Designs for Wellness – Samuel Tyuluman, MD

The duration of menopausal symptoms can last 10 or more years with hot flashes, night sweats, flushing, anxiety, sleep disruption, and heart palpitations.  Over the long term estrogen and testosterone deficiency also leads to vulvovaginal atrophy (VVA), causing atrophy of the vulva, vagina and lower urinary tract.  Over the years symptoms of menopause eventually resolve, however the physical changes of VVA are progressive and continue to adversely affect health, sexuality, and the quality of life.  The vagina narrows and the introitus contracts.  The vaginal surfaces becomes thin, dry, and sensitive.  Urinary urgency and incontinence are often a result of loss of normal hormonal support of the urinary tract.

Hormone replacement is the best treatment for menopausal symptoms and VVA but the Women’s Health Initiative started in 1991 associated an increased incidence of breast cancer with the oral hormone replacement PremPro (estrogen and medroxyprogesterone), placing post-menopausal women in a quandary – risk breast cancer or enjoy a normal premenopausal lifestyle. The media and many physicians assumed this study included ALL hormones, but the only hormone replacements studied were the oral medications PremPro and Premarin (estrogen only).   The study actually found that oral estrogen alone didn’t cause any increased risk for breast cancer.  These same studies indicated that estrogen alone may even reduce risk for breast cancer. The media didn’t bother to differentiate PremPro from Premarin leaving many women and physicians thinking all hormone therapy caused cancer.  The WHI published results can be found at https://www.nhlbi.nih.gov/whi/whi_faq.htm

A brief summary of the WHI findings on estrogen plus progesterone and estrogen only:

Compared with the placebo, estrogen plus progestin resulted in:

  • Increased risk of heart attack
  • Increased risk of stroke
  • Increased risk of blood clots
  • Increased risk of breast cancer
  • Reduced risk of colorectal cancer
  • Fewer fractures
  • No protection against mild cognitive impairment and increased risk of dementia (study included only women 65 and older)

Compared with the placebo, estrogen alone resulted in:

  • No difference in risk for heart attack
  • Increased risk of stroke
  • Increased risk of blood clots
  • Uncertain effect for breast cancer
  • No difference in risk for colorectal cancer
  • Reduced risk of fracture

Clearly the use of oral hormones with or without progesterone is not advisable.  The life time incidence of breast cancer increased 5% and stroke and blood clots increased for those using oral PremPro (estrogen and medroxyprogesterone) and Premarin based on WHI data. 

Breast cancer risk is influenced by many factors.  Estrogen with Progesterone is not the only contributor to increased breast cancer risk, it is actually a minor contributor. Compared to women who don't drink at all, women who have three alcoholic drinks per week have a 15% higher risk of breast cancer. Experts estimate that the risk of breast cancer goes up another 10% for each additional drink women regularly have each day.  For women who have never had breast cancer, a daily glass of wine increases breast cancer risk by 55% and the risk for dying from breast cancer by 20%.  These numbers are from studies published in the November 2011 issue of the American Journal of Epidemiology (http://aje.oxfordjournals.org/content/174/9/1044.full.pdf+html) that looked at more than 320,000 people and the November 2, 2011 issue of the Journal of the American Medical Association (http://jama.jamanetwork.com/article.aspx?articleid=1104569) that looked at more than 105,000 women enrolled in the Nurses’ Health Study.  Regular drinking — even as little as two or three drinks a week — raises breast cancer risk significantly more than that of PremPro. 

Any increased risk for breast cancer is not acceptable.  Menopausal symptoms can be treated and breast cancer risk can be reduced with the proper hormone balance and minor life style changes.  Recent research has shown that the use of estrogen and testosterone does not increase, but may decrease the incidence of breast cancer.  The use of hormone replacement, estrogen only and that including testosterone has been shown to reduce the risk of breast cancer in a number of studies done over the past 10 years, a few of which I have included here.  The use of progesterone, which is the hormone most associated with increased breast cancer risk should be minimized and used only as needed to decrease the incidence of endometrial (uterine) overstimulation and vaginal bleeding. 

Briefly:

1.     Initial studies by the NIH in 2009 “Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk.”  http://breast-cancer-research.com/content/11/5/212.

2.     The addition of testosterone to conventional hormone therapy for post-menopausal women does not increase and may indeed reduce the hormone therapy associated breast cancer risk- thereby returning the incidence to that of the normal untreated population.  Menopause, Vol. 11, No 5, 2004. http://www.htcapractitioner.com/wordpress/wp-content/uploads/2015/07/Dimitrakakis-04-Breast-cancer-incidence-in-postmenopausal-women-using-testosterone-in-addition-to-usual-hormone-therapy1.pdf

3.     Testosterone inhibits the stimulatory action of estradiol in normal human breast tissue in explant cultures.  Journal of Clinical Endocrinology and Metabolism 2012;97:E1116-27.

4.     Testosterone is breast protective and does not increase the risk of breast cancer.  Hickey TE, Robinson JLL, Carroll JS, Molecular Endocrinology 2012;26:1252-67. 

http://www.ncbi.nlm.nih.gov/pubmed/22745190

5.     Testosterone therapy in women: Myths and Misconceptions, https://dx.doi.org/10.1016/j.maturitas.2013.01.003.

6.     Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study.  NIH. http://dx.doi.org/10.1016/j.maturitas.2013.08.002.

7.     Management of Menopausal Symptoms, Obstet Gynecol 2015;126:859-76. Women’s Health Initiative hormone therapy trials: absolute risks (cases per 10,000 person years) shows that the incidence of invasive breast cancer decreased on estrogen alone as compared to placebo.  The original reference was to the article in JAMA 2013;310:1353-68.  http://jama.jamanetwork.com/article.aspx?articleid=1745676

 

Finally, the risk of breast cancer is decreased with a diet high in or supplemented with folate.  The risk of breast cancer is significantly increased with alcohol intake. This increase may be reduced with folate supplementation.  

1.     Research in 2004 showed that ensuring adequate folate intake seems particularly important for women at higher risk of breast cancer because of alcohol consumption. http://www.ncbi.nlm.nih.gov/pubmed/16103452

2.     Research in 2005 showed no clear support for an overall relationship between folate intake or blood folate levels and breast cancer risk was found. Adequate folate intake may reduce the increased risk of breast cancer that has been associated with moderate or high alcohol consumption. http://jnci.oxfordjournals.org/content/99/1/64.abstract

 3.     Research in 2014 showed that folate may have preventive effects against breast cancer risk, especially for those with higher alcohol consumption level; however, the dose and timing are critical and more studies are warranted to further elucidate the questions. http://www.nature.com/bjc/journal/v110/n9/full/bjc2014155a.html

In summary a balance between estrogen, testosterone, and progesterone can safely be used to treat menopausal symptoms and avoid the life style changes associated with VVA.  Furthermore significant reduction in breast cancer risk can be achieved by adding testosterone to usual hormone replacement, limiting alcohol intake, and having adequate folate levels either by supplement or by diet.

 

 

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