Vaginal Diazepam for Nonrelaxing Pelvic Floor Dysfunction: The Pharmacokinetic Profile.

BACKGROUND: Vaginal diazepam is frequently used to treat pelvic floor tension myalgia and pelvic pain despite limited knowledge of systemic absorption. AIM: To determine the pharmacokinetic and adverse event profile of diazepam vaginal suppositories. METHODS: We used a prospective pharmacokinetic design with repeated assessments of diazepam levels. Eight healthy volunteers were administered a 10-mg compounded vaginal diazepam suppository in the outpatient gynecologic clinic. Serum samples were collected at 0, 45, 90, 120, and 180 minutes; 8, 24, and 72 hours; and 1 week following administration of a 10-mg vaginal suppository. The occurrence of adverse events was assessed using the alternate step and tandem walk tests, the Brief Confusion Assessment Method, and numerical ratings. Plasma concentrations of diazepam and active long-acting metabolites were measured. Pharmacokinetic parameters were calculated by standard noncompartmental methods. RESULTS: The mean peak diazepam concentration (Cmax) of 31.0 ng/mL was detected at a mean time (Tmax) of 3.1 hours after suppository placement. The bioavailability was found to be 70.5%, and the mean terminal elimination half-life was 82 hours. The plasma levels of temazepam and nordiazepam peaked at 0.8 ng/mL at 29 hours and 6.4 ng/mL at 132 hours, respectively. Fatigue was reported by 3 of 8 participants. CLINICAL IMPLICATIONS: Serum plasma concentrations of vaginally administered diazepam are low; however the half-life is prolonged. STRENGTHS & LIMITATIONS: Strengths include use of inclusion and exclusion criteria aimed at mitigating clinical factors that could adversely impact diazepam absorption and metabolism, and the use of an ultrasensitive LC-MS/MS assay. Limitations included the lack of addressing the efficacy of vaginal diazepam in lieu of performing a pure pharmacokinetic study with healthy participants. CONCLUSION: Vaginal administration of diazepam results in lower peak serum plasma concentration, longer time to peak concentration, and lower bioavailability than standard oral use. Providers should be aware that with diazepam's long half-life, accumulating levels would occur with chronic daily doses, and steady-state levels would not be reached for up to 1 week. This profile would favor intermittent use to allow participation in physical therapy and intimacy. Larish AM, Dickson RR, Kudgus RA, et al. Vaginal Diazepam for Nonrelaxing Pelvic Floor Dysfunction: The Pharmacokinetic Profile. J Sex Med 2019;16;763-766.

TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol.

OBJECTIVE: To evaluate the pharmacokinetics of TX-004HR vaginal estradiol softgel capsules when used for treating moderate-to-severe dyspareunia in postmenopausal women with vulvar and vaginal atrophy. METHODS: A substudy of the REJOICE trial (multicenter, double-blind, placebo-controlled, phase 3) evaluated the pharmacokinetics of 4, 10, and 25-µg TX-004HR doses once/d for 2 weeks, followed by twice/wk for 10 weeks. Serum samples obtained at 2, 4, 6, 10, and 24 hours postdose on days 1 and 14, and once on day 84, were analyzed for area under the serum concentration-time curve, tmax, Cmin, Cavg, and Cmax for estradiol, estrone, and estrone conjugates. RESULTS: Seventy-two women (mean 59 y) participated. TX-004HR 4 µg showed no statistical differences from placebo in estradiol pharmacokinetic (PK) parameters. At 10 µg, estradiol Cmax was statistically higher than placebo on day 1, but was not different from placebo on day 14. With 25 µg, estradiol PK parameters were statistically higher than placebo. Estradiol Cavg values for 25 µg were 9.1 pg/mL on day 1 and 7.1 pg/mL on day 14. Estrone and estrone conjugate PK parameters with TX-004HR were lower than or similar to placebo across all doses. No drug accumulation was observed. CONCLUSIONS: Vaginal TX-004HR resulted in negligible to very low systemic absorption of estradiol. No statistical differences in estradiol PK parameters were observed on day 14 with 4 and 10 µg, and only minor increases were observed with 25 µg (within the normal postmenopausal range). This PK substudy, in conjunction with the primary efficacy results, demonstrated that TX-004HR provided local benefits of estradiol with limited systemic exposure.

Vitamin D3 deficiency is associated with female sexual dysfunction in premenopausal women.

PURPOSE: To assess female sexual functions in women who were affected by vitamin D3 deficiency. METHODS: A total of 50 women with FSD and 58 healthy women controls were included in the study, according to the Female Sexual Function Index (FSFI) questionnaire using a 26.55 cutoff value. Detailed medical histories were obtained from all sexual active women, and all women were evaluated in terms of possible presence of depression with the Beck Depression Inventory (BDI). Serum 25-hydroxyvitamin D3, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, total and free testosterone, estradiol, dehydroepiandrosterone-SO4 (DHEA-SO4), sex hormone-binding globulin (SHBG), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) levels were measured. RESULTS: Mean age of premenopausal women was 34.9 ± 6.3 years. The level of serum 25-hydroxyvitamin D3 was significantly lower in women with FSD compared with the controls (15.9 ± 8.4 and 26.3 ± 11.7 nmol/L, respectively). Desire (p = 0.0001), arousal (p = 0.0001), lubrication (p = 0.002), orgasm (p = 0.0001), satisfaction (p = 0.018), and pain (p = 0.010) domain scores were also correlated with the levels of serum 25-hydroxyvitamin D3. The BDI score showed a significant negative correlation with the total FSFI score (r = -0.492, p = 0.0001). The FSFI score not showed a significant correlation with the hormones (p > 0.05). CONCLUSION: There is a relationship with FSD and deficiency of vitamin D3. Also, increased depressive symptoms were associated with FSD.

Effect of one-month treatment with vaginal promestriene on serum estrone sulfate levels in cancer patients: a pilot study.

UNLABELLED: Vaginal promestriene was tested in gynecological cancer patients who suffered from severe vaginal dryness and dyspareunia. This form of estrogen has a low level of vaginal absorption and proved to be effective for vaginal atrophy. METHOD: 17 patients were treated with a 10mg soft vaginal suppository daily for one month. Plasma levels of estrone sulfate (E1S), used as the marker of overall estrogenicity, were measured by liquid chromatography in combination with mass spectrometry. RESULTS: Mean E1S levels changed from 533 (22-2920) to 374 (81-856) pg/ml (p=0.39). CONCLUSION: In highly symptomatic gynecological cancer patients the level of circulating estrone sulfate was not significantly affected by vaginal promestriene treatment overall, but a wide range of levels was noted pre and post treatment in individual patients.

Can oral contraceptives cause vestibulodynia?

AIM: To describe the clinical course of a young woman who developed vestibulodynia with introital dyspareunia while on oral contraceptive (OCs) and to provide a possible explanation for the etiology of her symptoms as well as her recovery after treatment. METHODS: A single case is presented including subjective reporting, laboratory evaluation, and quantitative sensory testing. RESULTS: After topical hormonal therapy, the patient reported resolution of her dyspareunia and and her laboratory values normalized.

The menopause and sexual functioning: a review of the population-based studies.

Sexual problems are among the most frequently presented health concerns of women attending menopause clinics. We examine rigorous observational studies of the menopausal transition to determine whether there are changes in sexual functioning associated with the menopausal transition and the relative roles of aging and hormonal factors. We detail the methodological limitations of menopause research. We then review studies documenting the effects of aging on women's sexual functioning prior to reviewing studies that document both aging and menopausal status. These latter studies are divided into both cross-sectional and longitudinal studies. In summary, there is an age-related decline in sexual functioning but an added incremental decline associated with the menopausal transition. There have been relatively few studies that have been prospective, population-based, utilised a validated measure of sexual functioning, and carried out concurrent hormonal sampling. The Melbourne Women's Midlife Health Project is a prospective, observational study of a community-based sample of Australian born women aged 45-55 at baseline. There were eight annual assessments using a self-report questionnaire based on the McCoy Female Sexuality Questionnaire and blood sampling for hormone levels. From early to late menopausal transition, the percentage of women with scores indicating sexual dysfunction rose from 42% to 88%. Decreasing scores correlated with decreasing estradiol but not with androgens. By the postmenopausal phase there was a significant decline in sexual arousal and interest, frequency of sexual activities, and the Total Score. There was a significant increase in vaginal dryness and dyspareunia and women's reports of their partner's problems in sexual performance. Women with low scores of sexual functioning were more likely to be distressed on the Female Sexual Distress Scale. In conclusion, there is a dramatic decline in female sexual functioning with the natural menopausal transition.