Hormone Replacement Therapy and Menopause: An Overview

Simon Kipersztok, M.D.
Professor
Division of Reproductive Endocrinology and Infertility
Department of Obstetrics and Gynecology
University of Florida College of Medicine
Gainesville, Florida

Life expectancy for women has now surpassed 80 years of age while the mean age of menopause has remained at around 52 years ¹.  As a result, women will spend more than a third of their lives in a state of hypoestrogenism. Acutely, the lack of estrogen leads to disturbing symptoms. Hot flashes are experienced by up to 85% of postmenopausal women and may last for longer than 5 years in up to 25% of them².  Similarly, many post-menopausal women experience vaginal dryness and dyspareunia. Hormone Replacement Therapy (HRT)^* will usually alleviate these acute symptoms.  HRT can also decrease the incidence of cardiovascular events and reduce cardiac mortality by 35-60% mostly in long-term users³.   HRT can increase bone mineral density and decrease the risk of fracture due to osteoporosis^4,5.  HRT may also reduce the risk of developing Alzheimer’s disease. Other benefits include a lower incidence of and mortality from colorectal cancer ^6,7,8 and a decrease in the risk of macular degeneration , a common cause of blindness in postmenopausal women ⁹.  Lastly, HRT can prevent aging changes in the skin¹⁰ and decrease tooth loss.¹¹

Despite observations that HRT offers many benefits to menopausal women controversy still exists about whether the overall benefits outweigh the risks. The HERS study (Heart and Estrogen/progestin Replacement Study) showed that continuous use of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) when used for secondary prevention (after the occurrence of a previous cardiovascular event) could significantly increase the risk of a second cardiac event and also increase mortality. The adverse effect was present within 8 months from the administration of HRT but disappeared by 12 months of use and by year 4 and 5 of use it caused a 35% reduction in coronary events.¹² The study did not have an estrogen-only control group. Therefore, no conclusions could be drawn about the effects of estrogen without the progestin. Despite this and other methodological flaws the study has prompted some clinicians to avoid using HRT in women with established cardiovascular disease. It has also raised concerns about the effects that HRT may have when used for the primary prevention of cardiovascular disease. While not completely settled, it is certain that this issue will be revisited in the future when the results of 12 ongoing trials of women’s health that include heart disease as an endpoint are published.³

Breast cancer risk is another source of concern for clinicians and patients. In counseling patients regarding breast cancer it is important to consider the following points. The predominance of the accumulated data indicate that a slight increase in the risk of breast cancer is seen in some current users of HRT who have been on HRT for longer than 5 years. This observation could be the result of a detection and surveillance bias. HRT use for less than 5 years or past use has not been shown to increase the risk of breast cancer. A recent study has suggested that the addition of a progestin to estrogen in HRTmay have a very small incremental effect on increasing breast cancer risk.¹³ A positive family history should not, by itself, serve as a contraindication to the use of HRT. Mortality from breast cancer diagnosed in HRT users is decreased due to early surveillance and because the tumors that are detected are generally less virulent and aggressive.¹⁴ The following statement summarizes the view of the vast majority of authorities who study this issue: "…Any increase in risk, if it exists at all, must be too small or must occur in too limited a population, otherwise it would have been observed more consistently in most of the well-designed, well-conducted, epidemiological studies…"¹⁵

The best HRT formulation has not been determined. Clinicians and patients can choose from a large number of estrogens, progestins and combinations of both. One of the oldest available formulations is CEE (Premarin). CEE has been effective in controlling many of the symptoms of hypoestrogenism and has the ability to improve cardiovascular health and prevent bone fragility. Other oral estrogen formulations such as 17-beta estradiol (Estrace), estropipate (Ogen) and esterified estrogens (Estratab and others) have similar effects. Transdermal patches containing 17-beta estradiol (Climara, Vivelle and others) are an alternative to oral estrogens eliminating first pass liver effects. CEE is the most studied estrogen compound and is the formulation used in two major ongoing prospective, randomized prevention trials. The WHI (Women’s Health Initiative) will assess the effects of hormone therapy and diet on coronary heart disease, cerebrovascular events, breast and colorectal cancer and osteoporotic fractures in 64,500 American women between 50 and 79 years. The University of Florida is one of the 40 clinical sites assisting in the data collection. Results will be published after completion of the study in the year 2006. The European Women’s International Study of long-duration estrogen after menopause (WISDOM) will be completed in the year 2017.

There are some individual differences among the various estrogens in their ability to favorably affect the lipid profile. However, alterations in the lipid profile account for only approximately one third of the cardiovascular benefits afforded by estrogens. As much as two thirds of the protective effects may involve alterations in the coagulation factors and direct effects on the reactivity of the coronary vessels.³

The concurrent use of a progestin or, alternatively, close endometrial surveillance is mandatory in estrogen users who have a uterus because of the risk of endometrial hyperplasia. Progestins available in the U. S. include MPA (Provera, Amen and others), micronized progesterone (MP - Prometrium), megestrol acetate (Megace), norethindrone acetate (Aygestin and in FemHRT combined with ethinyl estradiol; also in CombiPatch with 17-beta-estradiol), and norgestimate (in Ortho-Prefest with estradiol). Progestins often cause side effects that decrease HRT compliance such as bleeding, bloating and depression. Like with estrogens, there is little data comparing individual progestins with one another. The PEPI trial compared MP with MPA with regards to potential effects on HDL. The study showed that in contrast to MPA, MP did not significantly attenuate the beneficial effect that CEE had in raising HDL.¹⁶ Often, patients may need to try more than one HRT formulation. Since compliance with HRT is so poor and given the large number of formulations available, for each individual it is important to find the one that maximizes benefit and at the same time minimizes risk, side effects and cost. For some women the addition of supplemental androgens (oral methyltestosterone with esterified estrogens [Estratest] or testosterone implants) may be beneficial for general well being and improved libido.¹⁷

Alternatives to HRT are available. Bisphosphonates are safe and effective in the prevention and treatment of osteopenia and osteoporosis. ¹⁸ Available oral formulations of bisphosphonates include etidronate (Didronel - not FDA approved), alendronate (Fosamax) and risedronate (Actonel).^{19 20}In a small number of patients bisphosphonates can cause upper gastrointestinal discomfort associated with esophageal irritation. Serious adverse gastrointestinal events were significantly less common when a cumulative, once weekly or twice weekly dose of alendronate was taken instead of a daily dose. Bone mineral density changes were no different in the groups with the 3 different dosing regimens over 12 months. ²¹A once weekly regimen of alendronate was recently FDA approved. The use of calcium and vitamin D alone can also decrease hip fractures. ²²

Raloxifene (Evista), a selective estrogen receptor modulator, can serve as an alternative for HRT in some women. It can significantly decrease the incidence of estrogen receptor positive breast cancers, cause some beneficial lipid profile changes however not to the same degree as estrogens and it significantly decreases the incidence of vertebral fractures but not of non-vertebral fractures. Unlike estrogen it does not relieve vasomotor symptoms or vaginal dryness but it does not cause abnormal uterine bleeding, increase risk of endometrial hyperplasia or mastalgia. Like estrogen, it can increase the risk of venous thromboembolism by about 3 fold.²³

Nasal calcitonin can also increase bone density and reduce vertebral ²⁴ and possibly hip fractures.²⁵ A unique advantage of calcitonin is an analgesic effect in the presence of vertebral fractures ²⁶. Calcitonin, like bisphosphonates and raloxifene, has no effect on the relief of hypoestrogenic vasomotor or genitourinary symptoms.

Alternative therapies such as herbal products, dietary soy and supplemental phytoestrogens have become very popular among menopausal women. The use of herbal products in the U.S. is at best controversial and at worse dangerous. The marketing of herbal products bypasses regulation by the Food and Drug Administration. Safety, efficacy and bioequivalency of different marketed formulations cannot be clearly determined under those circumstances. Phytoestrogens are plant-derived estrogens usually from soy products. Research in this area is active. Soy phytoestrogens can moderately reduce hot flashes, reduce LDL, increase the ability of coronary arteries to vasodilate, may have a small effect on the prevention of bone loss and may reduce the risk of breast and uterine cancer. Low dose estrogen has been advocated by itself as an alternative to traditional HRT²⁷ and it has been postulated that using low dose estrogen in conjunction with soy phytoestrogens may prove beneficial. Phytoestrogens would be agonistic in the cardiovascular, central nervous and perhaps skeletal systems and protective in other areas where estrogen can have an adverse effect such as the breast and the uterus. This approach could eliminate the need for a progestin, which often causes undesirable side effects.²⁸

In summary, HRT is a highly effective therapy for postmenopausal women with symptoms related to low estrogen levels. It can offer some long term benefits especially in the central nervous, cardiovascular and skeletal systems. HRT has the potential of increasing the incidence of breast cancer in long term users although the prognosis in affected patients is very good. Many adequately designed studies on HRT are ongoing and they will hopefully shed more light on the benefits and risks of this therapy. Until then HRT use must be individualized and thoroughly scrutinized by patients and their clinicians. Reasonable alternatives to HRT are available for some specific problems experienced by postmenopausal women. Alternative therapies are being studied and may become more mainstream. Among these the use of phytoestrogens in the diet or as supplements looks promising.

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