Climacteric Vasomotor Instability

Hot flashes are the most prominent peri- and postmenopausal symptom.

They affect more than 70% of women and may persist for several years, although they usually abate spontaneously after 2 years. Hot flashes are characterized by a sensation of heat, sweating, flushing, and anxiety. The cause of hot flashes remains unclear, but they are considered to be a result of dysfunctional thermoregulation, which may be mediated by changes of central catecholamine secretion. This presumed etiology has guided the design of nonhormonal therapies,  most of which have been discovered serendipitously.

Bellergal (a combination of ergotamine, belladonna, and phenobarbital) has been used for many years for the treatment of hot flashes and is moderately helpful. Blurred vision, dry mouth, and gastrointestinal symptoms are frequent side effects, and these lead many women to abandon bellergal after several months.

Clonidine, a centrally active &lpha;-agonist, is also used to treat hot flashes.

Initially developed as an antihypertensive medication, clonidine has been shown in several studies to alleviate both the frequency and severity of hot flashes associated with estrogen deficiency or tamoxifen administration. Drowsiness and dry mouth are frequent side effects but are usually not severe enough to cause interruption of therapy. Orthostatic symptoms, however, may force discontinuation of clonidine and should be monitored closely, especially at the beginning of treatment.

Venlafaxine, a centrally acting inhibitor of serotonin and norepinephrine reuptake, has been demonstrated to be effective in managing hot flashes.

In a prospective randomized trial of breast cancer survivors (Loprinzi et al.,  2000),  daily administration of 75 mg of venlafaxine resulted in a 61% decrease in the frequency of hot flashes. A lower dose (37.5 mg daily) was less effective (37%  decrease in hot-flash frequency),  and a higher dose (150 mg) was associated with more frequent side effects, including decreased appetite, nausea, dry mouth, and constipation.

Gabapentin, a γ-aminobutyric acid analogue, has been found to have beneficial effects on vasomotor symptoms. In a recent randomized trial in breast cancer patients (Pandya et al., 2005), gabapentin at a dose of 900 mg per day reduced the frequency of hot flashes by 26% versus placebo. At this dose, patients experienced a 30% improvement in the severity of hot flashes. There was no statistically significant benefit in terms of symptoms when the dose of gabapentin was reduced to 300 mg per day. Somnolence and nausea are side effects of gabapentin.

Selective serotonin reuptake inhibitors, such as paroxetine and fluoxetine, are effective in the treatment of hot flashes. A prospective crossover trial of patients randomly assigned to paroxetine (10 or 20 mg daily) for 4 weeks followed by placebo for 4 weeks or placebo for 4 weeks followed by paroxetine (10 or 20 mg daily) for 4 weeks found that after 4 weeks, paroxetine reduced the frequency of hot flashes by greater than 40% versus placebo (Stearns et al., 2005).

The higher dose of paroxetine was not associated with benefits compared to the lower dose but was associated with a greater frequency of side effects. Potential side effects of paroxetine and other selective serotonin reuptake inhibitors include nausea, somnolence, and sexual dysfunction (anorgasmia and diminished libido).

Progestational agents are often considered in the management of hot flashes (Love et al., 1991). However, since progesterone is an ovarian hormone with significant potential to promote the proliferation of breast tissue, progesterone should not be used until carefully designed studies have determined its safety. Estriol, a relatively weak estrogen, has been used to relieve hot flashes and improve genitourinary symptoms.

It enjoys popularity among menopausal women and clinicians, especially in Europe, and is often discussed as an attractive alternative to HRT for women with a history of breast cancer. However, sufficient data regarding the safety of estriol in postmenopausal women are not available, and estriol should be considered as yet another estrogenic preparation.  Similarly,  the safety of prasterone (dehydroepiandrosterone),  an adrenal steroid frequently discussed as an alternative to estrogen, is not defined for postmenopausal women.

Nonprescription   nutritional   supplements   are   popular   remedies for the relief of climacteric symptoms.  Among these,  vitamin E was examined in a randomized trial of breast cancer survivors with hot flashes (Barton et al.,  1998)  and found to be ineffective.  It is important to remember that estrogenic compounds are widely distributed in natural foodstuffs and in herbal remedies for the treatment of menopausal symptoms.

The symptomatic benefit derived from supplements such as Chinese herbs and soy products may well be related to their estrogenic properties.  Phytoestrogens have been used for centuries by many cultures to relieve climacteric symptoms and are the subject of discussion and investigation as potential protective agents against the development of several cancers, including breast cancer.

However, phytoestrogens can clearly interact with the estrogen receptor both in vitro and in vivo;  their safety in patients with breast cancer remains unestablished. In a recent placebo-controlled study (MacGregor et al., 2005), soy protein was found to be ineffective in controlling climacteric symptoms in breast cancer survivors.