Each year, more than 1.3 million American women become menopausal in the U.S. The menopausal transition is marked by intense hormonal variability, and frequently accompanied by vasomotor symptoms (e.g., hot flashes, night sweats), sleep disturbance, and altered libido. In addition, as women become estrogen-deprived, they may also experience an increased risk for osteoporosis, cardiovascular disease, cognitive dysfunction, and depressive symptoms.

For many decades, women and health professionals were taught about the benefits and risks involving the use of hormone replacement therapy (HRT). Essentially, HRT had been administered to alleviate most of the physical symptoms associated with the menopausal transition (short-term HRT), and to help in preventing the clinical consequences of an estrogen-deficient state including osteoporosis and cardiovascular disease (long-term HRT). The list of potential benefits of short-term HRT was recently expanded with the results of two randomized placebo-controlled trials, in which the use of transdermal estradiol was shown to be efficacious for the treatment of perimenopausal women suffering from depression (including major depression). These preliminary but promising results strengthened an existing clinical impression that HRT could promote a greater “quality of life” and improve “psychological well-being”.

Despite the benefits observed with short-term use of HRT, there have been high expectations for the results of several large, prospective studies, which could provide us with more robust information on the risks and benefits of long-term HRT, whether used as a primary treatment or as a prophylactic intervention for osteoporosis, cardiovascular events, and dementia.

Some of these studies had their major findings published recently, causing both disappointment and apprehension. First, the results of the Heart and Estrogen/progestin Replacement Study (HERS), which included almost 3000 menopausal women with prior history of coronary heart disease (CHD), demonstrate that HRT had no overall effect (i.e., no protective impact) on CHD risk over time. Second, the Women’s Health Initiative Study (WHI), a multi-center, randomized, placebo-controlled primary prevention trial, designed to follow more than 16000 postmenopausal healthy women for 8 years, had to be stopped due to significant evidence of an increased risk for invasive breast cancer and cardiovascular events associated with the long-term use of HRT. Physicians and patients felt betrayed and, as a first reaction, many have decided to simply discontinue their HRT regimens abruptly. Others aren’t likely to abandon their prescription hormones, but are questioning their alternatives. Most women and their doctors are now facing a difficult dilemma: how to deal with their menopause-related physical and emotional symptoms? Some of them, of note, precipitated by the abrupt HRT discontinuation…

The results from the HERS and WHI studies should be carefully interpreted. The benefits and safety of long-term use of the specific HRT preparation employed in both studies (conjugated estrogens and medroxiprogesterone – the most widely used preparation in the U.S.) have been indubitably questioned. There may be safer alternatives available to help prevent cardiovascular disease and osteoporosis, such as the selective estrogen receptor modulators (SERMs) and diet supplementation. On the other hand, we should consider that:

Menopausal women who undergo an abrupt discontinuation of HRT may experience the occurrence or reemergence of intense somatic symptoms (as observed, for instance, among those who undergo a surgical menopause), interfering significantly with their sleep pattern, physical well-being and most probably their mood. Those who opt for discontinuing HRT should do it gradually, with clinical monitoring. Clinicians should be aware of an increased risk for mood instability, anxiety, and insomnia during or right after this process.

The short-term use of HRT (up to 3 to 5 years) has not been considered unsafe, and is the most efficacious treatment for vasomotor symptoms (i.e., night sweats, hot flushes). Importantly, existing data suggest that perimenopausal women who report hot flushes and menopause-associated insomnia are more likely to develop depression. Thus, health professionals should encourage a more individualized approach to making this clinical decision and continuing research on the pros and cons of short-term HRT for symptomatic women.

The results of the WHI study did not find evidence that the use of estrogen alone could lead to the same risks observed with the combination of estrogen and progestin. Therefore, it is plausible to think that progestin may play an important role on the increased risk for CHD and breast cancer. More studies are needed in this area.

There are many HRT preparations available, including different types of estrogens (e.g., 17 b estradiol, ethinyl estradiol) and progestins (norethindrone acetate, micronized progesterone). However, the WHI and HERS studies have yielded data only on the use of conjugated estrogens and medroxiprogesterone; long-term data on the use of other HRT regimens are still sparse. As already seen with distinct classes of antidepressants, the use of different hormonal therapies result in significant differences in terms of absorption, metabolism, and bioavailability. It has been suggested, for example, that estradiol provides a positive effect on mood, and may offer a different overall risk-benefit profile, given its similarity to endogenous sex hormones. Therefore, some women may feel more comfortable switching to a different HRT combination, even if using HRT for a short period of time.

The use of alternative treatments is not necessarily safe. Some of the so-called “natural” treatments for menopausal symptoms have a significant binding affinity for estrogen receptors, so their use may result in similar risks. On the other hand, preliminary studies suggest that antidepressants including the SSRIs (paroxetine, sertraline, citalopram, fluoxetine) and the serotonin-norepinephrine reuptake inhibitors or SNRIs (venlafaxine) promote significant improvement of vasomotor symptoms, and may constitute an interesting alternative for menopausal women with hot flushes, even in the absence of depressive symptoms.

It appears that HRT still plays an important role in promoting well-being among menopausal women. It is now imperative to better delineate its clinical indications, and to learn more about risks and benefits associated with different hormonal preparations.

Cláudio N. Soares, M.D., Ph.D.

Soares C, Almeida O, Joffe H, Cohen L: Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001; 58(6): 529-34.

Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women – Principal Results From the Women’s Health Initiative Randomized Controlled Trial. JAMA 2002; 288(3): 321-333