Alpha2-adrenergic receptor agonists
The alpha2-adrenergic receptor agonist clonidine has been used for treatment of hot flashes, but its efficacy has been modest at best in small trials of short duration (Table 1). The total daily doses used ranged from 0.5 mg to 1.5 mg, and side effects of dry mouth and dizziness were reported to cause relatively high discontinuation rates. While clonidine is an option, it should be reserved for patients who are intolerant of the other nonhormonal options discussed above.
Special considerations in breast cancer patients
Women with breast cancer merit special consideration, for several reasons. First, their cancer constitutes a contraindication to HT, so they are leading candidates for nonhormonal approaches to vasomotor symptom control. Second, chemotherapy itself may induce menopausal symptoms. Finally, vasomotor symptoms are often induced by other common (and longer-term) breast cancer therapies, including aromatase inhibitors (ie, anastrozole, exemestane, letrozole) in addition to tamoxifen, as mentioned above. Because SSRIs are strong inhibitors of CYP2D6, which is critical to tamoxifen metabolism, the SNRIs or gabapentin are preferred nonhormonal options in women taking tamoxifen.
Vitamin E: Scant evidence for symptom improvement, but a role in VTE prevention?
Vitamin E was frequently recommended in the past as a possible nonhormonal alternative to treat vasomotor symptoms, but small clinical trials have shown that it is not much more likely than placebo to be effective for this indication. Evidence from the Women’s Health Study indicates, however, that any value of vitamin E supplementation in this population may lie in reducing the risk of venous thromboembolism (VTE).24 In this large placebo-controlled trial, randomization to 600 IU of alpha-tocopherol every other day was associated with modest reductions in VTE overall and more significant reductions among the subgroup of women at highest risk for VTE—ie, those with a history of prior VTE or a prothrombotic mutation.
ALTERNATIVES TO SYSTEMIC ESTROGEN FOR OTHER MENOPAUSAL HEALTH ISSUES
New research is helping to define just how “low” low-dose topical therapy can go while still providing efficacy. A recent placebo-controlled trial compared 10-µg and 25-µg strengths of estradiol-containing vaginal tablets for vaginal atrophy in 230 postmenopausal women.26 Over the 12-week study, both doses of estradiol significantly improved vaginal maturation, lowered vaginal pH, and reduced the severity of vaginal symptoms compared with placebo. Although improvements were greater with the 25-µg dose, the results suggest that 10-µg topical estradiol is an effective option for women with vaginal atrophy who wish to minimize their exposure to estrogen.
Although there is insufficient evidence to support endometrial surveillance in asymptomatic women using vaginal estrogen, such surveillance may be indicated in women at high risk for endometrial cancer, in those requiring a higher dose for vaginal atrophy relief, and in those with spotting or breakthrough bleeding.25
Sexual dysfunction is not directly caused by the menopausal transition but is multifactorial, involving physical health, mental health, relationship dynamics, and partner availability, among other factors. The two most common complaints relating to sexual dysfunction in women at midlife are lack of desire and hypoarousal.
A number of therapies are currently under investigation for treatment of female sexual dysfunction at midlife. These include the same low-dose vaginal estrogen preparations used for vaginal atrophy as well as newer approaches currently in clinical testing, such as the melanocortin receptor agonist bremelanotide27,28 and topical alprostadil,29 both of which act by inducing sexual arousal. In a study of premenopausal women with sexual arousal disorder, bremelanotide increased both genital arousal and sexual desire.30
The most widely studied pharmacotherapy approach to sexual dysfunction has been testosterone replacement. A recent Cochrane review assessed the results of 23 trials that evaluated the addition of testosterone to HT (estrogen with or without progestogen) in 1,957 peri- and postmenopausal women.31 It found that adding testosterone to HT has a beneficial effect on sexual function in postmenopausal women but also confers the adverse effect of reducing levels of high-density lipoprotein cholesterol. The authors concluded that the impact of testosterone therapy on other health outcomes in estrogenized postmenopausal women is unclear, as is the existence of a benefit in sexual function for perimenopausal women.
In addition to systemic testosterone, a transdermal testosterone patch has been studied for treatment of sexual dysfunction in postmenopausal women; FDA evaluation of the patch is awaiting the availability of long-term safety data, although the testosterone patch for women is available in Europe.
According to a 2005 NAMS position statement on testosterone therapy,32 postmenopausal women presenting with symptoms of decreased sexual desire that causes personal distress may be candidates for testosterone therapy. The NAMS statement further clarifies that all other identifiable causes of sexual dysfunction should be considered and ruled out as appropriate. Because of a lack of safety and efficacy data on the use of testosterone therapy in unestrogenized women, testosterone therapy alone cannot be recommended in women not taking concomitant estrogen.32