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.

We can trace the answer back to July 2002 with the publication in the Journal of the American Medical Association of a landmark study – The Women’s Health Initiative (WHI). This prospective, randomized, double blind, controlled population study involved 25,000 postmenopausal women who received either Premarin and Provera (Prempro), Premarin only if the woman had had a hysterectomy, or placebo. This study had to be halted early for ethical reasons, as there were found to be significantly increased risks of heart attack, stroke, and pulmonary embolism attributed to treatment with Prempro.

The impact of the publication of the WHI study was swift and fierce. Doctors literally began to cut patients off from their hormonal therapy, thrusting many of them into a state of desperation. I know this because quite a few of these women became my patients.

Given this outcome why was the WHI even undertaken. Because prior to the WHI the conventional wisdom was that HRT protected women against cardiovascular diseases.

Estradiol had a known beneficial effect on the lipid profile. Specifically, in the absence of estradiol, which occurs in menopause, a women’s total cholesterol increases with an increase in the bad LDL cholesterol while the good HDL cholesterol actually decreases. The LDL that is present is also more likely to become oxidized. It is so-called oxidized-LDL cholesterol that is the real villain in producing heart disease. Finally, in the absence of estradiol the LDL changes shape into a smaller and denser unit, which is more likely to cause plaque formation.

Additionally, estradiol, by affecting various metabolic systems in the body, also produces vasodilation, meaning a relaxation of the arteries, thereby lowering blood pressure, and increasing the output of the heart.

Considering all these benefits of Estradiol what explains the startling outcome of the WHI?

There are certain problems with how the WHI was undertaken which explains why the outcome was the opposite of what was expected.

First, there were no human hormones used in the WHI. The idea that the outcomes from studies of a hormone excreted from a pregnant horse, Premarin (PREgnant MARe’s urINe), and a synthetic hormone-like drug, Provera, would apply to the use of actual bio-identical human hormones transdermally applied is misguided.

The second problem was that the Premarin used in the WHI was orally administered. Oral estrogen affects the body differently from estrogen applied to the skin in two important ways. One of these affects is that ALL oral estrogens, whether synthetic or natural, stimulates the clotting cascade thereby increasing the risk a woman will develop blood clots. Therefore young women who use oral contraceptive pills are at increased risk of having a blood clot in their legs known as a deep venous thrombosis. The other problematic affect of oral estrogen is that it increases silent inflammation in the body. Inflammation, it turns out, is an independent risk factor for developing cardiovascular disease. Transdermal estrogen, unlike oral delivery, does not increase clotting risk and does not increase inflammation.

The third problem with the WHI, and perhaps the most important, is that the average age of the woman in the study was 63 years old and was 12 years into menopause. This means that for over 12 years the arteries in these women underwent the accelerated degenerative changes associated with the absence of estrogen.

After the publication of the WHI, an idea began to emerge that timing, meaning how soon after menopause does a woman start HRT, is important with respect to whether that women will receive the cardiovascular protective benefits of estradiol. This idea is referred to rather banally as the Timing Hypothesis. The bottom line is that starting hormones at the onset of menopause, as opposed to waiting 12 years as occurred in the WHI, actually matters to the long term, intrinsic health value of using hormones. (2)

When women enter menopause, they lose their ability to produce meaningful amounts of the enormously powerful estrogen 17-beta-estradiol. As reviewed above the absence of this estradiol has the effect of producing in women a more atherogenic lipid profile. This helps to explain why at age 50 a woman has about 1/10th the chance of having a heart attack as a man but by age 65, in the absence of estradiol replacement therapy, her risk of a heart attack will be the same as a man. Implicit in this observation is that delaying the treatment of menopause, as was done in the WHI, allows heart disease to develop. (3)

In fact, ALL the concerning cardiovascular findings in the WHI regarding cardiovascular risk can not only be mitigated but actually reversed if a woman starts HRT soon after the onset of menopause, even with oral estrogen. What reversed means here is that the use of hormones will actually produce a huge benefit to a woman’s vascular health, thereby lowering her risk of heart disease versus women who take no hormones. This would be the inverse of the findings from the WHI study.

Stay tuned for Part 3 detailing other studies


  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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