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Women’s Health Initiative: Understanding the Effects of Estrogen and Bioidentical Hormones


The Women’s Health initiative (WHI) is an ongoing long-term public health study in the United States. The main goal of this study is to identify ways to reduce or prevent cardiovascular disease, breast cancer, colorectal cancer, and bone fractures in postmenopausal women. The study began in 1993 and assigned over 68,000 women aged 50-79 into randomized controlled trials on dietary modification, calcium and vitamin D supplementation, or hormone therapy. The initial study period ended in 2005, but follow-up studies have continued to take place periodically.

Women’s Health and Hormone Therapy

The hormone therapy (HT) clinical trials have received a lot of media coverage and drastically changed the way healthcare practitioners treat their postmenopausal patients. Let’s break down the study and its findings so you can make sense of all the sensation.

Women’s Health Initiative Study: Estrogen and Progesterone

Women in the primary HT clinical trial were randomly assigned to receive either Prempro medication or placebo.[1] Prempro contains conjugated equine estrogen (CEE); this type of estrogen is derived from the urine of pregnant mares. Prempro also contains Medroxyprogesterone acetate (MPA), a type of synthetic progesterone called a progestin. It is important to note that all women in this study had a uterus. The study participants underwent various initial and follow up screenings to assess their cardiovascular health, risk or presence of cancer, and reported bone fractures.[2]

Estrogen and Progesterone Hormone Therapy: A Risk to Women’s Health?

An independent data and safety monitoring board (DSMB) evaluated the study twice a year to see if it needed to be ended early for the safety of the participants. By May 2002 the DSMB concluded that the study group receiving Prempro showed adverse cardiovascular and breast cancer outcomes, which caused the trial to end early.[3] Another Women’s Health Initiative study investigating the effects of estrogen alone was happening at the same time. The estrogen in this trial was also CEE branded as Premarin. The risk-benefit balance for estrogen alone remained uncertain, so that clinical trial continued.[4]

Some results of the estrogen + progesterone (Prempro) versus placebo study[5],[6]:

  • The rate of coronary heart disease events increased by 29% in women taking Prempro
  • The rate of strokes was increased by 41% in women taking Prempro
  • The rate of venous thromboembolism (VTE) increased by 100% in women taking Prempro
  • The rate of invasive breast cancer increased by 26% in women taking Prempro

Both the estrogen + progesterone (Prempro) and estrogen only (Premarin) studies found:

  • Increased risk of stroke in women taking these hormones
  • Increased risk of pulmonary embolism in women taking these hormones
  • Reduced risk of diabetes in women taking these hormones
  • Reduced risk of hip fractures and total fractures in women taking these hormones

Estrogen and its Effect on Women’s Health

The estrogen only (Premarin) versus placebo study had some slightly different results[7][8]:

  • There were 204 cases of coronary heart disease in women receiving Premarin and 222 cases in the placebo group
  • There were 104 cases of invasive breast cancer in women receiving Premarin and 135 cases in the placebo group
  • There was no increased risk of heart attack in women receiving Premarin

Thus, the risk-benefit balance appears to be better in women who received only estrogen as part of their HT. Some women in the Women’s Health Initiative who received both estrogen only and estrogen + progesterone reported improved quality of life markers such as reduced hot flashes and night sweats, improved sleep, and reduced joint pain.[9]

Women’s Health: How Do We Reduce Cardiovascular Disease?

The increased risk of cardiovascular disease in particular was surprising to many patients and clinicians. Celebrities and media personalities immediately stopped their HT. Within three months of the Women’s Health Initiative publication, prescriptions for estrogen + progesterone medications rapidly decreased.

What We Know About Endogenous Estrogen and Women’s Health

The Women’s Health Initiative results were surprising because many human and animal studies have shown endogenous estrogen and estrogen receptors to have cardiovascular benefits. To name a few:[10]

  • Estrogen (estradiol) promotes vascular relaxation
  • Estrogen (estradiol) slows early atherosclerosis progression by improving lipid metabolism
  • Estrogen (estradiol) has antioxidant effects

The results of the Women’s Health Initiative posed a problem: How do we safely manage menopause symptoms and potentially reduce chronic disease risk for postmenopausal women?

Women’s Health and Bioidentical Hormones

The answer could be bioidentical hormones. Most traditional HT uses synthetic or semisynthetic hormones, such as conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA). However, bioidentical hormones are structurally identical to the hormones that occur naturally in the body.[11],[12]

Below is a brief review of several bioidentical hormones that have been studied in women:

  • 17β-Estradiol (E2) is the most studied bioidentical hormone. It is approved by the FDA for the management of menopause symptoms and osteoporosis prevention.[13] It may even have cardioprotective benefits, unlike CEE.[14]
  • Estriol (E3) has been shown to be effective for the treatment of postmenopausal symptoms and is well tolerated.[15]
  • Progesterone (P4) branded as Prometrium has been approved by the FDA for the treatment of postmenopausal symptoms and the prevention of endometrial hyperplasia.[16] One study found bioidentical progesterone to be comparable with MPA on improving quality of life makers and reducing inflammation. However, only bioidentical progesterone improved cognitive function and specific menstrual complaints. [17] The Postmenopausal Estrogen/Progestin Interventions trial detected no difference in efficacy or adverse effects between MPA and bioidentical progesterone. However, bioidentical progesterone had a better effect on lipid profiles.[18]

More long-term clinical trials, such as the Women’s Health Initiative, are necessary to determine the best way to manage postmenopausal symptoms and decrease the risk of chronic disease. However, bioidentical hormones seem to be a promising option for menopausal and postmenopausal women.

We hope this blog was able to take a complex (and potentially confusing) women’s health study outcome and make it digestible. Sanesco is committed to promoting the education and continued research of women’s health, which is why it will be our over-arching theme for 2018. Be sure to check Sanesco’s blog for more women’s health topics throughout the year. If you’re interested in finding a provider in our network to fit your needs, please visit our website or call today.


[1] Writing Group for the Women’s Health Initiative Investigators. (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. Jama288(3), 321-333.

[2] Ibid.

[3] Ibid.

[4] Ibid.

[5] Ibid.

[6] Manson, J. (2014). The Women’s Health Initiative: the latest findings from long-term follow-up. Women’s Health10(2), 125-128.

[7] Ibid.

[8] Shufelt, C. L., Merz, C. N. B., Prentice, R. L., Pettinger, M. B., Rossouw, J. E., Aroda, V. R., … & Manson, J. E. (2014). Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the WHI observational study. Menopause (New York, NY)21(3), 260.

[9] Manson op.cit.

[10] M Reslan, O., & A Khalil, R. (2012). Vascular effects of estrogenic menopausal hormone therapy. Reviews on recent clinical trials7(1), 47-70.

[11] Conaway, E. (2011). Bioidentical hormones: an evidence-based review for primary care providers. Journal of the American Osteopathic Association111(3), 153.

[12] Collins, J. J. (2008). Hormone therapy: it’s time for a second opinion. International journal of pharmaceutical compounding12(2), 123.

[13] Conaway op. cit.

[14] Ibid.

[15] Ibid.

[16] Ibid.

[17] Collins op. cit.

[18] Ibid.

Clinical Contributor

Marina Braine

Clinical Support Specialist at Sanesco International, Inc.

Marina Braine is a Clinical Support Specialist at Sanesco. She graduated from UNC-Asheville with her Bachelors of Science in Biology with a minor in French. She likes to keep active by hiking, running, and contra dancing around Asheville.


Ramona Richard, MS, NC

Ramona Richard, MS, NC

Ramona Richard graduated with honors from the University of California with a Bachelor’s Degree in psychology and graduated summa cum laude with a Master’s Degree in Health and Nutrition Education. She also holds a Standard Designated Teaching Credential from the State of California, is a California state-certified Nutrition Consultant and a member of the National Association of Nutrition Professionals.

Ramona has participated in nutrition education in both public and private venues, including high school and college presentations, radio and public speaking for the past 20 years. She is the owner of Radiance, a nutrition consulting company, the Director of Education for Sanesco International, and a medical technical writer.

Disclaimer: The information provided is only intended to be general educational information to the public. It does not constitute medical advice. If you have specific questions about any medical matter or if you are suffering from any medical condition, you should consult your doctor or other professional healthcare provider.

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