J Sex Med. 2011 Dec;8(12):3262-70. doi: 10.1111/j.1743-6109.2011.02447.x. Epub 2011 Aug 24.

Satisfying sexual events as outcome measures in clinical trial of female sexual dysfunction.

Kingsberg SA, Althof SE.

OB/GYN Behavioral Medicine, University Hospitals Case Medical Center Cleveland, OH, USA Case Western Reserve University School of Medicine, Cleveland, OH, USA Center for Marital and Sexual Health of South Florida, West Palm Beach, FL, USA.

Introduction. Assessing the sexual response in women with female sexual dysfunctions (FSDs) in clinical trials remains difficult. Part of the challenge is the development of meaningful and valid end points that capture the complexity of women's sexual response.

Aim. The purpose of this review is to highlight the shortcomings of daily diaries and the limitations of satisfying sexual events (SSEs) as primary end points in clinical trials of women with hypoactive sexual desire disorder (HSDD) as recommended by the Food and Drug Administration (FDA) in their draft guidance on standards for clinical trials in women with FSD.

Methods. Clinical trials in women with HSDD using SSEs as primary end points were reviewed.

Main Outcome Measures. The agreement between three outcome measures (SSEs, desire, and distress) was assessed to illustrate to what degree improvements in SSEs were in agreement with improvements in sexual desire and/or personal distress.

Results. Nine placebo-controlled randomized trials in women with HSDD were reviewed: seven with transdermal testosterone and two with flibanserin. In four trials, all using transdermal testosterone 300 µg/day had agreement between changes in SSEs, desire, and distress. In five studies (testosterone 300 µg/day, n = 2; testosterone 150 µg/day, n = 1; flibanserin n = 2), changes in SSEs did not correlate with changes in desire and/or distress and vice versa. It should be noted that in the flibanserin trials, SSEs did correlate with desire assessed using the Female Sexual Function Index but not when it was assessed using the eDiary.

Conclusions. Findings in the literature do not uniformly support the recommendations from the FDA draft guidance to use diary measures in clinical trials of HSDD as primary end points. Patient-reported outcomes appear to be better suited to capture the multidimensional and more subjective information collected in trials of FSD.

Kingsberg SA and Althof SE. Satisfying sexual events as outcome measures in clinical trial of female sexual dysfunction. J Sex Med **;**: **-**.

© 2011 International Society for Sexual Medicine.

Pubmed

J Sex Med. 2011 Nov;8(11):3160-72. doi: 10.1111/j.1743-6109.2011.02458.x. Epub 2011 Sep 20.

["The US Food and Drug Administration's (FDA) Reproductive Health Drugs Advisory Committee voted 10 to 1 on June 18 [2010] that flibanserin, 100 mg (Girosa; Boehringer Ingelheim), was not significantly better than placebo for hypoactive sexual desire disorder (HSDD); they also voted unanimously that the benefits did not compensate for its adverse effects." Medscape.com]

Continued efficacy and safety of flibanserin in premenopausal women with Hypoactive Sexual Desire Disorder (HSDD): results from a randomized withdrawal trial.

Goldfischer ER, Breaux J, Katz M, Kaufman J, Smith WB, Kimura T, Sand M, Pyke R.

Hudson Valley Urology, Poughkeepsie, New York, NY 12601, USA.

INTRODUCTION: Flibanserin is a 5-HT(1A) agonist/5-HT(2A) antagonist that has been shown to increase sexual desire and reduce distress in premenopausal women with Hypoactive Sexual Desire Disorder (HSDD).

AIM: To assess the efficacy and safety of flibanserin over 24 weeks of double-blind treatment vs. placebo in premenopausal women with HSDD who showed a predefined response after 24 weeks of open-label treatment with flibanserin. METHODS: Women (N = 738) were treated with open-label, flexible-dose flibanserin (50 mg or 100 mg/day) for 24 weeks. At week 24, women who showed a predefined response, measured using an eDiary, were randomized to 24 weeks of continued flibanserin therapy at optimized dosage (N = 163) or placebo (N = 170). The criteria for entering the double-blind phase were an increase from baseline to weeks 21-24 of ≥2 satisfying sexual events (SSE) and/or ≥4 "desire days." A "desire day" was one in which a woman reported more than "no" desire.

MAIN OUTCOME MEASURES: Coprimary endpoints were change from randomization to study end in SSE and desire score. Secondary measures included change in Female Sexual Function Index (FSFI) total and desire domain scores and Female Sexual Distress Scale-Revised (FSDS-R) total and Item 13 scores.

RESULTS: During the open-label period, mean SSE and desire score approximately doubled, and FSFI, FSDS-R total, and Item 13 scores improved. At the end of the double-blind period, flibanserin was superior to placebo in change from randomization in SSE, desire score, FSFI desire domain and total scores, and FSDS-R total and Item 13 scores (P < 0.05, for all). Flibanserin was well tolerated, and withdrawal reactions were not observed.

CONCLUSIONS: At the end of the 24-week randomized withdrawal phase of a 48-week trial in premenopausal women with HSDD, flibanserin was superior to placebo [by how much?] on measures of SSE, sexual desire, overall sexual function, and sexual distress. Flibanserin was well tolerated, and no withdrawal reactions were observed following discontinuation.

© 2011 International Society for Sexual Medicine.

Pubmed

Menopause. 2011 Nov 10. [Epub ahead of print]

Characteristics of premenopausal and postmenopausal women with acquired, generalized hypoactive sexual desire disorder: the Hypoactive Sexual Desire Disorder Registry for women.

Rosen RC, Maserejian NN, Connor MK, Krychman ML, Brown CS, Goldstein I.

From the 1Department of Epidemiology, New England Research Institutes Inc., Watertown, MA; 2Southern California Center for Sexual Health and Survivorship Medicine, Newport Beach, CA; 3Departments of Obstetricsand Gynecology, University of Tennessee Health Science Center, Memphis, TN; and 4San Diego Sexual Medicine, San Diego, CA.

OBJECTIVE: Little is known about the natural history of hypoactive sexual desire disorder (HSDD). We examined the sociodemographic, relationship, help seeking, sexual function, and medical characteristics of women with a clinical diagnosis of generalized, acquired HSDD by menopause status.

METHODS: This study was a cross-sectional baseline data analysis from the HSDD Registry for Women (N = 1,574, from 33 US clinical sites). HSDD was clinically diagnosed and confirmed. Validated measures of sexual function, relationship factors, and health, as well as newly developed questions on help seeking were assessed using the questionnaire.

RESULTS: Participants were predominantly married or living with a partner (81.7%) and represented a range of race/ethnic backgrounds and ages (mean ± SD, 42.9 ± 11.9 y). Most (56.8%) described their HSDD severity as "moderate to severe," with 26.5% rating the problem severe. Nonetheless, most women (69.8%) reported being happy in their relationship, and 61.8% were satisfied with their partner communication. Postmenopausal women had lower Female Sexual Function Index total scores, indicating worse sexual function (14.0 ± 7.5) than premenopausal women (16.7 ± 6.8, P < 0.001), although both groups had similarly low scores on the sexual desire domain (3.4 ± 1.3 vs 3.3 ± 1.4). Less than half of the overall sample had sought professional help, among whom hormonal treatments had been used by 23.7% of postmenopausal women and by 7.6% of premenopausal women.

CONCLUSIONS: Most women with HSDD were in long-term partner relationships with high levels of overall relationship satisfaction. Postmenopausal women were more likely to seek help for their disorder, despite similarly high levels of distress associated with HSDD. Further research is needed to examine treatment outcomes.

Pubmed

Arch Sex Behav. 2011 Sep 3. [Epub ahead of print]

Attentional and Affective Processing of Sexual Stimuli in Women with Hypoactive Sexual Desire Disorder.

Brauer M, van Leeuwen M, Janssen E, Newhouse SK, Heiman JR, Laan E.

Department of Sexology and Psychosomatic Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Hypoactive sexual desire disorder (HSDD) is the most common sexual problem in women [affecting 1 out of 10, 10%] . From an incentive motivation perspective, HSDD may be the result of a weak association between sexual stimuli and rewarding experiences. As a consequence, these stimuli may either lose or fail to acquire a positive meaning, resulting in a limited number of incentives that have the capacity to elicit a sexual response. According to current information processing models of sexual arousal, sexual stimuli automatically activate meanings and if these are not predominantly positive, processes relevant to the activation of sexual arousal and desire may be interrupted. Premenopausal U.S. and Dutch women with acquired HSDD (n = 42) and a control group of sexually functional women (n = 42) completed a single target Implicit Association Task and a Picture Association Task assessing automatic affective associations with sexual stimuli and a dot detection task measuring attentional capture by sexual stimuli. Results showed that women with acquired HSDD displayed less positive (but not more negative) automatic associations with sexual stimuli than sexually functional women. The same pattern was found for self-reported affective sex-related associations. Participants were slower to detect targets in the dot detection task that replaced sexual images, irrespective of sexual function status. As such, the findings point to the relevance of affective processing of sexual stimuli in women with HSDD, and imply that the treatment of HSDD might benefit from a stronger emphasis on the strengthening of the association between sexual stimuli and positive meaning and sexual reward.

Pubmed

J Sex Marital Ther. 2011 May;37(3):176-89.

Sexual desire, distress, and associated factors in premenopausal women: preliminary findings from the hypoactive sexual desire disorder registry for women.

Connor MK, Maserejian NN, De Rogatis L, Meston CM, Gerstenberger EP, Rosen RC.

New England Research Institutes, Watertown, Massachusetts 02472, USA.

This article presents data from a validation sample of 390 premenopausal women clinically diagnosed with hypoactive sexual desire disorder (HSDD) enrolled in the HSDD Registry for Women. Participants completed validated measures of sexual distress (e.g., Female Sexual Distress Scale Revised, Question 13) and sexual function including desire (e.g., Female Sexual Function Index). Results showed that lower levels of desire in these women were associated with diminished sexual satisfaction, increased sexually related distress, and fatigue or stress in the women's lives. In addition, the level of distress related to sexual desire decreased with age. The authors conclude that even among women with clinically diagnosed HSDD, the level of sexually related distress varies with situational factors, such as stress and fatigue.

Pubmed

Horm Behav. 2011 May;59(5):772-9. Epub 2011 Apr 14.

Sexual desire, sexual arousal and hormonal differences in premenopausal US and Dutch women with and without low sexual desire.

Heiman JR, Rupp H, Janssen E, Newhouse SK, Brauer M, Laan E.

The Kinsey Institute for Research in Sex, Gender, and Reproduction, Indiana University, Bloomington, IN 47405, USA.

The interaction between women's hormonal condition and subjective, physiological, and behavioral indices of desire or arousal remains only partially explored, in spite of frequent reports from women about problems with a lack of sexual desire. The present study recruited premenopausal women at two sites, one in the United States and the other in the Netherlands, and incorporated various measures of acute [rapid onset] changes in sexual desire and arousal. A sample of 46 women who met criteria for Hypoactive Sexual Desire Disorder (HSDD) was compared to 47 women who experienced no sexual problems (SF). Half of each group used oral contraceptives (OCs). The specific goal was to investigate whether there is a relationship between women's hormone levels and their genital [physical and measurable] and subjective [mental and not measurable] sexual responsiveness. Background demographics and health variables, including oral contraceptive (OC) use, were recorded and hormones (total testosterone (T), free testosterone (FT), SHBG, and estradiol) were analyzed along with vaginal pulse amplitude [a measure of blood engorgment] and self-report measures of desire and arousal in response to sexual fantasy, visual sexual stimuli, and photos of men's faces. Self-reported arousal and desire were lower in the HSDD than the SF group, but only for women who were not using oral contraceptives. Relationships between hormones and sexual function differed depending on whether a woman was HSDD or not. In line with prior literature, FT was positively associated with physiological and subjective sexual arousal in the SF group. The HSDD women demonstrated the opposite pattern, in that FT was negatively associated with subjective sexual responsiveness. The findings suggest a possible alternative relationship between hormones and sexual responsiveness in women with HSDD who have characteristics similar to those in the present study.

Copyright © 2011. Published by Elsevier Inc.

Pubmed

J Sex Med. 2011 May;8(5):1411-9. doi: 10.1111/j.1743-6109.2011.02216.x. Epub 2011 Feb 16.

Gepirone-ER treatment of hypoactive sexual desire disorder (HSDD) associated with depression in women.

Fabre LF, Brown CS, Smith LC, Derogatis LR.

Fabre-Kramer Pharmaceuticals, Houston, TX, USA.

Comment in J Sex Med. 2011 Oct;8(10):2954.

INTRODUCTION: There is currently no Food and Drug Administration (FDA)-approved treatment for hypoactive sexual desire disorder (HSDD). FDA approval of products utilizing testosterone has been delayed due to possible safety concerns. Flibanserin, a 5-HT(1A) agonist, 5-HT(2) antagonist, and gepirone-ER, a 5-HT(1A) agonist, have been shown to have activity in treatment of HSDD. However, more recently [June 2010], the FDA issued a non-approval letter for flibanserin.

AIM: To study the effect of gepirone-ER on HSDD in women with major depressive disorder (MDD).

METHODS: At baseline and post-treatment visits, a trained psychiatrist made diagnoses of HSDD based on Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria. Subjects meeting criteria for HSDD were followed to observe the effect of gepirone-ER (20-80 mg/day), comparator antidepressants (fluoxetine, 20-40 mg/day or paroxetine, 10-40 mg/day), or placebo in reversing DSM-IV diagnosis. A subpopulation of women with Hamilton Depression Rating Scale (HAMD-17) entry scores of 18 or less was evaluated. Adverse events (AEs) of sexual dysfunction were also collected.

MAIN OUTCOME MEASURE: Number (%) of patients who no longer met criteria for HSDD (percent resolved).

RESULTS: Eight hundred seventy-five women (18-64 years of age, average 38 years old, ~80% premenopausal) entered three studies; 668 (72.5%) completed. Only 161 (18.4%) met DSM-IV criteria for HSDD. Cumulatively, 63% of gepirone-ER-treated patients reversed their diagnosis of HSDD compared to 40% of placebo-treated patients at end point (8 weeks) (P = 0.007). Selective serotonin reuptake inhibitor-treated patients were not different from placebo. Significant results for gepirone-ER occurred by week 2 (P = 0.0001). Patients who were mildly depressed (HAMD scores of 18 or less) also improved at week 2 (P = 0.01) and week 8 (P = 0.07). Sexual dysfunction AEs were significantly less in gepirone-ER-treated patients than placebo (P = 0.013).

CONCLUSIONS: Gepirone-ER may have efficacy [capacity or power to produce a desired effect] in the treatment of HSDD among depressed and possibly nondepressed women. Efficacy occurs by week 2, and does not seem to be purely an antidepressant effect.

© 2011 International Society for Sexual Medicine.

Pubmed

J Psychopharmacol. 2011 Mar;25(3):370-8. Epub 2010 Jan 15.

Reversal of SSRI-induced female sexual dysfunction by adjunctive bupropion in menstruating women: a double-blind, placebo-controlled and randomized study.

Safarinejad MR.

Shahid Beheshti University MC, Tehran, Iran.

A significant number of patients undergoing treatment with selective serotonin reuptake inhibitors (SSRIs) report sexual dysfunction. SSRI-induced sexual dysfunction adversely affects quality of life and patient adherence to and compliance with treatment regimens. This trial examined the efficacy and safety of adjunctive bupropion in the treatment of SSRI-induced female sexual dysfunction. Sexual function was assessed by using the sexual function domains of the Female Sexual Function Index (primary efficacy outcome measure) and the Clinical Global Impression Scale adapted for sexual function (secondary efficacy outcome measure). End point treatment satisfaction was assessed using a Visual Analog Scale. A total of 218 women (25-45 years old) with SSRI-induced sexual dysfunction were randomized to receive 12 weeks of double-blind fixed dosed treatment with bupropion sustained release 150 mg b.i.d. (n = 109) or placebo (n = 109). The mean (SD) for Female Sexual Function Index total score was higher in the bupropion sustained release group (25.9 (5.12), 95% confidence interval (CI) 22.2-29.4) than in the placebo group (17.2 (4.9), 95% CI 15.8-20.1) (p = 0.001). Mean (SD) Clinical Global Impression Scale score for the bupropion group (2.4 (0.6), 95% CI 2.0-3.6) was significantly lower than that for the placebo group (4.2 (0.8), 95% CI 3.4-5.4) (p = 0.001). At the end of the trial the mean (SD) scores for desire (4.1 (0.7), 95% CI 3.5-4.8) (p = 0.001), arousal (4.4 (0.6), 95% CI 3.7-4.8) (p = 0.01), lubrication (4.4 (0.4), 95% CI 3.3-4.8) (p = 0.001), orgasm (4.4 (0.5), 95% CI 3.7-4.7) (p = 0.001), and satisfaction (4.2 (0.7), 95% CI 3.4-4.8) (p = 0.001) were significantly higher in the bupropion group. The highest improvement was observed in sexual desire, followed by lubrication. Compared with baseline, desire and lubrication domains increased by 86.4% (95% CI 64.9-102.2%, p = 0.001) and 69.2% (95% CI 44.7-82.6%, p = 0.001) in the bupropion group. Adjunctive treatment with bupropion sustained release during a 12-week period significantly improved key aspects of sexual function in women with SSRI-induced sexual dysfunction.

Pubmed

J Sex Med. 2011 Mar;8(3):742-53. doi: 10.1111/j.1743-6109.2010.02146.x. Epub 2010 Dec 8.

Predictors of sexual desire disorders in women.

Brotto LA, Petkau AJ, Labrie F, Basson R.

Obstetrics/Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada.

INTRODUCTION: A historic belief was that testosterone was the "hormone of desire." However, recent data, which show either minimal or no significant correlation between testosterone levels and women's sexual desire, suggest that nonhormonal variables may play a key role.

AIM: To compare women with hypoactive sexual desire disorder (HSDD) and those with the recently proposed more symptomatic desire disorder, Sexual Desire/Interest Disorder (SDID), on the relative contribution of hormonal vs. nonhormonal variables.

METHODS: Women with HSDD (N = 58, mean age 52.5) or SDID (N = 52, mean age 50.9) participated in a biopsychosocial assessment in which six nonhormonal domains were evaluated for the degree of involvement in the current low desire complaints. Participants provided a serum sample of hormones analyzed by gas chromatography-mass spectrometry or liquid chromatography/mass spectrometry/mass spectrometry.

MAIN OUTCOME MEASURES: Logistic regression was used to assess the ability of variables (nonhormonal: history of sexual abuse, developmental history, psychosexual history, psychiatric status, medical history, and sexual/relationship-related factors; hormonal: dehydroepiandrosterone [DHEA], 5-diol, 4-dione, testosterone, 5-α-dihydrotestosterone, androsterone glucuronide, 3α-diol-3G, 3α-diol-17G, and DHEA-S; and demographic: age, relationship length) to predict group membership.

RESULTS: Women with SDID had significantly lower sexual desire and arousal scores, but the groups did not differ on relationship satisfaction or mood. Addition of the hormonal variables to the two demographic variables (age, relationship length) did not significantly increase predictive capability. However, the addition of the six nonhormonal variables to these two sets of predictors significantly increased ability to predict group status. Developmental history, psychiatric history, and psychosexual history added significantly to the predictive capability provided by the basic model when examined individually.

CONCLUSIONS: Nonhormonal variables added significant predictive capability to the basic model, highlighting the importance of their assessment clinically where women commonly have SDID in addition to HSDD, and emphasizing the importance of addressing psychological factors in treatment.

© 2010 International Society for Sexual Medicine.

Pubmed

CNS Spectr. 2011 Feb 1. pii: Kingsberg. [Epub ahead of print]

Female Sexual Disorders: Assessment, Diagnosis, and Treatment.

Kingsberg SA, Knudson G.

Case Western Reserve University School of Medicine.

Sexual health is important to overall health and quality of life. Sexual problems have been associated with relationship problems and may interfere with overall health and they may also be a marker for other undiagnosed comorbid medical conditions. In order for healthcare professionals to manage the sexual health concerns of their patients, it is important for them to understand what constitutes good sexual health. To that end, it is necessary to have a working knowledge of the evolving theoretical models offered to describe a healthy sexual response as well as an understanding of the neurobiology of sexual function. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Revised lists six primary female sexual disorders: hypoactive sexual desire disorder, sexual aversion disorder, female sexual arousal disorder, female orgasmic disorder, dyspareunia, and vaginismus. Despite a growing awareness of the high prevalence of sexual disorders they are not typically identified nor treated. There are a number of reasons why clinicians fail to identify and treat sexual problems including insufficient training in sexual medicine and communication skills, time-constraints, and embarrassment. Treatment for female sexual problems is usually individualized and may include a combination of office-based education and basic counseling, cognitive-behavioral psychotherapy, pharmacotherapy, and treatment of concomitant medical conditions.

Pubmed

Gynecol Endocrinol. 2011 Jan;27(1):39-48.

Safety and tolerability of testosterone patch therapy for up to 4 years in surgically menopausal women receiving oral or transdermal oestrogen.

Nachtigall L, Casson P, Lucas J, Schofield V, Melson C, Simon JA.

New York University School of Medicine, New York, NY 10016, USA.

Two clinical trials previously demonstrated the safety of 300μg/day transdermal testosterone patch (TTP) treatment for up to 6 months in 1094 surgically menopausal women with hypoactive sexual desire disorder (HSDD). Adverse events (AE), clinical laboratory tests, vital signs, physical examinations and mammograms were evaluated in open-label extensions of these two trials for up to 4 years and are presented in this article. Nine hundred and sixty-seven patients received at least one application of the TTP resulting in 1092 patient-years of exposure. There was no increase over time in the rate of new occurrences or severity of AEs, serious AEs, or withdrawals due to AEs. The most common AEs associated with treatment were application site reactions and unwanted hair growth; however, most were mild and rarely resulted in study withdrawal. No clinically meaningful changes in serum chemistry, haematology, lipid profile, carbohydrate metabolism, renal and liver function or coagulation parameters were noted with up to 4 years of therapy. Consistent with age-appropriate expected rates, three cases of invasive breast cancer were observed. No important changes in the safety or tolerability profile of TTP were revealed with long-term use for up to 4 years in otherwise healthy oophorectomised women with HSDD on concomitant oestrogen.

Pubmed

Womens Health (Lond Engl). 2011 Jan;7(1):95-107.

Hypoactive Sexual Desire Disorder and current pharmacotherapeutic options in women.

Palacios S. Palacios Institute of Woman's Health, Antonio Acuña, 9, 28009, Madrid, Spain.

Hypoactive Sexual Desire Disorder (HSDD) is the most common female sexual dysfunction. The diagnosis of HSDD requires the existence of personal distress or interpersonal difficulties associated with low sexual desire, that cannot be explained by any other psychiatric affection and that is not exclusively due to a disease or substance. HSDD can have a serious effect on emotional wellbeing and interpersonal relationships, and it occurs in premenopausal and postmenopausal women. The Decreased Sexual Desire Screener is a shortened diagnostic method designed to help doctors who are not specialized in female sexual dysfunction to diagnose acquired HSDD in women. There is evidence that treatment with androgens or with estrogens is effective in HSDD; however, important unanswered questions still exist. Presently, new therapeutic strategies to combat HSDD are being researched, including novel methods of testosterone provision and drugs that act upon the CNS [Central Nervous System].

Pubmed

Menopause Int. 2010 Dec;16(4):162-8.

Menopause and sexual desire: the role of testosterone.

Nappi RE, Albani F, Santamaria V, Tonani S, Martini E, Terreno E, Brambilla E, Polatti F.

Department of Morphological, Eidological and Clinical Sciences, Research Centre for Reproductive Medicine, University of Pavia, Pavia, Italy.

The present short review underlines the role of testosterone (T) in the motivational and satisfaction components of women's sexuality and critically discusses the strategies to treat hypoactive sexual desire disorder (HSDD), a condition of low desire associated with personal and/or interpersonal difficulties, which is more common in surgical menopausal women. There are multiple ways androgens target the brain regions (hypothalamic, limbic and cortical) involved in sexual function and behaviour. Even though circulating available androgens have been implicated in several domains of sexual response, they seem to be related weakly to symptoms, such as low sexual desire, poor sexual arousal, orgasm and diminished well-being in postmenopausal women. The possibilities of treating low sexual desire/HSDD are multifaceted and should include the combination of pharmacological treatments able to maximize biological signals driving the sexual response, and individualized psychosocial therapies in order to overcome personal and relational difficulties. Transdermal T has been shown to be effective at a dose of 300 µg/day both in surgically and naturally menopausal women replaced with estrogen or not, without any relevant side-effects. However, the decision to treat postmenopausal women with HSDD with T is mainly based on clinical judgement, after informed consent regarding the unknown long-term risks.

Pubmed

Menopause. 2010 Nov-Dec;17(6):1114-21.

Hypoactive sexual desire disorder in a population-based study of Brazilian women: associated factors classified according to their importance.

Abdo CH, Valadares AL, Oliveira WM Jr, Scanavino MT, Afif-Abdo J.

Department and Institute of Psychiatry, Medical School, University of São Paulo (FMUSP), São Paulo, Brazil.

Comment in Menopause. 2010 Nov-Dec;17(6):1097-8.

OBJECTIVE: The etiology of hypoactive sexual desire disorder (HSDD) is known to be multifactorial, involving biological, psychosexual, and context-related factors. The objective of the present study was to analyze the factors associated with female HSDD and to stratify these factors according to their importance.

METHODS: This was a population-based, hierarchical study conducted in Brazil, based on data from previous research on the Brazilian Sexual Life Study, conducted between November 2002 and February 2003 in various Brazilian cities. The primary study consisted of a self-administered and anonymous questionnaire, addressing sociodemographic parameters, general health, life habits, behavior, and complaints related to sexual function. The association between HSDD and various other factors was assessed. The data were evaluated by hierarchical multiple regression analysis.

RESULTS: The prevalence of HSDD in this sample was 9.5%. Associations were found with cardiovascular disease, breast cancer, posttraumatic stress, poorer education level, being older, being married, a lack of information on sexuality in childhood/adolescence, and a limited sexual repertoire. Women who consumed moderate amounts of alcohol were found to be less likely to have HSDD.

CONCLUSIONS: Analysis of the associated factors classified in order of importance and analysis of the characteristics of the sexual relationships provide additional information to currently available data on the traditional concepts of HSDD.

Pubmed

J Womens Health (Larchmt). 2010 Nov;19(11):2001-9. Epub 2010 Oct 7.

Healthcare utilization in women diagnosed with hypoactive sexual desire disorder: interim baseline results from the HSDD Registry for Women.

Maserejian NN, Parish S, Shifren JL, Huang L, Gerstenberger E, Rosen RC.

New England Research Institutes, Inc., Watertown, Massachusetts 02472, USA.

OBJECTIVE: To investigate treatment seeking and utilization of women diagnosed with hypoactive sexual desire disorder (HSDD) in the clinical setting.

METHODS: We used interim baseline data from the ongoing HSDD Registry for Women (n = 724, enrolled at 27 clinical sites across the United States in 2008-2009). The recent diagnosis of generalized, acquired HSDD was confirmed by clinician's administration of the validated diagnostic Decreased Sexual Desire Screener. Treatment-seeking behavior was categorized as formal (discussion with a healthcare provider or use of off-label prescription treatment for HSDD) or informal/none (over-the-counter products, anonymous media, or no help seeking).

RESULTS: Over half (n = 386, 53%) of these women with clinically diagnosed HSDD had not sought formal healthcare for their decreased sexual desire problem. Among formal healthcare seekers, 36% remained untreated, whereas 64% received some form of treatment. The most common treatments reported were nonprescription lubricants or arousal creams (36%) and off-label prescription medications (20%). Women were more likely to have sought formal help if they were married/cohabiting, were postmenopausal, had private health insurance, had > 5 current prescription medications, had depression symptoms, had a longer duration of sexual desire problems, or reported that the partner relationship or sense of femininity/sexual self was threatened by HSDD.

CONCLUSIONS: In these women with HSDD, less than half had sought healthcare, but of those who had sought healthcare, almost two thirds received some form of treatment. Regardless of treatment-seeking behavior, most women had a strong desire to "feel like a normal person again" regarding sexuality, which was the most common motivating factor for treatment seeking.

Pubmed

Postgrad Med. 2010 Nov;122(6):128-36.

Low sexual desire--is it all in her head? Pathophysiology, diagnosis, and treatment of hypoactive sexual desire disorder.

Simon JA.

Department of Obstetrics and Gynecology, George Washington University, Washington, DC 20036, USA.

Hypoactive sexual desire disorder (HSDD) is thought to be the most prevalent form of female sexual dysfunction (FSD), affecting up to 1 in 10 US women. Hypoactive sexual desire disorder is defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) as persistent or recurrent deficiency or absence of sexual fantasies and thoughts, and/or desire for, or receptivity to, sexual activity, which causes personal distress or interpersonal difficulties and is not caused by a medical condition or drug. This definition has recently received criticism and recommendations for changes encompass the inclusion of duration, intensity, and frequency, and the elimination of distress as a diagnostic criterion. More recently, it has been suggested that arousal and desire be combined into one disorder for the upcoming DSM-V. Causes of low desire include chronic medical conditions, medications, surgeries, and psychosocial factors, but not necessarily increased age; both pre- and postmenopausal women can have HSDD, although the frequency appears to vary by age. Sexual function requires the complex interaction of multiple neurotransmitters and hormones, both centrally and peripherally, and sexual desire is considered the result of a complex balance between inhibitory and excitatory pathways in the brain. For example, dopamine, estrogen, progesterone, and testosterone play an excitatory role, whereas serotonin and prolactin are inhibitory. Thus, decreased sexual desire could be due to a reduced level of excitatory activity, an increased level of inhibitory activity, or both. A number of validated self-report and clinician-administered instruments are available for assessing female sexual function; however, most have been used primarily in clinical research trials. The Decreased Sexual Desire Screener (DSDS) was developed for practicing clinicians who are neither trained nor specialized in FSD to assist in making an accurate diagnosis of generalized acquired HSDD. As our understanding of the pathophysiology of HSDD increases, it may become easier for physicians to identify and treat women with low sexual desire.

Pubmed

J Sex Med. 2010 Oct;7(10):3449-59. doi: 10.1111/j.1743-6109.2010.01938.x.

Flibanserin: initial evidence of efficacy on sexual dysfunction, in patients with major depressive disorder.

Kennedy S.

University Health Network-Psychiatry, Toronto, ON, Canada.

INTRODUCTION: Flibanserin, a novel 5-HT(1A) agonist and 5-HT(2A) antagonist, has the potential to treat sexual dysfunction.

AIM: Provide historical perspective on the rationale for development of flibanserin to treat sexual dysfunction, based on post hoc analyses of data.

MAIN OUTCOME MEASURES: The Arizona Sexual Experiences (ASEX) scale and the Hamilton depression rating scale (HAMD) Genital Symptoms item.

METHODS: Sexual function outcomes are presented from four double-blind, randomized controlled studies involving a total of 369 men and 523 women diagnosed with Major Depressive Disorder. Each study had an active treatment arm to confirm assay sensitivity on the primary antidepressive endpoint. Two studies placebo, flibanserin (50mg bid), or fluoxetine (20mg qd) for 6 weeks and two involved placebo, flibanserin (50-100mg bid), or paroxetine (20-40mg qd) for 8 weeks.

RESULTS: Individual study completion rates were 77-80%. At baseline, 38% of men and 67% of women reported sexual dysfunction. Assay sensitivity was not demonstrated in the fluoxetine trials and sexual function outcomes were inconsistent. Flibanserin and placebo were associated with low rates of treatment-emergent sexual dysfunction in women during the paroxetine studies. In one study, 70% of flibanserin-treated women with baseline sexual dysfunction reported improvement in sexual function, compared with 30% of placebo-treated women. Mean change from baseline on the HAMD "Genital Symptoms" item in one paroxetine study was significantly better among flibanserin- than placebo-treated women at weeks 4, 6, and 8 (P<0.05). Sexual function adverse events across flibanserin groups were generally comparable to placebo.

CONCLUSIONS: Although these studies were not designed or powered to compare sexual function outcomes, results suggested a potential benefit of flibanserin on sexual function, particularly on female sexual desire, and provided a rationale to evaluate the efficacy of flibanserin as a treatment for female hypoactive sexual desire disorder.

© 2010 International Society for Sexual Medicine.

Pubmed

Curr Opin Obstet Gynecol. 2010 Oct;22(5):375-80.

Female sexual dysfunction and adolescents.

Greydanus DE, Matytsina L.

Pediatrics & Human Development, Michigan State University College of Human Medicine, MSU/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo, MI 49008-1284, USA.

PURPOSE OF REVIEW: To review recent publications in the area of sexual dysfunction in females including the adolescent age group.

RECENT FINDINGS: Though as many as 40% of adult females have a sexual dysfunction, the incidence among adolescent females is unknown. Though over half of adolescents are sexually active, sexual dysfunction is not a term universally accepted among the general public as well as researchers. Research on sexual dysfunction in females typically starts with age 18 years or over. Causes of sexual dysfunction include medical disorders, gynecological problems, which started from the adolescent age, psychiatric disorders, and complications of medications such as selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and others. Management includes identification of the specific sexual dysfunction and treatment of the underlying condition, including surgical treatment in such cases as absent vagina or obstetrics fistula. Psychological therapy is helpful when psychological factors are contributory to the dysfunction. Pharmacologic principles of management cases can, for example, include treatment of gynecological problems such as pelvic inflammatory disease (PID) or endometriosis as a cause of sexual dysfunction or include removal of the offending drug, use of glutamatergic strategies or trazodone in SSRI-association dysfunction, and addition of bupropion or other medications in select cases. No medication is FDA-approved for sexual dysfunction in females.

SUMMARY: Sexual dysfunction in females includes lack of sexual desire, sexual pain disorders (as dyspareunia), anorgasmia, and sexual arousal dysfunction. Acceptance of the high incidence of sexual dysfunction in all female populations is necessary to appreciate this phenomenon in the adolescent cohort, because some gynecological disease can arise from the adolescent age and can cause sexual dysfunction. Some sexual dysfunctions require immediate treatment, including surgical in the case of congenital anomaly, ovarian cyst, or tumor. Current understanding is based on extrapolation of research in the adult population. Management principles include removal of offending drugs and treatment of underlying disorders. Research in the adolescent population is recommended for more understanding and acceptance of this phenomenon in this age group.

Pubmed

J Sex Med. 2010 Oct;7(10):3439-48. doi: 10.1111/j.1743-6109.2010.01934.x.

The presentation of hypoactive sexual desire disorder in premenopausal women.

Maserejian NN, Shifren JL, Parish SJ, Braunstein GD, Gerstenberger EP, Rosen RC.

New England Research Institutes, Inc., Watertown, MA 02472, USA.

INTRODUCTION: Little is known about the clinical presentation [Dr's Office] of hypoactive sexual desire disorder (HSDD) in premenopausal women or their perceptions of sexual problems.

AIM: Describe characteristics of premenopausal women with clinically diagnosed acquired, generalized HSDD, and investigate factors perceived to contribute to desire problems.

METHODS: Cross-sectional analysis of baseline data from premenopausal women with clinically diagnosed and confirmed HSDD enrolled during the first year of the HSDD Registry for Women (N=400).

MAIN OUTCOME MEASURES: Relationship, demographic, and clinical characteristics were assessed by clinician's medical history review and self-administered questionnaire. Sexual desire function was measured by the validated Female Sexual Function Index (FSFI).

RESULTS: Over 85% of women cited multiple factors that contributed to ongoing decreased desire (mean 2.9± 2.3 factors, range 0-12). Most commonly cited contributing factors were "stress or fatigue" (60.0%), "dissatisfaction with my physical appearance" (40.8%), and other sexual difficulties (e.g., inability to reach orgasm) (33.5%). Exploratory analyses of the FSFI score confirmed that self-image (P=0.002) and other sexual problems (P<0.001) were significantly associated with decreased desire. Almost all (96%) participants were currently in a partner relationship. Antidepressant medication was currently used by 18.0% of women, hormonal contraceptives by 28.5%, and hormonal medications (for noncontraceptive reasons) by 7.3%. Physical functioning was consistent with general population norms (SF-36 mean±standard deviation, 53.3±7.6 vs. norm of 50±10), while overall mental functioning was slightly lower (SF-36, 44.7±10.6).

CONCLUSIONS: Within this sample of premenopausal women with clinically diagnosed HSDD, decreased sexual desire was associated with multiple factors, including poor self-image and stress or fatigue. Clinicians presented with premenopausal women expressing sexual desire problems should assess patients' perceptions of their condition to develop a comprehensive, patient-oriented management plan. Therapy may need to address issues with low self-esteem and mood and offer practical coping mechanisms for stress and fatigue.

© 2010 International Society for Sexual Medicine.

Pubmed

Menopause. 2010 Sep-Oct;17(5):962-71.

Role of androgens in women's sexual dysfunction.

Basson R, Brotto LA, Petkau AJ, Labrie F.

Department of Psychiatry, Vancouver Hospital, Vancouver, British Columbia, Canada.

OBJECTIVE: Although suspected, androgen deficit in women with sexual dysfunction has never been established. Given that serum testosterone levels are of limited value, we sought to compare total androgen activity in women with and without hypoactive sexual desire disorder (HSDD). Intracellular production in target tissues is the major source of testosterone in older women and can now be measured. Androgen metabolites, specifically androsterone glucuronide (ADT-G), reflect intracellular and ovarian sources of testosterone. Thus, we predicted significantly lowered levels of metabolites in women with sexual dysfunction.

METHODS: A detailed assessment of the sexual function of women without depression, without serious relationship discord, or receiving medications affecting sexual function included 121 women with HSDD and 124 sexually healthy community controls. Sexual function was assessed using structured interviews, validated questionnaires, and steroid analysis-mass spectrometry levels of ADT-G, testosterone, and precursor hormones.

RESULTS: No group differences in serum levels of testosterone or ADT-G were found. Significantly lower levels of two precursor hormones, dehydroepiandrosterone sulfate and androstene-3β,17β-diol, were found in women with sexual dysfunction (P = 0.006 and P = 0.020, respectively). The variability of metabolite and precursor levels was substantial for all women.

CONCLUSIONS: Significantly lower levels of the two precursor steroids dehydroepiandrosterone sulfate and androstene-3β,17β-diol but not the major androgen metabolite ADT-G were found in women with HSDD. Although the significance of the former awaits further study, androgen deficiency in women with HSDD was not confirmed. Given the unknown long-term effects of testosterone supplementation, women receiving testosterone therapy should be informed that a deficit of testosterone activity in women with HSDD has not been identified.

Pubmed

BJU Int. 2010 Sep;106(6):832-9. Epub 2010 Feb 11.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of bupropion [an antidepressant] for treating hypoactive sexual desire disorder in ovulating women.

Safarinejad MR, Hosseini SY, Asgari MA, Dadkhah F, Taghva A.

Urology and Nephrology Research Centre, Shahid Modarress Hospital, Shahid Beheshti University, Tehran, Iran.

OBJECTIVE: To compare the efficacy of sustained-release (SR) bupropion to placebo in treating hypoactive sexual desire disorder (HSDD) in ovulating women.

PATIENTS AND METHODS: After a 1-week, placebo lead-in phase, 232 treatment-seeking women with regular menstrual cycles were randomly assigned to bupropion SR 150 mg/daily (116) or placebo (116) for 12 weeks under double-blind conditions. Efficacy was assessed with the Brief Index of Sexual Functioning for Women (BISF-W), the Personal Distress Scale (PDS), the global efficacy question (GEQ; 'Did the treatment you received during the 12-week improve meaningful your sexual desire?') and overall patient satisfaction question ('Are you satisfied with the efficacy of your treatment?').

RESULTS: The mean (sd) composite score on the BISF-W, increased from 15.8 (2.6) and 15.5 (2.2) at baseline to 33.9 (4.2) and 16.9 (2.6) in the bupropion and placebo groups, respectively (P= 0.001). The odds ratio (95% confidence interval) for response in the bupropion group relative to placebo was 3.2 (2.1-6.3). The thoughts/desire score more than doubled in patients treated with bupropion (P= 0.001). At the 12-week evaluation the reduction in the PDS scale was 29.4% in bupropion and 4.7% in the placebo group (P= 0.01). In response to the GEQ, of patients in the bupropion and placebo groups, 65.3%, and 4.3%, respectively, responded 'Definitely yes' (P= 0.001). Of patients in the bupropion and placebo groups, 71.8%, and 3.7%, respectively, were definitely satisfied with the efficacy of their treatment, (P= 0.001). After 12 weeks of treatment, 82 women (78.1%) in the bupropion and five (4.9%) in the placebo group were willing to continue therapy (P= 0.001).

CONCLUSIONS: The results from this study indicate that bupropion SR is an effective and well-tolerated treatment for HSDD in ovulating women. Further controlled trials are warranted.

Pubmed

Maturitas. 2010 Sep;67(1):78-83. Epub 2010 Jun 16.

Hormonal and psycho-relational aspects of sexual function during menopausal transition and at early menopause.

Nappi RE, Albani F, Santamaria V, Tonani S, Magri F, Martini E, Chiovato L, Polatti F.

Research Center for Reproductive Medicine, Dept of Morphological, Eidological & Clinical Sciences, University of Pavia, Pavia, Italy.

OBJECTIVE: The aim of the present observational, cross-sectional study was to examine the effects of hormonal and psycho-relational variables on sexual function during menopausal transition and at early postmenopause in women with hot flushes.

STUDY DESIGN: The sample comprised 138 women referred to a clinic for the treatment of hot flushes. They were categorised according to their stage of menopausal transition using the STRAW criteria: early menopausal transition (EMT) if their menstrual cycle was 7 or more days different from normal; late perimenopause (LMT) if they had experienced 60 days or more of amenorrhoea; and early postmenopause (EPM) if their amenorrhoea had lasted for at least 12 months but less than 4 years.

MAIN OUTCOME MEASURES: Sexual function was measured by using the Female Sexual Function Index (FSFI), while anxiety (state and trait), depression, eating disorder and marital adjustment were evaluated by validated self-report questionnaires. Levels of free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS) and estradiol (E2) were also measured.

RESULTS: Overall sexual function varied significantly with stage of menopause, with total FSFI score less in EPM [early postmenopause] than in EMT [early menopausal transition] (p=.009). A similar pattern was evident on FSFI sub-scales for sexual desire (p=.02), arousal (p=.01) orgasm (p=.01) and also pain (p=.02), but not for lubrication and satisfaction. Ratings for anxiety, depression and eating disorder did not differ across the menopausal sub-groups, and neither did ratings of marital adjustment. Both FT (p=.01) and DHEAS (p=.03) levels were slightly reduced at EPM in comparison with EMT, as were E2 levels (p=.001 EMT versus LMT; p=.0001 LMT versus EPM). In multiple regression analyses, plasma FT level was the only factor to predict FSFI full score (beta=.48; p=0.004) in women at EMT, while in women at LMT the depression score was the only factor to do so (beta=-.62; p=0.0001). The best model predicting FSFI full score at EPM included levels of DHEAS and E2 levels and state anxiety score. [How do these results compare to women who are not experiencing hot flushes?]

CONCLUSIONS: Hormonal and some psychological variables are relevant to sexual function in symptomatic women during menopausal transition and at early menopause but their role differs with the specific stage of reproductive ageing.

Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Pubmed

Contraception. 2010 Aug;82(2):147-54. Epub 2010 Mar 31.

Effects of two combined hormonal contraceptives with the same composition and different doses on female sexual function and plasma androgen levels.

Strufaldi R, Pompei LM, Steiner ML, Cunha EP, Ferreira JA, Peixoto S, Fernandes CE.

ABC School of Medicine, Santo André, Brazil, Av. Príncipe de Gales, 821, Santo André, 09060-650 SP, Brazil.

BACKGROUND: This study was conducted to compare the effects of two contraceptive pills with different doses of the same components, on plasma androgen levels and female sexual function among women without previous sexual dysfunction.

STUDY DESIGN: The participants were randomized into two groups, to receive pills containing ethynylestradiol (EE) 30 mcg and levonorgestrel (LNG) 150 mcg or EE 20 mcg and LNG 100 mcg, for six cycles. Sexual function was assessed using a standardized questionnaire [Female Sexual Function Index (FSFI)]. Hormone assays were performed at baseline and after the sixth cycle.

RESULTS: Forty-nine women were included in the EE30/LNG150 group and 48 in the EE20/LNG100 group. EE30/LNG150 group presented 54% and 67% decreases of total testosterone and free androgen index, respectively, with statistical significance. EE20/LNG100 presented reductions of 20% and 42%, respectively, but without statistical significance. Both groups showed improvements in the FSFI "desire" score, but with statistical significance only for EE20/LNG100 group.

CONCLUSIONS: EE30/LNG150 decreased plasma androgen levels, but there was no impairment in sexual desire, on the other hand, sexual desire score increased with EE20/LNG100 formulation.

Copyright 2010 Elsevier Inc. All rights reserved.

Pubmed

Int J Womens Health. 2010 Aug 9;2:167-75.

Management of hypoactive sexual desire disorder in women: current and emerging therapies.

Nappi RE, Martini E, Terreno E, Albani F, Santamaria V, Tonani S, Chiovato L, Polatti F.

Research Center for Reproductive Medicine, Section of Obstetrics and Gynecology, Department of Morphological, Eidological and Clinical Sciences.

Hypoactive sexual desire disorder (HSDD) is a common [?] [~10%] multifactorial condition which is characterized by a decrease in sexual desire that causes marked personal distress and/or interpersonal difficulty. The general idea that HSDD is a sexual dysfunction difficult to treat is due to the large number of potential causes and contributing factors. Indeed, a balanced approach comprising both biological and psycho-relational factors is mandatory for accurate diagnosis and tailored management in clinical practice. There are currently no approved pharmacological treatments for premenopausal women with HSDD, while transdermal testosterone is approved in Europe for postmenopausal women who experience HSDD as a result of a bilateral oophorectomy. Even though the role of sex hormones in modulating the sexual response during the entire reproductive life span of women is crucial, a better understanding of the neurobiological basis of sexual desire supports the idea that selective psychoactive agents may be proposed as nonhormonal treatments to restore the balance between excitatory and inhibitory stimuli leading to a normal sexual response cycle. We conclude that the ideal clinical approach to HSDD remains to be established in term of efficacy and safety, and further research is needed to develop specific hormonal and nonhormonal pharmacotherapies for individualized care in women.

Pubmed

J Sex Med. 2010 Jul;7(7):2458-68. Epub 2010 Apr 26.

Differentiating components of sexual well-being in women: are sexual satisfaction and sexual distress independent constructs?

Stephenson KR, Meston CM.

Psychology Department, The University of Texas at Austin, Austin, TX 78712-0187, USA.

Erratum in J Sex Med. 2010 Nov;7(11):3803.

INTRODUCTION: Sexual satisfaction and sexual distress are common outcome measures in studies of sexual health and well-being. However, confusion remains as to if and how the two constructs are related. While many researchers have conceptualized satisfaction and distress as polar opposites, with a lack of satisfaction indicating high distress and vice versa, there is a growing movement to view satisfaction and distress as relatively independent factors and measure them accordingly.

AIM: The study aimed to assess the level of independence between sexual satisfaction and distress in female clinical and nonclinical samples. METHODS: Ninety-nine women (mean age = 25.3) undergoing treatment (traditional sex therapy and/or gingko biloba) for sexual arousal disorder with or without coexistent hypoactive sexual desire disorder and/or orgasmic disorder completed surveys assessing sexual satisfaction, sexual distress, sexual functioning, and relational functioning at pretreatment, mid-treatment, posttreatment, and follow-up. Two hundred twenty sexually healthy women (mean age = 20.25) completed similar surveys at 1-month intervals.

MAIN OUTCOME MEASURES: Sexually dysfunctional women completed the Sexual Satisfaction Scale for Women (SSS-W), the Female Sexual Function Index (FSFI), and the Dyadic Adjustment Scale. Sexually healthy women completed the SSS-W, the FSFI, the Relationship Assessment Scale, and the Dimensions of Relationship Quality Scale.

RESULTS: Sexual satisfaction and distress were generally closely and inversely related; however, distress was more closely related to sexual functioning variables than was satisfaction in the clinical sample, and satisfaction was more closely related to relational variables than was distress in the nonclinical sample. Additionally, satisfaction and distress showed partially independent patterns of change over time, and scales of distress showed a larger change in response to treatment than did scales of satisfaction.

CONCLUSION: Although sexual satisfaction and distress may be closely related, these findings suggest that they are, at least, partially independent constructs. Implications for research on sexual well-being and treatment outcome studies are discussed.

Pubmed

J Sex Med. 2010 Jul;7(7):2499-508. Epub 2010 May 26.

Management of female sexual problems: perceived barriers, practice patterns, and confidence among primary care physicians and gynecologists.

Abdolrasulnia M, Shewchuk RM, Roepke N, Granstaff US, Dean J, Foster JA, Goldstein AT, Casebeer L.

CE Outcomes, LLC, Birmingham, Alabama 35211, USA.

INTRODUCTION: Although approximately 40% of women report female sexual problems--and particularly sexual desire disorders, there are numerous practical, professional, and personal barriers to their diagnosis and management by treating clinicians.

AIM: To identify practice patterns, perceptions, and barriers to the diagnosis and management of female sexual problems among U.S. practicing primary care physicians (PCPs) and obstetrician/gynecologists (OB/GYNs).

METHODS: A random sample of practicing U.S. PCPs and OB/GYNs were sent a case-vignette survey by e-mail and fax. Response to the survey was considered consent. A regression model was analyzed to assess predictors of confidence.

MAIN OUTCOME MEASURE: Frequency and variability in diagnostic tests ordered and treatment recommendations provided for a patient with diminished sexual desire. Percent of physicians who reported they were confident in treating hypoactive sexual desire disorder (HSDD) and percent who reported significant barriers to initiating a dialogue about sexual health with female patients.

RESULTS: A total of 505 responses were analyzed (8.8% response rate). Of respondents, 21% of OB/GYNs and 38% of PCPs stated they were not at all confident in treating HSDD. The majority of physicians would order a thyroid panel (PCP = 63%, OB/GYN = 53%) to assess a patient's diminished desire and recommended counseling and stress management to treat a patient with sexual complaints (PCP = 48%, OB/GYN = 54%). Regression results identified time constraints, the perceived lack of effective therapies, perceptions regarding patient-physician gender discordance, years in practice, number of patients seen per week, and perceptions regarding continuing medical education and practice experience as significant and independent predictors of confidence in treating HSDD patients.

Pubmed

J Sex Marital Ther. 2010 Jul;36(4):360-80.

Why did passion wane? A qualitative study of married women's attributions for declines in sexual desire.

Sims KE, Meana M.

Department of Psychology, University of Nevada, Las Vegas, Las Vegas, Nevada, USA.

The high prevalence of sexual desire complaints in women have led a number of researchers and theorists to argue for a reconceptualization of female sexual desire that deemphasizes the drive model and places more focus on relational factors. Lacking in this effort has been a critical mass of qualitative research that asks women to report on their causal attributions for low desire. In this study, the authors conducted open-ended interviews with 19 married women who had lost desire in their marriage and asked what causal attributions they made for their loss of sexual desire and what barriers they perceived to be blocking its reinstatement. Three core themes emerged from the data, all of which represented forces dragging down on sexual desire in the present sample: (a) institutionalization of the relationship, (b) over-familiarity, and (c) the de-sexualization of roles in these relationships. Interpersonal and intrapersonal sexual dynamics featured more prominently than did relationship problems in women's attributions. The authors discuss the results in terms of clinical implications in the psychosocial component of treatment for hypoactive sexual desire disorder.

Pubmed

Int J Gynaecol Obstet. 2010 Jul;110(1):7-11.

The pathophysiology of hypoactive sexual desire disorder in women.

Clayton AH.

Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22903, USA.

Hypoactive sexual desire disorder (HSDD) is defined as a deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty. The dysfunction cannot be better accounted for by another psychiatric disorder (except another sexual dysfunction) and must not be due exclusively to the physiological effects of a substance or a general medical condition. HSDD occurs in approximately 1 in 10 adult women in the USA and its prevalence appears to be similar in Europe. A number of potential causative and contributory factors to low sexual desire have been identified, reflecting the interplay among hormonal, neurobiological, and psychosocial factors. One theory is that sexual desire is controlled in the brain by a balance between inhibitory and excitatory factors. In general, dopamine, estrogen, progesterone, and testosterone play an excitatory role in sexual desire, whereas serotonin, prolactin, and opioids play an inhibitory role. It is hypothesized that decreased sexual desire may be due to a reduced level of excitatory activity, an increased level of inhibitory activity, or both. A greater understanding of the complex pathophysiology of HSDD would improve the identification and management of women for whom low sexual desire is a concern.

Copyright (c) 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Pubmed

Expert Opin Pharmacother. 2010 Jun;11(9):1489-99.

Transdermal menopausal hormone therapy: delivery through skin changes the rules.

Buster JE.

Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Warren Alpert Medical School of Brown University, Women and Infants Hospital, 101 Dudley, Providence, Rhode Island 02905, USA.

IMPORTANCE TO THE FIELD: Transdermal hormone therapy is replacing oral estrogens and androgens as safe enhancements of life quality for postmenopausal women. Estradiol and testosterone are dosed into the microvascular circulation directly through skin so there is no first-pass hepatic transformation or deactivation of the dosed estradiol or testosterone.

AREAS COVERED IN THIS REVIEW: This review critically examines recent clinical trials describing experience with transdermal estradiol and testosterone in postmenopausal women. Transdermal estradiol is effective in the treatment of vasomotor symptoms (VMS) and can provide its benefits at higher levels of safety than have been heretofore possible with oral estrogens. Transdermal testosterone is effective in the treatment of hypoactive sexual desire disorder (HSDD) documented in multiple, well-powered randomized clinical trials with demonstrated high levels of safety.

WHAT THE READER WILL GAIN: The reader will learn that transdermal estradiol and testosterone, in properly selected postmenopausal women, significantly and safely enhance life quality, are likely to become increasingly popular, and will probably replace oral hormone therapy.

TAKE HOME MESSAGE: Transdermal delivery of native estradiol for VMS and testosterone for HSDD has significant advantages in safety and efficacy over traditional oral preparations which are now available for clinical use.

Pubmed

J Sex Med. 2010 May;7(5):1747-56. Epub 2010 Mar 10.

The HSDD registry for women: a novel patient registry for women with generalized acquired hypoactive sexual desire disorder.

Rosen RC, Connor MK, Maserejian NN.

New England Research Institutes, Inc., Watertown, MA 02472, USA.

INTRODUCTION: Hypoactive sexual desire disorder (HSDD) is a clinically challenging disorder in women. Little is known about the natural history of the disorder and long-term consequences. A longitudinal registry can address these needs.

AIM: To design and implement a registry study of HSDD in women to characterize the natural history of HSDD and current treatment practices.

METHODS: A longitudinal multicenter registry study has been initiated at clinical sites across the United States. A total of 1,500 women (approximately 1,000 premenopausal, 500 postmenopausal) with clinically-diagnosed HSDD, confirmed by the Decreased Sexual Desire Screener, will be recruited over 24 months at up to 40 clinical sites. Participants will be followed with in-clinic or remote, computer-assisted follow-up. Data from the initial implementation phase was analyzed to assess feasibility of the protocol. A qualitative substudy (N = 40) was conducted to assess content validity of the participant questionnaire.

MAIN OUTCOME MEASURES: The primary outcome measure for the Registry study is a patient-based global impression of change in HSDD. Secondary outcome measures are derived from two sources: (i) self-administered questionnaire completed by the participant, and (ii) medical history review completed by the clinician. The questionnaire includes validated measures of sexual function, quality of life, relationship factors, and physical and mental health, as well as newly developed questions on treatments and medications.

RESULTS: As of February 12, 2009, 290 women (209 premenopausal, 81 postmenopausal) had been recruited from 15 clinical sites. Results of the initial implementation phase and qualitative substudy on the participant questionnaire show that the Registry protocol is highly feasible and the questionnaire consisting of previously validated scales and selected new items has high content validity.

CONCLUSIONS: As the first longitudinal registry study in female sexual dysfunction, the HSDD Registry will contribute to a broader understanding of the impact and treatment needs of women with clinically diagnosed HSDD.

Pubmed

J Sex Med. 2010 Apr;7(4 Pt 1):1454-63. Epub 2010 Feb 5.

Women's motivations for sex: exploring the diagnostic and statistical manual, fourth edition, text revision criteria for hypoactive sexual desire and female sexual arousal disorders.

Carvalheira AA, Brotto LA, Leal I.

Research Unit of Psychology & Health, University Institute of Applied Psychology, Lisbon, Portugal.

INTRODUCTION: There are problems with the existing definition of hypoactive sexual desire disorder (HSDD) in that desire for sex and sexual fantasy are not a universal experience.

AIMS: To explore: (i) women's motivations to engage in sexual activity; (ii) frequency and predictors of sexual fantasies; (iii) sexual arousal; (iv) recognition of sexual arousal; and (v) association between relationship duration and these variables.

METHODS: Three thousand six hundred eighty-seven women completed a web-based survey of previously pilot-tested items.

MAIN OUTCOME MEASURES: Investigator-derived self-report questions of sexual desire and arousal, and sexual fantasies.

RESULTS: Among women who easily became aroused, 15.5% reported only engaging in sex if they felt sexual desire at the outset whereas 30.7% typically or always accessed desire only once they were aroused. Women in longer-term relationships engaged in sex with no sexual desire more often (42%) than women in short-term relationships (22.4%) (P < 0.001). The percentage of women that reported fantasies only sometimes was 52.5%. A logistic regression revealed that religion (odds ratio [OR] = 1.45; P < 0.001), difficulty getting aroused (OR = 0.511; P < 0.001), responsive desire (OR = 0.919; P < 0.05), and frequency of orgasm (OR = 1.11; P < 0.05) were significantly associated with sexual fantasy. After controlling for age, relationship duration was negatively associated with frequency of initiating sex (r = -0.116, P < 0.001), women's satisfaction with their own sexuality (r = -0.173, P < 0.001) and sexual satisfaction with the partner (r = -0.162, P < 0.001).

CONCLUSIONS: Results reflect diversity in women's motivations for sex, and there is evidence that responsive desire occurs in women with and without arousal difficulties. We strongly recommend relationship duration as well as adequacy of partner sexual stimulation to be recognized in any future diagnostic framework of dysfunction. Clinical implications as well as those for future diagnostic nomenclature are considered.

Pubmed

Arch Sex Behav. 2010 Apr;39(2):221-39.

The DSM diagnostic criteria for hypoactive sexual desire disorder in women.

Brotto LA.

Department of Obstetrics and Gynaecology, University of British Columbia, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada.

Hypoactive Sexual Desire Disorder (HSDD) is one of two sexual desire disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and is defined by the monosymptomatic criterion "persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity" that causes "marked distress or interpersonal difficulty." This article reviews the diagnosis of HSDD in prior and current (DSM-IV-TR) editions of the DSM, critiques the existing criteria, and proposes criteria for consideration in DSM-V. Problems in coming to a clear operational definition of desire, the fact that sexual activity often occurs in the absence of desire for women, conceptual issues in understanding untriggered versus responsive desire, the relative infrequency of unprovoked sexual fantasies in women, and the significant overlap between desire and arousal are reviewed and highlight the need for revised DSM criteria for HSDD that accurately reflect women's experiences. The article concludes with the recommendation that desire and arousal be combined into one disorder with polythetic criteria.

Pubmed

Soc Sci Med. 2010 Apr;70(7):1084-90. Epub 2010 Jan 28.

Framing disease: the example of female hypoactive sexual desire disorder.

Jutel A.

Otago Polytechnic, School of Midwifery, Private Bag 1910, Dunedin, New Zealand.

Disease classification is an important part in the process of medicalisation and one important tool by which medical authority is exerted. The demand for, or proposal of a diagnosis may be the first step in casting life's experiences as medical in nature. Aronowitz has written about how diagnoses result from social framing mechanisms (2008) and consensus (2001), while Brown (1995) has demonstrated a complex range of interactions between lay and professionals, institutions and industries which underpin disease discovery. In any case, there are numerous social factors which shape the diagnosis, and in turn, provide a mechanism by which medicalisation can be enacted. Focussing on diagnostic classification provides an important perspective on the human condition and its relationship to medicine. To illustrate how layers of social meaning may be concealed in a diagnosis, this paper uses as heuristic the relatively obscure diagnosis of Female Hyposexual Desire Disorder which is currently surfacing in medical and marketing literature as a frequent disorder worthy of concern. I describe how this diagnosis embodies long-standing fascination with female libido, a contemporary focus on female hypersexuality, and commercial interest of the pharmaceutical industry and its medical allies to reify low sexual urge as a pathological disorder in women.

(c) 2010 Elsevier Ltd. All rights reserved.

Pubmed

Climacteric. 2010 Apr;13(2):121-31.

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

Panay N, Al-Azzawi F, Bouchard C, Davis SR, Eden J, Lodhi I, Rees M, Rodenberg CA, Rymer J, Schwenkhagen A, Sturdee DW.

Imperial College Hospitals & Chelsea and Westminster Hospital, London, UK.

OBJECTIVE: To evaluate the efficacy and safety of a transdermal testosterone patch (TTP, 300 microg/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 [normal] 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.

Pubmed

Drug Saf. 2010 Mar 1;33(3):213-21. doi: 10.2165/11533720-000000000-00000.

Drug utilization of Intrinsa (testosterone patch) in England: interim analysis of a prescription-event monitoring study to support risk management.

Osborne V, Hazell L, Layton D, Shakir SA.

Drug Safety Research Unit, Bursledon Hall, Southampton, UK.

BACKGROUND: Intrinsa is a transdermal testosterone patch that is indicated for use in hypoactive sexual desire disorder (HSDD) in women who have undergone bilateral oophorectomy and hysterectomy (surgically-induced menopause) receiving concomitant oestrogen therapy.

OBJECTIVE: To describe the utilization characteristics of the patients prescribed testosterone patch (Intrinsa) based on an interim analysis of an ongoing Prescription-Event Monitoring study in England, and to assess, where possible, if the product is being used within the licensed therapeutic indication.

METHODS: In this interim analysis, patients were identified from dispensed prescriptions that had been issued by general practitioners (GPs) for Intrinsa from March 2007. 'Green form' questionnaires were sent to GPs 6 months following the date of the first prescription for Intrinsa for each individual patient, requesting information including age, sex, start and stop dates of treatment (if stopped), prescribing indication and reasons for stopping. Additional questions were asked regarding the patient's menopausal status and use of concomitant oestrogen therapy.

RESULTS: The interim cohort consisted of 756 patients. The majority of patients were reported to be female (746 [98.7%]) with a median (interquartile range) age of 50 years (44-55 years). The most commonly reported indication was the licensed indication of HSDD in 580 patients (76.7%). Just under one-half of the patients (n = 364 [48.1%]) were reported to have been hysterectomized and bilaterally oophorectomized (surgically-induced menopause) prior to starting Intrinsa; 127 patients (16.8%) were naturally menopausal. For 222 patients (29.4%) the GP specified that the patient was not using concomitant oestrogen therapy. Overall, only 219 patients (29.0%) in the cohort were being prescribed Intrinsa according to the manufacturer's recommendations.

CONCLUSIONS: This study has highlighted that some clinicians are prescribing this product outside the recommended terms of the licence, with less than 30% of patients receiving Intrinsa according to prescribing guidelines. All events experienced by these patients will be analysed to detect any possible adverse events from using Intrinsa outside of the licensed therapeutic indication. The findings support the ongoing postmarketing risk management of the product.

Pubmed

Maturitas. 2009 Jul 20;63(3):213-9. Epub 2009 May 31.

The role of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women.

Krapf JM, Simon JA.

The George Washington University, 2150 Pennsylvania Ave, NW #6A429, Washington, DC 20037, USA.

At least 16 million women over the age of 50 currently experience low sexual desire, with approximately 4 million women exhibiting hypoactive sexual desire disorder (HSDD). Although early research established that testosterone therapy improves sexual desire in postmenopausal women, safer and more efficacious administration routes were explored. Large randomized, double-blinded placebo-controlled studies demonstrate that transdermal testosterone improves sexual function and activity in postmenopausal women with HSDD. Large multi-center Phase III trials further confirm the positive effects of the testosterone patch in the treatment of HSDD. More recent studies are exploring the utility of testosterone gels. Based upon data from two recent clinical relevance studies, physicians can be reassured that postmenopausal women with HSDD report a meaningful benefit with testosterone therapy, and further, women will only continue therapy if they experience a meaningful benefit. Although most trials combined testosterone with estrogen/progesterone therapy, the recent APHRODITE trial examined testosterone alone, showing increased sexual desire with mild adverse events. Concerns regarding the long-term safety profile of transdermal testosterone must be addressed before the FDA will approve a testosterone product for women. Although some fear an increased risk of breast cancer with exogenous testosterone administration, recent studies support the idea that androgens can play a role in suppressing the proliferative effects of estrogen and progesterone. Long-term safety data is now being collected and analyzed and Phase III trials focusing on long-term risks are underway. In the meantime, transdermal testosterone appears to be a safe and effective therapy for postmenopausal women with HSDD.

Pubmed

J Sex Med. 2009 Jan;6(1):175-83.

Clinically relevant changes in sexual desire, satisfying sexual activity and personal distress as measured by the profile of female sexual function, sexual activity log, and personal distress scale in postmenopausal women with hypoactive sexual desire disorder.

DeRogatis LR, Graziottin A, Bitzer J, Schmitt S, Koochaki PE, Rodenberg C.

Johns Hopkins University School of Medicine and Center for Sexual Medicine at Sheppard Pratt-Department of Psychiatry, Baltimore, MD, USA.

INTRODUCTION: Transdermal testosterone patch (TTP) treatment produced statistically significant improvements in a satisfying sexual activity (SSA), sexual desire, and personal distress in postmenopausal women suffering from hypoactive sexual desire disorder (HSDD), but clinical significance of these changes was not determined.

AIM: To quantify the magnitude of change in three principal outcomes measures determined by HSDD patients as associated with the perception of meaningful benefit with TTP therapy.

METHODS: The criteria for defining responders were determined using anchoring methodology and receiver operating characteristics analysis to establish minimum important differences (MIDs) in a representative subsample of 132 patients in two randomized, controlled trials in surgically menopausal women with HSDD (N = 1,094). Perceived benefit was established based upon the question "Overall, would you say that you experienced a meaningful benefit from the study patches?". These data defined responders and established MIDs for changes in sexual desire, SSA, and personal distress. The MIDs were applied to the two trials to establish responder rates in each treatment group.

MAIN OUTCOME MEASURES: Changes in score that correspond to the MID for sexual desire, SSA, and personal distress, and responder rates in each treatment group based upon these values.

RESULTS: Increases in frequency of SSA of greater than 1 activity/4 weeks, increases in sexual desire score of > or = 8.9, and decreases in the personal distress score of > or = 20.0 were identified as threshold improvements best able to differentiate responders and nonresponders. The responder rate was significantly higher (P < 0.001) in the testosterone group vs. placebo for all three outcomes measures (sexual desire, 50% vs. 34%; SSA, 44% vs. 30%; personal distress, 51% vs. 39%).

CONCLUSIONS: Changes in sexual desire, SSA, and personal distress observed with TTP treatment in surgically menopausal women with HSDD were clinically significant and were associated with a meaningful treatment benefit.

Pubmed

Climacteric. 2011 Dec;14(6):609-21. Epub 2011 Sep 26.

Historical milestones in the development of tibolone (Livial(?)).

Kloosterboer HJ.

Kloosterboer Consultancy and Constructions , The Netherlands.

ABSTRACT For a new chemical entity, tibolone had a very long development period of 25 years before it was finally approved for the treatment of climacteric complaints. The reasons for this long development were its complex and fast metabolism and the poor standardization and sensitivity of analytical techniques and clinical methods. In the beginning of the new millennium, the results of primate studies and dose-finding studies in early postmenopausal women showed that tibolone had clear tissue-selective effects: it prevented hot flushes and bone loss, which are estrogen-related effects, while the estrogen-sensitive organs like breast and endometrium were not stimulated. In tissue, measurements of tibolone metabolites revealed that estrogenic metabolites were present in brain, but these metabolites were found as inactive conjugates in breast and endometrium. Attempts to find new indications for tibolone in large clinical trials failed because these studies were performed in elderly women who had already past the menopause many years ago and so unexpected side-effects became apparent due to altered metabolism and gene activation.

Pubmed

Maturitas. 2011 Dec;70(4):354-60. Epub 2011 Oct 22.

Progestogens and venous thromboembolism among postmenopausal women using hormone therapy.

Canonico M, Plu-Bureau G, Scarabin PY.

Centre for Research in Epidemiology and Population Health, U1018, Hormones and Cardiovascular Disease, Villejuif, France.

Hormone therapy (HT) is the most effective treatment for correcting menopausal symptoms after menopause. HT initially consisted of estrogens alone and progestogens were secondly added to estrogens for preventing the risk of endometrial cancer associated to estrogens use. Venous thromboembolism (VTE), including deep vein thrombosis [blood clot within blood vessel] and pulmonary embolism [blockage of respiratory artery], is a major harmful effect of HT. It is now well known that oral and transdermal estrogens are differentially associated with VTE risk but progestogens may be another important determinant of the thrombotic risk among HT users. Both randomized controlled trials and meta-analysis of observational studies suggested that the VTE risk was higher among users of estrogens plus progestogens than among users of estrogens alone. With respect to the different pharmacological classes of progestogens, there is evidence for a deleterious effect of medroxyprogesterone acetate on VTE risk. In addition, observational studies showed that norpregnane derivatives were significantly associated with an increased VTE risk whereas micronized progesterone could be safe with respect to thrombotic risk. The effect of tibolone on VTE risk remains uncertain. In conclusion, progestogens may have differential effects on VTE risk according to the molecules and therefore represent an important potential determinant of the thrombotic risk among postmenopausal women using estrogens.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Pubmed

Maturitas. 2011 Dec;70(4):365-72. Epub 2011 Oct 26.

Effects of tibolone on climacteric symptoms and quality of life in breast cancer patients--data from LIBERATE trial.

Sismondi P, Kimmig R, Kubista E, Biglia N, Egberts J, Mulder R, Planellas J, Moggio G, Mol-Arts M, Kenemans P.

Academic Department of Obstetrics and Gynaecology, University of Torino Medical School, Mauriziano Umberto I Hospital, Turin, Italy.

BACKGROUND: Climacteric symptoms such as hot flushes and vaginal dryness are very common in breast cancer patients, resulting either from age or adjuvant therapy. Tibolone, a synthetic steroid, is effective in reducing these symptoms in healthy post-menopausal women, but this has never been studied in a large breast cancer population.

OBJECTIVES: The primary objective of LIBERATE trial was to study safety of tibolone 2.5mg daily versus placebo as primary, in symptomatic breast cancer survivors. The aim of this present paper was to report effects of tibolone on climacteric symptoms, vaginal dryness and health-related quality of life in the study population. This trial is registered with ClinicalTrials.gov, n. NCT00408863.

METHODS: The trial was conducted between June 2002 and July 2007. Concerning quality of life variables, a daily Diary Cards during the first three months and the Climacteric Symptoms Form and at each visit were used to register frequency and intensity of hot flushes. Mean vaginal dryness scores were calculated on the basis of individual ratings at baseline and at week 104. A subset of patients assessed their quality of life filling in the Women's Health Questionnaire (WHQ).

RESULTS: Of the 3148 women recruited, 3133 received trial medication (1575 in the tibolone group and 1558 in the placebo group). The median duration of treatment was 2.75 years. In total 3098 women (1556 on tibolone, 1542 on placebo) were included in the intention-to-treat (ITT) population for efficacy analysis. Data on vaginal dryness are available for 2144 patients and 883 women (438 on tibolone, 445 on placebo) answered to WHQ. The mean change in number of hot flushes per day was 2.74 (43.1%) in the tibolone group and -1.77 (-27.5%) in the placebo group (p<0.0001) at week 12 and -4.62 (-65.6%) on tibolone as compared to -3.73 (-52.5%) on placebo (p<0.0001) at week 104. For the composite score the mean changes at week 12 were -0.19 (-10.6%) and -0.14 (-7.7%), respectively (p=0.0006). Vaginal dryness score improved at week 104 in the tibolone group as compared to placebo (-0.46 versus -0.29, respectively; p<0.0001). Across the assessments up to two years with WHQ, tibolone was more effective than placebo in improving sexual health, sleep quality and mood domains. Women using tamoxifen showed less improvement in climacteric symptoms with tibolone, than women only receiving tibolone without any adjuvant therapy.

CONCLUSION: The results of the LIBERATE trial show that tibolone is effective in symptomatic breast cancer patients and improves their quality of life. However, this finding should be judged within the context of the main outcome of the trial, showing that tibolone increases the risk of recurrence. The use of tibolone in women with breast cancer will remain contraindicated and any off-label use incurs a now proven risk.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Pubmed

Cancer Causes Control. 2011 Aug;22(8):1075-84. Epub 2011 Jun 3.

Menopausal hormone therapy and risk of ovarian cancer in the European prospective investigation into cancer and nutrition.

Tsilidis KK, Allen NE, Key TJ, Dossus L, Kaaks R, Bakken K, Lund E, Fournier A, Dahm CC, Overvad K, Hansen L, Tjønneland A, Rinaldi S, Romieu I, Boutron-Ruault MC, Clavel-Chapelon F, Lukanova A, Boeing H, Schütze M, Benetou V, Palli D, Berrino F, Galasso R, Tumino R, Sacerdote C, Bueno-de-Mesquita HB, van Duijnhoven FJ, Braem MG, Onland-Moret NC, Gram IT, Rodríguez L, Duell EJ, Sánchez MJ, Huerta JM, Ardanaz E, Amiano P, Khaw KT, Wareham N, Riboli E.

Cancer Epidemiology Unit, University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford, OX3 7LF, UK.

The association between menopausal hormone therapy (HT) and risk of ovarian cancer was assessed among 126,920 post-menopausal women recruited into the European Prospective Investigation into Cancer and Nutrition. After an average of 9-year follow-up, 424 incident ovarian cancers were diagnosed. Cox models adjusted for body mass index, smoking status, unilateral ovariectomy, simple hysterectomy, age at menarche, number of full-term pregnancies, and duration of oral contraceptives were used. Compared with baseline never use, current use of any HT was positively associated with risk (HR [hazard ratio], 1.29; 95% CI [confidence interval], 1.01-1.65), while former use was not (HR, 0.96; 95% CI, 0.70-1.30). Current estrogen-only HT was associated with a 63% higher risk (HR, 1.63; 95% CI, 1.08-2.47), while current estrogen plus progestin was associated with a smaller and non-significant higher risk (HR, 1.20; 95% CI, 0.89-1.62). Use of tibolone was associated with a twofold greater risk (HR, 2.19; 95% CI, 1.06-4.50), but was based on small numbers. In conclusion, women who currently use HT have a moderate increased risk of ovarian cancer, and which may be stronger for estrogen-only than estrogen plus progestin preparations.

Pubmed

Womens Health (Lond Engl). 2011 May;7(3):355-61.

Hormone therapy administration in postmenopausal women and risk of stroke.

Renoux C, Suissa S.

Center For Clinical Epidemiology, Jewish General Hospital-Lady Davis Research Institute, Montreal, Quebec, Canada.

HRT, consisting of estrogens alone, or in combination with a progestogen, is widely used for the relief of symptoms in postmenopausal women. Early observational studies have suggested that HRT might be associated with a reduced risk of cardio- and cerebro-vascular events. These encouraging results prompted randomized controlled trials assessing the risks and benefits of HRT in primary and secondary prevention of arterial vascular events. However, these clinical trials and further observational studies did not confirm the protective effect of HRT; it is now established that HRT increases the risk of stroke. This increased risk is mainly related to an increased risk of ischemic [decreased blood flow] stroke. Oral estrogen alone and combined with progestogen are associated with a similar increased risk, which may be dose dependent. Conversely, a low dose of transdermal estrogens with or without a progestogen does not seem to be associated with such an increased risk of stroke, whereas the impact of tibolone, a synthetic steroid, remains uncertain. In summary, there is now a large amount of evidence demonstrating that HRT is associated with increased risk of stroke, in particular, ischemic subtype.

Pubmed

Int J Cancer. 2011 Apr 1;128(7):1644-51. doi: 10.1002/ijc.25762. Epub 2011 Jan 12.

Endometrial cancer associated with various forms of postmenopausal hormone therapy: a case control study.

Jaakkola S, Lyytinen HK, Dyba T, Ylikorkala O, Pukkala E.

Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland.

This study evaluates the effect of different modes of estradiol-progestagen therapy (EPT) regimens on the postmenopausal endometrial cancer risk in Finland. Women diagnosed with endometrial cancer in 1995-2007 at the age of 50-80 years were identified from the Finnish Cancer Registry (N = 7,261). For each case, three age-matched controls were retrieved from the Finnish Population Register. The use of EPT since 1994 was ascertained from the national Medical Reimbursement Register. Odds ratios (ORs) for different EPT regimens were calculated with conditional logistic regression analysis, adjusted for parity and ages at the deliveries. For use of <5 years, the OR for sequential EPT was 0.67 (95% confidence interval 0.52-0.86), for continuous EPT 0.45 (0.27-0.73), and for estradiol plus levonorgestrel-releasing intrauterine device system (LNG-IUS) 0.39 (0.17-0.88). A decreased risk persisted for the use of continuous EPT and estradiol plus LNG-IUS of up to 10 years. The use of long-cycle EPT showed a tendency toward an elevated risk both for exposure of <5 years (1.40; 0.82-2.38) and for estimated use of >5 years (1.63; 1.12-2.38). For an estimated exposure of >10 years, the risk for endometrial cancer was elevated for both users of long-cycle EPT (2.95; 2.40-3.62) and sequential EPT (1.38; 1.15-1.66). Norethisterone acetate and medroxyprogesterone acetate as parts of EPT did not differ in their endometrial cancer risk. The use of tibolone showed no endometrial risk. The use of sequential and long-cycle EPT is associated with an increased risk of endometrial cancer, whereas the use of continuous EPT or estradiol plus LNG-IUS shows a decreased risk.

Copyright © 2011 UICC.

Pubmed

Climacteric. 2010 Apr;13(2):147-56.

Comparative effects of conventional hormone replacement therapy and tibolone on climacteric [end of menstruation] symptoms and sexual dysfunction in postmenopausal women.

Ziaei S, Moghasemi M, Faghihzadeh S.

Departments of Obstetrics & Gynecology, Tarbiat Modares University, Tehran, Iran.

Comment in Climacteric. 2010 Feb;13(1):99.

OBJECTIVE: To compare the effects of tibolone with those of conventional hormone replacement therapy on climacteric symptoms and sexual function in postmenopausal women.

MATERIALS AND METHODS: In a randomized, controlled trial, 140 postmenopausal women were allocated into three groups. Of the subjects included, 47 women received 2.5 mg tibolone + one Cal+D tablet (500 mg calcium and 200 IU vitamin D) daily; 46 women received 0.625 mg conjugated equine estrogen + 2.5 mg medroxyprogesterone (CEE/MPA) + one Cal+D tablet daily; and 47 women received only one Cal+D tablet as the control group. The Greene Climacteric Scale (GCS) questionnaire was used to detect the efficacy of treatment on climacteric symptoms. Rosen's Female Sexual Function Index (FSFI) was used for sexual function evaluation. Sex hormone binding globulin (SHBG), free estradiol index (FEI) and free testosterone index (FTI) were measured before and after treatment. The women were followed up for 6 months

RESULTS: After treatment, all subscores in the GCS improved in the tibolone and CEE/MPA groups (p < 0.01), except the sexual subscore in the CEE/MPA group, compared with baseline. There were significant differences in the FSFI in the tibolone and CEE/MPA groups in comparison to the control group after treatment. Tibolone, in comparison to CEE/MPA, significantly lowered SHBG levels and increased the FTI and FEI and improved the desire, arousal and orgasm sexual domains of the FSFI (p < 0.001).

CONCLUSION: Tibolone may be an alternative to conventional hormone replacement therapy in the treatment of climacteric symptoms and sexual dysfunction in postmenopausal women.

Pubmed

Gynecol Endocrinol. 2011 Mar;27(3):163-9. Epub 2010 May 26.

Effects of menopause and tibolone on different cardiovascular biomarkers in healthy women.

Vassalle C, Cicinelli E, Lello S, Mercuri A, Battaglia D, Maffei S.

Fondazione G. Monasterio CNR-Regione Toscana and Institute of Clinical Physiology, CNR, Pisa, Italy.

BACKGROUND AND AIM: The effects of tibolone on cardiovascular risk is not yet fully understood today. We designed this study to assess the effect of the menopausal status and tibolone treatment (2.5 mg/day for 3 months) on different biomarkers of cardiovascular risk in healthy women.

METHODS: Blood arterial pressure were measured, and blood samples collected for glucose, lipid profile (total cholesterol, high density lipoproteins, HDL, low density lipoproteins, and triglycerides), inflammatory (C-reactive protein, Interleukin-6, IL-6, tumor necrosis factor alpha, TNF alpha) and oxidative stress (hydroperoxides and antioxidant capacity) evaluation in 15 premenopausal (mean age: 30 +/- 4 years) and 15 postmenopausal (mean age: 52 +/- 3, mean time from menopause 1.4 +/- 0.4 years) women before and after tibolone treatment.

RESULTS: The menopausal status is associated with increased systolic and diastolic pressure (p<0.05), higher IL-6 (p<0.05) and TNF alpha (p<0.01), and lower antioxidants (p<0.01). However, blood pressure (p<0.05), glucose (p<0.05), TNF alpha (p<0.05) and HDL (p<0.05) fell after tibolone, which did not significantly affect levels of the other biochemical parameters.

CONCLUSIONS: As menopause is associated with increased blood pressure, inflammation and oxidative stress, tibolone restores blood pressure and has beneficial effect on inflammation and glycemia without worsening oxidative stress, although it also reduces HDL levels. Such modifications should be taken into account when tailoring menopausal therapies to specific requirements of each woman.

Pubmed

Maturitas. 2011 Feb;68(2):148-54. Epub 2010 Dec 23.

Management of menopausal symptoms in breast cancer patients.

Loibl S, Lintermans A, Dieudonné AS, Neven P.

German Breast Group, GBG Forschungs GmbH, Neu-Isenburg, Germany.

In breast cancer patients, menopausal symptoms such as hot flashes, urogenital problems, musculoskeletal symptoms and cognitive dysfunction are common, regardless of age at diagnosis. They affect quality of life and systemic therapy will worsen this. Endocrine and/or chemotherapy may induce temporary or permanent ovarian failure and can exacerbate these symptoms. Hormone therapy (HT) has been studied in breast cancer survivors, but safety has been questioned. The HABITS trial investigating estrogen-based HT, as well as the LIBERATE trial investigating tibolone, found a reduction in disease-free survival for those treated. Alternative strategies are needed, as menopause symptoms may reduce compliance with breast cancer treatments. This article reviews recently published strategies to tackle menopausal problems in breast cancer patients. Antidepressants may help with hot flashes. Acupuncture and hypnosis can also be used but the evidence is conflicting. For urogenital problems vaginal moisturizers or topical estrogens can be employed. A musculoskeletal syndrome induced by aromatase inhibitors (AIs) is frequently encountered and currently there are no effective treatment strategies. Bisphosphonates reduce AI-induced bone resorption and can also increase disease-free and overall survival. Standard-dose endocrine and chemotherapy are associated with a decline in cognitive function.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Pubmed

Recent Results Cancer Res. 2011;188:115-24.

Hormone replacement therapy and breast cancer.

Howell A, Evans GD.

Genesis Prevention Centre, University Hospital of South Manchester, Manchester, UK.

There is evidence that hormone replacement therapy (HRT) may both stimulate and inhibit breast cancers, giving rise to a spectrum of activities, which are frequently hard to understand. Here we summarise the evidence for these paradoxical effects and, given the current data, attempt to give an indication where it may or may not be appropriate to prescribe HRT. It is clear that administration of oestrogen-progestin (E-P) and oestrogen alone (E) HRT is sufficient to stimulate the growth of overt breast tumours in women since withdrawal of HRT results in reduction of proliferation of primary tumours and withdrawal responses in metastatic tumours. E-P, E including tibolone are associated with increased local and distant relapse when given after surgery for breast cancer. For women given HRT who do not have breast cancer the only large randomised trial (WHI) of E-P or E versus placebo has produced some expected and also paradoxical results. E-P increases breast cancer risk as previously shown in observational studies. Risk is increased, particularly in women known to be compliant. Conversely, E either has no effect or reduces breast cancer risk consistent with some but not all observational studies. Two observational studies report a decrease or at least no increase in risk when E-P or E are given after oophorectomy in young women with BRCA1/2 mutations. Early oophorectomy increases death rates from cardiovascular and other conditions and there is evidence that this may be reversed by the use of E post-oophorectomy. HRT may thus reduce the risk of breast cancer and other diseases (e.g., cardiovascular) in young women and increase or decrease them in older women.

Pubmed

Duodecim. 2011;127(3):235-42.

[Hormone therapy and risk for breast cancer in Finnish postmenopausal women].

[Article in Finnish]

Lyytinen H, Ylikorkala O.

HYKS:n naistenklinikka, HUS.

Breast cancer is a heterogenous disease and hormonal factors are involved. Since national differences exist in the use of postmenopausal hormone therapy (HT) and other risk factors, associations between HT and breast cancer should be studied nationally. In Finland, estrogen-progestin therapy is associated with higher breast cancer risk than estrogen-only therapy. Also tibolone and levonorgestrel releasing intauterine device combined with estrogen are accompanied with an increased risk of breast cancer. Hormone therapy possibly promotes the growth of the existing undetectable cancer.

Pubmed

Am J Epidemiol. 2010 Dec 15;172(12):1394-403. Epub 2010 Oct 20.

Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition.

Allen NE, Tsilidis KK, Key TJ, Dossus L, Kaaks R, Lund E, Bakken K, Gavrilyuk O, Overvad K, Tjønneland A, Olsen A, Fournier A, Fabre A, Clavel-Chapelon F, Chabbert-Buffet N, Sacerdote C, Krogh V, Bendinelli B, Tumino R, Panico S, Bergmann M, Schuetze M, van Duijnhoven FJ, Bueno-de-Mesquita HB, Onland-Moret NC, van Gils CH, Amiano P, Barricarte A, Chirlaque MD, Molina-Montes ME, Redondo ML, Duell EJ, Khaw KT, Wareham N, Rinaldi S, Fedirko V, Mouw T, Michaud DS, Riboli E.

Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, Medical Sciences Division, University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, United Kingdom.

Estrogen-only menopausal hormone therapy (HT) increases the risk of endometrial cancer, but less is known about the association with other types of HT. Using Cox proportional hazards regression, the authors examined the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women recruited into the European Prospective Investigation into Cancer and Nutrition between 1992 and 2000. After a mean follow-up period of 9 years, 601 incident cases of endometrial cancer were identified. In comparison with never users of HT, risk of endometrial cancer was increased among current users of estrogen-only HT (hazard ratio (HR) = 2.52, 95% confidence interval (CI): 1.77, 3.57), tibolone (HR = 2.96, 95% CI: 1.67, 5.26), and, to a lesser extent, estrogen-plus-progestin HT (HR = 1.41, 95% CI: 1.08, 1.83), although risks differed according to regimen and type of progestin constituent. The association of HT use with risk was stronger among women who were older, leaner, or had ever smoked cigarettes. The finding of a strong increased risk of endometrial cancer with estrogen-only HT and a weaker association with combined HT supports the hypothesis that progestins have an attenuating effect on endometrial cancer risk. The increased risk associated with tibolone use requires further investigation.

Pubmed

Prescrire Int. 2010 Dec;19(111):281.

Tibolone and breast cancer.

[No authors listed]

Tibolone is a synthetic steroid marketed for the treatment of menopausal symptoms. A cohort study of women with no history of breast cancer showed that tibolone was associated with an increased risk of breast cancer. In women with a history of breast cancer, a placebo-controlled trial showed a higher risk of breast cancer recurrence with tibolone. A placebo-controlled trial of half the standard dose of tibolone showed no increased risk of breast cancer but was interrupted due to an increased risk of stroke. In practice, it is better simply not to use tibolone.

Pubmed

Gynecol Endocrinol. 2010 Nov;26(11):804-14.

Tibolone in postmenopausal women: a review based on recent randomised controlled clinical trials.

Biglia N, Maffei S, Lello S, Nappi RE.

Gynecological Oncology Department, University of Turin, Mauriziano Umberto I Hospital, Turin, Italy.

AIM: To critically discuss the use of tibolone (T), in light of a series of very recent double-blind placebo (PL) controlled trials (LISA, LIFT, OPAL, THEBES, LIBERATE) conducted worldwide in a large number of postmenopausal women (PMW).

METHODS: The most relevant publications on T therapy in PMW were considered with emphasis on menopausal symptoms, quality of life, sexuality, bone, cardiovascular system (CVS) and oncologic risk.

RESULTS: T significantly relieves climacteric symptoms and improves mood and sexual well-being (LISA). T is as effective as estrogen-progestin therapy in preventing bone loss and reducing the relative risk of vertebral and non-vertebral fractures (LIFT). By using surrogate endpoints of the individual risks for the CVS, studies show mixed results, but a favourable effect on acute miocardial infarction and thromboembolism has been documented (THEBES, LIFT, OPAL). Although findings about endometrial and colon cancer are reassuring, conclusive data on breast cancer risk with T are not available and an increased risk of recurrence in women with previous breast cancer emerged (LIBERATE).

CONCLUSIONS: T is effective in treating menopausal syndrome with a good tolerability profile. In spite of some unsolved issues in term of safety, T is still a good treatment option for early PMW.

Pubmed

Am J Med. 2005 Dec 19;118 Suppl 12B:88-92.

Therapeutic effects of progestins, androgens, and tibolone for menopausal symptoms.

Liu JH.

Department of Reproductive Biology, Case Western Reserve University, Cleveland, Ohio, USA.

Therapeutic strategies using progestins, androgens, and synthetic steroids such as tibolone are based on the understanding that estrogen, progesterone, and androgen receptors are localized to reproductive target tissues, brain, and bone. Unfortunately, these sex steroid receptors are widely distributed and localized to other tissues, often resulting in unintended effects. Progestins at high doses have been shown to be effective at reducing hot flashes by approximately 80% to 90%. Side effects include weight gain, mastalgia, fluid retention, vaginal discharge, and dry mouth. Dehydroepiandrosterone (DHEA), an adrenal-derived androgen, can be considered a prohormone that is peripherally converted to more potent androgens and estrogens. In studies with small numbers of subjects, DHEA has been reported to reduce vasomotor symptoms, increase sexual arousal, and improve cognitive performance. With regard to use of other androgens, there are no current testosterone preparations approved by the US Food and Drug Administration (FDA) for use in menopausal women. In phase 3 trials, a testosterone transdermal matrix patch has been shown to be effective in treatment of hypoactive sexual desire disorder in menopausal women on estrogen therapy. Tibolone, a synthetic steroid with estrogenic, androgenic, and progestational properties has been shown to be effective in the treatment of vasomotor symptoms and in preserving bone density, and it may provide positive effects on sexual function. The beneficial effects of these compounds in the menopausal woman for treatment of vasomotor symptoms, general well-being, cognitive deficits, bone loss, mood disorders, and sexual function are discussed. The overall clinical trial evidence for benefits and side effects also is presented.

Pubmed