Disorder In Premenopausal Women Research Articles

Effects of Timing of Flibanserin Administration Relative to Alcohol Intake in Healthy Premenopausal Women: A Randomized, Double-Blind, Crossover Study

IntroductionFlibanserin is approved in the United States and Canada for the treatment of acquired, generalized, hypoactive sexual desire disorder in premenopausal women. Sedation-related side effects are among the most prevalent adverse events. Although infrequent, hypotension and syncope remain safety concerns because of possible interaction of flibanserin with alcohol. AimTo evaluate the impact of the timing of alcohol consumption on flibanserin safety and tolerability. MethodsIn this single-center, randomized, double-blind, placebo-controlled, 4-treatment crossover study, 64 healthy premenopausal women (mean age 32.5 ± 8.7 years; range 20‒52 years) received once-daily flibanserin 100 mg or placebo during each of two 10-day treatment periods. Study medication was administered on days 1–3 to achieve steady state. On days 4, 6, 8, and 10, after a standard breakfast, participants consumed 0.4 g/kg ethanol (approximately equivalent to two 5-oz glasses of wine) administered with orange juice 2, 4, or 6 hours before taking study medication or orange juice alone (no ethanol) 2 hours before taking study medication. OutcomesThe primary endpoint was percentage of participants experiencing syncope or orthostatic hypotension–associated adverse events requiring medical intervention. Secondary endpoints included the incidence of hypotension, the incidence of orthostatic hypotension, and rates of adverse events of special interest (syncope, orthostatic hypotension, dizziness, and somnolence). Results1 participant experienced a primary endpoint event (syncope) during treatment with placebo taken 4 hours after ethanol consumption. Within each ethanol dose–timing treatment, there were no statistically significant differences for flibanserin compared with placebo. Rates of hypotension were 53.3–66.7% after flibanserin dosing and 57.4–63.3% after placebo dosing. Rates for orthostatic hypotension were 0.0–5.0% after flibanserin dosing and 1.7–6.6% after placebo dosing. Clinical ImplicationsEthanol interaction with flibanserin was not observed in this study. Strengths & LimitationsThis study provides information regarding the use of flibanserin after the consumption of moderate amounts of ethanol (0.4 g/kg). However, daytime administration of flibanserin is not consistent with the drug’s indicated bedtime dosing. ConclusionFlibanserin, at steady state taken 2, 4, or 6 hours after 0.4 g/kg of ethanol intake did not increase the incidence of hypotension, orthostatic hypotension, or syncope compared with either flibanserin alone or ethanol alone.Simon JA, Clayton AH, Kingsberg SA, et al. Effects of Timing of Flibanserin Administration Relative to Alcohol Intake in Healthy Premenopausal Women: A Randomized, Double-Blind, Crossover Study. J Sex Med 2019;16:1779–1786.

Four solid forms of flibanserin: Insight into the crystal structures, properties, stability, and solid-state transition

Flibaserin is a drug for the treatment of hypoactive sexual desire disorder in pre-menopausal women. Four solid forms of flibanserin were discovered, including form A, form I, form II, and form III. The properties of these forms were characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and Fourier transform infrared spectroscopy. Single-crystal structures of form A and form I were identified by single-crystal X-ray diffraction. The host molecule conformations, H-bonding interactions, as well as packing arrangements of these single crystals were analyzed. Besides, stability and solid-state transition of these forms were investigated.

DNA methylation in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the leading endocrine and metabolic disorder in premenopausal women characterized by hyperandrogenism and abnormal development of ovarian follicles. To date, the PCOS etiology remains unclear and has been related to insulin resistance, obesity, type 2 diabetes mellitus, cardiovascular disease and infertility, among other morbidities. Substantial evidence illustrates the impact of genetic, intrauterine and environmental factors on the PCOS etiology. Lately, epigenetic factors have garnered considerable attention in the pathogenesis of PCOS considering that changes in the content of DNA methylation, histone acetylation and noncoding RNAs have been reported in various tissues of women with this disease. DNA methylation is changed in the peripheral and umbilical cord blood, as well as in ovarian and adipose tissue of women with PCOS, suggesting the involvement of this epigenetic modification in the pathogenesis of the disease. Perhaps, these defects in DNA methylation promote the deregulation of genes involved in inflammation, hormone synthesis and signaling and glucose and lipid metabolism. Research on the role of DNA methylation in the pathogenesis of PCOS is just beginning, and several issues await investigation. This review aims to provide an overview of current research focused on DNA methylation and PCOS, as well as discuss the perspectives regarding this topic.

FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women

FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women

025 Direct Determination of Kinetic and Equilibrium Binding of Flibanserin to 5HT1A and 5HT2A Receptors

Flibanserin is a 5HT1A receptor agonist and 5HT2A receptor antagonist that has been approved in the US and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women. The most frequently experienced adverse events associated with flibanserin use include sedation-related symptoms. Activation of 5-HT1A receptors has been shown to generally promote wakefulness and inhibit sleep while inhibition of 5-HT2A receptors has been shown to reduce wakefulness. Previous receptor binding studies have indirectly estimated flibanserin’s equilibrium affinity constants to different receptors by using a second, more readily available radiolabeled ligand. Furthermore, dissociation rates of flibanserin from 5HT1A and 5HT2A receptors have not been described in the literature. The objective of this study was to directly characterize equilibrium binding and kinetic dissociation parameters of flibanserin for 5HT1A and 5HT2A receptors. Flibanserin binding was determined in membrane preparations of cell lines overexpressing human 5HT1A receptors or human 5HT2A receptors. Membranes were incubated with 100 nM flibanserin for 3 h at 37°C and dissociation was induced by 10-fold dilution and immediate addition of 400-fold molar excess of WAY100635 (5HT1A subtype-selective receptor antagonist) or eplivanserin (5HT2A subtype-selective receptor antagonist) and aliquots were removed at varying time points for measurement. For saturation binding studies, cell membranes were incubated with increasing concentrations of flibanserin in the absence or presence of at least 200-fold molar excess of either WAY100635 or eplivanserin for 3 h at 37°C to determine total and non-specific binding. Membranes were collected with vacuum onto polyethylenimine-treated glass fiber filters, washed and extracted. Flibanserin was quantified by liquid chromatography and tandem mass spectrometry using positive ion mode electrospray ionization.

Evaluation of Flibanserin Safety: Comparison with Other Serotonergic Medications.

Flibanserin, a multifunctional serotonin agonist and antagonist, is approved by the U.S. Food and Drug Administration (FDA) for treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women. During the FDA's review of flibanserin, concerns were raised about the risks of hypotension, syncope, and sedation-related adverse events, which increase with alcohol use. Based on the results of an alcohol challenge study, the FDA required a boxed warning and alcohol contraindication in the flibanserin prescribing information, as part of a risk evaluation and mitigation strategy program. To evaluate the adverse event profile of flibanserin in the context of that seen with other medications that affect serotonin in the brain and are commonly prescribed for women. This was a review of data provided in the product prescribing information for flibanserin, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, other serotonergic antidepressants, and triptans. The incidence of adverse events was assessed. The incidences of hypotension, syncope, and sedation-related adverse events (eg, dizziness, somnolence, fatigue) in studies of flibanserin were within the ranges observed for serotonergic antidepressants; the rates of these adverse events were generally lower with triptan medications. Other flibanserin-associated adverse events (eg, nausea, insomnia, dry mouth) occurred more commonly in patients taking antidepressant medications. Although medications that affect the serotonin system have varying adverse event profiles (likely mediated by differences in serotonin-related mechanisms of action, specific brain structures affected, and effects on other neurotransmitter systems), the occurrence of central nervous system-related adverse events was not dissimilar between flibanserin and serotonergic antidepressants. Kingsberg SA, McElroy SL, Clayton AH. Evaluation of Flibanserin Safety: Comparison with Other Serotonergic Medications. Sex Med Rev 2019;7:380-392.

Effect of Paraoxonase1 (PON1) gene polymorphisms on PON1 activity, HDL, LDL and MDA levels in women with polycystic ovary syndrome (PCOS): A case-control study

Polycystic ovary syndrome (PCOS) is considered as one of the most common endocrine disorders in premenopausal women with varied pathophysiology. In this study we investigated the association between -108C/T and 55L/M polymorphisms of Paraoxonase1 (PON1) gene with PCOS. PON1 gene codes for the antioxidant enzyme PON1 which is an HDL associated enzyme that prevents oxidative modification of low-density lipoprotein. A total of 192 women with PCOS and 212 control women from an ethnic population (Kashmir) were included in the study. The PON1 polymorphism was genotyped using PCR-RFLP technique. Clinical, Biochemical parameters were analyzed, and HOMA-IR was used to estimate insulin resistance. Serum PON1 activity and MDA levels were also measured. The frequencies of variant PON1 -108TT genotype and T allele were significantly higher in women with PCOS than controls (31.25%Vs15.09%) and (56.77%Vs41.27%) respectively. The -108TT genotype remained a significant predictor for PCOS (OR-odds ratio = 3.8051, 95%CI = 2.101–6.8914, χ2-chi square = 20.19, P < .05). Fasting insulin and HOMA-IR were significantly raised in PCOS women than controls (P = .000). Serum PON1 activity and HDL-Cholesterol were significantly decreased whereas MDA and LDL-Cholesterol were significantly raised in PCOS women than controls (P = .000). A significant difference was observed between PON1 -108C/T genotypes and weight, waist, waist/hip, BMI, FG score, glucose 1 h, fasting insulin, HOMA, FGIR, QUICKI, LDL-C, testosterone, PON1 activity and MDA (P < .05). Compared with the -108CC genotype, carriers with -108TT genotype of PON1 had significantly raised cholesterol and MDA, and decreased HDL-C and PON1 activity (P < .05). No significant difference was found in the PON1 55L/M genotype and allele frequencies between PCOS women and healthy controls. In conclusion, -108C/T Polymorphism but not 55L/M Polymorphism is a risk factor for PCOS and deranged biochemical, hormonal and lipid profile in Kashmiri women.

Sex, drugs, and rhetoric: The case of flibanserin for 'female sexual dysfunction'.

In August, 2015, the US Food and Drug Administration approved Addyi (flibanserin) for the treatment of Hypoactive Sexual Desire Disorder in premenopausal women. Ten months before that, the FDA had held a Patient-Focused Drug Development Public Meeting to address the 'unmet need' for a pharmaceutical to treat that condition. I attended that meeting as a rhetorical observer. This essay is an account of persuasive strategies used on, and then by, the FDA, as it considered approving a drug that was not convincingly either safe or effective. The essay turns on three texts: the 'Even the Score' pro-drug campaign that informed the patient-focused meeting, the text of the meeting itself, and the FDA's own published report of the event. I describe how a pharmaceutical company (Sprout, then owners of flibanserin) recruited, and then ventriloquized, both health professionals and members of the public to pressure the FDA to approve a sex drug for women - claiming that not to do so was evidence of sexism. I argue, with rhetorical evidence, that the case for approving flibanserin had already been won before Sprout submitted its application.

Flibanserin for hypoactive sexual desire disorder in premenopausal women.

Flibanserin is a mixed 5-HT1A agonist and 5-HT2A antagonist for treatment of premenopausal women with hypoactive sexual desire disorder. It is the first FDA-approved treatment for this disorder and can improve the number of satisfying sexual events. The drug has been associated with hypotension and syncope.

Licorice ethanol extract improves symptoms of polycytic ovary syndrome in Letrozole-induced female rats

BackgroundLicorice (Glycyrrhizae radix et rhizome, GRR) has long been used as an ingredient in Korean traditional medicinal herbal formulas for various metabolic and reproductive diseases. Polycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women. In the present study, we examined the effects of GRR extract on PCOS-like symptoms in female rats. MethodsSymptoms of PCOS were induced by Letrozole treatment for 4 weeks in 6-week-old female SD rats, after which the effects of GRR extract on recovery of normal hormonal levels and polycystic ovaries were assessed. Serum levels of luteinizing hormone (LH), follicular-stimulating hormone (FSH), LH/FSH ratio, and follicular cysts were evaluated, followed by the expression levels of known follicular phase markers such as Kitl, Cyp11a1, and Ptgs2. ResultsThe serum level of FSH was reduced only in the Lestrozole treatment group (PCOS), whereas significant recovery of FSH level was observed in the Letrozole and GRR co-treatment group (PCOS+GRR). Serum LH levels were not altered in any of the groups. Furthermore, the LH/FSH ratio (known biomarker for PCOS) was elevated only in the Letrozole treatment group (PCOS), whereas it was significantly reduced in the Letrozole and GRR co-treatment group (PCOS+GRR). For histological changes, follicular cysts, antral follicles, and increased thickness of the theca- and granulosa layers were observed in the PCOS group, whereas these alterations were remarkably reversed by GRR treatment. ConclusionThese results suggest that GRR extract inhibits the symptoms of PCOS by regulating imbalanced hormonal levels and irregular ovarian follicles.

027 Effect of Alcohol Consumption on the Safety and Tolerability of Flibanserin in Premenopausal Female Volunteers

Addyi (flibanserin 100mg), is an orally administered, centrally-acting treatment for hypoactive sexual desire disorder in premenopausal women. Alcohol use is contraindicated due to Phase I study data suggesting increased risk of hypotension and syncope. Because the design of that alcohol challenge study [i.e., morning dosing of Addyi with high doses of ethanol (0.4–0.8 g/kg) consumed within 10 min] is inconsistent with prescribed dosing (q.h.s) and quantity of alcohol consumed in the general population, we assessed the effects of low-moderate alcohol use in premenopausal women taking Addyi as prescribed. Premenopausal women providing informed consent (n=24; mean age=38±6 y; mean BMI=24±3 kg/m2) consumed 1-2 glasses (125-250ml) of sulfite-free wine (12.5% ethanol) with a standardized 3-course dinner in a clinical research unit. Addyi was administered with 240 ml of water 5 min before bedtime (2.5 h after dinner). Subjects were awakened 8 h after dosing. Vital signs were assessed before and after dinner, and upon waking the next morning. Primary endpoints were the incidence and severity of adverse events (AEs) and changes in vital signs. Secondary endpoints were self-reported feeling of well-being and self-reported quality of sleep.

PND6 - Unmet Needs in the Management of Hypoactive Sexual Desire Disorder in Premenopausal Women

To gain insight into the diagnosis and management of hypoactive sexual desire disorder (HSDD) among premenopausal women reporting a diagnosis or symptoms of HSDD. A 30-minute, IRB-approved survey was designed to explore the patient experience and physical, social, mental, emotional, and economic burden related to HSDD. Inclusion criteria were ≥18 years of age, a diagnosis or symptoms of HSDD in accordance with the Decreased Sexual Desire Screener, currently in a stable, monogamous relationship with a partner for ≥6 months. Women with a bilateral oophorectomy or hysterectomy were excluded. 314 premenopausal women were included in the analysis. HSDD was most commonly managed by OB/GYNs (47.8%) or PCPs (35.5%). Among respondents who discussed their HSDD symptoms with their physician/therapist (n=203), 82.3% initiated the conversation themselves. While respondents generally had a positive perception of their physicians/therapists, 24.4% of respondents believed their HCPs were not aware of HSDD as a medical condition, and 16.7% of respondents felt their HCP did not take their concerns seriously. The most commonly prescribed treatments, lubricants (51.6%) and meditation/yoga (36.6%), were nonpharmacologic, which have no documented efficacy. Antidepressants or anti-anxiety medications were prescribed to 14.6% of respondents. Respondents who received nonpharmacologic treatments (n=243) generally found treatments safe but 35.8% cited poor efficacy; common reasons for ineffectiveness included no change in interest in sexual activity (65.8%) and inability to “stay in the moment” during sexual activity (57.6%). Although HSDD is recognized as a medical condition by ISSWSH (consensus review) and the APA (DSM-IV-TR), diagnosis and treatment are largely patient-initiated rather than HCP-driven. There is a need for improved HCP education, as many lack knowledge of how to diagnose and treat HSDD. Prescription patterns, which tend toward nonpharmacologic treatments, also suggest a lack of understanding of disease etiology and/or a paucity of approved and efficacious treatment options.

Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in premenopausal women. Heterogeneous by nature, PCOS is defined by a combination of signs and symptoms of androgen excess and ovarian dysfunction in the absence of other specific diagnoses. The aetiology of this syndrome remains largely unknown, but mounting evidence suggests that PCOS might be a complex multigenic disorder with strong epigenetic and environmental influences, including diet and lifestyle factors. PCOS is frequently associated with abdominal adiposity, insulin resistance, obesity, metabolic disorders and cardiovascular risk factors. The diagnosis and treatment of PCOS are not complicated, requiring only the judicious application of a few well-standardized diagnostic methods and appropriate therapeutic approaches addressing hyperandrogenism, the consequences of ovarian dysfunction and the associated metabolic disorders. This article aims to provide a balanced review of the latest advances and current limitations in our knowledge about PCOS while also providing a few clear and simple principles, based on current evidence-based clinical guidelines, for the proper diagnosis and long-term clinical management of women with PCOS.

Non-targeted profiling of circulating microRNAs in women with polycystic ovary syndrome (PCOS): effects of obesity and sex hormones

PurposeCirculating micro-ribonucleic acids (miRNAs) are small noncoding RNA molecules that influence gene transcription. We conducted the present profiling study to characterize the expression of circulating miRNAs in lean and obese patients with polycystic ovary syndrome (PCOS), the most common endocrine and metabolic disorder in premenopausal women. Basic ProceduresWe selected 11 control women, 12 patients with PCOS and 12 men so that they were similar in terms of body mass index. Five control women, 6 men and 6 patients with PCOS had normal weight whereas 6 subjects per group were obese. We used miRCURY LNA™ Universal RT microRNA PCR for miRNA profiling. Main FindingsThe expression of 38 miRNAs and was different between subjects with PCOS and male and female controls. The differences in 15 miRNAs followed a pattern suggestive of androgenization characterized by expression levels that were similar in patients with PCOS and men but were different compared with those of control women. The expression of 13 miRNAs in women with PCOS was similar to that of control women and different compared with the expression observed in men, suggesting sexual dimorphism and, lastly, we observed 5 miRNAs that were expressed differently in women with PCOS compared with both men and control women, suggesting a specific abnormality in expression associated with the syndrome. Obesity interacted with the differences in several of these miRNAs, and the expression levels of many of them correlated with the hirsutism score, sex hormones and/or indexes of obesity, adiposity and metabolic dysfunction. Principal ConclusionsThe present results suggest that several serum miRNAs are influenced by PCOS, sex hormones and obesity. Our findings may guide the targeted search of miRNAs as clinically relevant markers for PCOS and its association with obesity and metabolic dysfunction in future studies.

015 Efficacy of Flibanserin by Duration of Hypoactive Sexual Desire Disorder in Premenopausal Women

Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, is indicated for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. This post hoc analysis evaluated the efficacy of flibanserin treatment by duration of HSDD. Data were pooled from three 24-week, double-blind, placebo-controlled studies of flibanserin in premenopausal women with HSDD. Patients were stratified by HSDD duration (>6 months to 2 years, >2-5 years, and >5 years). Key measures of efficacy were the Female Sexual Function Index desire domain (FSFI-d) score, the Female Sexual Distress Scale-Revised item 13 (distress due to low desire; FSDS-R-13) score, and the number of satisfying sexual events (SSE). This analysis included 2344 premenopausal women (HSDD duration >6 months to 2 years, n=705; duration >2-5 years, n=830; duration >5 years, n=809) who received flibanserin 100 mg qhs or placebo. Improvement from baseline to week 24 in FSFI-d score (least-squares [LS] mean change) was significantly greater for flibanserin compared with placebo in women with HSDD for >6 months to 2 years (1.0 vs 0.8; P=0.010), >2-5 years (0.9 vs 0.6; P=0.004), and >5 years (0.9 vs 0.5; P<0.0001). Similarly, significantly greater improvement on the FSDS-R-13 (LS mean change) for flibanserin versus placebo was observed in women with HSDD duration of >6 months to 2 years (-1.0 vs -0.7; P=0.017), >2-5 years (-0.8 vs -0.6; P=0.027), and >5 years (-0.8 vs -0.5; P<0.0001) For SSE, improvement (LS mean change) with flibanserin relative to placebo was significantly different for HSDD duration >6 months to 2 years (2.7 vs 1.6; P=0.018) and duration >5 years (1.9 vs 1.2, P=0.003), but did not reach statistical significance, though trended, for duration of >2-5 years (1.9 vs 1.3; P=0.053). The most common adverse events associated with flibanserin (>5% of flibanserin-treated patients, overall) were somnolence (12.8% for flibanserin vs 3.4% for placebo) and dizziness (10.6% vs 1.5%).

Effects of Flibanserin on the Pharmacokinetics of a Combined Ethinylestradiol/Levonorgestrel Oral Contraceptive in Healthy Premenopausal Women: A Randomized Crossover Study

PurposeThis study aimed to investigate the effect of steady-state exposure to flibanserin, a 5-HT1A agonist/5-HT2A antagonist approved for the treatment of hypoactive sexual desire disorder in premenopausal women, on the single-dose pharmacokinetics of the contraceptive steroids ethinylestradiol and levonorgestrel in healthy premenopausal women. MethodsHealthy female volunteers (N = 24) received 2 single doses of a combined oral contraceptive containing ethinylestradiol 30 μg and levonorgestrel 150 μg, either alone (reference) or preceded by treatment with flibanserin 100 mg once daily for 14 days (test). The 2 treatments were given in randomized order, with a 4-week washout period following the last administration of the first treatment. Plasma concentrations of ethinylestradiol and levonorgestrel were measured over 48 hours after dosing for the determination of pharmacokinetic parameters; the primary end points were Cmax and AUC0–∞ of ethinylestradiol and levonorgestrel. FindingsOf the 24 women enrolled (mean age, 38.0 years), 23 completed the study. Mean (SD) Cmax and AUC0–∞ values of ethinylestradiol were 66.7 (16.3) pg/mL and 693 (268) pg · h/mL, respectively, following the oral contraceptive alone, and 72.7 (25.5) pg/mL and 740 (235) pg · h/mL, respectively, when the oral contraceptive was preceded by flibanserin. In both cases, the 90% CIs of the reference/test ratios of Cmax and AUC0–∞ were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of ethinylestradiol. Similarly, the mean (SD) Cmax and AUC0–∞ values of levonorgestrel were 5.0 (1.6) ng/mL and 52.2 (18.7) ng · h/mL, respectively, with the oral contraceptive alone, and 5.0 (1.6) ng/mL and 53.3 (20.4) ng · h/mL, respectively, following flibanserin; again, in both cases, the 90% CIs of the reference/test ratios were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of levonorgestrel. All adverse events were mild to moderate in intensity (incidence: 12.5% and 70.8% with ethinylestradiol/levonorgestrel treatment alone and following administration of flibanserin, respectively). ImplicationsPretreatment with flibanserin 100 mg once daily for 2 weeks did not produce a clinically relevant change in oral contraceptive drug exposure following single-dose administration of ethinylestradiol/levonorgestrel. This finding is relevant to women with hypoactive sexual desire disorder who might prefer oral contraceptives to other forms of birth control. EudraCT No: 2006-006960-46.

Consequences of advanced aging on renal function in chronic hyperandrogenemic female rat model: implications for aging women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine and reproductive disorder in premenopausal women, characterized by hyperandrogenemia, metabolic syndrome, and inflammation. Women who had PCOS during their reproductive years remain hyperandrogenemic after menopause. The consequence of chronic hyperandrogenemia with advanced aging has not been studied to our knowledge. We have characterized a model of hyperandrogenemia in female rats and have aged them to 22–25 months to mimic advanced aging in hyperandrogenemic women, and tested the hypothesis that chronic exposure to hyperandrogenemia with aging has a deleterious effect on renal function. Female rats were chronically implanted with dihydrotestosterone pellets (DHT 7.5 mg/90 days) that were changed every 85 days or placebo pellets, and renal function was measured by clearance methods. Aging DHT‐treated females had a threefold higher level of DHT with significantly higher body weight, mean arterial pressure, left kidney weight, proteinuria, and kidney injury molecule‐1 (KIM‐1), than did age‐matched controls. In addition, DHT‐treated‐old females had a 60% reduction in glomerular filtration rate, 40% reduction in renal plasma flow, and significant reduction in urinary nitrate and nitrite excretion (UNOxV), an index of nitric oxide production. Morphological examination of kidneys showed that old DHT‐treated females had significant focal segmental glomerulosclerosis, global sclerosis, and interstitial fibrosis compared to controls. Thus chronic hyperandrogenemia that persists into old age in females is associated with renal injury. These data suggest that women with chronic hyperandrogenemia such as in PCOS may be at increased risk for development of chronic kidney disease with advanced age.

Phase I Randomized Placebo-controlled, Double-blind Study of the Safety and Tolerability of Bremelanotide Coadministered With Ethanol in Healthy Male and Female Participants

PurposeThis was a Phase I study to evaluate the safety, tolerability, and hemodynamic and pharmacokinetic effects of bremelanotide (BMT) coadministered with ethanol to healthy male and female participants. MethodsThis was a randomized, placebo-controlled, double-blind, 3-period, 3-way crossover study. Individuals meeting the inclusion/exclusion criteria received BMT or placebo with or without ethanol at the research facility for 7 consecutive days. Participants were randomized to receive 1 of 6 treatment paths; each participant received single intranasal doses of BMT (20 mg) or placebo on days 1, 4, and 7, with or without oral ethanol (0.6 g/kg) while in a fasted state. The intranasal 20-mg dose of BMT has an exposure equivalent to ~1 to 2 times the subcutaneous dose currently being evaluated in Phase III studies. Vital signs, self-rated sedation scores, nursing and medical observations, and spontaneous reporting by participants provided the basis for evaluation of adverse events. A physical examination and a resting 12-lead electrocardiogram were performed at baseline and on study day 7. Blood and urine samples were obtained for clinical safety profile laboratory tests. FindingsA total of 24 participants were enrolled (12 men; 12 women) and completed the study. Single doses of 20 mg intranasal BMT, administered with or without 0.6 g/kg ethanol, were found to be safe and generally well tolerated with mean maximum ethanol concentrations exceeding 80 mg/dL in women. No clinically significant pharmacokinetic interactions were found between ethanol and BMT either overall or by sex. No significant drug-related hypotensive or orthostatic hypotensive effects were noted. Treatment with BMT did not result in an increased frequency of treatment-emergent adverse events, and no participants discontinued the study because of adverse events. Physical examination, electrocardiography, and laboratory tests disclosed no clinically significant changes. ImplicationsFemale sexual dysfunction is a multifactorial condition with anatomic, physiologic, medical, psychological, and social components. BMT is a synthetic peptide analogue of the naturally occurring hormone α-melanocyte–stimulating hormone and a melanocortin receptor agonist that is being developed for the treatment of hypoactive sexual desire disorder. Its mechanism of action involves activation of endogenous melanocortin hormone pathways involved in the sexual desire and arousal response. The results of this Phase I study found that BMT and ethanol can be safely coadministered and are generally well tolerated with no reports of drug-related serious adverse events. Phase III trials of subcutaneous BMT for the treatment of hypoactive sexual desire disorder in premenopausal women are in progress. ClinicalTrials.gov identifiers NCT02338960 and NCT02333071.

What Women Want—An Explorative Study on Women's Attitudes Toward Sexuality Boosting Medication in a Sample of Swiss Women

IntroductionThe recent approval of flibanserin to treat hypoactive sexual desire disorder in premenopausal women has once again fueled the ongoing debate about medicalization of female sexual problems and the necessity of such a drug. AimTo investigate women's attitudes toward sexuality-boosting medication (SBM) and the role of factors potentially associated with these attitudes, including sexual functioning, sexual quality of life, relationship satisfaction, and personality, in an exploratory survey. MethodsA population sample of 159 women 18 to 73 years old (mean = 31.8) participated in this cross-sectional online survey. Study variables were assessed using a combination of validated questionnaires and self-constructed questions. Main Outcome MeasuresDescriptive statistics in the form of proportions and percentages and correlation and moderation analyses. ResultsSixty-one percent of women were willing to take SBM, mostly to increase orgasm frequency and intensity and sexual desire. Likeliness to take SBM correlated negatively with age (r = −0.24; P < .005) and with levels of arousal, lubrication, orgasm, and sexual satisfaction (P < .05 for all comparisons). Higher relationship satisfaction and conscientiousness moderated the association between willingness to take SBM and desire levels (P < .05 for the two comparisons). For desired properties of SBM, 48.2% of women considered an onset of action of “up to 1 hour” ideal, 41% preferred “less than 15 minutes,” and 66.9% considered a window of action of “an hour” to be ideal. ConclusionThe demand for a drug to enhance sexual performance in women exists and ideally should target desire and orgasm intensity and frequency. By taking such as drug, women hope to benefit in increased sexual satisfaction and fun with sex. Furthermore, the willingness to take SBM seems to greatly depend on the woman's relationship satisfaction and some personality characteristics.Gutsche M, Burri A. What Women Want—An Explorative Study on Women's Attitudes Toward Sexuality Boosting Medication in a Sample of Swiss Women. J Sex Med 2017;14:404–412.

Effect of aerobic exercise in improving the quality of life in polycystic ovarian disease.

Polycystic ovarian syndrome (PCOS) is a most common endocrine disorder in premenopausal women and is characterized by chronic ovulatory dysfunction and hyperandrogenism. It is the most common cause of infertility but it also should be considered a multifaceted disease. Weight gain and fat accumulation are predisposing factor of PCOS. Life-style modification including increasing physical activity is the first line approach in managing PCOS. The aim of the study is to evaluate the effect of aerobic exercise in improving the quality of life, reducing BMI and number of follicles in Polycystic Ovarian disease (PCOD). Based on inclusion and exclusion criteria, 30 subjects between age group 18 to 25years were selected. For all the subjects, ultrasound scan was done to find out the number of follicles. For all the patients aerobic exercise was given for 8 weeks, 3 sessions per week each lasting for 45 minutes. After 8 weeks the post test values was noted. The results were measured in terms of BMI, PCOD-Questionnaire, and ultrasonogram (USG). The pretest and post test values were calculated using Paired t test. This study showed statistically significant improvement in BMI (P < 0.0001), quality of life (P= 0.0035) and reduction in the number of follicles in the ovary (P < 0.0001). From this study it is clinched that the aerobic exercise improves the quality of life in overweight PCOD women by reducing BMI, the number of follicles and the regulation of menstrual cycle.