Sheila O'Neill

Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: Results from the INTIMATE NM1 Study

Objective: To evaluate the efficacy and safety of a testosterone patch for the treatment of women with hypoactive sexual desire disorder after natural menopause. Design: A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was conducted in naturally menopausal women with hypoactive sexual desire disorder receiving a stable dose of oral estrogen with or without progestin (N = 549). Women were randomized to receive testosterone 300 &mgr;g/day or placebo patches twice weekly for 24 weeks. The primary efficacy measure was change from baseline in frequency of total satisfying sexual activity over a 4-week period (weeks 21-24). Results: A total of 483 women (88%) were included in the primary analysis population (those with baseline sex hormone binding globulin levels ≤160 nmol/L). The change from baseline in number of total satisfying sexual episodes was significantly greater for testosterone compared with placebo (participants with baseline sex hormone binding globulin levels ≤160 nmol/L, mean change of 2.1 ± 0.28 versus 0.5 ± 0.23 episodes/4 weeks; P < 0.0001; intent-to-treat population, mean change from baseline of 1.9 ± 0.26 versus 0.5 ± 0.21 episodes/4 weeks, P < 0.0001). Testosterone also produced statistically significant improvements compared with placebo in all secondary efficacy measures, including sexual desire and personal distress. The testosterone patch was well tolerated. Conclusions: Testosterone patch treatment increased the frequency of satisfying sexual activity and sexual desire, decreased personal distress, and was well tolerated in naturally menopausal women with hypoactive sexual desire disorder.

Safety and Efficacy of a Testosterone Metered-Dose Transdermal Spray for Treating Decreased Sexual Satisfaction in Premenopausal Women: A Randomized Trial

Context Testosterone levels in women gradually decline with age, and supplemental testosterone may improve sexual satisfaction in postmenopausal women. Contribution Sexually active women age 35 to 45 years with low serum free testosterone levels and low sexuality scores were randomly assigned to placebo or 3 doses of transdermal testosterone for 16 weeks. Sexually satisfying encounters increased in all 4 groups. Compared with placebo, the number increased by 0.8 per month with the intermediate dose (P = 0.04) but not with the other doses. Caution The study was too brief to measure adverse events reliably. Implication We need more evidence before prescribing testosterone supplementation to premenopausal women in clinical practice. The Editors Testosterone levels in women decline with age from the midreproductive years (1, 2) and do not change during menopause (2, 3 ). Testosterone therapy seems to improve sexual well-being in postmenopausal women (49), but few comparable data are available for premenopausal women. Women with low testosterone levels after menopause probably had low levels before menopause (3), and sexual well-being before menopause is a strong predictor of postmenopausal sexual well-being (10). These findings suggest that testosterone therapy may benefit women presenting with low libido in their late reproductive years. Premenopausal women often report decreased sexual interest, arousal, and pleasure (11, 12), yet they have few treatment options. In a randomized, placebo-controlled, crossover trial, testosterone administered as a transdermal cream improved sexual function and well-being in premenopausal women with low libido and low testosterone levels (13). However, the study enrolled few patients, efficacy was based on a 30-day recall rather than a daily event diary, and the women took only 1 dose of testosterone. We sought to determine the efficacy and safety of several doses of testosterone, administered transdermally by a metered-dose spray system, in increasing self-reported sexual satisfaction among premenopausal women who had decreased sexual satisfaction. Methods Participants We recruited potential participants by using radio and published press advertisements, and we screened them by telephone for suitability. Enrollment was from September 2003 to May 2004. The inclusion criteria were age 35 to 45 years, premenopausal status (regular menstrual cycles and follicle-stimulating hormone level <40 IU/L), body mass index (BMI) between 18 and 32 kg/m2, sexual activity (1 sexual event per 28 days, alone or with a partner) but with a low sexuality score (Sabbatsberg Sexual Self-Rating Scale [14] score <42), no evidence of severe clinical depression on the Beck Depression Inventory (score <28) (15), and early-morning serum free testosterone levels of 3.8 pmol/L or less (1.1 pg/mL). In addition, each woman had to have experienced a decrease in satisfactory sexual activity of sufficient concern to seek medical advice or treatment and answer yes to each of the following questions: In previous years did you find sexual activity satisfying? Has there been a decline in your satisfaction with sexual activity? Would you like to use a hormonal treatment that may improve the level of satisfying sexual activity? All volunteers had general good health on history and physical examination and had had a Papanicolaou smear within the past year. Volunteers had to have had 3 satisfactory sexual events (SSEs) at most over 28 days at baseline (week 0) and, if in an established relationship, their partner present at least 50% of the time. We excluded women who were planning a pregnancy or were breastfeeding; had relationship problems, poor feelings for their partner, or dyspareunia; had received pharmacotherapy for depression within 8 weeks of screening or were taking medication known to interfere with normal sexual function (such as -blockers and -blockers); or had ever used androgen therapy. We also excluded women with a history of acne or hirsutism or treatment with antiandrogens for hirsutism in the previous 5 years, past cancer other than nonmelanotic skin cancer, uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg), any major chronic major illness that would impair overall health and well-being, genital bleeding of unknown cause, intake of more than 3 standard alcoholic drinks per day or addictions to any drugs or medication within the past 5 years, and use of medications known to interfere with sex steroid metabolism. The use of thyroid hormone was acceptable if the dose was expected to remain stable throughout the study. The protocol required all participants to use a medically acceptable form of contraception, including oral contraceptive pills, and to have a negative pregnancy test result at screening. All women gave voluntary, written informed consent and were specifically advised that the effects of the study doses of testosterone in the setting of pregnancy or breast-feeding were unknown. We stressed the necessity of contraception, and all participants received contraceptive counseling. Women who declined contraception were excluded. We obtained study approval from the human research and ethics committee at each institution. The study met the Clinical Trial Notification requirement of the Therapeutic Goods Administration of Australia and the requirements for an Investigational New Drug Application for the U.S. Food and Drug Administration. Design The study was a multicenter, randomized, double-blind, placebo-controlled trial. Eligible patients were first asked to complete a 4-week diary to characterize baseline sexual function. We invited women who met the eligibility criteria for baseline sexual activity to enter the placebo-controlled treatment stage of 16 weeks followed by 4 further weeks after therapy was discontinued. Treatments Participants were randomly assigned to receive 1 of 3 different doses of testosterone or placebo. The formulation (50 g of testosterone per L) was constant for each active dose, and the dose varied by applying different amounts of formulation with a metered-dose spray (Acrux Limited, West Melbourne, Victoria, Australia) (16). On the basis of previous pharmacokinetic studies, the highest dose (two 90-L sprays) should have increased mean serum free testosterone levels to approximately the 75th percentile of the normal range for premenopausal women (17.3 pmol/L [5.0 pg/mL]). The normal range is 3.8 pmol/L (1.1 pg/mL) to 21.84 pmol/L (6.3 pg/mL). The other study groups received half (one 90-L spray) and one third (one 56-L spray) of the highest dose of testosterone or placebo. Participants randomly assigned to placebo were further randomly assigned to 1 of 3 placebo subgroups (one 90-L spray, two 90-L sprays, or one 56-L spray) that corresponded with the 3 active treatment groups. Because findings were similar in the 3 placebo subgroups, we combined them into 1 group in the analysis. Doses were applied topically to the abdomen once a day for 16 weeks. One multidose applicator was dispensed every 4 weeks. Randomization Computer-generated randomization schedules for each center were created in blocks of 12 without stratification. The study statistician (who was not otherwise involved in the conduct of the study) generated and held the randomization schedules. The randomization sequence was generated by using the Ranuni function (SAS software, SAS Institute, Cary, North Carolina). Each unique code number in the schedule referred to a randomly allocated treatment: either a specific dose of testosterone or 1 of the 3 placebo groups. At each center, the study staff sequentially assigned participants as they became eligible to the next unassigned treatment code on the list and then identified the treatment assignment corresponding to the code number. Both participants and center staff remained blinded to treatment assignment throughout the study. Outcome Measures The primary end point (the frequency of SSEs) was recorded in the 28-day patient diary, which was completed daily and collected at week 16. Secondary end points were the frequency of SSEs recorded in the 28-day patient diaries collected at weeks 4, 8, 12, and 20; frequency of total sexual events at weeks 4, 8, 12, 16, and 20; and mean (over each 28-day evaluation period) composite and subscale scores for the Sabbatsberg Sexual Self-Rating Scale (Appendix Figure) and Psychological General Well-Being Index. The Sabbatsberg Sexual Self-Rating Scale (17) is a multiple-choice questionnaire covering 7 aspects of sexuality: sexual interest, sexual activity, satisfaction of sexual life, experience of sexual pleasure, sexual fantasy, orgasm capacity, and sexual relevancy. This scale has been validated in premenopausal women (14). The range of possible composite scores was 0 (low) to 56 (high). The Psychological General Well-Being Index (18) is a validated, 22-item multiple-choice questionnaire with subscales for anxiety, depressed mood, positive well-being, self-confidence, general health, and vitality. The range of possible composite scores is 0 (most negative affective experience) to 110 (most positive affective experience). Patients self-administered questionnaires at screening; baseline (week 0); and weeks 8, 16, and 20. The Appendix provides details of biological measurements. Appendix Figure. Sabbatsberg Sexual Self-Rating Scale. Reproduced with permission from Acta Obstet Gynecol Scand Suppl. 1977;64:1-91. Safety Assessments We compared the rates of adverse events in the 3 treatment groups with rates in the placebo group. We monitored specific known androgenic side effects, including hirsutism, by using the FerrimanGallwey scale (19) and acne by using the Palatsi scale (20), and we asked participants about voice changes at each visit after baseline. All events known to be consequences of excessive androgen use were classified as treatment-related, and all others were classified

A validated self-administered female pelvic floor questionnaire

Introduction and hypothesisThe aim of this study was to validate a self-administered version of the already validated interviewer-administered Australian pelvic floor questionnaire.MethodsThe questionnaire was completed by 163 women attending an urogynecological clinic. Face and convergent validity was assessed. Reliability testing and comparison with the interviewer-administered version was performed in a subset of 105 patients. Responsiveness was evaluated in a subset of 73 women.ResultsMissing data did not exceed 4% for any question. Cronbach’s alpha coefficients were acceptable in all domains. Kappa coefficients for the test–retest analyses varied from 0.64–1.0. Prolapse symptoms correlated significantly with the pelvic organ prolapse quantification. Urodynamics confirmed the reported symptom stress incontinence in 70%. The self and interviewer-administered questionnaires demonstrated equivalence. Effect sizes ranged from 0.6 to 1.4.ConclusionsThis self-administered pelvic floor questionnaire assessed pelvic floor function in a reproducible and valid fashion and due to its responsiveness, can be used for routine clinical assessment and outcome research.

Factors affecting sexuality in older Australian women: sexual interest, sexual arousal, relationships and sexual distress in older Australian women

Objective To investigate the sexual behavior, sexual relationships, sexual satisfaction, sexual dysfunction and sexual distress in a population of older urban Australian women. Method In 2004, 474 women participating in the Longitudinal Assessment of Ageing in Women (LAW) Study completed a series of questionnaires about sexuality. They included the Short Personal Experiences Questionnaire (SPEQ), Relationship Assessment Scale (RAS), Female Sexual Distress Scale (FSDS), questions concerning past sexual abuse based on the Sex in Australia Study, and questions comparing present and past sexual interest and activity. Results The percentage of women with partners ranged from 83.3% in the 40 – 49-year age group to 46.4% women in the 70 – 79-year age group. The sexual ability of partners diminished markedly with age, with only 4.8% of the partners using medication to enable erections. Only 2.5% of women reported low relationship satisfaction. The incidence of sexual distress was also low, being reported by only 5.7% of women. Younger women and women with partners had higher levels of distress than older women. Indifference to sexual frequency rose from 26.7% in women aged 40 – 49 years to 72.3% in the 70 – 79-year age group. Past sexual abuse was recalled by 22.7% of women and 11.6% recalled multiple episodes of abuse. Women who recalled abuse had lower scores for satisfaction with sexual frequency. Conclusions It appears from this study that there is a wide range of sexual experience amongst aging women, from never having had a sexual partner, to having solitary sex, to having a relationship with or without sex into the seventh decade. As women age, they experience a decrease in sexual activity, interest in sex, and distress about sex. This may be associated with the loss of intimate relationships as part of separation, divorce or bereavement. Decreased sexual activity with aging may be interpreted as a biological phenomenon (part of the aging process) or as sexual dysfunction, or it may be the result of adapting to changed circumstances.

Greene Climacteric Scale: norms in an Australian population in relation to age and menopausal status.

Objectives The aim of this study was two-fold: to assess climacteric symptoms and provide normative data for the Greene Climacteric Scale during the menopause transition, and to investigate the prevalence of climacteric symptoms in a representative sample of postmenopausal Australian women. Method A cohort of 500 premenopausal, perimenopausal and postmenopausal women aged 40–80 years participated in the Longitudinal Study of Ageing in Women (LAW study) at the Royal Brisbane and Womens Hospital, Brisbane, Australia. In year 1 of the study (2001), all participants completed the Greene Climacteric Scale and information regarding their menopausal status and the use of hormone therapy (HT) was obtained through a clinical interview with a qualified medical practitioner. Results The 50–59-year age group achieved the highest scores on the vasomotor and the depression scales in comparison to other age groups. Significant differences were also evident on the vasomotor and the depression scales on the basis of menopausal status, especially in perimenopausal women. Approximately 10% of women in the 60–79-year age group continued to experience vasomotor symptoms. Conclusion Vasomotor symptoms, as assessed by the Greene Climacteric Scale, are common during the menopause transition and remain elevated for some years in a minority of older postmenopausal women. The norms presented in this study are appropriate for use in an Australian population.

Hormones down under: hormone therapy use after the Women's Health Initiative.

Aims:  The primary objective was to describe the usage pattern of hormone therapy (HT) in a sample of urban Australian women in 2001 and to assess the characteristics of users vs. non‐users. The second objective was to determine whether there had been any change in usage since the publication of the results of the combined oestrogen plus progestagen arm of the Womens Health Initiative (WHI) in 2002.

Postmenopausal hormone therapy and cognition: Effects of timing and treatment type

Abstract Setting Hormone therapy used for the management of postmenopausal symptoms in older women appears to result in variable effects on cognitive function, depending on study design, subjects, tests used, and types of therapy. Objective To determine the effects of estrogen-only and estrogen plus progestogen preparations on cognitive performance (cognitive status, general and working memory) when taken ‘early’ and ‘late’ from the onset of menopause. Method The study consisted of 410 women who were participants in a longitudinal study, first recruited at age 40–80 years. They were tested for change over 5 years as an observational cohort by the Mini-Mental State Examination, National Adult Reading Test and the Wechsler Memory Scale Version 3. Cognitive decline, measured by age-adjusted scores, was defined as ≥10% negative change in each individual woman. Results Controlling for age and lifestyle factors, and using the criterion of decrease in score ≥10% over 5 years for ‘cognitive decline’, ‘early start’ of hormone therapy (<3 years from menopause) was strongly associated with reduction in risk by the Mini-Mental State Examination (estrogen-only preparation, p = 0.005) but with increase in risk for general memory (with estrogen plus progestogen preparation, p = 0.02). Overall, there were no major effects on subgroups with type/timing of hormone therapy in relation to testing for a negative change in cognitive function. Conclusion ‘Early start’ of estrogen-only hormone therapy was associated with reduced risk of global cognitive decline, and ‘early start’ estrogen-only and estrogen/progestogen hormone therapies showed increased risks of general memory decline. Even though this study did not have the power to discriminate between minor and mixed effects, it suggests that cognitive effects of hormone therapies may be mixed, depending on cognitive domain and timing of use/type of preparation.

An interviewer-administered validated female pelvic floor questionnaire for community-based research

Objective: The aim of this study was to design and validate an interviewer-administered pelvic floor questionnaire suitable for community-dwelling women to assess female bladder, bowel, and sexual function; pelvic organ prolapse; and condition-specific quality-of-life issues. Design: The questionnaire was developed and administered during interviews of 493 community-dwelling women aged 40 to 79 years originally recruited from an age-stratified random sample from the electoral roll who were involved in a longitudinal study of aging in women. Full psychometric testing was performed. To assess discriminant validity, 55 consecutive patients attending a tertiary referral urogynecology clinic served as a comparison group. Results: Face validity: The interviewer-administered questionnaire was easily administered and missing data did not exceed 2%. Discriminant validity: The questionnaire clearly discriminated the community population from the urogynecology patients in all pelvic floor domains. Convergent validity: The bladder function domain score correlated with the validated short version of the Urogenital Distress Inventory score. Bowel function scores correlated highly with corresponding items in an established bowel questionnaire. Prolapse symptoms correlated significantly with the pelvic organ prolapse quantification. Sexual function score (n = 257) correlated with the validated McCoy Female Sexuality Questionnaire score. Reliability: Cronbachs &agr; for the bladder, bowel, prolapse, and sexual function domains was adequate (&agr; ≥ 0.7). Kappa values in the test-retest analyses varied between 0.63 and 1.0 (test-retest reproducibility). Conclusions: The interviewer-administered questionnaire assesses all aspects of pelvic floor function including condition-specific quality-of-life issues in a reliable and valid fashion. It is suitable for researchers investigating pelvic floor function.

The menopausal transition does not appear to accelerate age-related increases in arterial stiffness

ABSTRACT Objective Arterial stiffness is an independent marker of cardiovascular risk that increases with age, hypertension, diabetes and hyperlipidemia, both for men and women (although more pronounced in women). This study was designed to establish whether menopause augments the age-dependent change. Methods The study evaluated pulse wave analysis and pulse wave velocity using applanation tonometry in 468 women (aged 40–80 years) sampled from the general population. In multiple linear regression models, age was the predominant correlate of increasing aortic augmentation pressure (p < 0.0001), augmentation index (p < 0.0001), augmentation index adjusted to a heart rate of 75 beats/min (p < 0.0001) and carotid-femoral pulse wave velocity (p < 0.0001). Results Analysis of covariance showed no significant difference in adjusted mean of augmentation pressure, augmentation index or pulse wave velocity between menopause groups (pre-, peri-, postmenopause). Adjusted means of augmentation pressure and pulse wave velocity were comparable between women on hormone therapy (n = 130) and non-users (n = 338). Conclusions The results of the present study challenge the assertion by some researchers that menopause accelerates age-dependent changes in arterial stiffness.

Age-Related Changes in Heart Function by Serial Echocardiography in Women Aged 40–80 Years

AIM To determine if a defined set of echocardiographic parameters at entry and exit of a longitudinal study over 5 years showed changes with aging. METHODS The cohort consisted of 484 randomly recruited women aged 40-80. They were examined by two echocardiography cardiologists, independent of the medical information for these women. RESULTS Across the age decades (40-49, 50-59, 60-69, 70-79 years), body weight and body surface area (BSA) did not vary, and diastolic blood pressure (DBP) was stable; systolic blood pressure (SBP) progressively increased. There was gradual decline in left ventricular (LV) diastolic function, increase in LV muscle mass, and decrease in LV end-diastolic volume (LVEDV). The serial decrease in rate of change over 5 years in ejection fraction (ET) was small but significant across the four age decades. CONCLUSIONS As expected, there were age-related changes in cardiac structure and function over time in women who showed no apparent cardiovascular disease (CVD) at entry to the study. The direction of these serial changes was toward the development of LV stiffness and likelihood of subsequent heart failure. The clinical significance of the decrease in rate of change in EF remains unclear.