Treatment for hypoactive sexual desire.

Flibanserin acts at cortical, limbic, hypothalamic, and brainstem nuclei to inhibit serotonin release by binding to 5-HT1A autoreceptors and block postsynaptic action of serotonin at 5-HT2A receptors. This gradually disinhibits the turnover of other monoamines like dopamine and noradrenaline that are critical for sexual desire.

Preparation and In Vitro and In Vivo Evaluation of a Testosterone Film Forming Gel for the Treatment of Hypoactive Sexual Desire Disorder in Women.

Hypoactive sexual desire disorder (HSDD) is one of the most common sexual complaints in women. Currently, there is an unmet need for a drug treatment for this disorder. The purpose of this study was to develop a testosterone (TS) film forming gel used for women to treat HSDD by measuring the tackiness, peel adhesion force, tensile strength, and elasticity of the formulation. Diethylene glycol monoethyl ether (Transcutol P), an efficient penetration enhancer, was added to the optimized formulation and the transdermal permeation characteristics in vitro were studied using Franz-diffusion cells. The quantitative determination of TS was performed by high-performance liquid chromatography (HPLC). After 24 h, Transcutol P at 3% had the largest cumulative amount of drug and enhancement ratio of TS of 75.14 µg/cm2 and 2.82, respectively. After the screening of film forming polymers and penetration enhancers, the optimal formulation was as follows: glycerol (1%, w/w); 12.5% sodium carboxymethylcellulose (CMC-Na) aqueous solution (0.5%, w/w); 2.5% Carbomer ethanol solution (0.5%, w/w); Transcutol P ethanol solution (3%, w/w) containing 0.5% TS; and 8% Poly vinyl alcohol (PVA) aqueous solution (30%, w/w). The optimized film forming gel had good uniformity and the release of TS in vitro was close to 100% within 24 h. In vivo studies showed the formulations had optimal area under blood drug concentration curve values in the order of 3% Transcutol P > 1% Transcutol P > 5% Transcutol P > control preparation. The formulation with 3% Transcutol P provided the highest permeation effect both in vitro and in vivo. The safety of this formulation was further evaluated with a skin irritation test. It could effectively improve the rabbit skin irritation observed with a marketed transdermal patch Androderm®. The present study provides a promising approach for the development of a novel TS film forming gel for the treatment of HSDD in women.

Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options.

BACKGROUND: The neurobiology of sexual response is driven in part by dopamine and serotonin-the former modulating excitatory pathways and the latter regulating inhibitory pathways. Neurobiological underpinnings of hypoactive sexual desire disorder (HSDD) are seemingly related to overactive serotonin activity that results in underactive dopamine activity. As such, pharmacologic agents that decrease serotonin, increase dopamine, or some combination thereof, have therapeutic potential for HSDD. AIM: To review the role of serotonin in female sexual function and the effects of pharmacologic interventions that target the serotonin system in the treatment of HSDD. METHODS: Searches of the Medline database for articles on serotonin and female sexual function. OUTCOMES: Relevant articles from the peer-reviewed literature were included. RESULTS: Female sexual response is regulated not only by the sex hormones but also by several neurotransmitters. It is postulated that dopamine, norepinephrine, oxytocin, and melanocortins serve as key neuromodulators for the excitatory pathways, whereas serotonin, opioids, and endocannabinoids serve as key neuromodulators for the inhibitory pathways. Serotonin appears to be a key inhibitory modulator of sexual desire, because it decreases the ability of excitatory systems to be activated by sexual cues. Centrally acting drugs that modulate the excitatory and inhibitory pathways involved in sexual desire (eg, bremelanotide, bupropion, buspirone, flibanserin) have been investigated as treatment options for HSDD. However, only flibanserin, a multifunctional serotonin agonist and antagonist (5-hydroxytryptamine [5-HT]1A receptor agonist and 5-HT2A receptor antagonist), is currently approved for the treatment of HSDD. CLINICAL IMPLICATIONS: The central serotonin system is 1 biochemical target for medications intended to treat HSDD. STRENGTHS AND LIMITATIONS: This narrative review integrates findings from preclinical studies and clinical trials to elucidate neurobiological underpinnings of HSDD but is limited to 1 neurotransmitter system (serotonin). CONCLUSION: Serotonin overactivity is a putative cause of sexual dysfunction in patients with HSDD. The unique pharmacologic profile of flibanserin tones down inhibitory serotonergic function and restores dopaminergic and noradrenergic function. Croft HA. Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options. J Sex Med 2017;14:1575-1584.

Hormonal effect on the relationship between migraine and female sexual dysfunction.

It is not a well-established finding in migraine that female sexual dysfunction (FSD) emerging as a natural course of disease, as a result of accompanying depression/anxiety, or an underlying endocrinological abnormality. Our aim is evaluating the relationship among frequency and severity of migraine, FSD, depression, anxiety, and related hormones in migrainous women. We examined 80 migrainous female and 62 controls cross sectionally. Beck Depression and Anxiety Inventories, Female Sexual Dysfunction Inventory, Migraine Disability Assessment Test, and hormonal analysis were done. Independent risk factors were identified by logistic regression analysis and cut-off values were measured with Receiver Operating Curve. FSD was not related to frequency or severity of migraine. Although depression and anxiety was related to arousal and lubrication, they had limited effect in FSD. There were correlations between prolactin (PRL), desire and lubrication, follicular-stimulating hormone FSH and orgasm, luteinizing hormone (LH), and pain. Also FSH-LH combination and PRL were found as independent factors for FSD. FSH-LH combination and PRL were found as independent factors which had effect on FSD in migraine. Our study is a precursor study about the effect of several hormones on FSD and migraine relationship. Hormonal effect on FSD in migraine will be clearer with future studies.

Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder.

Flibanserin is a novel multifunctional serotonin agonist and antagonist (MSAA) that improves sexual functioning in premenopausal women who suffer from reduced sexual interest and desire.

Chronic stress and sexual function in women.

INTRODUCTION: Chronic stress is known to have negative effects on reproduction, but little is known about how it affects the sexual response cycle. The present study examined the relationship between chronic stress and sexual arousal and the mechanisms that mediate this relationship. AIM: The aim of this study is to test the relationship between chronic stress and sexual arousal and identify mechanisms that may explain this relationship. We predicted that women experiencing high levels of chronic stress would show lower levels of genital arousal and dehydroepiandrosterone (DHEAS) and higher levels of cortisol and cognitive distraction compared with women with average levels of stress. METHODS: Women who were categorized as high in chronic stress (high stress group; n=15) or average in chronic stress (average stress group; n=15) provided saliva samples and watched an erotic film while having their genital and psychological arousal measured. MAIN OUTCOME MEASURES: Main outcome measures were vaginal pulse amplitude, psychological arousal, salivary cortisol, salivary DHEAS, and heart rate and compared them between women with high and average levels of chronic stress. RESULTS: Women in the high stress group had lower levels of genital, but not psychological arousal, had higher levels of cortisol, and reported more distraction during the erotic film than women in the average stress group. The main predictor of decreased genital sexual arousal was participants' distraction scores. CONCLUSIONS: High levels of chronic stress were related to lower levels of genital sexual arousal. Both psychological (distraction) and hormonal (increased cortisol) factors were related to the lower levels of sexual arousal seen in women high in chronic stress, but distraction was the only significant predictor when controlling for other variables.

A phase 2a multicenter, double-blind, placebo-controlled, crossover trial to investigate the efficacy, safety, and toleration of CP-866,087 (a high-affinity mu-opioid receptor antagonist) in premenopausal women diagnosed with female sexual arousal disorder (FSAD).

INTRODUCTION: Female sexual arousal disorder (FSAD) is a condition that can affect women of all ages and have a significant negative impact on emotional well-being. AIMS: The aim of this study is to prospectively evaluate the effects of CP-866,087, a selective mu-opioid receptor antagonist, in premenopausal women with FSAD. METHODS: The study included 51 women (20-45 years of age) with FSAD. All women received placebo and two of three planned doses of CP-866,087 (1, 3, and 10 mg) for 6 weeks in each of three double-blind treatment periods. Efficacy was determined through a series of measures to assess sexual functioning, sexual activity, sexual distress, and perceived meaningful benefit as a result of treatment. In addition, a semi-structured exit interview was conducted at the end of the fourth treatment period or withdrawal to provide a more in-depth, qualitative description of the participants' symptoms, response to treatment, and treatment satisfaction to augment the quantitative assessments. MAIN OUTCOME MEASURES: The within-subject differences from placebo in the change from baseline were compared across a range of measures of sexual function. Summary statistics and 90% confidence intervals were calculated. A qualitative analysis of the exit interview was conducted based on grounded theory methods. RESULTS: Although improvements were seen with CP-866,087 in the key efficacy end points, there was no clinical treatment benefit over placebo. The exit interview analysis suggested that being part of the study and taking positive action to search for a solution to the women's sexual disorder may have been a significant factor in the behavioral changes that were seen, as opposed to the drug treatment itself. CONCLUSIONS: Discerning the potential benefit of pharmacotherapy in a heterogeneous condition such as FSAD is challenging. Participation in a clinical trial combined with a commitment to actively engage in sexual activity may in itself create an environment that is conducive to symptom improvement.

Targeting the central melanocortin system for the treatment of metabolic disorders.

A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such as obesity and cachexia, as well as anorexia nervosa. Setmelanotide, which functions by engaging the central melanocortin circuitry, was approved by the FDA in 2020 for use in certain forms of syndromic obesity. Furthermore, the FDA approvals in 2019 of two peptide drugs targeting melanocortin receptors for the treatment of generalized hypoactive sexual desire disorder (bremelanotide) and erythropoietic protoporphyria-associated phototoxicity (afamelanotide) demonstrate the safety of this class of peptides. These approvals have also renewed excitement in the development of therapeutics targeting the melanocortin system. Here, we review the anatomy and function of the melanocortin system, discuss progress and challenges in developing melanocortin receptor-based therapeutics, and outline potential metabolic and behavioural disorders that could be addressed using pharmacological agents targeting these receptors.

[Treatment of premature ejaculation]. / Leczenie wytrysku przedwczesnego.

Premature ejaculation is the most common sexual dysfunction in men. Its prevalence rate in Europe and in United States is estimated to be between 20% and 30%. The diagnosis of premature ejaculation is based on three main criteria: increased intravaginal ejaculatory latency time (IELT), lack of control over ejaculation and interpersonal psychological disturbances. Premature ejaculation is classified as lifelong (primary) or acquired (secondary) and might be facilitated by chronic prostatitis, diabetes mellitus, hyperthyroidism, obesity. The exact etiology of the disease remains unclear, although 5-HT (5-hydroxytryptamine) receptors are known to have a significant role. The use of SSRIs (selective serotonine reuptake inhibitors) is old and efficient form of therapy for premature ejaculation. Other drugs like tramadol, clomipramine, local anaesthetics and PDE-5 (phosphodiesterase 5) inhibitors also have some efficacy in the treatment of premature ejaculation. To minimize adverse effects the "on demand" therapy is preferred to the daily treatment. Simple questionnaires for patients are used to assess treatment effects.

Sexual desire, sexual arousal and hormonal differences in premenopausal US and Dutch women with and without low sexual desire.

The interaction between women's hormonal condition and subjective, physiological, and behavioral indices of desire or arousal remains only partially explored, in spite of frequent reports from women about problems with a lack of sexual desire. The present study recruited premenopausal women at two sites, one in the United States and the other in the Netherlands, and incorporated various measures of acute changes in sexual desire and arousal. A sample of 46 women who met criteria for Hypoactive Sexual Desire Disorder (HSDD) was compared to 47 women who experienced no sexual problems (SF). Half of each group used oral contraceptives (OCs). The specific goal was to investigate whether there is a relationship between women's hormone levels and their genital and subjective sexual responsiveness. Background demographics and health variables, including oral contraceptive (OC) use, were recorded and hormones (total testosterone (T), free testosterone (FT), SHBG, and estradiol) were analyzed along with vaginal pulse amplitude and self-report measures of desire and arousal in response to sexual fantasy, visual sexual stimuli, and photos of men's faces. Self-reported arousal and desire were lower in the HSDD than the SF group, but only for women who were not using oral contraceptives. Relationships between hormones and sexual function differed depending on whether a woman was HSDD or not. In line with prior literature, FT was positively associated with physiological and subjective sexual arousal in the SF group. The HSDD women demonstrated the opposite pattern, in that FT was negatively associated with subjective sexual responsiveness. The findings suggest a possible alternative relationship between hormones and sexual responsiveness in women with HSDD who have characteristics similar to those in the present study.

Role of 5-HT(1A) receptors in fluoxetine-induced lordosis inhibition.

The selective serotonin reuptake inhibitor (SSRI), fluoxetine (Prozac(R)), is an effective antidepressant that is also prescribed for other disorders (e.g. anorexia, bulimia, and premenstrual dysphoria) that are prevalent in females. However, fluoxetine also produces sexual side effects that may lead patients to discontinue treatment. The current studies were designed to evaluate several predictions arising from the hypothesis that serotonin 1A (5-HT(1A)) receptors contribute to fluoxetine-induced sexual dysfunction. In rodent models, 5-HT(1A) receptors are potent negative modulators of female rat sexual behavior. Three distinct experiments were designed to evaluate the contribution of 5-HT(1A) receptors to the effects of fluoxetine. In the first experiment, the ability of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635), to prevent fluoxetine-induced lordosis inhibition was examined. In the second experiment, the effects of prior treatment with fluoxetine on the lordosis inhibitory effect of the 5-HT(1A) receptor agonist, (+/-)-8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), were studied. In the third experiment, the ability of progesterone to reduce the acute response to fluoxetine was evaluated. WAY100635 attenuated the effect of fluoxetine; prior treatment with fluoxetine decreased 8-OH-DPAT's potency in reducing lordosis behavior; and progesterone shifted fluoxetine's dose-response curve to the right. These findings are consistent with the hypothesis that 5-HT(1A) receptors contribute to fluoxetine-induced sexual side effects.

Body image is a major determinant of sexual dysfunction in stable HIV-infected women.

BACKGROUND: Prevalence and factors associated with sexual dysfunction in HIV-positive women are poorly known. METHODS: This was a cross-sectional study in a cohort of HIV-infected women. Clinically stable women were invited to participate in a female sexual dysfunction (FSD) evaluation with Female Sexual Function Index (FSFI) exploring desire, arousal, lubrication, orgasm, pain and satisfaction. An FSFI score <23 was used for defining FSD. Variables evaluated included body appearance satisfaction, interference of body changes with habits, social life and attitudinal aspects of body image, health-related quality of life, hormonal assessment, menopause, cumulative exposure to antiretroviral drug classes and immune-virological parameters. Lipodystrophy was defined according to the HIV Outpatient Study definition. RESULTS: A total of 185 women completed the FSFI. The mean (+/-SD) age was 42 years (+/-5), 27% had CDC stage C, the mean (+/-SD) CD4+ T-cell count was 508 cells/microl (+/-251) and median HIV RNA was 1.7 log10 copies/ml (interquartile range 1.7-2.6). Among 161 evaluable patients, 59 (32%) reported FSD. In a multiple linear regression analysis, desire, arousal and satisfaction domains were associated with interference of body changes with habits, social life and attitudinal aspects of body image (beta = 0.22, 95% confidence interval [CI] 0.06-0.37; beta = 0.29, 95% CI 0.10-0.48; and beta = 0.20, 95% CI 0.02-0.38, respectively). Lubrication and orgasm domains were associated with body image satisfaction (beta = -0.49, 95% CI -0.88 - -0.10 and beta = -0.58, 95% CI -1.00 - -0.16, respectively). No significant associations with sex hormones, CDC stage, CD4+ T-cell count, HIV RNA viral load and cumulative exposure to antiretroviral drug classes were found. In women with FSD, severity of self-perceived abdominal fat accumulation showed a trend towards lower FSFI scores (ANOVA P = 0.02). CONCLUSIONS: FSD was highly prevalent in this cohort. Self-perceived body changes was identified as its major determinant.

Sex steroid hormones in diabetes-induced sexual dysfunction: focus on the female gender.

INTRODUCTION: Diabetes is associated with gender-specific changes in sex steroid hormones. However, the mechanisms responsible for these associations as well as the link to sexual dysfunction are not well understood. AIM: To discuss key clinical and laboratory findings linking diabetes, sex steroid hormones, and sexual dysfunction, with particular focus on the female gender. METHODS: A comprehensive literature review was conducted using the PubMed database. Search terms were used in appropriate combinations, including diabetes, insulin, insulin sensitivity, androgen, estrogen, sexual function, women, men, estrogen receptor, and androgen receptor. Over 400 citations were selected, based on topical relevance, and examined for study methodology and major findings. MAIN OUTCOME MEASURES: Data from peer-reviewed publications. RESULTS: Imbalances in sex steroid hormone levels are strongly associated with diabetes and this may negatively impact upon sexual function. Although numerous factors are likely to contribute to the development of diabetes and its complications, the role of sex steroid hormones must be acknowledged. CONCLUSIONS: Research related to diabetic women and sexual dysfunction is severely lacking. Identifying underlying causes for a given hormonal imbalance in diabetic patients, as well as determination of genetic and age-dependent factors, will become important in identifying the subpopulations in which hormonal replacement regimens will be most effective. Investigation into treating diabetic patients with adjunct hormonal therapies or steroid hormone receptor modulators holds much promise.

[Sexological problems in neurological disorders: neurosexology]. / Szexológiai problémák neurológiai kórképekben: neuroszexológia.

The author has examined this complex subject-matter as he has not found any publications dealing with the interconnection between neurology and sexuality in the Hungarian literature available to him. Healthy sexual behavior determines the individual's quality of life. This, however requires a coordinated, complex functioning bound to very complex structures and their unimpaired functions: peripheral receptor-->peripheral nerve-->radix-->spinal cord-->definite, functionally interrelated structures of the brain (prae-optic areas, hypothalamus, amygdala, limbic system and the cerebral cortex, mainly the orbitofrontal area). The functioning of these structures and the healthy sexuality are also influenced by steroid hormones, neurochemical regulations, neurotransmitters, the monoamin system, opioids, GABA, neuroendocrine hormones (oxytocin, prolactin, gonadotrop realising hormone). The author deals in detail with the impairment for some reason of neurological structures participating in sexuality, which may lead to sexual dysfunctions.

Global Consensus Position Statement on the Use of Testosterone Therapy for Women.

This Position Statement has been endorsed by the International Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, The International Society for the Study of Women's Sexual Health, The North American Menopause Society, The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia, The Royal College of Obstetricians and Gynecologists, The International Society of Endocrinology, The Endocrine Society of Australia, and The Royal Australian and New Zealand College of Obstetricians and Gynecologists.

The Bio-Psycho-Social Dimension in Women's Sexual Desire: 'Argumentum ad novitatem'.

Sexual desire includes complex motivation and drive. In the context of biological and cognitive- emotive state art of science, it is often a neglected field in medicine. In regard to the treatment, study on women's sexual function received less attention compared to the men's sexuality. In the past, this endeavor was relatively not well disseminated in the scientific community. Recently, there was a revolutionized surge of drug targets available to treat women with low sexual desire. It is timely to review the relevant biological approach, especially in the context of pharmacotherapy to understand this interesting clinical entity which was modulated by numerous interactive psychosocial inter-play and factors. The complex inter-play between numerous dimensional factors lends insights to understand the neural mechanism, i.e. the rewards centre pathway and its interaction with external psychosocialstimulus, e.g. relationship or other meaningful life events. The function of hormones, e.g. oxytocin or testosterone regulation was described. The role of neurotransmitters as reflected by the introduction of a molecule of flibenserin, a full agonist of the 5-HT1A and partial agonist of the D4 to treat premenopausal women with low sexual desire was deliberated. Based on this fundamental scientific core knowledge, we suggest an outline on know-how of introduction for sex therapy (i.e. "inner-self" and "outer-self") where the role of partner is narrated. Then, we also highlighted on the use of pharmacological agent as an adjunct scope of therapy, i.e. phosphodiasterase-5 (PDE-5) inhibitors and hormonal treatment in helping the patient with low sexual desire.

Bremelanotide: First Approval.

Bremelanotide (Vyleesi™) is a melanocortin receptor agonist recently approved in the USA for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty. It is a self-administered, on-demand subcutaneous therapy. Initially developed by Palatin Technologies who sponsored the Phase 3 clinical trials, bremelanotide was subsequently out-licensed to AMAG Pharmaceuticals Inc. for exclusive North American rights to develop and commercialize the drug, including submitting the New Drug Application to the US FDA. Bremelanotide is a synthetic peptide analogue of the neuropeptide hormone alpha melanocyte-stimulating hormone (α-MSH) with high affinity for the melanocortin type 4 receptor (thought to be important for sexual function), giving it the potential to modulate brain pathways involved in sexual response. This article summarizes the milestones in the development of bremelanotide leading to this first regulatory approval.

[Hypothalamus may be involved in psychogenic erectile dysfunction].

OBJECTIVE: To study the changes of hypothalamus metabolism in patients with psychogenic erectile dysfunction (ED) so as to get some clues to the possible pathogenic factors and pathophysiological mechanism of the problem. METHODS: Six cases of psychogenic ED and 4 normal volunteers were studied by positron emission tomography (PET) for the characteristics of hypothalamus glucose metabolism. Following audiovisual sexual stimulation, the concentration of fluorine-18-fluorodeoxyglucose (18 F-FDG) was determined and the ratio of the left (right) hypothalamus count to the cerebrum count was calculated. RESULTS: Audiovisual sexual stimulation significantly increased 18F-FDG in the volunteers (left: 1.026 +/- 0.115 vs 2.400 +/- 0.210; right: 1.003 +/- 0.187 vs 2.389 +0.196, P < 0.05) as compared with the psychogenic ED patients (left: 2.781 +/- 0.156 vs 2.769 +/- 0.223; right: 2.809 +/- 0.129 vs 2.793 +/- 0.217, P > 0.05). CONCLUSION: Psychogenic ED may not be simply a functional disease; the hypothalamus may be involved in the pathophysiology of the problem.

Testosterone therapy in women: its role in the management of hypoactive sexual desire disorder.

Disorders of sexual dysfunction occur in nearly half of women during their life, and hypoactive sexual desire disorder accounts for most of those complaints. Although the relationship between low endogenous testosterone levels and sexual desire disorders in women has not been empirically established, clinical trials have shown that exogenous testosterone therapy improves arousability, sexual desire and fantasy, frequency of sexual activity and orgasm, and satisfaction and pleasure from the sexual act. Its therapeutic role in bone mineral density, fatigue, well-being and hot flashes requires more study before specific recommendations can be made. Potential adverse effects of testosterone therapy include hirsutism, acne and deepening of the voice along with changes in lipid profiles. While less well understood, concern after increased risks for breast cancer and cardiovascular events has been raised about this therapy. Testosterone therapy is available in various formulations; the most commonly used are oral and transdermal, including patches, gels, creams and ointments.