Hormone therapy for the management of menopausal symptoms: pharmacotherapy update

Nearly 50 million women each year are projected to reach menopause by 2030. Many of these women will experience vasomotor symptoms such as night sweats and hot flashes as they enter the menopausal transition. Up until the release of the findings of the Women's Health Initiative (WHI) studies, women were frequently prescribed hormone therapy (HT) to alleviate bothersome and sometimes debilitating menopausal symptoms as well as to prevent osteoporosis and coronary heart disease (CHD). Although the WHI studies were the first large, randomized, controlled trials that contradicted what was historically believed about the benefits of HT in postmenopausal women, important limitations including baseline demographics of WHI participants and investigation of only one HT strength/dosage form exist. HT may be a reasonable pharmacotherapy option for the management of menopausal symptoms following complete patient evaluation by experienced clinicians. Updated recommendations addressing management of menopausal symptoms, a new HT product containing the spironolactone-analogue drospirenone (DRSP), and discontinuation methods of HT are also discussed in this review.     

Non-hormonal treatment strategies for vasomotor symptoms: a critical review

Hot flashes (or flushes) are the most commonly reported symptoms during the menopause transition and early postmenopausal years, particularly in Western societies; they affect 60-90% of women and can lead to significant physical discomfort and functional impairment. The emergence of hot flashes and night sweats (also known as vasomotor symptoms [VMS]) coincide with a period in life that is also marked by dynamic changes in hormone and reproductive function that interconnect with the aging process, changes in metabolism, lifestyle behaviours and overall health. Estrogen-based therapies have long been the treatment of choice for women suffering from VMS. More recent concerns over long-term safety of menopausal hormone treatments, however, have led physicians and patients to pursue non-hormonal strategies to alleviate their symptoms. In this article, we review most of the efficacy and safety data on non-hormonal treatments for VMS published over the past 20 years. We discuss the evidence for treating symptomatic women in different clinical scenarios, e.g. VMS with and without concomitant depression or VMS following the use of anti-estrogen therapies. Overall, efficacy data support the use of some psychotropic medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and gabapentin. Complementary and alternative methods for VMS also showed limited but promising results, although more definitive studies are warranted. Clinicians should therefore be able to tailor treatment strategies for those who are unable or unwilling to use hormones to alleviate VMS and improve overall functioning and quality of life.     

Ospemifene use in postmenopausal women

Background: Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen agonists and antagonists. These drugs have been intensively studied over the past decades and have proven to be a highly versatile group for the treatment of different conditions associated with menopause, including hormone-responsive cancer and osteoporosis. However, currently available SERMS are also responsible for side effects such as thromboembolic disorders, or gynecological symptoms (especially vaginal dryness and hot flushes). Objective/methods: The purpose of this article is to review the clinical trials of ospemifene, a new SERM in Phase III development for the treatment of vulvar and vaginal atrophy. The medical literature was reviewed for appropriate articles containing the terms ‘ospemifene’ and ‘SERMs’. Results/conclusions: The recently released results from a pivotal Phase III study in postmenopausal women demonstrated statistically significant improvements of ospemifene 60 mg/day in symptoms of vulvar and vaginal atrophy over the use of non-hormonal vaginal lubricant. Ospemifene also appeared to be well tolerated, with few patients experiencing side effects. The additional positive results on bone and the breast observed in preclinical studies need to be clinically confirmed to extend the therapeutic potential of this new SERM.     

The safety of veralipride

The perimenopausal period, from 1 to 4 years, is characterised by vasomotor symptoms, or hot flushes, and other effects due a deficit of estrogens. Approximately 85% of women have hot flushes for 1 year and 25 – 50% continue for up to 5 years. The cause of hot flushes has been linked to dysfunction of the thermoregulatory centre caused by estrogen withdrawal. One proposal for the aetiology of hot flushes is that the thermoregulatory zone is shifted downward in patients who experience hot flushes. Estrogen withdrawal creates a change of the central opioid system and a thermoregulatory instability. Estrogen and/or progestin replacement is the treatment of choice for this distressing symptom. However, steroid replacement may be associated with risks and complications, and is limited in some subjects by well-known contraindications. Veralipride, a synthetic benzamide derivative with antidopaminergic action, is effective in reducing the frequency and severity of hot flushes associated with menopausal hypoestrogenism, gaining interest as a non-hormonal treatment for climacteric flushing. In recent years, extrapyramidal disorders associated with veralipride therapy have been reported and are often due to drug misuse. Adverse effects include acute dyskinesia or Parkinsonism, which may occur after many months of treatment. An association between adverse effects and mistake of administration has been described. This article discusses available data on the benefits and risks of veralipride therapy for menopausal symptoms.     

The safety of veralipride

The perimenopausal period, from 1 to 4 years, is characterised by vasomotor symptoms, or hot flushes, and other effects due a deficit of estrogens. Approximately 85% of women have hot flushes for 1 year and 25 - 50% continue for up to 5 years. The cause of hot flushes has been linked to dysfunction of the thermoregulatory centre caused by estrogen withdrawal. One proposal for the aetiology of hot flushes is that the thermoregulatory zone is shifted downward in patients who experience hot flushes. Estrogen withdrawal creates a change of the central opioid system and a thermoregulatory instability. Estrogen and/or progestin replacement is the treatment of choice for this distressing symptom. However, steroid replacement may be associated with risks and complications, and is limited in some subjects by well-known contraindications. Veralipride, a synthetic benzamide derivative with antidopaminergic action, is effective in reducing the frequency and severity of hot flushes associated with menopausal hypoestrogenism, gaining interest as a non-hormonal treatment for climacteric flushing. In recent years, extrapyramidal disorders associated with veralipride therapy have been reported and are often due to drug misuse. Adverse effects include acute dyskinesia or Parkinsonism, which may occur after many months of treatment. An association between adverse effects and mistake of administration has been described. This article discusses available data on the benefits and risks of veralipride therapy for menopausal symptoms.     

Evaluating the evidence for over-the-counter alternatives for relief of hot flashes in menopausal women

ObjectiveTo review the literature on alternative over-the-counter (OTC) therapies for the treatment of hot flashes in menopausal women.Data sourcesA literature search was conducted using PubMed, International Pharmaceutical Abstracts, and Medline from inception to June 2010, combining the term hot flash individually with black cohosh, isoflavones, red clover, soy, vitamin E, ginseng, dong quai, evening primrose oil, wild yam, kava, and melatonin. All publication types including human participants and published in English were eligible for review. These articles, relevant abstracts, and additional references were used to collect pertinent data.Study selection and data extractionClinical trials comparing the above single-ingredient agents with placebo or active treatment were selected. In addition, only studies assessing the effects of these single-ingredient agents on vasomotor symptoms in menopausal women were included.Data synthesisSince the Women's Health Initiative and Heart and Estrogen/Progestin Replacement Study II, women have sought lifestyle changes and other drug therapies as alternatives to menopausal hormone therapy to relieve hot flashes associated with menopause. The currently available literature is conflicting in regard to efficacy and does not support the use of alternative OTC therapies for hot flash management associated with menopause. In addition, long-term safety data are lacking for any of these therapies.ConclusionWomen should be encouraged to implement therapeutic lifestyle changes to assist them with hot flash management. Based on the current literature, alternative OTC therapies do not have consistent, beneficial data to support their use in hot flash management.     

Physiology of thermoregulatory dysfunction and current approaches to the treatment of vasomotor symptoms

Vasomotor symptoms (VMS), including hot flushes and night sweats, are the most common symptoms associated with menopause. Although the physiology of hot flushes is not fully defined, understanding the complex thermoregulatory circuitry that underlies VMS is important for the development of new therapies. This circuitry is composed of three distinct, yet interconnected, components: core body temperature, neurochemical messaging and peripheral vasculature. Evidence suggests that multiple physiological systems, including the neuroendocrine system, are important in the maintenance of thermoregulatory control. Causative roles of declining ovarian steroid levels in initiating thermoregulatory dysfunction are well documented. This paper reviews the physiology involved in the underlying thermoregulatory dysfunction that presumably causes VMS and discusses how this physiology relates to current and future VMS treatment options.     

Treatment of hot flushes in breast and prostate cancer

Hot flushes, the most common health problem reported by menopausal-age women, can lead to significant morbidity and affect the social life, ability to work and sleep pattern of the sufferer. Women treated for breast cancer and men receiving androgen ablation for prostate cancer experience hot flushes that are more frequent, severe and longer lasting than those experienced by the general menopausal population. In women with breast cancer, hot flushes can result from chemotherapy-induced menopause, hormonal therapy, or ovarian suppression. In men with prostate cancer, hot flushes occur after surgical or medical castration. Hormone replacement therapy with oestrogen-based compounds has been a mainstay of treatment for hot flushes during the perimenopausal period. However, recent studies have shown that, in healthy menopausal women, hormone replacement therapy is associated with an increased risk of breast cancer, myocardial infarction, thrombo-embolic events and stroke. Thus, identifying nonhormonal agents that can control hot-flush symptoms is essential to the quality of life of a growing population of cancer survivors. The most promising agents act on the CNS and include selective serotonin reuptake inhibitors, as well as venlafaxine and gabapentin.     

A risk-benefit assessment of estrogen therapy in postmenopausal women

Estrogen therapy is extremely effective in relieving menopausal symptoms such as hot flushes, night sweats, urogenital atrophy and certain psychological symptoms. The short term side effects from this therapy are usually mild and self-limiting. They are more common in women who commence hormone replacement therapy some years after the menopause than in those who start treatment at about the time of the ovarian failure. Pre-existing gynaecological conditions such as fibroids and endometriosis can be worsened by estrogen therapy. The majority of published studies suggest a beneficial effect of postmenopausal estrogen therapy on cardiovascular and cerebrovascular disease. These effects may be mediated by favourable changes in lipids, but other mechanisms may also be involved. It is uncertain whether the adverse changes in lipids caused by progestogen therapy will reduce any of the benefits of estrogen therapy on the cardiovascular system. Osteoporosis is the major bone disease of the Western world; long term estrogen therapy will prevent its development in most postmenopausal women. The risk of endometrial carcinoma is increased with unopposed estrogen therapy; this increased risk appears to be abolished if a progestogen is added at an adequate dose and duration for each cycle. The risk of ovarian or cervical cancer is not increased with estrogen therapy. There may be an increased risk of breast carcinoma with long term postmenopausal estrogen use, but the studies show inconsistent results.     

Bazedoxifene when paired with conjugated estrogens is a new paradigm for treatment of postmenopausal women

Importance of the field: The concept of the tissue selective estrogen complex (TSEC) combining a selective estrogen receptor modulator (SERM) with one or more estrogens, aims to provide comparable efficacy to combination estrogen and progestin therapy for symptomatic menopausal women with a uterus without the need for a progestin.

Areas covered in this review: Published multi-center randomized blinded clinical trials with bazedoxifene alone and paired in combination with conjugated estrogens show an effect in hot flashes, vaginal atrophy, quality of life measures, sleep, bone density, and breast and uterine safety.

What the reader will gain: A new concept for menopausal women, bazedoxifene with conjugated estrogens (BZA-CE) TSEC, appears to provide the selective benefits of a SERM with additional benefits of estrogen without the need for a progestin. Preclinical studies with bazedoxifene alone showed that it was antagonistic in the uterine and breast tissue while an agonist in the bone. Phase II and III clinical studies of BZA-CE reveal relief from hot flashes and vaginal atrophic changes, and improvement in bone density, quality of life and sleep without breast or uterine stimulation.

Take home message: Bazedoxifene paired with conjugated estrogens in postmenopausal women relieves vasomotor symptoms and vulvovaginal atrophic changes with prevention of bone loss. Adverse events include a twofold increase risk of venous thrombosis. No evidence of stimulation of the breast, uterus or ovary was seen.     

Selective serotonin reuptake inhibitors fluvoxamine and paroxetine restore forced exercise-induced temperature dysregulation in ovariectomized mice

Hot flushes are one of the most frequent symptoms in menopausal women. Selective serotonin reuptake inhibitors (SSRIs) are considered to be first-line therapy for the treatment of hot flushes in women for whom hormone therapy is contraindicated. Recently, we have proposed forced exercise-induced flushing of tail skin in ovariectomized mice as a new experimental model of temperature dysregulation in menopausal hot flushes. In the present study, to validate this animal model as a tool for testing potential compounds for the treatment of menopausal hot flushes, we examined the effects of two SSRIs (fluvoxamine and paroxetine) on forced exercise-induced flushing of tail skin in ovariectomized mice, and compared it with that of estradiol replacement (1 mg/kg/week for 3 weeks, i.m.). Treatment with fluvoxamine (20 mg/kg, i.p.) or paroxetine (10 mg/kg, i.p.) completely inhibited forced exercise-induced flushing of tail skin in ovariectomized mice, and the effect of each was comparable to that of estradiol replacement. It is believed that the present findings provide the first experimental evidence to support the anti-flushing effects of SSRIs, such as fluvoxamine and paroxetine, in a clinical setting. An animal model with forced exercise probably serves as a useful experimental tool for evaluating the effects of different agents on hot flushes.     

Oral investigational drugs currently in phase I or phase II for the amelioration of menopausal symptoms

Introduction: Menopausal symptoms have a substantial effect on the quality of life of many women; hence, investigations for the amelioration of menopausal symptoms continue to be necessary. The two main approaches to the amelioration of symptoms are hormone therapy (HT) and non-hormonal therapy.

Areas covered: This review provides a background for understanding the types of menopausal symptoms and their underlying physiology. The early clinical development of natural estrogen (estetrol, E4), neurokinin 3 receptor (NK3R) antagonists, and other non-hormonal therapies are covered. The status and outcome of these novel treatment modalities are also discussed.

Expert opinion: The recent observation in the Women’s Health Initiative (WHI) trials that HT was not associated in the long-term with all-cause mortality, brings renewed interest in the development of new treatment modalities in postmenopausal women. Estetrol (E4), a native estrogen with selective action in tissues, is a potential next-generation HT with improved cardiovascular and breast safety. NK3R antagonists may become an interesting new modality for the amelioration of hot flushes in women with contraindications to estrogens.     

Soybean isoflavones eliminate nifedipine-induced flushing of tail skin in ovariectomized mice

Hot flushes are one of the most frequent symptoms in menopausal women. We investigated effect of soybean isoflavones (Soyaflavone HG) on nifedipine-induced flushing in ovariectomized mice. Ovariectomy markedly aggravated nifedipine-induced increase in tail skin temperature. Soyaflavone HG (10 mg/kg, p.o., once a day for 5 days) inhibited nifedipine-induced flushing in ovariectomized mice. The inhibitory effect of Soyaflavone HG was significantly reversed by an estrogen-receptor antagonist, ICI 182,780, suggesting that Soyaflavone HG prevents nifedipine-induced flushing partially through estrogen receptors. We presented the experimental evidence suggesting that soybean isoflavones including Soyaflavone HG have the benefits for menopausal hot flushes.     

Nanoparticle delivery for transdermal HRT

Nanomedicine is an emerging technology and the first nano-engineered medical products have come to light in the last decade. Transdermal drug delivery has significant advantages compared to other routes of drug administration. Nanoparticles unique physical and chemical properties enable transport of substances directly into the skin. The objective of this paper is to review different aspects of nanoparticle delivery, generally, and discuss its current use for transdermal hormone therapy. Transdermal estrogen therapy remains the most effective treatment for bothersome menopausal symptoms, particularly in those women for whom the potential adverse effects associated with “first pass” hepatic metabolism are to be avoided. Available alternatives for transdermal estrogen delivery include patches, gels, sprays and lotions. Other non-oral therapies which likewise avoid “first pass” hepatic metabolism include: subcutaneous implants and vaginal rings. Some of the transdermal products are associated with mild adverse skin effects such as redness and irritation, but more severe and bothersome consequences include blistering and tattooing. Even the mild adverse skin effects are frequently cited as reasons for discontinuation. Micellar nanoparticle estradiol emulsion (MNPEE) is a lotion-like therapy which constitutes an alternative transdermal delivery system not requiring the permeation enhancers or temporary skin digestion, both of which increase the possibility of irritation. MNPEE's advantages include low fluctuation of plasma estradiol concentrations, infrequent skin related adverse effects, and pleasant cosmetic-like moisturizing properties. The efficacy of MNPEE for management of menopausal vasomotor symptoms has been demonstrated in a randomized placebo controlled trial,¹ and the product is FDA approved for management of moderate to severe vasomotor symptoms. None of the observed adverse effects in the MNPEE group were statistically different from the placebo group.¹ Studies addressing inadvertent transference of estradiol to the male partners of menopausal women using this delivery technology have demonstrated small, but real amounts of transference, which do not exceed the normal physiological male estradiol range. MNPEE is safe and effective for treatment of vasomotor symptoms and represents the commercial validation of nanoparticle technology for transdermal delivery of estrogen therapy (ET) for postmenopausal women with vasomotor symptoms.     

Expectancy mediated effects of marijuana on menopause symptoms

Background Medical marijuana alleviates a variety of symptoms, including those associated with menopause, such as insomnia, irritability, depression and joint pain. However, little work has addressed the use of marijuana in a population of menopausal women, or the role of menopausal women’s marijuana treatment expectancies in regard to consumption. We hypothesized that menopausal women who used marijuana would expect it to alleviate symptoms that have responded well to the plant in previous research. Based on the marijuana expectancy literature, we also hypothesized that links from menopause symptoms to marijuana use would arise via indirect paths through expectancies. Methods Menopausal and post-menopausal women (N = 115) who endorsed lifetime marijuana use completed an online survey assessing their frequency of use, average intoxication – a proxy for quantity, menopause symptoms, and expectancies of relief from menopause symptoms. Results Women expected marijuana to improve joint/muscle discomfort, irritability, sleep problems, depression, anxiety and hot flashes, but not sex problems, heart discomfort, exhaustion, vaginal dryness and bladder problems. Expectancies mediated the links between menopause symptoms and frequency of use. Average intoxication did not correlate with symptoms or expectations of relief. Symptoms, expectancies, and frequency of marijuana use were all independent of marijuana-related problems. Conclusions Particularly as the population ages, increased research on how medical marijuana might help menopause symptoms without increasing marijuana-related problems could prove heuristic.     

Forced exercise-induced flushing of tail skin in ovariectomized mice, as a new experimental model of menopausal hot flushes

Hot flushes are the most common complaint of menopausal women. In the present study, a new animal model of hot flushes was established. Tail skin temperature was measured with a thermo tracer after mice were subjected to a forced exercise task using a motor driven treadmill. In ovariectomized mice, forced exercise for 10 min was most effective in increasing tail skin temperature over that of sham-operated mice. This elevation was blocked by estradiol replacement (1 mg/kg per week for 3 weeks), suggesting that our model simulates menopausal hot flushes.     

Efficacy and Tolerability of a Low-dose of Oesclim® (25 mcg Daily) in the Management of Symptomatic Menopausal Women: A French Open-label Study

Summary

Objective: To establish the proportion of symptomatic postmenopausal women, whose HRT treatment is initiated on Oesclim® 25, who can be satisfactorily maintained on this low dose after two months. Study design and patients: This was an open-label, multicentre, non-comparative, four-month treatment study. Treatment was initiated with Oesclim® 25 (17β-oestradiol transdermal patch, 25 mcg/day). Dosage could be increased to Oesclim® 50 if required after two months, according to clinical evaluation. Sequential treatment with an oral progestagen was also given for ≥12 days/month in all non-hysterectomised women. A total of 1465 women were included in the study.

Results: 82.3% (CI: 80.1–84.4) of patients remained on Oesclim® 25 across the whole study. The mean number of hot flushes was reduced similarly by 93% and 94% at month 4 in the Oesclim® 25 group and Oesclim® 50 group, respectively. However, at month 2 the decrease in hot flushes and other menopausal symptoms was less marked until the dose was adjusted, in patients switching to Oesclim® 50. In a global evaluation, 97.5% of the investigators and 95.7% of the patients rated the overall efficacy of the treatment as good/very good. Overall, treatment initiated at a low dose was well tolerated throughout the study, with a trend showing Oesclim® 25 as being better tolerated than Oesclim® 50.

Conclusion: Oesclim® low dose (25 mcg) can effectively reduce symptoms in most postmenopausal women with a very satisfactory level of tolerability. The risk/benefit ratio observed is probably one key reason for good patient compliance.     

The statins fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals

Statins have pleiotropic vascular protective effects that are independent of their cholesterol-lowering effects. The aim of the present study was to determine if statins have anti-flushing actions in an animal model of forced exercise-induced temperature dysregulation in menopausal hot flushes, and to clarify the critical role of statins in regulating vascular reactivity in the tail arteries of ovariectomized rats. Administration of fluvastatin or pravastatin (3mg/kg/day for 7days, p.o.) significantly ameliorated the flushing of tail skin in ovariectomized mice, and the effect of each statin was comparable with that of estrogen replacement (1mg/kg/week for 3weeks, i.m.). In phenylephrine-pre-contracted rat-tail arteries, ovariectomy inhibited acetylcholine-induced relaxation, but augmented sodium nitroprusside-induced relaxation. These ovariectomy-altered vasodilator responses were restored by fluvastatin treatment as well as by estrogen replacement. Nitrite/nitrate levels in the plasma of ovariectomized animals showed significantly lower values than those in sham-operated animals; this ovariectomy-reduced production of nitric oxide was improved by fluvastatin treatment. These data provide the first experimental evidence that statins such as fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals. Thus, therapeutic methods that target improvement of vasomotor dysfunction could be novel strategies for reducing menopausal hot flushes.     

Physiological aspects of menopausal hot flush

Eighteen hot flushes experimenced by eight menopausal women were studied and compared with the effects of warming in six premenopausal women. The hot flushes were associated with an acute rise in skin temperature, peripheral vasodilatation, a transient increase in heart rate, fluctuations in the electrocardiographic (ECG) baseline, and a pronounced decrease in skin resistence. Although premenopausal women had greater maximum increases in skin temperature and peripheral vasodilatation, they showed a much smaller decrease in skin resistance and no changes in heart rate or ECG baseline. These findings suggest that the onset of the hot flush is associated with a sudden and transient increase in sympathetic drive. Further investigations may lead to the development of a more specific alternative to oestrogen for relieving menopausal hot flushes.