Nick Panay

Testosterone for Low Libido in Postmenopausal Women Not Taking Estrogen

BACKGROUND The efficacy and safety of testosterone treatment for hypoactive sexual desire disorder in postmenopausal women not receiving estrogen therapy are unknown. METHODS We conducted a double-blind, placebo-controlled, 52-week trial in which 814 women with hypoactive sexual desire disorder were randomly assigned to receive a patch delivering 150 or 300 microg of testosterone per day or placebo. Efficacy was measured to week 24; safety was evaluated over a period of 52 weeks, with a subgroup of participants followed for an additional year. The primary end point was the change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes. RESULTS At 24 weeks, the increase in the 4-week frequency of satisfying sexual episodes was significantly greater in the group receiving 300 microg of testosterone per day than in the placebo group (an increase of 2.1 episodes vs. 0.7, P<0.001) but not in the group receiving 150 microg per day (1.2 episodes, P=0.11). As compared with placebo, both doses of testosterone were associated with significant increases in desire (300 microg per day, P<0.001; 150 microg per day, P=0.04) and decreases in distress (300 microg per day, P<0.001; 150 microg per day, P=0.04). The rate of androgenic adverse events - primarily unwanted hair growth - was higher in the group receiving 300 microg of testosterone per day than in the placebo group (30.0% vs. 23.1%). Breast cancer was diagnosed in four women who received testosterone (as compared with none who received placebo); one of the four received the diagnosis in the first 4 months of the study period, and one, in retrospect, had symptoms before undergoing randomization. CONCLUSIONS In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 microg of testosterone per day resulted in a modest but meaningful improvement in sexual function. The long-term effects of testosterone, including effects on the breast, remain uncertain. (ClinicalTrials.gov number, NCT00131495.)

IMS Updated Recommendations on postmenopausal hormone therapy

The past decade has seen marked fluctuations inopinions concerning the merits and risks ofpostmenopausal hormone therapy. In July 2002,menopause management faced a major turningpoint when the first data from the Women’sHealth Initiative (WHI) trial were released. Thestudy was categorized as a primary preventiontrial for coronary heart disease, although the factthat mean age at recruitment was 63 years was notgiven enough importance at that time. WHIinvestigators concluded that hormone therapy(HT) was not cardioprotective, and, in fact, itsrisk–benefit ratio did not favor the use ofpostmenopausal hormones for prevention ofchronic diseases. As a result, there was a dramaticchange in prescription habits following recom-mendations to reserve HT for very symptomaticwomen, and to limit its use to the ‘shortestduration needed’ and ‘to the lowest effectivedosage’. This was the atmosphere in which theInternational Menopause Society (IMS) initiatedthe IMS Workshop held in Vienna (December2003) and the IMS Position Paper that was basedon the Workshop discussions. Looking at globalperspectives, and being independent of local orregional constraints imposed by official healthauthorities, this IMS Statement called for a morebalanced approach in the interpretation of thescientific data on hormone use that were availablein 2003. Since then, additional information hasbeen accumulated from both arms of the WHIstudy, observational trials and from other studies,allowing a more comprehensive review on allissues related to the use of hormones in thepostmenopausal period. In view of the above, theIMS Board decided that it is time to update the2004 Statement and to enlarge its scope tomenopause management and adult women’shealth in general. More than 30 experts from thevarious fields of menopause medicine reviewed thelatest information in a Workshop held in Budapestin February 2007.The following Recommendations express theviews of the IMS on the principles of hormonetherapy in the peri- and postmenopausal periods.Throughout the Recommendations, the term HTwill be used to cover all therapies includingestrogens, progestogens, combined therapies andtibolone.The previous IMS Statement in 2004 is stillvalid and serves as a basis for the current UpdatedRecommendations.We are aware of the geographical variationsrelated to different priorities of medical care,different prevalence of diseases, and country-specific attitudes of the public, the medicalcommunity and the health authorities towardmenopause management, which may all impacton hormone therapy. The following recommenda-tions, therefore, give a global and simple overviewthat serves as a common platform on issues relatedto the various aspects of hormone treatment.These Recommendations were reviewed and dis-cussed by representatives of more than 60National and Regional Menopause Societies fromall continents. These Recommendations can beeasily adapted and modified according to localneeds.

Testosterone treatment of HSDD in naturally menopausal women: the ADORE study

Objective To evaluate the efficacy and safety of a transdermal testosterone patch (TTP, 300 μg/day) in naturally menopausal women with hypoactive sexual desire disorder (HSDD). Methods A total of 272 naturally menopausal women, predominantly not using hormone therapy, were randomized in this 6-month, placebo-controlled, double-blind, multicenter study to receive twice weekly either TTP or an identical placebo. Efficacy endpoints measured were the 4-week frequency of satisfying sexual episodes (SSE) using the Sexual Activity Log, the sexual desire domain of the Profile of Female Sexual Function and distress by the Personal Distress Scale. Safety was assessed by adverse events, laboratory parameters and hormone levels. Results The TTP group demonstrated significant improvements in SSE (p = 0.0089) as well as in sexual desire (p = 0.0007) and reduced personal distress (p = 0.0024) versus placebo at 6 months (intent-to-treat analysis, n = 247). The results were significant for all three endpoints in the subgroup (n = 199) not using hormone therapy. Similar numbers of women treated with placebo and TTP discontinued (n = 39, 27.5% vs. n = 26, 20%), reported adverse events (including application site reactions) (n = 101, 71.1% vs. n = 81, 62.3%) and withdrew due to adverse events (n = 20, 14.1% vs. n = 9, 6.9%). No clinically relevant changes were noted in laboratory parameters. Serum free and total testosterone levels increased from baseline in the TTP group (geometric means 5.65 pg/ml and 67.8 ng/dl, respectively, at week 24) within the physiological range; no changes were seen in estradiol and sex hormone binding globulin levels. Conclusions TTP was effective in treating HSDD and improving sexual function in this study of naturally menopausal women with and without concurrent hormone therapy.

Updated practical recommendations for hormone replacement therapy in the peri- and postmenopause.

Henry Burger, Australia; David Archer, USA; David Barlow, UK; Martin Birkhauser, Switzerland; Joaquim Calaf-Alsina, Spain; Marco Gambacciani, Italy; Andrea Genazzani, Italy; Peyman Hadji, Germany; Ole Erik Iversen, Norway; Herbert Kuhl, Germany; Rogerio A. Lobo, USA; Thierry Maudelonde, France; Manuel Neves e Castro, Portugal; Morris Notelovitz, USA; Santiago Palacios, Spain; Tomasz Paszkowski, Poland; Eitan Peer, Israel; Amos Pines, Israel; Goran Samsioe, Sweden; John Stevenson, UK; Sven Skouby, Denmark; David Sturdee, UK; Tobie de Villiers, South Africa; Malcolm Whitehead, UK; Olavi Ylikorkala, Finland

Premature ovarian failure: a growing concern

Premature ovarian failure (POF) has been estimated to affect about 1% of women younger than 40 years, 0.1% under 30 and 0.01% of women under the age of 20. However, as the cure rates of cancers in childhood and young women continue to improve, it is likely that the incidence of prematurely menopausal women will rise rapidly. The recent adverse media reports on hormone replacement therapy (HRT) could not have come at a worse time. We live in an era when the naturally menopausal population is growing, but of even greater concern is the impact that the reporting of data from the Women’s Health Initiative (WHI) study and the Million Women Study (MWS) has had on the growing population of young women who have suffered premature ovarian failure. Data suggest that 37% of women with POF considered stopping HRT because of breast cancer fears following the original WHI/MWS reports and only 44% were aware that the reports did not apply to their age group. In the past, the focus of medical care has been on improvement of survival rates. Very little attention has been given to the maintenance of quality of life in the short term and to the avoidance of the long-term sequelae of a premature menopause. One of the main reasons for this has been the bias of economic expenditure and medical endeavor to the prolongation of life (e.g. cancer treatments) rather than towards optimizing quality of life in cancer survivors. Should this trend continue, we are in danger of creating a population of young women who have been given back the gift of life but left without the physical and/or psychological zest to live it to its full. We need urgently to determine the scale of the problem, initially by the trawling of data from all clinics that manage women with POF. The data will undoubtedly demonstrate extreme variations in management and deficiencies will emerge. Armed with this information, departments of health can then be petitioned to provide appropriate funding for the setting up of multidisciplinary units for the management of the particular psychological and physical needs of women with POF. Of even more concern are the young women who are not attending recognized clinics and are essentially ‘lost to follow up’. The reality is that we will never know the true scale of the problem. POF is a difficult diagnosis for women to accept, and a carefully planned and sensitive approach is required when informing patients of the diagnosis. In a recent study, 71% of women with spontaneous POF were unsatisfied with the manner in which they were informed by their clinician. As a minimum, the initial investigation of patients presenting with erratic periods, for which pregnancy should be excluded, should include measurement of serum follicle stimulating hormone (FSH), estradiol and thyroid hormones. If the FSH level is in the menopausal range, the test should be repeated before the diagnosis is made, as levels can fluctuate. It is particularly concerning that, in a recent study, 50% of women with amenorrhea had to consult three physicians before any sort of testing of ovarian reserve was performed. Evaluation of other hormones of ovarian origin, such as inhibin B and antimullerian hormone, improves the predictive value of ovarian reserve testing but is not indicated on a routine basis. In the long term, the polygenic inheritance of risk for spontaneous POF will be unravelled and banks of genes will be tested to give an individual her precise risk of suffering POF. CLIMACTERIC 2008;11:1–3

Menopause – natural selection or modern disease?

Menopause is now a midlife phenomenon; an increasing number of women live half of their lives in a hormone-defi cient state, many with progressively deteriorating health. We spend too much time treating disease rather than preventing it, according to a recent International Menopause Society white paper 1 . So is menopause a natural process which should just be accepted or is it a modern disease worthy of treatment? Views on the menopause tend to be polarized to one extreme or the other, with very few people ‘ sitting on the fence ’ . In order to unravel the ‘ menopause conundrum ’ , it is necessary to explore the causes, consequences and attitudes towards menopause from anthropological, evolutionary, historical and modern perspectives.

Endometrial safety and tolerability of AERODIOL ® (intranasal estradiol) for 1 year

OBJECTIVE the purpose of this study was to assess the endometrial safety and patient acceptability of a pulsed estrogen therapy provided by S21400 (intranasal 17 beta-estradiol) in the treatment of postmenopausal symptoms. DESIGN postmenopausal women (n=408) entered an open-label, community based, multicentre trial. Patients received S21400 plus sequential (>90% of patients) or continuous progestogen. Treatment was initiated with a standard daily dose of 300 microg but dose adaptation was possible every 3 months from 150 to 600 microg daily. Endometrial biopsies were performed at entry and at 12 months, and bleeding patterns were recorded at 3-monthly intervals throughout the trial. RESULTS 71% of patients received 300 microg per day S21400 throughout the study, 3% had their dose decreased, 19% had their dose increased and 7% had their dose both decreased and increased. Three hundred and eleven biopsies were obtained after 12 months of treatment, there were no cases of endometrial hyperplasia. The 95% confidence interval [CI] for the rate of incidence was 0-1.2%. Cyclical bleeding occurred in 82% of sequential treatment cycles. Unexpected bleeding occurred in 5% of the treatment cycles. Presence of unexpected bleeding varied according to the treatment regimen, 15 and 4% of the cycles with combined continuous and sequential regimen, respectively. Unexpected bleeding was mostly spotting. Nasal treatment was well accepted. Nasal symptoms (itching sensation, rhinorrhea and sneezing) were mostly mild in intensity and they led to treatment withdrawal in approximately 3% of patients. The rate of treatment continuation was 85% at 1 year. CONCLUSIONS S21400, in combination with continuous or sequential progestogen, exhibits good endometrial safety and patient acceptability in postmenopausal women.

Vulvovaginal atrophy – a tale of neglect

The impact of vulvovaginal atrophy ( VVA ) on quality of life continues to be underestimated according to an expert review published in this issue of Climacteric 1 . The reasons for this are multiple and complex. Women are reluctant to complain about the problem for risk of personal embarrassment and for social and cultural reasons. Health care providers are reluctant to bring the problem up in consultation because they are uncomfortable discussing sexual issues and for fear of triggering extensive complex dialogue with limited time to deal with the consequences; they also lack knowledge as to the available effective treatment options, both hormonal and non-hormonal. Even though we have an a g ing population where more than 50% of postmenopausal women suffer with VVA, the subject is avoided both in social conversation and in the media. Women and their sexual partners are , in effect, suffering in silence. Whilst social and cultural taboos are diffi cult to deal with, we believe that there are a number of action points which the wider medical profession (doctors, pharma companies, health departments and regulators) should be urgently addressing to improve the situation. First and foremost, formal research into VVA should be expanded to confi rm the scale of the problem and the impact it has on quality of life . Although highly informative, all VVA surveys such as VIVA 2 are unavoidably biased by the type and size of study population selected , and information is limited by the choice of questions asked. Is the scale of the VVA problem even larger than we think because women are reluctant to admit to having symptoms? Also, women are often confused by the meaning of terms such as ‘ vaginal dryness ’ ; to them, this could mean ‘ lack of normal discharge ’ , ‘ absence of lubrication during intercourse ’ , or both. The ‘ most bothersome symptom ’ question, now mandatory in FDA-approved studies, attempts to individuali z e VVA problems, but runs the risk of devaluing other VVA symptoms which also impact on overall well being and quality of life. The formal assessment of quality of life in relation to VVA remains an unaddressed issue both in research and clinical practice. In the absence of specifi c VVA quality-of-life rating scales, sexual quality-of life scales are currently used as ‘ surrogates ’ to assess the effect of VVA symptoms , but what about the impact on women who are not sexually active? There has been some recent progress in this area through adaptation of a dermatology quality-of-life scale 3 . However, by the admission of the authors of the paper, there is considerable work still to be done. The ultimate goal must be to devise a practical, validated questionnaire which accurately assesses the impact of VVA symptoms on personal, social and professional aspects of quality of life. Despite guidelines issued by the International Menopause Society and other societies 4,5 , there continues to be confusion regarding key issues in the use of local estrogen therapy, particularly in primary care. Unfounded concerns are often raised, despite these issues having been clarifi ed by the society recommendations. The most commonly raised concerns include:

Are oestrogens useful for the treatment of depression in women

The relationship between mood changes and the menstrual cycle has been recognized for many years. Initial treatments involved removal of the ovaries to prevent fluctuation of oestradiol, but this was also associated with the long-term effects of hypo-oestrogenism such as osteoporosis or heart disease. More recently, the use of high-dose oestrogen has been explored with some success. A diagnosis of hormone-related depression is made on the history, where the problem is worse at a time of hormone fluctuation such as occurs in the premenstrual phase, in the postnatal period and in the years leading up to the menopause. Many women may only feel well for a minority of days in the month and the problem can become chronic. Antidepressant medication is not usually successful, although this is often the preferred treatment for general practitioners and psychiatrists, possibly because of the potential side-effects of high-dose oestrogen administration. This chapter covers the diagnosis and treatment of premenstrual depression, postnatal depression and depression occurring in the climacteric period to emphasize the chronic nature of the problem and the best ways of diagnosing and relieving this distressing condition.

Bioidentical hormones: what is all the hype about?

Since the publication of the Women’s Health Initiative (WHI) study, we have been trying to fully understand why some of the study participants ran into problems. It is now generally accepted that these problems primarily arose due to an older generation of women being given a relative overdose of hormone replacement therapy (HRT). There has subsequently been a trend towards using lower doses and restricting HRT initiation to women younger than 60 years. However, it is also possible that the adverse outcomes in the WHI were not necessarily due to a HRT class effect. Fundamental differences exist between conjugated equine estrogens and 17b-estradiol and between medroxyprogesterone acetate (MPA) and natural progesterone. It is possible that these differences might have also accounted for the adverse outcomes in the WHI that were contrary to the cardiovascular outcomes seen in previous trials. This Editorial explores the possibility that different outcomes might be achieved, not only by varying the dose and age of initiation, but by the use of bioidentical hormones.