LINDA FRENCH, MD East Lansing, Michigan From the Department of Family Practice, Michigan State University, East Lansing. The author reports no competing interests. Reprint requests should be addressed to Linda French, MD, Associate Professor, Department of Family Practice, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu. (J Fam Pract 2002; 51:271-276)
In a meta-analysis43 including 26 RCTs of the effects of hormone replacement therapy (HRT) on depressed mood, estrogen showed limited effectiveness in improving mood. The addition of synthetic progestins reduced the estrogen effect. More recent short trials of unopposed transdermal estrogen showed benefit.44,45 Other reviews46,47 have concluded that ERT or HRT has little effect in the treatment of psychological symptoms, including anxiety, cognitive, and affective symptoms. As an adjuvant to psychotropic therapy, it may have limited effect. There is insufficient evidence to support prophylactic ERT or HRT to prevent depression in women whose medical history includes prior postpartum depression.47 Estrogens do not affect the ability of a woman with moderate to severe vasomotor symptoms to cope with stress.48 Clinical trials reporting the effects of testosterone treatment on mood in women were not identified.
Women with mild psychological and predominantly vasomotor symptoms may benefit from a trial of HRT before psychotropic medication. For women who meet criteria for a diagnosis of major depression, initial treatment with an antidepressant alone or concurrent with HRT is advisable.
Sleep disturbance
In a survey of more than 6000 women aged 40 to 64 years, 30% of HRT users reported sleep improvement that they attributed to therapy.49 Other standard approaches to insomnia, such as sleep hygiene measures and progressive relaxation techniques, can also be used. If sleep apnea is suspected, a sleep study may be indicated.
Sexual dysfunction
In a systematic review50 of HRT for climacteric sexual dysfunction, vaginal dryness improved with ERT in 7 of 8 studies. Dyspareunia improved in only 1 of 6 studies using transdermal 17-beta-estradiol. Orgasm increased in only 1 of 5 trials using ethinyl estradiol. Sexual interest increased in none of 7 studies that used conjugated estrogens. However, taking testosterone appeared to increase sexual interest. The evidence regarding the safety and efficacy of androgens (testosterone and dehydroepiandrosterone [DHEA]) for the treatment of sexual dysfunction in perimenopause is incomplete; therefore, these drugs should not routinely be prescribed.51
Bone
Although HRT prevents the rapid bone loss observed in the early menopausal period, this effect is lost when treatment is stopped. The positive effect of estrogen alone on bone mineral density was not diminished by medroxyprogesterone acetate (MPA) or micronized progesterone over a 3-year follow-up period.52 The long-term effects of MPA on fracture risk in postmenopausal women have not been reported. Use of transdermal progesterone alone does not prevent bone loss.38
Cancer
Estrogen alone for women with an intact uterus is currently considered unacceptable because adding the hormone poses endometrial cancer risk. An exception is low-dose estrogen administered intravaginally; this method does not alter the endometrium.53
Estrogen alone or in combination with progestins has been associated with an increased risk of breast cancer in many observational studies and meta-analyses. A comprehensive reanalysis54 of 51 mostly observational studies, including 52,705 cases of breast cancer and more than 100,000 controls, examined the association of breast cancer with HRT, predominantly unopposed estrogen. These authors concluded that there is an increase in incidence of breast cancer of 0.2%, 0.6%. and 1.2% with 5, 10, and 15 years of use, respectively. Thus, 1 additional case of breast cancer occurs for every 167 women treated for 10 years (number needed to harm [NNH] = 167). Two recent observational studies have documented up to a fourfold increase in breast cancer with estrogen plus progesterone over estrogen alone.55,56
Cardiovascular disease
HRT has been widely advocated for prevention of coronary artery disease (CAD), based on many observational studies. A meta-analysis57 of 25 studies published through 1997 gave a relative risk (RR) of 0.7 (CI 0.65-0.75) for coronary events in women using HRT. However, a consistent bias in these studies of selecting healthy, compliant women for inclusion may explain the observed benefit.
A meta-analysis58 of 22 trials of 4124 women comparing HRT with placebo, no therapy, or vitamins, in which cardiovascular events were secondary endpoints, revealed that there was no benefit regarding cardiac events and there were small increases in absolute risk of stroke and venous thromboembolism (VET). In the Heart and Estrogen/Progestin Replacement (HERS) study,59 conjugated equine estrogens (CEE) plus MPA, administered to women with established CAD for a mean of 4.1 years, did not reduce risk of cardiovascular events. An increase in events, particularly VET and stroke,60 occurred in the first year of use. Small increases in the absolute risks of stroke61,62 and VTE63,64 have also been described in observational studies.
Randomized trial evidence is currently lacking for a role of HRT in the primary prevention of cardiovascular disease. A large study of low-risk postmenopausal women, the Women’s Health Initiative,65 is currently under way. Its objective is to investigate strategies for the prevention and control of some of the most common causes of morbidity and mortality in postmenopausal women. The study includes 27,000 women randomized to CEE plus MPA or placebo. Results are expected in 2007. The American Heart Association now recommends against estrogen therapy with or without progestin solely for the prevention of heart disease.66 Long-term effects of androgens on cardiovascular risk have not been studied; concerns exist about their use.51
