American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause

AACE Menopause Guidelines Revision Task Force

Disclosures

Endocr Pract. 2006;12(3):315-337. 

In This Article

Nonhormonal Therapy for Menopause

History. Menopause is defined as the absence of menses for 12 consecutive months. Perimenopause is the transitional period between normal menses and menopause. Hot flashes have been reported in up to 70% of women undergoing natural menopause and in almost all women undergoing surgical menopause.[45] A prospective study of 436 women found that 31% experienced hot flashes during perimenopause, even before any changes occurred in menses.[46]

Hot Flashes. Hot flashes are the number one complaint of peri-menopausal and postmenopausal women. A hot flash can be described as a warm sensation that begins at the top of the head and progresses toward the feet, frequently followed by chills. A hot flash may last for a few seconds or for several minutes and may occur as frequently as every hour to several times per week.

Risk Factors. Modifiable and nonmodifiable risk factors for hot flashes should be evaluated. Modifiable factors that have been shown to increase the risk of hot flashes include cigarette smoking,[47,48] body mass index >30 kg/m2,[48,49] and lack of exercise[49] (LOE 2c). Nonmodifiable risk factors include maternal history, menopause younger than 52 years of age, and abrupt menopause—induced by a surgical procedure,[50] chemotherapy, or irradiation. Approximately 65% of patients with a history of breast cancer have hot flashes,[51] and adjuvant therapy with tamoxifen or tamoxifen plus chemotherapy is associated with substantial worsening of menopause-related symptoms.[52]

Differential Diagnosis. It is important to exclude other causes of hot flashes, as clinically indicated. The differential diagnosis may include hyperthyroidism, pheochromocytoma, carcinoid, panic disorder, diabetes, and side effects to medications such as antiestrogens or selective estrogen receptor modulators.

Pathophysiologic Factors. The physiologic mechanism whereby a hot flash occurs is thought to be a result of elevated body temperature leading to cutaneous vasodilatation, which results in flushing and sweating in association with a subsequent decrease in temperature, chills, and potentially relief. One belief is that within the hypothalamic thermoregulatory zone there is an interthreshold zone, defined as the threshold between sweating and shivering. Available evidence indicates that, after menopause, this interthreshold zone becomes narrowed.[53] Proposed triggers for this change in interthreshold zone include serotonin (5-hydroxytryptamine), norepinephrine, and estrogen deprivation. The estrogen effect on hot flashes is thought to be attributable to withdrawal of estrogen rather than decreased estrogen levels.[54]

Because of the prevalence of hot flashes during the perimenopausal and postmenopausal period and the risks, controversies, and fears surrounding the use of estrogen therapy, various alternative therapies for managing these symptoms have been sought. An important fact to know is that, in most studies, interventions for menopausal symptoms have a 20% to 30% placebo response rate within 4 weeks after initiation of treatment, with some randomized trials having more than a 50% placebo response rate.[55] In most women, treatment of hot flashes can be discontinued within 1 year, but about a third of the menopausal women have symptoms for up to 5 years (10% of whom have symptoms for up to 15 years). In light of the high placebo response rate and the natural regression of symptoms over time in most women, double-blind RCTs are needed to evaluate the efficacy of each therapeutic option appropriately. Additionally, because of the varied duration of time these treatments are used, both the short-term and long-term effects must be properly evaluated. Of note, other than estrogen, no therapy has been approved by the FDA for the treatment of hot flashes in women. Estrogen remains the most studied and most effective therapy for vasomotor symptoms attributable to menopause. No RCTs comparing estrogen and other pharmacologic agents have been published. The level of evidence for each therapeutic intervention is presented in the subsequent material.

Lifestyle changes designed to maintain a cool environment and aid heat dissipation may help with mild to moderate symptoms. The use of fans, air conditioning, and light cotton clothing may be helpful. Relaxation therapy may also be beneficial in some patients, although RCTs are needed for accurate assessment (LOE 3).

A summary of the various agents and the related published studies[56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78] is presented in Table 4 . As previously mentioned, no therapy other than estrogen has been approved by the FDA for treatment of vasomotor symptoms.

Antidepressant. The most studied medications in the antidepressant class include venlafaxine, paroxetine, and fluoxetine. Venlafaxine is both a serotonin and a norepinephrine reuptake inhibitor. There have been 3 published RCTs in which these medications were used[57,58,59] (LOE 2). Side effects of these agents may include nausea, dry mouth, insomnia, fatigue, sexual dysfunction, and gastrointestinal disturbances.

Clonidine. Clonidine is a central α2-adrenergic agonist and can be given orally or transdermally. A summary of results of trials that used clonidine preparations is shown in Table 4 [60,61,62,73] (LOE 2). Side effects, including dry mouth, postural hypotension, fatigue, and constipation, often limit the use of this medication.

Gabapentin. Gabapentin is an analogue of γ-aminobutyric acid and has an unknown mechanism of action. It is approved by the FDA for treatment of seizure disorders but has also been used to treat neuropathic pain. A small RCT[64] has demonstrated significant reductions in hot flashes ( Table 4 ), but larger trials are needed to study long-term efficacy and safety (LOE 2). Side effects may include fatigue, dizziness, and peripheral edema.

Progesterone and Progestins. Oral, intramuscular, and topical formulations of progestins have been used in the treatment of hot flashes. There have been 3 RCTs of orally administered progesterone[56,68,69] and 1 RCT of oral versus intramuscular administration of progesterone[70] ( Table 4 ) (LOE 2). Although these studies showed effectiveness in reducing hot flashes, the associated side effects, including withdrawal bleeding and weight gain, often limit the use of this medication.

Progesterone cream is classified as a supplement; therefore, it can be purchased without a prescription, and its contents are neither standardized nor regulated. Progesterone cream is derived from a plant precursor sterol, which in its unaltered or "natural" form is unable to be converted to progesterone by the human body. Commercial preparations of progesterone creams vary widely and may contain an unaltered, unusable form of progesterone or a variant that has been derived from plant sterols but modified in the laboratory to a form that can be utilized by the body.

Two RCTs of transdermal progesterone have been reported in the literature,[71,72] and these studies yielded conflicting results ( Table 4 ) (LOE 2c). Because of the paucity of data and the variability of these preparations, in addition to possible systemic effects, progesterone creams should not be recommended for the treatment of hot flashes.

In 1994, the US Congress passed the Dietary Supplement Health and Education Act that defined dietary supplements as a separate regulatory category and outlined ways in which information about supplements could be advertised. It is important to be aware that this act does not require scientific evidence demonstrating safety or efficacy of supplements, and it does not regulate or require standardization of the manufacturing of supplements. Moreover, demonstration of harm from a supplement must be reported before the FDA will intervene or regulate that supplement. Despite these loose regulations and the intended benefits, supplements have the potential for interaction with other medications and medical conditions as well as the potential to cause harm.

In 1998, alternative medicine visits by patients outnumbered visits to conventional primary physicians. Seventy percent of these visits were never discussed with the primary physician. In 44% of such visits, the patients were 50 to 64 years old.[79] In one study, predictive factors for use of alternative care included higher education and chronic medical problems.[80] Some third-party carriers have begun providing coverage for alternative therapies (albeit at a premium). One survey of 100 post-menopausal women at a San Francisco health conference found that women who used dietary supplements for relief of menopausal symptoms had the highest perceived quality of life, felt most in control of their symptoms, and had a sense of empowerment.[81] In general, women are now living a third of their lives after menopause, and in light of the trend of increasing use of alternative medical therapies, the use of supplements for the management of hot flashes is likely to increase.

Phytoestrogens. Phytoestrogens, which can be subclassified as shown in Figure 1, are sterol molecules produced by plants with weak estrogenic activity. They are similar in structure to human estrogens and have been shown to interact and have estrogenlike activity with the estrogen receptor (greater activity at the beta receptor).[82] Plant sterols are used as a precursor for biosynthetic production of mass manufactured pharmaceutical-grade sterols.

Subclassification of phytoestrogens, plant sources of weak estrogenic activity.

Isoflavones, a type of phytoestrogen, have been investigated in the treatment of hot flashes because women in Asia, whose diets characteristically contain 40 to 80 mg of isoflavones daily (in comparison with a typical American diet that contains <3 mg daily), have low rates of hot flashes.[83] Consumption of 1 g of soy yields between 1.2 and 1.7 mg of isoflavones. Because of the large amount of soy that must be consumed to achieve an intake of isoflavones that is typical of an Asian diet, a market for isoflavone concentrates (a nutraceutical) has developed.

Multiple RCTs examining the effects of soy or isoflavone consumption on the reduction of hot flashes have yielded inconsistent results[65,66,67,74,75] ( Table 4 ) (LOE 2).

Some studies of the effects of soy on hot flashes have examined raw soy consumption, whereas others have examined the effects of consumption of isoflavones. In addition, different amounts and formulations of these products were used in the various studies; thus, comparisons between studies are difficult. Isoflavones can be broken down to form daidzein, which can be further metabolized by intestinal bacteria into equol—a stable compound with estrogenic activity.[84,85] Only 30% to 50% of adults are able to excrete equol after a soy food challenge,[86] and differences in the ability to metabolize soy may explain variations in the response to soy treatment.

If women are interested in using soy, the average amount of isoflavones studied has been 40 to 80 mg daily for up to 6 months. It may take several weeks for any effect to occur, and women should be encouraged to use whole food sources, rather than supplements, because of the risk of overdosage and the lack of known long-term effects with use of isoflavone supplements. Women should be counseled that data regarding estrogenic effects of soy have been inconclusive; therefore, women with a personal or strong family history of hormone-dependent cancers (breast, uterine, or ovarian) or thromboembolic or cardiovascular events should not use soy-based therapies (grade D). Some evidence has indicated that soy can stimulate estrogen-dependent breast cancer cells in vitro.[86] Of note, a recent double-blind RCT of use of soy protein in older postmenopausal women did not yield differences in cognitive function, bone mineral density, or plasma lipids.[87] Long-term randomized controlled safety and efficacy studies in postmenopausal women with vasomotor symptoms are needed.

Black Cohosh. In Germany, black cohosh has been used for many years in the treatment of hot flashes. Most studies of black cohosh have used a commercial preparation, "Remifemin," which is reported to contain 1 mg of triterpene glycoside, calculated as 27-deoxyactein in each 20-mg tablet.

There are 3 published randomized, placebo-controlled trials of black cohosh—2 in the English-language literature[76,77] (LOE 2) and 1 in German[88]—which yielded inconsistent results. Although this therapy is thought to be generally safe, there have been rare case reports of hepatitis associated with preparations containing black cohosh.[89] Of importance, no safety trials of black cohosh have been conducted for longer than 6 months. Package labeling generally recommends use for no more than a 6-month period.

Vitamin E. The use of vitamin E for reduction of hot flashes in patients with a history of breast cancer has been reported in one randomized, placebo-controlled trial[78] ( Table 4 ) (LOE 2). At the conclusion of that study, there was no difference in results between vitamin E and placebo.

Vitamin E is considered relatively safe. In a review of studies of vitamin E, no adverse effects had been reported with dosages of 800 IU of vitamin E daily and even higher doses in some studies.[90,91] Evaluation of data from the WHI study indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women.[92] According to the investigators, "these data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women" (grade D).

For women who cannot or do not wish to use estrogen for control of severe vasomotor symptoms, lifestyle changes should be implemented first. If pharmacologic therapy is needed, the most effective nonestrogen class of agents is the antidepressants. Venlafaxine is probably the most beneficial in this class. If antidepressants are not tolerated or cannot be used, then clonidine or megestrol may be considered, although side effects may occur more frequently with these agents. Gabapentin can be considered as a promising new therapeutic option, although both long-term efficacy and safety remain to be substantiated. Data on most nutritional supplements are limited by the lack of placebo-controlled trials and by existing trials that have generally shown no differences between therapy and placebo. Because soy may have some estrogen agonist properties, long-term safety issues, especially in patients with breast cancer, remain of concern for high-dose therapy. A healthful diet that incorporates some soy protein seems reasonable (grade C).

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