Cost-Effectiveness of perioperative Vaginally Administered estrogen in postmenopausal women undergoing prolapse surgery (EVA trial): study protocol for a multicenter double-blind randomized placebo-controlled trial.

BACKGROUND: Surgery for pelvic organ prolapse (POP) is associated with high recurrence rates. The costs associated with the treatment of recurrent POP are huge, and the burden from women who encounter recurrent POP, negatively impacts their quality of life. Estrogen therapy might improve surgical outcome for POP due to its potential beneficial effects. It is thought that vaginal estrogen therapy improves healing and long-term maintenance of connective tissue integrity. Hence, this study aims to evaluate the cost-effectiveness of perioperative vaginal estrogen therapy in postmenopausal women undergoing POP surgery. METHODS: The EVA trial is a multi-center double-blind randomized placebo-controlled trial conducted in the Netherlands comparing the effectiveness and costs-effectiveness of vaginal estrogen therapy. This will be studied in 300 postmenopausal women undergoing primary POP surgery, with a POP-Q stage of ≥ 2. After randomization, participants administer vaginal estrogen cream or placebo cream from 4 to 6 weeks preoperative until 12 months postoperative. The primary outcome is subjective improvement of POP symptoms at 1 year follow-up, measured with the Patient Global Impression of Improvement (PGI-I) scale. Secondary outcomes are POP-Q anatomy in all compartments, re-interventions, surgery related complications, general and disease specific quality of life, sexual function, signs and complaints of vaginal atrophy, vaginal pH, adverse events, costs, and adherence to treatment. Follow up is scheduled at 6 weeks, 6 months and 12 months postoperative. Data will be collected using validated questionnaires and out-patient visits including gynecological examination performed by an independent gynecologist. DISCUSSION: This study investigates whether perioperative vaginal estrogen will be cost-effective in the surgical treatment of POP in postmenopausal women. It is hypothesized that estrogen therapy will show a reduction in recurrent POP symptoms and a reduction in reoperations for POP, with subsequent improved quality of life among women and cost savings. Trial registrationNetherlands Trial Registry: NL6853; registered 19-02-2018, https://www.trialregister.nl/trial/6853 . EudraCT: 2017-003144-21; registered: 24-07-2017.

Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure.

OBJECTIVE: To describe general and sexual well-being in women with premature ovarian failure (POF) and to investigate whether there is a relationship between androgen levels and sexual functioning. DESIGN: Women with POF and healthy volunteers with regular menstrual cycles participated. Participants completed a written questionnaire and underwent hormonal screening. The questionnaire included standardized measures: the Questionnaire for Screening Sexual Dysfunctions, the Shortened Fatigue Questionnaire, and the Symptom Check List-90. Serum hormone measurements included estradiol, total testosterone, bioavailable testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. RESULTS: Eighty-one women with POF and 68 control women participated in the study. Compared with control women, women with POF reported more complaints of anxiety, depression, somatization, sensitivity, hostility, and psychological distress. Overall women with POF were less satisfied with their sexual life. They had fewer sexual fantasies and masturbated less frequently. Sexual contact was associated with less sexual arousal, reduced lubrication, and increased genital pain. However, the frequency of desire to have sexual contact and the frequency of actual sexual contact with the partner did not differ between women with POF and control women. Women with POF had lower levels of estradiol, total testosterone, and androstenedione. Multiple regression analysis revealed that androgen levels had only a weak influence on sexual functioning; higher total testosterone levels were associated with increased frequency of desire for sexual contact, and higher androstenedione levels were associated with elevated frequency of sexual contact. CONCLUSIONS: Women with POF have diminished general and sexual well-being and are less satisfied with their sexual lives than control women. Although women with POF had lower androgen levels, we did not find an important independent role for androgens in various aspects of sexual functioning.

Vaginal application of testosterone: A study on pharmacokinetics and the sexual response in healthy volunteers.

INTRODUCTION: Androgen substitution is advocated to improve sexual functioning in women with androgen insufficiency. Nevertheless, the role of androgens in female sexual functioning is not yet unraveled. Even less is known about changes in androgens and the female sexual response. AIM: The aim of the study is to describe the pharmacokinetics of a single dose of vaginally applied testosterone. In addition, the study aims to gain more insight into the relation between acute changes in testosterone levels and the sexual response in women. METHODS: A randomized, double-blind, crossover study design was used to compare a single vaginal dose of testosterone propionate (2 mg) with placebo. Ten healthy premenopausal women participated. Serum levels of testosterone, free testosterone, and estradiol were measured. The sexual response was measured before application of medication and 4 and 8 hours after application. Erotic video fragments and erotic fantasies were used as stimuli. The genital sexual response was measured using vaginal plethysmography. The subjective sexual response was measured using a visual analog scale. RESULTS: Vaginal administration of testosterone propionate induced a significant rise in serum testosterone levels and free testosterone levels, but not in serum estradiol levels. Peak levels were reached after 5.5 hours (range 2-12 hours). Mean peak levels of testosterone were 7.71 nmol/L after testosterone propionate and 2.99 nmol/L after placebo (P < 0.005). Mean peak levels of free testosterone were 0.12 nmol/L after testosterone propionate and 0.04 nmol/L after placebo (P < 0.005). Despite marked elevated levels of androgens this study was unable to detect a direct effect on the genital or subjective sexual response. CONCLUSIONS: A single dose of vaginally applied testosterone propionate elevates serum levels of testosterone and free testosterone within 6 hours. Nevertheless, this acute rise in androgens has no effects on the female sexual response.

Effects of a preovulatory single low dose of mifepristone on ovarian function.

OBJECTIVES: To investigate the effect of a single low dose of mifepristone on ovarian function, when administered in the preovulatory period. METHODS: Healthy women with regular menstrual cycles were studied during two consecutive menstrual cycles. Either mifepristone or placebo was given in a randomized double-blind order when the leading follicle reached a diameter between 15 and 17 mm. Daily ultrasound and serum hormone measurements were obtained until follicular collapse. Statistical analysis was performed using Wilcoxon signed-rank test. RESULTS: Eight women entered the study, although one woman had to be excluded afterwards from analysis because her LH surge had already appeared on the day of treatment. The LH surge was delayed from day 14 to 17 (P = 0.01). Mifepristone caused a 3-day delay in follicular collapse, occurring on day 16 in control cycles and on day 19 in mifepristone treatment cycles (P = 0.02). The median cycle length was 26 days in control cycles and 30 days in mifepristone treatment cycles (P = 0.03). Progesterone measurement 7 days after follicular collapse did not differ significantly between both cycles. CONCLUSIONS: A single 10-mg dose of mifepristone administered during the preovulatory phase of the cycle delays the LH surge and postpones ovulation.