as well as increasing so called “silent inflammation” throughout her body. Silent inflammation is an independent risk factor for developing heart disease. (8, 9) These two factors are so impactful that almost all the cardiovascular risks associated with the WHI study of 2002 can be eliminated simply by switching oral to a transdermal bio-identical hormone replacement therapy.

Supportive of the above conclusion is an analysis published in the prestigious journal Stroke in 2016 which found that between 22 and 30 extra cases of stroke and blood clots in the legs or lungs per 10,000 HRT users could have been avoided every year if women used transdermal rather than oral estrogens.(10)

All the above information still does not explain how it was that my two patients who already had advanced coronary artery disease had their disease progression halted or slightly reversed. My patients were started on high dose hormonal therapy 3 decades after their surgical menopause and they already had heart disease. Is there way to understand this phenomenon? I believe there is.

Another extremely important contribution estradiol produces in support of a healthy vascular system is its attribute of stimulating the production of bone marrow derived stem cells called Endothelial Progenitor Cells (EPC). These cells rejuvenate and regenerate the vascular system and in doing so diminish atherosclerosis. (11)

Estradiol stimulates the increased production of these powerful stem cells in a concentration dependent fashion meaning that the more estradiol she has in her blood stream the more of the EPC she will produce. The more EPC a woman produces the lower her risk of all vascular disease, which includes heart disease and stroke.

It is through the increased production of EPC which, I believe, explains why my two patients had the remarkable outcome they did. Recall that PR is a high dose hormone replacement protocol, which restores a menopausal woman a youthful level of estradiol.

Hopefully, through reading this posting you have come to appreciate the life enhancing and life affirming benefits of transdermal bio-identical hormone replacement therapy, especially the value of estradiol in the context of the Physiologic Restoration Protocol (PR), in the life of a postmenopausal woman.

I will end with a quote that reveals part of why I am so passionate about offering the women of my practice bio-identical HRT.

“It is important to realize that postmenopausal HRT is the only primary prevention therapy in women that has been demonstrated to reduce total mortality and to extend life.” Howard Hodis, M.D., Professor of Medicine. Harry J. Bauer and Dorothy Bauer Rawlins Professorship in Cardiology and Medicine. University of Southern California (12)


  1. Hodis HN and Mack WJ. The Timing Hypothesis: A Paradigm Shift in the Primary Prevention of Coronary Heart Disease in Women: Part 1, Comparison of Therapeutic Efficacy. J Am Geriatr Soc. 2013 Jun;61(6): 1005-1010
  2. Hodis HN and Mack WJ. The Timing Hypothesis: A Paradigm Shift in the Primary Prevention of Coronary Heart Disease in Women: Part 1, Comparison of Therapeutic Efficacy. J Am Geriatr Soc. 2013 Jun;61(6): 1005-1010
  3. Fonseca MIH, et al. Impact of Menopause and Diabetes on Atherogenic Lipid Profile: is it worth to analyze lipoprotein subfractions to assess cardiovascular risk in women. Diabetol Metab Syndr. 2017 Apr 7;9:22
  4. Schierbeck LL et al. Effect of Hormone Replacement Treatment on Cardiovascular Events in Recently Postmenopausal Women: Randomized Trial. BMJ. 2012;345:e6409
  5. Hodis HN, et al. Vascular Effects of Early versus Late Post Menopause Treatment with Estradiol. N Engl J Med. 2016 Mar 31;374(130:1221-1231
  6. Hodis HN and Mack WJ. The Timing Hypothesis: A Paradigm Shift in the Primary Prevention of Coronary Heart Disease in Women: Part 1, Comparison of Therapeutic Efficacy. J Am Geriatr Soc. 2013 Jun;61(6): 1005-1010
  7. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297(13):1465-1477
  8. Canonico M, et al. Postmenopausal Hormone Therapy and Risk of Stroke: Impact of the Route of Estrogen Administration and Type of Progestogen. Stroke. 2016 Jul;47(7):1734-1741
  9. Vongpatanasin W. et al. Differential Effects of Oral versus Transdermal Estrogen Replacement Therapy on C-Reactive Protein in Postmenopausal Women. J Am Coll Cardio. 2003 Apr 16;41(8):1358-63
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The goal of WHN is to expand the Standard of Care by promoting, advocating, and advancing women's wellbeing and longevity through clinical research and education about the benefits of Physiologic Restoration to reduce the symptoms of hormone imbalance, chronic disease and degenerative decline.
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