For genital atrophy, vaginal estrogen tablets and the 3-month estrogen-releasing ring offer women effective treatment of atrophic symptoms with less systemic estrogen absorption than creams. Many of my patients also find the tablets and ring less messy than creams.
Randolph: Safe is a relative term. Any pharmacologic intervention has its own set of side effects. Even “natural” alternatives may have unknown consequences. Vasomotor symptoms may be improved by selective serotonin reuptake inhibitors (SSRIs), especially venlafaxine, or clonidine hydrochloride, an antihypertensive. High-dose progestins also have been effective, but the WHI data raise the possibility that MPA may contribute to a long-term increased health risk. Diet, exercise, and statin therapy all are proven to decrease the risk of CHD. Bisphosphonates and calcitonin, in conjunction with adequate calcium and vitamin D, are at least as effective as HRT in reducing fragility fractures. Raloxifene also reduces the fracture risk and appears to lower the risk of breast cancer through the first 4 years of use.2 However, it has unknown cardiac effects.
Luciano: For the prevention of osteoporosis we have several alternatives, as Dr. Randolph mentioned. Parathyroid hormone also may be available in the near future. Clonidine, a centrally acting antihypertensive agent, has been used successfully as a viable alternative to HRT in the management of vasomotor symptoms, based on the premise that these symptoms are precipitated by a discharge of catecholamine from thermoregulatory centers at the base of the hypothalamus.3 Clonidine may be prescribed as an oral tablet or transdermal patch at a daily dose of 0.1 mg. Adverse reactions are uncommon and include orthostatic hypotension, bradycardia, Raynaud’s phenomenon, and angioedema.
Fitzpatrick: Unfortunately, the efficacy and safety of these alternatives to HRT are not always well proven. Exceptions include the use of oral bisphosphonates or SERMs for the prevention and treatment of osteoporosis. Salmon calcitonin is another option. There is a large body of evidence indicating that these medications will increase BMD. A reduction in hip and vertebral spinal fractures has been well established with the bisphosphonates. As was pointed out earlier, each of these medications has its own side-effect profile that must be considered when counseling patients. For women who are unable to take any of these therapies, intravenous (IV) bisphosphonates are an additional safe alternative.
When it comes to finding alternative therapies for hot flushes, the issue becomes much more complicated. To date, other compounds used to treat hot flushes lack the efficacy of estrogen. Here again, side-effect profiles vary greatly. The most commonly used alternatives to HRT are the SSRIs, including venlafaxine and fluoxetine, and clonidine. Megestrol acetate is thought to be potent in its ability to reduce hot flushes, but side effects may limit its use. It also falls into the progestogen class of compounds.
As for phytoestrogens and other herbal remedies, many questions remain unanswered. Soy protein, which contains isoflavones, has been shown to have no benefit in the reduction of hot flushes in several randomized controlled trials.4,5 Similarly, red clover and dong quai are associated with a number of problems. Little benefit has been shown for these compounds in the attenuation of hot flushes. In Europe, black cohosh is probably the most widely used herbal remedy, and there is some evidence of its efficacy.
The safest alternatives are recommendations we should make for all of our patients: exercise, wearing layered clothing, and keeping the environment cool. The avoidance of spicy foods and alcohol also is thought to reduce symptoms. In addition, 1 small randomized controlled trial shows benefits from deep breathing.
Case studies from our panel
A 50-year-old perimenopausal woman at the peak of vasomotor symptoms asks for help in making the transition to menopause. I inform her that she is the ideal candidate for “short-term” cyclic hormone replacement therapy (HRT) with a 20-μg ethinyl estradiol (EE2) oral contraceptive (OC), continuous conjugated equine estrogen (CEE), or 17 estradiol and cyclic progestin. Annual discontinuation would allow her to assess her symptoms and decide whether she wants to resume therapy for further symptomatic relief. Most women will use this approach for 1 or 2 years and then consider alternatives.
A 42-year-old surgically menopausal woman asks about the Women’s Health Initiative (WHI) findings, as she has been taking HRT for a number of years. I explain that she is the type of patient most likely to have significant symptoms of sex-steroid withdrawal for an extended period of time. Continuous estrogen replacement at the lowest dose sufficient to control symptoms remains quite appropriate, since the long-term risk-benefit profile of unopposed estrogen is unclear and is likely to remain so until that arm of the WHI is reported. It is probably prudent to periodically discontinue—perhaps annually—HRT to assess for symptoms and reassess the treatment strategy.
A 65-year-old woman who initiated HRT for vasomotor symptoms and has continued the therapy for long-term health benefits comes in for an examination. I carefully inform her of the actual risks identified in the estrogen-progestin arm of the WHI, then offer her the option of discontinuing HRT to assess her symptoms and reevaluate her goals and alternatives. I also advise her—as I do all my patients—to get regular exercise, eat a balanced diet low in fat and calories, refrain from smoking, examine her breasts regularly and get an annual mammogram, and take daily calcium and vitamin D supplements.—JOHN RANDOLPH, JR., MD