Update: Weighing the Merits of Hormone Replacement

In the wake of the Women's Health Initiative's sobering new findings, what are the true indications for hormone replacement, and how does the clinician accurately assess for those indications? The authors address these questions and provide a menu of choices for designing a hormone replacement regimen—which, now more than ever, is a highly individual matter.

By Sophia Ouhilal, MD and Nanette Santoro, MD

Health management during menopause and the postmenopausal years is a rapidly evolving field and a major focus for women and clinicians. The recent, much-publicized findings of the Women's Health Initiative have resulted in a need to reassess the merits of hormone replacement. Many clinicians are left confused about the optimal way to manage menopausal patients. Currently, the median age of menopause is 51.3 years and the average life expectancy for a woman is 79.7 years, so the postmenopausal years generally represent about one-third of a woman's life span.

By 2030, 17% of the population in the United States will be 65 years of age or older. With this growing postmenopausal population, health care providers have to provide more counseling regarding hormone replacement therapy (HRT). Topics such as osteoporosis, cardiovascular disease, and breast cancer are central to a discussion of this subject. It is the goal of this article to provide a review of the issues related to HRT and offer an approach to management given the most recent data available.

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MENOPAUSE: WHAT HAPPENS AND WHEN

Menopause is defined as the cessation of menstruation following the loss of ovarian function. It is typically preceded by a series of clinical changes, including menstrual irregularities, collectively referred to as the perimenopause. As women age, there is an accelerated loss of their remaining follicle pool. As a consequence, the hormone inhibin progressively declines, and this in turn contributes to a rise in follicle-stimulating hormone (FSH). The ovaries also become progressively less responsive to gonadotropins—FSH and luteinizing hormone (LH) secreted by the anterior pituitary—as the number of primordial follicles approaches zero. Eventually, the primordial follicles are completely depleted and follicle development stops. In the absence of folliculogenesis and ovulation, estrogen production comes to a halt, resulting in the final cessation of menses and the onset of menopause.

For half of all women, the perimenopause will happen between ages 45 and 50. The mean age of natural menopause is 50 to 51. Smoking, family history, very low body mass index, and chronically compromised ovarian blood flow from repeated infections or surgeries may lead to an earlier onset of menopause. It occurs prematurely (defined as before age 40) in 1% to 2% of the population. Menopause may be induced at any age either surgically (after bilateral oophorectomy) or medically (after chemotherapy or radiation therapy).

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APPROACH TO THE PATIENT OF MENOPAUSAL AGE

There are several aspects of general and reproductive health that should be addressed in history-taking with the female patient who may be peri- or postmenopausal (see below for the key questions to ask).

Physical examination should include measurement of blood pressure, weight, and height. A breast examination should also be performed. The gynecological exam should start with an inspection of the external genital organs. Manifestations of urogenital aging include a thinner, smoother, and smaller vagina; pale and sometimes friable mucosa; reduced cervical mucus; and signs of atrophy in the labia minora. The urethral meatus may be thinned and retracted and pelvic organ prolapse may be observed. Annual cervical cytology should be considered, with care taken to sample both the exocervix with the spatula and the endocervix with a cytobrush. An annual bimanual examination should be performed to assess the uterus and ovaries.

Tests that help to determine menopausal status include measurement of FSH, LH, and estradiol. Typically, in menopausal patients, both FSH and LH levels are significantly increased. Concentrations of FSH are more consistently elevated than LH levels, with a ratio of FSH to LH almost always greater than 1. In a study assessing 72 postmenopausal women, FSH concentration was 132.4 +-5.6 mIU/ml and LH 93.8+/-5.4 mIU/ml. Estradiol concentrations are expected to be low in postmenopausal women, averaging 13 pg/ml, but may vary considerably within the first year after the final menstrual period. These measurements may be obtained as supporting evidence, but usually are not needed if a woman is at least 45 years old and has symptoms consistent with menopause. In fact, with patients who are still menstruating, FSH and LH are not very helpful at all because they can fluctuate so widely during the perimenopausal transition. A single result that falls outside the range that is normal for women of reproductive age cannot be relied upon to forecast cessation of menses.

Finally, a baseline bone osteodensitometry may be warranted. As yet there is no clear consensus as to the optimal role of screening bone osteodensitometry in women, but we recommend that it be done when the patient has risk factors for osteoporosis or is undecided about whether or not to take HRT.

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ASSESSING INDICATIONS, RISKS, AND BENEFITS

Once the clinician determines that menopause is definitely or very probably under way, a thorough evaluation of risks and benefits should be performed. Does the patient have an interest in initiating HRT and if so, why? What are her concerns? Does she have bothersome menopausal symptoms? Is she at risk for osteoporosis, cardiovascular disease, or breast cancer? Are there lifestyle modifications such as smoking cessation, exercise, and diet (including calcium intake) that should be addressed? With the answers to these questions in mind, the practitioner must then make a careful presentation of possible indications, contraindications (see table below, left), side effects (see table below, right), and alternatives for HRT, and identify an optimal HRT regimen should the patient decide in favor of it.

Menopausal symptoms. The vasomotor symptoms commonly termed "hot flushes" are one of the most bothersome and prevalent problems reported by menopausal patients. In the first three months of menopause, these symptoms may affect up to 70% of women. More than 80% of women who have hot flushes will experience them for more than a year. With time, the frequency and intensity decrease, but they persist for five years after menopause in 35% of women. Nocturnal hot flushes are also frequently associated with sleep deprivation and fatigue. The exact etiology of the flush is still unclear, but it seems to represent an alteration in central thermoregulatory function. What is certain is that estrogen therapy relieves this symptom.

Urogenital atrophy, caused by the combination of low estrogen and aging tissue, is another frequent concern for menopausal women. Common symptoms include decreased lubrication, dyspareunia, postcoital bleeding, dysuria, urinary frequency or urgency, and pelvic organ prolapse. Urogenital atrophy and dyspareunia may also affect sexuality. While HRT will clearly relieve vaginal dryness and atrophy, its benefits are uncertain for urinary symptoms. A trial of local estrogen therapy may be attempted after a careful risk-benefit assessment with the patient. Adding a progestin may be warranted in women with a uterus to protect against endometrial hyperplasia.

Osteoporosis. Osteoporosis is a major source of morbidity and mortality, affecting more than 25% of Americans, 80% of whom are women. One in ten patients with hip fractures will die in the following year, and of the remainder only half will regain their prior autonomy. Osteoporosis prevention is a well-established indication for estrogen replacement therapy. The WHI study showed that women taking combined estrogen and progestin therapy had a decreased risk of hip fracture (0.66 [95% CI 0.45-0.98]). Estrogen prevents bone resorption and decreases bone loss by inhibiting osteoclast activity. The greatest effect on bone mineral density occurs when HRT is started soon after menopause, but a positive impact is seen even when it is started much later.

Proven alternatives to HRT for this indication are bisphosphonates such as alendronate and etidronate. Selective estrogen reuptake modulators (SERMs) are another possible choice that may offer bone and breast cancer protection without promoting endometrial hyperplasia, but they provide no relief for vasomotor symptoms.

Cardiovascular disease. The role of HRT in cardiovascular disease was increasingly controversial until the WHI results. Estrogen's positive cardiovascular effects were attributed to favorable adjustments in lipid and lipoprotein levels, coronary artery vasodilation, and reduction of atherosclerosis. However, estrogen may also raise triglyceride levels and exert prothrombic or proinflammatory effects.

In order to better understand the latest data on HRT and cardiovascular health, a historical perspective may be useful. Prior to the late 1990s, numerous observational studies including the Nurses Health Study and the Walnut Creek Study documented a 40% to 50% reduction in coronary heart disease risk in women using HRT. These were followed by several prospective trials. The PEPI (Postmenopausal Estrogen/Progestin Interventions) trial, a double-blind, randomized multicenter study comparing estrogen alone with cyclical and continuous combined estrogen-progestin treatment, showed a favorable impact of estrogen on cardiovascular risk factors.

The HERS (Heart and Estrogen/Progestin Replacement Study) was a prospective, randomized, double-blind placebo-controlled trial examining the impact of continuous combined HRT in women with pre-existing heart disease. The purpose was to evaluate the benefits of HRT in a population at extremely high risk for cardiovascular events. Surprisingly, the investigators found a significant increase in adverse cardiovascular events in the first year of hormone use, and no overall benefit after four years of follow-up. Other recent studies have confirmed the results of the HERS trial. Investigators from the University of Washington evaluated patients with myocardial infarction events in a case-control study and found that for current users of estrogen, the longer the duration of use the greater the benefit. A second look at data from the Nurses Health Study, a cohort study of secondary prevention of coronary heart disease, revealed an early risk of adverse coronary events resembling that of the HERS trial that decreased as use continued.

On July 17, 2002, the Women's Health Initiative (WHI) study evaluating combined estrogen and progestin use in postmenopausal women was halted after an average follow-up of 5.2 years. The study's safety monitoring board concluded that the risks of combined HRT use outweighed the benefits in this population. This trial arm, sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health, looked at the effects of combined HRT use in healthy postmenopausal women with a uterus and is the first randomized primary prevention trial of postmenopausal hormones. The trial was stopped mainly because of a true increased risk for cardiovascular disease and breast cancer for women taking combined estrogen and progestin.

Specifically, the investigators found a relative breast cancer risk of 1.26 [95% confidence interval (CI) 1.00-1.59], a relative coronary heart disease risk of 1.29 [CI 1.02-1.63], a relative stroke risk of 1.41 [CI 1.07-1.85], and a relative pulmonary embolism risk of 2.13 [CI 1.39-3.25]. What that meant for individual women was seven more coronary heart disease events, eight more strokes and eight more pulmonary emboli per 10,000 women taking combined estrogen and progestin. These surprising results, published in JAMA in July, clearly indicate that estrogen-progestin should not be initiated or continued for primary prevention of coronary heart disease. Women at risk for cardiovascular disease who decide to discontinue combined estrogen-progestin treatment can consider alternatives such as statin therapy and lifestyle modifications such as exercise and smoking cessation. Key points to communicate to patients about the findings are listed in the box below.

Breast cancer. The WHI found a true increased risk for breast cancer in women taking combined estrogen and progestin after 5.2 years of follow-up. The magnitude of the actual risk was small for individual women: eight additional cases of breast cancer per 10,000 women. This increased risk was not reported in women with prior hysterectomy taking estrogen only. It is also important to note that this increased risk of breast cancer did not appear during the first four years of estrogen and progestin use. This confirms what was suspected by many observational studies reporting a small increase in breast cancer risk after five to ten years but none on a short-term basis. All patients on HRT should be made aware of this small but significant risk.

The Gail model, which can be used in the office while counseling the patient, has been regarded as a helpful tool for individual risk estimates. However, in the WHI trial, Gail model risk assessment scores were poorly predictive of the subsequent development of breast cancer.

Endometrial cancer. With unopposed estrogen, there is a two- to tenfold increase in endometrial cancer risk. This risk increases with the duration of use, the dose of estrogen, and the age of the patient. To counter this risk, a progestin should be added for 12 to 14 days per month in all women with a uterus.

Colorectal cancer. The WHI study found that women taking combined estrogen and progestin had a decreased risk of colorectal cancer (0.63 [95% CI 0.43-0.92]).

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CHOOSING A REGIMEN FOR HRT

Estrone and estradiol are the biologically active "in vivo" estrogens but are difficult to absorb when given orally. To improve their bioavailability, they may be conjugated. They are then presented as sodium sulfates or stabilized by adding piperazine or an ester group. They can also be micronized. This process results in the formation of tiny particles that are more easily absorbed.

Conjugated estrogens are a mixture of chemical, animal, or botanical products. Conjugated equine estrogens, derived from pregnant horse mare urine, also contain additional bioactive estrogens such as 17-dihidroequilin. Estropipate contains estrone solubilized by sulfate and stabilized by piperazine. Estradiol can be given parenterally, transdermally, or intravaginally. It has to be micronized in order to be absorbed per os. A transdermal administration will avoid a first passage in the liver. Estradiol is also available in a gel form.

The progestins used in HRT fall into two categories: progesterone or its metabolites (medroxyprogesterone acetate, medrogestone, and megestrol), and 19 nor-testosterone derivatives (norethinedrone and norethinedrone acetate).

Two novel regimens allow combined estrogen and progestin therapy in a single pill form. Prempro contains a combination of conjugated equine estrogens and medroxyprogesterone acetate. FemHRT is a combination of ethinyl estradiol and norethinedrone acetate. For details of other HRT preparations, see the tables below.

Selecting a regimen involves deciding on whether to use patch systems and whether to provide cyclical versus continuous combined therapy. Finding the right combination for each patient may require trying different approaches (see table below for examples). As a general rule, one should always offer combined estrogen-progestin therapy to protect the endometrium from hyperplasia and cancer, except in women who have already undergone a hysterectomy.

Cyclical treatment will result most often in monthly withdrawal bleeds, whereas continuous combined therapy usually leads to menses cessation. Four in ten patients on continuous regimens will experience bleeding during the first three to six months, but 95% will become amenorrheic within a year. The presence or absence of bleeding may influence patient and physician preference. Persistent abnormal bleeding should be evaluated. Although the most frequent cause is atrophy, endometrial hyperplasia and neoplasia may present as such and warrant further workup such as an endometrial biopsy. The use of the patch may depend on patient preference. Medical conditions such as liver disease or situations where first pass liver metabolism is to be avoided may also warrant the selection of the patch.

Up to 10% of women may develop side effects associated with HRT. Common estrogen-related complaints include breast tenderness, headaches, and nausea. These may diminish with time if the dosage is reduced (from 0.625 to 0.3 mg of Premarin, for example) or a different estrogen preparation is substituted. Starting below the recommended dose in women who have not been exposed to estrogen for many years may help circumvent some side effects. Complaints such as hot flushes, vaginal dryness, or spotting due to atrophy may signify a need to increase the estrogen dose (from 0.625 mg of Premarin to 0.9 mg, for example). In such a case, one should exert care in also increasing the progestin dose to properly protect the endometrium (5 mg of Provera for continuous regimens or 10 mg for cyclical regimens is usually sufficient). If the patient's symptoms persist, they may not be related to hypoestrogenism and may need to be further investigated. Often some tweaking of the regimen to maintain adequate estrogen levels over 24 hours is all that is needed. Use of a transdermal patch, twice-daily dosing, or simply nighttime dosing with attention to the timing of the daily dose may produce a better therapeutic response. For dosage equivalencies between oral and transdermal preparations, see table 5. When treating women with vasomotor symptoms, it is also important to allow estrogen to have its full effect, which can sometimes take weeks.

Progestin-related side effects include bloating, mood swings, and breast discomfort. Micronized progesterone (Prometrium) may have sedative effects and is best taken at bedtime. If the patient is on cyclical therapy, changing her to a continuous regimen may improve these symptoms. Alternatively, a different progestogen may be better tolerated (for example, switching from Provera to Prometrium or vice versa).

A management strategy that includes a thorough evaluation, an understanding of the issues at stake, and an ability to select an appropriate regimen will help optimize the health of menopausal women.

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