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Hormone Replacement Therapy in Women
Assessment and Plan: Hormone Replacement Therapy in Women
Women opting to have hormone therapy prescribed to them must understand the risks and benefits of hormone therapy.
The Women’s Health Initiative (WHI) trial (1) which treated post-menopausal women with conjugated estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day, or placebo was discontinued after 5.2 years.
Higher rates of stroke, heart attack, breast cancer, deep venous thrombosis and pulmonary embolism were noted to be associated with use of estrogen and progestin compared to placebo.
Those over 65 years of age on hormones experienced less fractures, lower risk of endometrial cancer, and lower risk of colon cancer.
There was no improvement in cognitive impairment, and there was an increase in risk of dementia in women 65 years of age or older. Estrogen alone increased the risk of stroke, deep venous thrombosis and pulmonary embolism, but did not change the risk of a heart attack and colorectal cancer compared to placebo.
The effect of estrogen alone on breast cancer risk was unknown, but estrogen alone reduced the risk of having a fracture
Hormone therapy started earlier in menopause at least by the age of 60 may result in a lower risk of adverse outcomes as opposed to starting it after the age of 60 (2).
Salpeter, SR et al reported in a meta-analysis that (17):
Hormone therapy lowered the risk of cardiac events in women less than 10 years from menopause or age under 60, but women who were older did not have this benefit.
There was an increase in cardiac events in older women during the first year, but then a lower risk of cardiac events was seen after 2 years.
A separate meta-analysis by Salpeter, SR found that women on hormone replacement therapy under age 60 had a lower mortality, but did not affect mortality in women over age 60 (18).
Hormone replacement therapy and endometrial cancer: After over 13 years of follow-up since the WHI started, it was found that endometrial cancer risk was lowered by 35%. (10).
U.S. Food and Drug Administration (FDA) stated indications on hormone replacement therapy include (3):
Treatment of vasomotor symptoms such as hot flashes and vaginal or vulvar atrophy, but not solely for the prevention of heart disease or osteoporosis.
Hormonal therapy is to be used at the lowest dosage able to control symptoms for the shortest period of time.
Hormonal therapy may be considered in women with osteoporosis unable to take other non-hormonal osteoporosis medications.
FDA approved hormone therapy products available at retail pharmacies may be more safe than non-FDA approved or compounded hormones. Non-FDA approved hormones may not have strict oversight to ensure standardized or consistent doses of hormones. These products are mentioned in the main report.
Contraindications for the use of hormone replacement therapy (12):
Abnormal bleeding of the genital area.
Patients with breast cancer in the past or present.
Suspected breast cancer, neoplasia suspected or known to be related to estrogen.
Present or past pulmonary embolism or deep venous thrombosis.
Myocardial infarction or stroke currently or within the past year, liver disease or elevated liver function tests.
Allergy to any ingredients.
Current or possible pregnancy.
Adverse effects of hormone replacement therapy: Uterine cancer , breast cancer, ovarian cancer, stroke, myocardial infarction, pulmonary embolism, deep venous thrombosis, dementia, gallbladder problems, painful breasts, abnormal mammogram, abnormal vaginal bleeding, loss of hair, abdominal pain, nausea, and vomiting (3). Avoid exposure of estrogen to children and pets as breast and nipple enlargement has been reported.
Recommendations of the U.S. Preventive Services Task Force (USPSTF) for Menopausal Hormone Therapy (4,5):
It is against the recommendation of the USPSTF to treat postmenopausal women with combinations of estrogen and progestin for the prevention of chronic illnesses in postmenopausal women.
The USPSTF advises against the use of estrogen in postmenopausal women with hysterectomy for prevention of chronic illness.
The USPSTF stated that hormone therapy used in postmenopausal women may lower the risk of fractures but increases the risk for stroke, blood clots, gallbladder problems, and may result in urinary incontinence. The USPSTF also states that estrogen used alone may decrease the risk of breast cancer, but combination estrogen and progestin has been found to increase the risk of breast cancer and likely dementia.
Bio-identical hormones:
According to the U.S. Food and Drug Administration (FDA), the term “bio-identical” may be used to falsely promote hormones as safe because they are sourced from plants or identical to that produced in the human body. In fact as of 2010, the FDA stated that the term “bio-identical” was not recognized by the FDA as a medical term.
Many have been persuaded by marketing to believe that phytoestrogens are different than the estrogens contained in other sources.
The standpoint of the FDA is that regardless of where the hormones are derived, the benefits and risks are similar.
The FDA has approved hormone products with defined dosages which are formulated and manufactured under a high standard.
The FDA has warned that “bio-identical” hormones from compounding pharmacies have a higher degree of risk because they not monitored by the FDA strictly to ensure that these formulations are safe or effective.
The FDA has not approved any medication or formula containing the hormone estriol due to unknown safety or effectiveness. (6) Consumers and healthcare providers may educated by being directed to the link: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm049311.htm
Estradiol levels were found to be significantly lower in compounded estradiol creams compared to the patch, but progesterone serum levels were found to be comparable in both compounded and conventional forms of oral progesterone (8).
According to Holtorf, women taking progesterone as part of their hormone replacement expressed a greater satisfaction, may have less risk of breast cancer and may avoid negative heart disease related events compared to synthetic progestins. (19)
Both Bio-identical hormones with combinations of estrogen, progesterone, dehydroepiandrosterone (DHEA), and testosterone as well as FDA approved estrogen replacement have all been found to be associated with endometrial cancer shown in multiple case reports.
Conjugated horse estrogen such as Premarin was noted to be associated with a higher risk of venous thrombosis and a non-statistically significant greater risk of heart attack compared to estradiol. The conjugated horse estrogen did not increase the risk of stroke, but was noted to lead to higher measurements of clot promoting substances in the blood. Further research is needed to confirm these findings. (9)
Preventive Health Advisor recommends the use of FDA approved plant-sourced estradiol and progesterone products derived from yams or soy instead of conjugated estrogens sourced from horse urine. An example of these products include the oral medication Estrace, from Bristol-Myers Squibb, Vivelle or Estraderm from Novartis Pharmaceuticals, and Climara from Berlex Laboratories. Micronized progesterone (Prometrium) is “bioidentical.”
Should estrogen be taken by patch or a pill?: Goodman, MP performed a review of the available research between 1990 and 2010 including comparisons between oral and transdermal estrogen delivery. The author noted the following findings to support transdermal delivery over oral pills as the superior method (13,14):
Dose comparison of transdermal estrogen and oral estrogen: A daily 50 mcg transdermal estradiol patch is approximately equivalent to Premarin at a dose of 0.625 mg daily.
Transdermal estrogen may have less effect on lowering amount of free testosterone compared to the oral form.
Transdermal estrogen might lower risk of weight gain and metabolic syndrome than oral estrogen.
Transdermal estrogen may result in less production of inflammatory and pro-coagulant proteins by the liver compared to oral formulation.
Transdermal estrogen does not require metabolism by the liver and results in more stable estrogen levels than oral estrogen.
Should estrogen alone or estrogen plus progesterone be used for hormone replacement therapy?:
Estrogen plus progesterone therapy is prescribed for women with a uterus.
Progesterone is used to oppose the estrogen to reduce the risk of endometrial hyperplasia and endometrial cancer. For women without a uterus, estrogen only therapy is used.
The benefits of combination estrogen and progesterone hormone therapy started early during the course of menopause or in cases of premature menopause, include a lower risk of cardiovascular disease, mortality, bone density loss, and possibly dementia. However, the risk of breast cancer increases after continuing hormone therapy after 3-5 years, and therefore it should not be used for more than up to 5 years. (14)
The KEEPS study (15), followed 729 women early in menopause, 45 to 54 years of age for 4 years using either placebo, 0.45 mg of low dose oral conjugated estrogen or 50 mcg of transdermal estrogen plus a cycle of progesterone each month.
The study did not find any increase in risk of deep venous thrombosis, pulmonary embolism, cardiovascular disease, stroke, transient ischemic attack, breast cancer, or endometrial cancer.
The hormone therapy did not significantly affect atherosclerotic change determined by measuring carotid intimal thickness.
Weight gain and hormone replacement therapy: Hormone replacement therapy is believed by many women to lead to weight gain. On the contrary, a study showed that less accumulation of body fat occurred during menopause in women on hormone replacement therapy for 5 years (16).
Patient education: The U.S. Department of Health and Human Services of the National Institutes of Health produced the following information for consumers to review when deciding whether to take menopausal hormone replacement therapy available at the link: http://www.nhlbi.nih.gov/health/women/pht_facts.pdf
Use of androgens in hormonal therapy: Similar to the reduction in estrogen and progesterone production seen in aging women, Haring, R et al found a progressive decline of androstenedione and testosterone levels in women as they age (25). The authors found that total testosterone decreased by 32%, the free testosterone decreased by 43%, and androstenedione decreased by 70% when comparing the third to the eighth decade of life (25).
Testosterone use in pre and post-menopausal women:
The FDA has not approved any testosterone products for use in women, but it is used off-label in the form of creams, implanted pellets, patches, troches, injections, and is sometimes compounded by pharmacies.
Braunstein described the following views of the Endocrine Society and the North American Menopause Society regarding the use of testosterone in menopausal women (20):
Both organizations concur that measuring free or total testosterone levels are inaccurate, and there is no correlation established between testosterone levels and sexual performance.
Both societies recognize testosterone to be low in oophorectomy, adrenal insufficiency, hypoactive pituitary gland, therapy with glucocorticoids, oral estrogen, and in chronic disease.
Sexual function is restored when testosterone is used with estrogen following oophorectomy.
The North American Menopause Society expressed that whether testosterone is taken by pill or otherwise, the research available shows improvement in sexual desire when added to postmenopausal estrogen therapy.
The Endocrine Society Clinical Practice Guidelines advise against routine use of testosterone by post-menopausal women because it is an insufficient indication and cited a lack of safety data with long term use.
Testosterone use in pre-menopausal women: Currently there is no medical authority which recommends the routine use of testosterone in pre-menopausal women. Further research is needed to ensure safety and beneficial outcomes of testosterone used in this population.
There is some evidence that testosterone therapy may help symtpoms, but it is not recommended. Testosterone therapy for 2 years without estrogen at an average dose of 121 mg in the form of an implanted pellet improved symptoms as measured by the Health Related Quality of Life Menopause Rating Scale in the majority of menopausal and pre-menopausal patients (22).
Testosterone safety:
Testosterone has been determined to have adverse effects on mainly the skin such as hirsuitism (undesirable hair growth in women) and acne when taken for under 6 months (20).
When taken for over 6 months the long term safety is unknown.
Some of the research shows positive improvements in bone mass (mild), cognitive ability, body composition, and heart disease but more research is needed (21).
Dehydroepiandrosterone (DHEA) use in women:
DHEA is not recommended as supplement for treatment of pre or post-menopausal symptoms due to a lack of research on safety, poor efficacy, and unknown long term effects.
A 3 month, randomized double-blind placebo controlled study evaluated the use of 50 mg of DHEA or placebo taken by 60 peri-menopausal women with changes in mood and generally not feeling well (23):
DHEA levels increased by 242%.
Testosterone increased by 94.8%.
Cortisol decreased by 13.2%.
HDL cholesterol decreased by 10.1%.
Lipoprotein A decreased by 18.1%, but was not far different than placebo.
Notable improvement was not seen in mood, sexual function, recall, sadness, and overall wellness.
In a study, DHEA products were tested for the amount of active ingredient, and out of 45 DHEA products, there was found to be a wide variability of active DHEA present between the range of 0 to 109.5% of the stated amounts (24).
Androstenedione supplement use in women is not recommended.
Kicman, AT et al found that a single 100 mg dose of androstenedione increased testosterone concentrations in women significantly to beyond normal range (26).
The risks of both short and long term use of androstenedione by women clearly outweigh the benefits.
The adverse effects of androstenedione are similar to testosterone.
These adverse effects include hirsuitism (undesirable hair growth in women) and acne (20).
