Non-Estrogenic Approaches for the Treatment of Climacteric Symptoms

By Albertazzi, P

ABSTRACT Non-estrogenic alternatives for the treatment of climacteric symptoms have their origin lost in history. Recent clinical trial data have shown that lifestyle and diet adjustment have some effect in improving both hot flushes and mood.

Over-the-counter phytotherapeutic extracts are very popular and women often try a variety of products before resorting to traditional medicine. Preparations containing isoflavones in variable doses, such as soy extract and red clover, or extracts from evening primrose, Cimifuga racemosa, ginseng and black cohosh are often used for treating the climacteric syndrome. The scientific support for their efficacy certainly does not equal their popularity.

The most tested pharmacological alternatives to estrogens are serotonin reuptake inhibitors (SSRIs). All available SSRIs have undergone trials for the relief of hot flushes. In spite of the difference between the compounds in both half-life and engagement of serotonin receptors, they appear to have very similar effectiveness in reducing hot flushes. At their best, SSRIs reduce hot flushes by 50-60%, compared with 80% for estrogen, and their effect appears only in the short term. SSRIs have mood-improving effects that appear to be independent of the effect on hot flushes. When used for the treatment of the climacteric syndrome, SSRIs do not adversely affect libido. Dependence is a major concern in women when offered this type of treatment, but does not appear to be a problem with this class of drugs. Withdrawal symptoms have never been reported in trials for hot flushes but are known to occur when SSRIs are used in the long term. In order to avoid these symptoms, the dose should be tapered slowly. Gabapentin, a drug used for the treatment of neuropathic pain and epilepsy, has shown that, in high doses, it has an efficacy similar to that of estrogen; however, this needs further confirmation.

Key words: CLIMACTERIC SYMPTOMS, PLANT-DERIVED REMEDIES, PROGESTOGEN, GABAPENTIN, NEUROTRANSMITTER MODULATORS

INTRODUCTION

Estrogen was first approved by the Food and Drug Administration (FDA) in 1941 for the treatment of hot flushes and night sweats. The following 50 years witnessed a growing popularity of this hormone; in the 1990s, it became an antidote for almost all major and minor ailments related to aging. Women would look to estrogen not only to treat their hot flushes, vaginal dryness and bone protection but also to improve libido, mood, memory, sleep, aching joints and, last but not least, wrinkles. The faith in the health-preserving effects of estrogen was such that, at one point, it was tried for the treatment of coronary disease in men! It was not until the abrupt halt of the Women’s Health Initiative study in 2002 that estrogens – in the public eye – turned almost overnight from a panacea into a deadly poison. Symptoms of menopause, however, did not cease to exist with the demise of hormone therapy. Having lost faith in conventional estrogens, women started increasingly to look for alternatives.

For the treatment of menopausal problems, a medical book from the Renaissance recommended a herbal treatment consisting of a decoction of myrrh and apples. It also suggested that, in the case of failure, women may wish to pour the concoction in their sandals and walk1. This is possibly the earliest recognition of exercise as a form of treatment for menopausal complaints. In 1837, Thomas Graham wrote in his book Diseases of Females that, except for attention to diet and exercise, ‘little or nothing is requested for the management of ordinary cases of Menopause’2. With such a history, it is not surprising that dietary changes, herbs and exercise still constitute the most commonly used remedies for menopause.

EXERCISE AND LIFESTYLE FACTORS

Evidence, mostly from small clinical trials, has shown that women who exercise regularly at around the time of menopause have a lower prevalence of neurovegetative symptoms compared with women who do not exercise3. These data have recently been corroborated by a fairly large clinical trial4. Exercising women had better mood profiles, lower somatic symptoms and difficulties in memory concentration compared with sedentary women. The degree of neurovegetative symptoms appeared to be inversely proportional to the amount of the exercise performed. Physical exercise is known to increase levels of beta-endorphin, a neurotransmitter known to affect thermoregulation. Exercise would thus reverse the decrease in beta-endorphin levels caused by withdrawal of menopausal estrogen withdrawal.

Greater body mass index is a risk factor for more vasomotor symptoms, as are smoking, high caffeine and alcohol consumption. This supports the importance of lifestyle factors in modulating climacteric symptoms5.

Pace respiration and relaxation techniques have also been tried with some success. Studies are, however, small and of short duration6.

PLANT-DERIVED REMEDIES

Plants have a long tradition in menopausal treatment; some, such as soy and red clover, contain estrogen-like compounds but, for the majority of herbal preparations used for menopausal complaints, such as primrose oil, black cohosh (Cimifuga racemosa), Angelica sinensis and ginseng, the mechanism of action and the effectiveness of compounds are unknown.

One study has shown that an extract of black cohosh is as effective as estrogen in reducing hot flushes7, but this finding has been refuted by four other studies8-11.

While clinical trials have failed to highlight any concerns about the safety of black cohosh, there have been several case reports of possible hepatotoxicity with the use of over-the-counter preparations. It is difficult to know if these were due to a direct toxic effect of the plant itself or to contaminants present in over- the-counter products of poor quality.

Clinical studies on soy (Glycine max L.) and isoflavone extracts have given mixed results12. The composition and dose of soy supplements vary widely across studies, making comparisons and definitive conclusions difficult. Although these products appear reasonably safe, one study challenged the long-term safety of high- dose soy isoflavone extract (150 mg/day for 5 years) on the uterine endometrium.

Clinical data from controlled trials, assessing the efficacy of semi-purified isoflavone red clover (Trifolium pratense L.) leaf extracts in reducing hot flush frequency and severity or in relieving symptoms, are contradictory. The largest study showed no benefit for reducing symptoms associated with menopause for two different red clover isoflavone products compared with placebo. No significant adverse events have been reported in the literature. A single clinical trial does not support the use of dong quai (Angelica sinensis L.), ginseng (Panax ginseng C.A. Mey), or evening primrose seed oil (Oenothera biennis L.) for improving menopausal symptoms13.

What is common to all plant extracts is that they can be bought over the counter without prescription, thus empowering women; furthermore, as they are not regulated as drugs, they can be sold without the need to mention adverse effects. This may lead to a false sense of safety.

PROGESTOGENS

Several different progestogens have been used in the treatment of hot flushes, mostly in patients who had suffered from breast cancer. Oral medroxyprogesterone acetate at daily doses of 1014 to 200 mg15 has reduced hot flushes by 87% in placebo-controlled studies. Similarly effective and well tolerated was 500 mg of the depot preparation injected intramuscularly every 2 weeks16 or oral mergestrol acetate at a dose of 40 mg/ day17. The major questions about progestogen preparations remain their effects on the risk of breast cancer, particularly in women at high risk of disease18.

Several creams allegedly containing ‘natural progesterone’ are produced from the wild yam plant and sold over the counter for the relief of osteoporosis and for prevention of osteoporosis. Two studies performed with preparations derived from the wild yam have been published to date. Leonetti and colleagues found that a cream containing the equivalent of 20 mg progesterone per day relieved hot flushes partially or completely in 83% of participating women, compared with only 19% of women in the placebo group19, while Komesaroff and colleagues found no effects with a preparation containing 100 mg wild yam extract20. This variability in results may possibly be explained by the lack of standardization of these preparations that are sold over the counter as supplements.

GABABENTIN

Gabapentin is a y-aminobutyric acid analogue used in epilepsy, neurogenic pain and migraine. Gabapentin has also been used in the treatment of hot flushes but its mechanism of action is unknown. Gabapentin has been shown in two case studies21,22 to approximately halve the frequency of hot flushes. Three randomized, placebo- controlled studies have been performed to date and doses up 900 mg/ day gabapentin reduced the frequency of hot flushes by approximately 45-50%23-25. However, doses of 2400 mg/day gabapentin appear to reduce hot flushes by 70%, similar to standard doses of conjugated equine estrogen (CEE). Side-effects did not differ significantly in the gabapentin arm compared with the CEE arm in the 12 weeks of the study. The dose of gabapentin was increased by 400 mg over a 12-day period26. The study by Loprinzi and colleagues25 also showed that gabapentin did not have a synergic effect when used in association with a serotonin reuptake inhibitor (SSRI) antidepressant. NEUROTRANSMITTER MODULATORS

The relationship between serotonin and temperature control has long been recognized. Hot flushes appear to be triggered by a small elevation in core body temperature (T^sub c^), acting via a narrowed thermoneutral zone. This narrowing of the ‘buffer zone’ that controls temperature homeostasis may be due to improper activation of central neurotransmitters such as noradrenaline and serotonin (5- hydroxytryptamine, 5-HT). Serum levels of serotonin are lower in postmenopausal women and estrogen treatment is known to normalize them. It has been suggested that estrogen withdrawal causes a reduction in circulating serotonin, resulting in an upregulation of the 5-HT2A receptor in the hypothalamus6.

SSRIs are licensed as antidepressants; they act within the brain to increase the amount of serotonin in the synaptic gap by inhibiting its reuptake. A variety of serotonin receptors are present in the central nervous system, and some have conflicting functions. As different SSRIs have different receptor specificity and different half-lives, in recent years they have all been tested in the quest to find the compound with the most specific activity on temperature control.

Interestingly, the effect of SSRIs on depression and mood improvement does not predict the effect on hot flushes, suggesting two separate mechanisms of action. Many SSRIs are known to cause withdrawal symptoms, such as dizziness, numbness, tingling, gastrointestinal disturbances, headache, sweating, anxiety and sleep disturbances. When used as an antidepressant, they may also negatively affect libido. Fortunately, none of these problems has been encountered when they are used in the short term for hot flushes. But, when SSRI are used for longer than 4-6 weeks, it is advisable to taper the dose to prevent withdrawal symptoms.

When offered these drugs, women voice their concern about the possibility of ‘getting hooked’. Fortunately, a recent position statement of the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK has dismissed any risk of dependence with these drugs27.

Venlafaxine is the SSRI most frequently prescribed as an alternative to estrogens for the treatment of climacteric syndrome. It possesses the effects of both a SSRI and a serotonin- noradrenaline reuptake inhibitor (SNRI). Ironically, amongst the SSRIs, this is the one that appears to carry the major risk of cardiotoxicity. This risk, however, is mostly related to overdosing, which is unlikely to happen in a non-depressed patient who used venlafaxine for the treatment of the climacteric syndrome. However, the MHRA in 2004 suggested the need for baseline ECG before commencing treatment and restricted venlafaxine prescription to psychiatrists only. This restriction was lifted in May 2006(27). In the UK, prescription of venlafaxine is restricted to psychiatrists only in severely depressed patients, hospitalized and for doses higher than 300 mg/day. Hence, the 75 mg/day dose, the maximum dose used for hot flushes, can be freely prescribed by gynecologists or general practitioners. The need for a baseline ECG has been lifted but venlafaxine is still contraindicated in patients with cardiac ventricular arrhythmia and in patients with uncontrolled hypertension. Regular blood pressure monitoring is indicated and the dose of venlafaxine may need adjustment or the drug stopped if blood pressure becomes abnormally high.

Venlafaxine at a dose of 75 mg/day approximately halves the severity of hot flushes. The effect is statistically significant but only marginally superior to the effect of placebo28,29. Dry mouth, decreased appetite, nausea and constipation were the reported side- effects and the intensity and prevalence of these were dose- related.

In late June 2006, an active metabolite of venlafaxine, desvenlafaxine succinate, was submitted by Wyeth Pharmaceuticals to the FDA for the treatment of severe vasomotor symptoms30. If approved, desvenlafaxine will be the only alternative to estrogen licensed for the treatment of hot flushes.

The effectiveness of fluoxetine and citalopram, two other very commonly used antidepressants, appears to be similar to that of venlafaxine. Fluoxetine and citalopram are the only SSRIs that have been studied long term. In 150 women, no benefit was observed with either SSRI at the end of a 9-month trial over placebo31. Discontinuation rates at 9 months were 40% in the placebo group, 34% in the fluoxetine group and 34% in the citalopram group. Ineffectiveness of treatment was the most common reason for discontinuation, rather than side-effects. Both fluoxetine and citalopram improved depression and did not have any adverse effect on libido.

Four studies have examined the effects of paroxetine on hot flushes, suggesting significant improvements in the ratings of severity of hot flushes, as well as general and emotional well- being and mental fatigue, depression, sleep, anxiety and quality of life28. The controlled-release (CR) formulation of paroxetine has been shown to be equally effective28. A recent, stratified, randomized, double-blind, cross-over trial in 151 women was designed to test the effectiveness of 10 mg and 20 mg paroxetine versus placebo. The efficacies were similar with the two doses and superior to that of placebo, but women were more likely to continue paroxetine at the lowest dose. Sexual function did not appear to be compromised with either dose. The 10 mg dose of paroxetine was associated with a significant improvement in sleep compared with placebo32.

Citalopram had a similar effect as other SSRIs on hot flushes and showed a beneficial effect on anger, tension and depression, as well as improved mood. It reduced hot flushes by 53% at 4 weeks33, but no effect was found at 9 months.

Mitazapine is an antidepressant that antagonizes several serotonin receptors. It is also a presynaptic alpha^sub 2^- antagonist and it increases both central noradrenergic and serotoninergic transmission. In spite of its complex mechanism of action, the limited data available do not show any advantage over other SSRIs.

Sertraline is the latest of the SSRIs to be tested; it has a significant effect in reducing the number of hot flushes but the effect does not appear superior o those of other SSRIs34.

CONCLUSION

In addition to lifestyle and dietary modification, serotonin reuptake inhibitors are the most useful short-term option for the treatment of hot flushes when sex hormones are to be avoided. The long-term benefits of SSRIs, however, are not known. Reductions in hot flushes are similar for all the compounds tested and are not related to their effect on mood. The effect on hot flushes is not dose-dependent, thus permitting the use of low doses. When used to treat hot flushes, SSRIs do not seem to adversely affect libido. Tolerability is generally good, particularly for low doses, and no withdrawal reactions have been reported when these compounds are used to treat climacteric symptoms. Women can be reassured that these drugs do not cause dependence. High doses of gabapentin appear to be well tolerated and have an effect similar to that of estrogen in the relief of climacteric symptoms. However, these data come from only one trial and need further confirmation.

Conflict of interest Nil.

Source of funding Nil.

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P. Albertazzi

Contraception and Reproductive Health Services, Central Abacus, Liverpool, UK

Correspondence: Dr P. Albertazzi, Contraception and Reproductive Health Services, Central Abacus, 40-46 Dale Street, Liverpool L2 5SF, UK

Copyright Taylor & Francis Ltd. Oct 2007

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