Jan L. Shifren

Transdermal Testosterone Treatment in Women with Impaired Sexual Function after Oophorectomy

BACKGROUND The ovaries provide approximately half the circulating testosterone in premenopausal women. After bilateral oophorectomy, many women report impaired sexual functioning despite estrogen replacement. We evaluated the effects of transdermal testosterone in women who had impaired sexual function after surgically induced menopause. METHODS Seventy-five women, 31 to 56 years old, who had undergone oophorectomy and hysterectomy received conjugated equine estrogens (at least 0.625 mg per day orally) and, in random order, placebo, 150 microg of testosterone, and 300 microg of testosterone per day transdermally for 12 weeks each. Outcome measures included scores on the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and a sexual-function diary completed over the telephone. RESULTS The mean (+/-SD) serum free testosterone concentration increased from 1.2+/-0.8 pg per milliliter (4.2+/-2.8 pmol per liter) during placebo treatment to 3.9+/-2.4 pg per milliliter (13.5+/-8.3 pmol per liter) and 5.9+/-4.8 pg per milliliter (20.5+/-16.6 pmol per liter) during treatment with 150 and 300 microg of testosterone per day, respectively (normal range, 1.3 to 6.8 pg per milliliter [4.5 to 23.6 pmol per liter]). Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm in the Brief index of Sexual Functioning for Women (P=0.03 for both comparisons with placebo). At the higher dose the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from base line. The positive-well-being, depressed-mood, and composite scores of the Psychological General Well-Being Index also improved at the higher dose (P=0.04, P=0.03, and P=0.04, respectively, for the comparison with placebo), but the scores on the telephone-based diary did not increase significantly. CONCLUSIONS In women who have undergone oophorectomy and hysterectomy, transdermal testosterone improves sexual function and psychological well-being.

Sexual problems and distress in United States women: prevalence and correlates.

OBJECTIVE: To estimate the prevalence of self-reported sexual problems (any, desire, arousal, and orgasm), the prevalence of problems accompanied by personal distress, and to describe related correlates. METHODS: The 31,581 female respondents aged 18 years and older were from 50,002 households sampled from a national research panel representative of U.S. women. Correlates of each distressing sexual problem were evaluated using multiple logistic regression techniques. RESULTS: The age-adjusted point prevalence of any sexual problem was 43.1% and 22.2% for sexually related personal distress (defined as a score of at least 15 on Female Sexual Distress Scale). Any distressing sexual problem (defined as reporting both a sexual problem and sexually related personal distress, Female Sexual Distress Scale score of at least 15) occurred in 12.0% of respondents and was more common in women aged 45–64 years (14.8%) than in younger (10.8%) or older (8.9%) women. Correlates of distressing sexual problems included poor self-assessed health, low education level, depression, anxiety, thyroid conditions, and urinary incontinence. CONCLUSION: The prevalence of distressing sexual problems peaked in middle-aged women and was considerably lower than the prevalence of sexual problems. This underlines the importance of assessing the prevalence of sexually related personal distress in accurately estimating the prevalence of sexual problems that may require clinical intervention. LEVEL OF EVIDENCE: III

Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis.

The human endometrium undergoes a complex process of vascular and glandular proliferation, differentiation, and regeneration with each menstrual cycle in preparation for implantation. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific angiogenic protein that appears to play an important role in both physiological and pathological neovascularization. To investigate whether VEGF may regulate human endometrial angiogenesis, we examined VEGF messenger ribonucleic acid (mRNA) and protein throughout the menstrual cycle and studied the regulation of VEGF by reproductive steroids in isolated human endometrial cells. By ribonuclease protection analysis, VEGF mRNA increased relative to early proliferative phase expression by 1.6-,2.0-, and 3.6-fold in midproliferative, late proliferative, and secretory endometrium, respectively. In histological sections, VEGF mRNA and protein were localized focally in glandular epithelial cells and more diffusely in surrounding stroma, with greatest VEGF expression in secretory endometrium. Consistent with these in vivo results, the treatment of isolated human endometrial cells with estradiol (E2), medroxyprogesterone acetate (MPA), or E2 plus MPA significantly increased VEGF mRNA expression over the control value by 3.1-, 2.8-, and 4.7-fold, respectively. The VEGF response to E2 was rapid, with steady state levels of VEGF mRNA reaching 85% maximum 1 h after the addition of steroid. E2 also caused a 46% increase in secreted VEGF protein, and the combination of E2 and MPA caused an 18% increase. VEGF expression in endometriosis, an angiogenesis-dependent, estrogen-sensitive disease was similar to that seen in eutopic endometrium. Peritoneal fluid concentrations of VEGF were significantly higher in women with moderate to severe endometriosis than in women with minimal to mild endometriosis or no disease. VEGF, therefore, may be important in both physiological and pathological angiogenesis of human endometrium, as it is an estrogen-responsive angiogenic factor that varies throughout the menstrual cycle and is elevated in women with endometriosis.

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.

Angiogenesis and Macrophage Activation in Endometriosis

Recent studies suggest that the symptoms associated with endometriosis are the result of local peritoneal inflammation. Increased concentrations of activated pelvic macrophages and lymphocytes and the elevated levels of specific cytokines and growth factors reviewed above support this hypothesis. The precise roles of these soluble factors are currently unknown, but we propose that a complex network of endometrial cytokines are normally regulated by hormones produced during the ovulatory cycle. Ectopic endometrial implants also are subject to these same endocrine cues. The secretion of these proinflammatory proteins by endometriosis lesions into the peritoneal microenvironment appears to cause a recruitment of capillaries and activated inflammatory cells to the implant. Future therapeutic strategies directed to ameliorate the inflammatory reaction associated with endometriosis should not ignore the likely physiological actions of many of the same bioactive molecules in normal eutopic endometrial function.

Impact of varying stages of endometriosis on the outcome of in vitro fertilization-embryo transfer.

Purpose:The impact of severity of endometriosis on the outcome of in vitro fertilization (IVF) was analyzed in an uncontrolled, retrospective study in an academic IVF program.Methods:Sixty-one patients with a primary diagnosis of endometriosis undergoing 85 cycles of IVF were included in the study. Patients were divided according to the severity of disease based on the revised American Fertility Society (AFS) classification into groups A (stages I/II, or minimal/mild) and B (stages III/IV, or moderate/severe). Group A included 32 patients undergoing 45 IVF-embryo transfer (ET) cycles; group B included 29 patients undergoing 40 IVF cycles. Exclusion criteria were age older than 40 years, basal day 3 follicle stimulating hormone (FSH) greater than 20 IU/L, male-factor infertility, assisted hatching, and gamete intrafallopian transfer cases. Stimulation for IVF cycles was standard using pituitary down-regulation with gonadotropin-releasing hormone agonist in a midluteal protocol. Controlled ovarian hyperstimulation (COH) was achieved using a combination of FSH and human menopausal gonadotropin. Outcomes assessed included response to COH and number, maturity, and quality of oocytes retrieved. Fertilization, implantation, and pregnancy rates after IVF-ET were also analyzed.Results:The response to COH and the number, maturity, and quality of the oocytes was comparable between patients with varying severity of endometriosis. Fertilization rates for oocytes of patients in group B (stages III/IV) were significantly impaired compared to those in group A (stages I/II) (P = 0,004). The rates for implantation, clinical pregnancy, and miscarriage were comparable between the two groups.Conclusions:The reduced fertilization potential of the oocytes obtained from patients with severe endometriosis in the absence of male-factor infertility suggests an adverse biological impact of the advanced disease on the oocytes. The outcome of IVF-ET, however, is unaffected by increasing severity of endometriosis. This suggests that IVF may compensate for or overcome this reduction in the biological potential of the oocytes associated with severe disease, thus accounting for a comparable outcome irrespective of the severity of endometriosis.

A randomized, controlled pilot study of acupuncture treatment for menopausal hot flashes

Objective:To investigate the feasibility of conducting a randomized trial of the effect of acupuncture in decreasing hot flashes in peri- and postmenopausal women. Design:Fifty-six women ages 44 to 55 with no menses in the past 3 months and at least four hot flashes per day were recruited from two clinical centers and randomized to one of three treatment groups: usual care (n = 19), sham acupuncture (n = 18), or Traditional Chinese Medicine acupuncture (n = 19). Acupuncture treatments were scheduled twice weekly for 8 consecutive weeks. The sham acupuncture group received shallow needling in nontherapeutic sites. The Traditional Chinese Medicine acupuncture group received one of four treatments based on a Traditional Chinese Medicine diagnosis. Usual care participants were instructed to not initiate any new treatments for hot flashes during the study. Daily diaries were used to track frequency and severity of hot flashes. The mean daily index score was based on the number of mild, moderate, and severe hot flashes. Follow-up analyses were adjusted for baseline values, clinical center, age, and body mass index. Results:There was a significant decrease in mean frequency of hot flashes between weeks 1 and 8 across all groups (P = 0.01), although the differences between the three study groups were not significant. However, the two acupuncture groups showed a significantly greater decrease than the usual care group (P < 0.05), but did not differ from each other. Results followed a similar pattern for the hot flash index score. There were no significant effects for changes in hot flash interference, sleep, mood, health-related quality of life, or psychological well-being. Conclusions:These results suggest either that there is a strong placebo effect or that both traditional and sham acupuncture significantly reduce hot flash frequency.

The North American Menopause Society recommendations for clinical care of midlife women

In celebration of the 25th anniversary of The North American Menopause Society (NAMS), the Society has compiled a set of key points and clinical recommendations for the care of midlife women. NAMS has always been a premier source of information about menopause for both healthcare providers and midli

Endocrine Aspects of Women's Sexual Function

INTRODUCTION Endocrine changes during aging as well as endocrine disorders may either directly or indirectly modulate female sexual function by altering sex hormones, or by impacting on vascular, neurogenic, or psychologic factors. AIM To review information on the impact of the hormonal changes associated with aging or those caused by endocrine disorders on female sexual function and current information on the risks and benefits of hormonal treatments. METHODS Committee members outlined topics and reviewed the published literature on endocrine aspects of female sexual function over a 2-year period. Presentation of the recommendations were presented at the International Consultation on Sexual Medicine Paris, France 2009 and revised accordingly. MAIN OUTCOME MEASURES Quality of data published in the literature and recommendations were based on the GRADES system. RESULTS Recommendations and guidelines concerning the role of sex hormones and endocrine disorders in female sexual function were derived. CONCLUSIONS Hormones are only one component of the many factors that contribute to normal sexual function in women. Further research is needed as to the impact of hormones and endocrine disorders on female sexual dysfunction and the benefits and risks of hormonal therapies.

Help-Seeking Behavior of Women with Self-Reported Distressing Sexual Problems

OBJECTIVE The objective was to describe the healthcare and information-seeking behavior of women with self-reported sexual problems and accompanying sexually related personal distress identified from a large, population-based U.S. survey. METHODS Women (n = 3,239) aged > or =18 years with self-reported sexual problems of desire, arousal, and/or orgasm accompanied by sexually related personal distress were identified from a cross-sectional mailed survey of 50,002 U.S. households sampled from a national research panel. Healthcare and information-seeking behavior was examined as four ordered categories: sought formal medical advice, sought informal advice, sought information from anonymous sources, and did not seek help or information. Correlates of help seeking for each type of distressing sexual problem were modeled with multivariable proportional odds regression. RESULTS Just over a third of women with any distressing sexual problems had sought formal care, most often from a gynecologist or primary care physician; about 80% of the time, the woman, rather than the physician, initiated the conversation. Only 6% of women who sought medical advice scheduled a visit specifically for a sexual problem. Factors related to help seeking were having a current partner and interacting with the healthcare system. Barriers were poor self-perceived health and embarrassment about discussing sexual topics with a physician. CONCLUSIONS Our results suggest inadequacies in the U.S. medical care system in addressing sexual problems in women. Gynecologists and primary care physicians, by including discussions about sexual health during routine visits, can increase the likelihood that adequate care can be offered.