Highlights from the ESSM Virtual Meeting: Female Sexual Dysfunction

Lara Tiranini

Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy

Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy

Even this year at ESSM in Amsterdam and in virtual mode women’s sexual health has been in the spotlight.  We have collected the most relevant information of our listening to the ESSM sessions and produced the present summary.  Thanks to all the speakers for their fantastic job during the COVID-19 pandemic.

The vagina, a dynamic organ

Dr. Nunzia Verde from Sant’Antimo (Napoli, Italy) focused on “vaginal microbiome through life and female genitourinary health”.

The vagina is an important component of female sexual function and attention should be given to vaginal intracrinology of sex steroid hormones as well as to protective role of the vaginal microbiota, which is a complex ecological system composed of commensal, symbiotic and pathogenic organisms. It inhabits the vaginal surface and it maintains its own homeostasis though mutualistic relationships with the host. This habitat is normally dominated by a limited number of species of lactic acid bacteria, which act collectively against various urogenital diseases as a first line defence for several types of infections. Vaginal microbiome changes during the female lifespan. At neonatal age, Lactobacillus species are predominant due to the prenatally inherited high maternal estrogenic levels. Six weeks post-birth and during infancy, vaginal microbiome progress to a complete loss of Lactobacillus dominance. After puberty and during the fertile age, the increasing sex hormones and their fluctuations over the menstrual cycles determine a rise in Lactobacillus species. More specifically, puberty and pregnancy are characterized by high levels of estrogens, which promote vaginal epithelium hyperplasia and cellular glycogen content. Glycogen is then metabolized to lactic acid by Lactobacillus species, thus determining a vaginal pH of 3.5-4.5 suitable for adhesion, colonization and survival of Lactobacillus and other bacterial species. After the onset of menopause, the decline of estrogens causes a transition to a microbiome similar to the prepubertal state characterized by an increased pH and a loss of Lactobacillus dominance.

Vaginal microbiome is clustered into six bacterial community state types (CSTs), four of which are dominated by different species of Lactobacillus (L. crispatus, gasseri, iners, jensenii) whereas two have a low relative abundance of Lactobacillus. CSTs dominated by L. crispatus and L. iners are more prevalent in premenopausal women, while CSTs with a low abundance of Lactobacillus are typical of postmenopausal women and are associated to vulvovaginal atrophy (VVA). Indeed, microbioma with low prevalence of Lactobacillus determines the highest risk of VVA. Vaginal communities of postmenopausal women manifested a predominance of Lactobacillus spp. under various types of hormone therapy (HT) and significantly differed from postmenopausal women not taking HT. It was observed that treatment with ultra-low dose vaginal estriol plus Lactobacillus significantly increases the vaginal epithelial maturation, improves the clinical symptoms of VVA and restores the lactobacillary microflora.

Even androgens are considered a suitable option to treat genitourinary syndrome of menopause (GSM) because androgen receptors (AR) are well expressed in lower genital tract and in the brain. In a double blind randomized clinical trial (RCT), low doses of intravaginal testosterone improved vaginal dryness, dyspareunia, sexual responsiveness, and the overall sexual satisfaction, but without affecting sexual desire or arousal. In women with female sexual dysfunction (FSD), systemic testosterone administration, either alone or combined with local estrogens, improved clitoral haemodynamic parameters as well as sexual function. Moreover, vaginal tissues, especially smooth muscle cells, express enzymes that convert dehydroepiandrosterone (DHEA) into testosterone and dihydrotestosterone (DHT) and an in vitro study demonstrated that increasing dose of DHEA induces an increase in androstenedione and testosterone, but not in estrogens, in the culture medium. AR activation in human vagina is able to support relaxant and contractile vaginal capacity as well as to modulate inflammation.

Rossella Nappi from Pavia (Italy) summerized her view on “chronic low-grade inflammation and female genital tissues: impact on sexuality”.  

Inflammation is one of the seven pillars of aging, together with metabolism, stress, epigenetics, macromolecular damage, proteostasis, and stem cells regeneration. The chronic, sterile low-grade inflammation that occurs during aging is called inflammaging.  Indeed, it alters the homeostasis of numerous systems, as the endocrinological and immunological ones, and may predispose to the development of many age-related chronic and degenerative diseases. A large class of factors as smoke, infections, obesity, genetics, and the decrease of sexual hormones could contribute to the systemic low-grade pro-inflammatory state. Visceral adiposity is considered the starting condition through the release of inflammatory cytokines (TNF alpha, C-reactive protein, IL-6) which promote endothelial dysfunction and inhibition of anti-inflammatory factors as adiponectin.

The relationship between inflammation and sexual dysfunction has been well characterized. Obesity, metabolic disease, and diabetes are known risk factors for sexual dysfunction in both sexes. Metabolic syndrome is associated with a proinflammatory state that determines a decreased availability and activity of nitric oxide (NO), and with hypogonadism, thus contributing to erectile dysfunction through the multiple and overlapping effects of chronic low-grade inflammation and low testosterone levels. In a multicenter cross-sectional study, it was observed that sexual activity, quality of sexual life and sexual interest were positively associated with health in middle age and later in life and were higher in men than in women. However, even if sexually active life expectancy was longer for men, they lost more years of sexually active life because of poor health compared to women. Therefore, in women other factors as psycho-relational aspects may be more important than organic biomedical conditions.

GSM is an organic condition characterized by the involution of urogenital tissues in response to changes in hormonal levels after menopause and aging process and plays a major role in sexuality. It was observed that VVA is more common in women with comorbidities, as angina, osteoporosis, or migraine, meaning that VVA may be associated with aging and not only to the lack of hormones. The hormonal change of menopause activates mechanisms underlying the concept of geroscience that investigates the aging biology and several functional substrates of health, including low-grade inflammation. Vaginal aging is related to the lack of estrogens inducing structural and functional changes of urogenital tissues through genomic and non-genomic mechanisms, such as an altered permeability of epithelium, an increased elastin turnover, an altered NO-synthase activity, and modification of microbiota. However, also DNA-methylation, a biomarker that distinguish between chronological and biological age, is affected. In women, DNA-methylation is strongly related to pro-inflammatory (CRP, IL-6) and metabolic (triglycerides) factors, as it is well-known in men. Both the post-menopausal hormonal deprivation and HT extensively influence gene expression in vaginal tissues, altering various mechanisms of wound healing, angiogenesis, cell migration, inflammation, apoptosis, steroidal and carbohydrate metabolism. Even microbiota if affected with loss of epithelial barrier integrity, decreased protective immune mediators and increased inflammatory mediators.

Androgens play a role in women’s well-being. They decline with age (women around 60 years have half the androgens they had at 40 years) and contribute to climacteric syndrome together with the lack of estrogens.  Androgens play a crucial role in urogenital tissues where they maintain vaginal epithelium proliferation, mucin production, density of nerve fibers, blood flow, and strength of muscular layers of the pelvic floor. The age-related decline in androgens impairs these mechanisms, downregulates antimicrobial molecules and stimulates pro-inflammatory mediators, thus contributing to GSM. Androgens have anti-inflammatory properties as suggested by a model of smooth muscle cells (SMC) with inflammation: the activation of androgen receptors (AR) suppresses the inflammatory response in human SMCs and reduces their potential to initiate or maintain inflammation, thus representing a valid therapeutic option. Therefore, the future management of GSM and sexuality should consider also inflammaging through the identification of women at higher risk of low-grade inflammation who could benefit from treatments with hormones and other anti-inflammatory molecules.

Jim Pfaus from Prague reported on “methods of objective investigation of the female sexual response”.

The vaginal sexual response is regulated by the autonomic nervous system: the parasympathetic nervous system promotes sexual arousal, while the sympathetic nervous system inhibits blood flow and promotes orgasm and climax. Methods for the objective evaluation of female sexual function are classified according to the phase of sexual response. Genital sexual arousal is investigated with vaginal or clitoral photoplethysmography, thermography, external clitoral and labia morphology, lubrication and pH changes; also galvanic skin response and vital signs as heart rate and breathing rate give information about arousal; the brain is studied with EEG and neuroimaging as fMRI and PET. Sexual desire is evaluated with eye-tracking (gaze duration, fixation, distraction), attention to visual stimuli, EEG, fMRI, PET. Orgasm needs vaginal or clitoral photoplethysmography, thermography, anal/pelvic/vaginal/uterine contractions, neuroendocrine markers as prolactin, and EEG, fMRI, PET.

Female sexual response cycle phases are characterized by vaginal and labia engorgement especially during the orgasmic phase. The aroused vagina has a particular physiological signature: a rapid increase in blood flow that increase pH and pO2, and an enhanced surface fluid lubrication. Moreover, glans clitoris becomes responsive to tactile stimulation: the increased blood flow through the spongiosum of the clitoris and labia increases the diameter of the glans clitoris, reduces the diameter of vaginal introitus and vaginal canal, and exposes more tactile sensory nerve endings. Vaginal and clitoral photoplethysmography gives information about the vaginal blood volume, pulse amplitude, and temperature changes. Vaginal luminal pressure is evaluated by a balloon method. Genital thermography investigates the heat in the genital organs by comparing the same genital points before and after a visual sexual stimulus. Eye tracking method evaluates the fixation time, the objective of fixation, the dwell time, the number of fixations, the scan path and the heat maps, independently from the conscious activity. Heat maps can distinguish between romantic love and sexual desire according to the objective of fixation and the number and duration of fixation: eye gaze in romantic love is targeted to face while sexual desire is associated to body fixation, with differences according to gender. Women with hypoactive sexual desire disorder (HSDD) manifest lower number of fixation and less duration of fixation when compared to controls.

A recent study by Sansone et al. in Rome (Italy) investigated the subjective evaluation of clitoral orgasm (CO) and vaginally activated orgasm (VAO), which are often difficult to differentiate owing to the anatomy of the clito-urethro-vaginal complex (CUV). In an online survey during the COVID-19 pandemic, it was observed that 40.9% of heterosexual women have both VAO and CO, 35.1% of women have only CO, and 20.1% only VAO. Orgasmic intensity was higher for VAO compared to clitoral orgasms, women who experienced VAO had better FSFI scores, but women able to climax through both kinds of stimulation had even better profiles. Therefore, partnered sex through vaginal penetration, with or without clitoral stimulation, may represent the best scenario to perceive more intense orgasms.

Stimulation of the clitoris, vagina, and cervix activate multiple regions of the brain, including somatosensory cortex, limbic structures, hypothalamus and medial preoptic area (mPOA). In response to visual sexual stimuli, women without HSDD activate brain regions as mPOA, while women with HSDD activate prefrontal cortex and not mPOA, according to excitation and inhibition in response to visual sexual cues. More studies are needed to correlate measures of genital sexual arousal (photopletismography) to brain outcomes (EEG, fMRI). Finally, prolactin is an objective neuroendocrine marker of orgasm and it increases after orgasm reached with genital stimulation as well as without genital stimulation.

Data on the role of prolactin (PRL) in the physiologic range in the female sexual response are scanty. As assessed in a study by Maseroli et al under publication, in a clinical sample of pre and postmenopausal women consulting for FSD prolactin has been evaluated in the early follicular phase of menstrual cycle. Among FSD women with normo-PRL levels, those with the lowest levels demonstrated a poorer sexual desire than those with PRL in the highest quintile. Moreover, PRL levels inferior to 209 mU/L could predict HSDD and a higher sexual inhibition for fear of performance failure. Therefore, measuring PRL in women with FSD may be useful to predict the presence of HSDD or a sexual inhibitory trait.

The role of sexual inhibition and sexual excitation in female sexuality

The well-known international expert in the psychology of sexual behaviour Jim Pfaus from Prague started from the Masters and Johnson model describing the human sexual response, which moves through four stages: excitement, plateau, orgasm, and resolution. The excitement stage encompasses arousal and desire, and it corresponds to the activation of dopamine (DA), norepinephrine (NE), oxytocin (OT), vasopressin, and melanocortins (MCs). When orgasm is reached, a wide range of inhibitory systems (including β-endorphin and serotonin) are turned on, especially in the prefrontal cortex, and pave the way to resolution which correspond to refractoriness. Therefore, sexual function moves from excitation to inhibition and the autonomic nervous system governs sexual response. The parasympathetic nervous system controls sexual arousal and genital blood flow to produce erection, while the sympathetic nervous system controls orgasm, climax and ultimately leads to the inhibition of the blood flow. Excitation and inhibition may be considered a dual control model of sexual response, where physiological and organic issues and psychosocial, cultural and behavioral issues balance excitation and inhibition in the sexual tipping point model. Drugs or mental states can activate neurochemical substrates of excitation (DA, NE, OT, MCs) or reduce inhibition, but they can also activate inhibitory molecules (serotonin, opioids) or inhibit excitation.

There are several neural excitatory systems for arousal and desire and among them dopamine and noradrenaline. Dopamine (DA) plays an important role in post-desire arousal: it activates the mesolimbic system, which controls motivation and attention, the nigrostriatal system that controls movements, and the diencephalic system, which controls the endocrine and autonomic regulation, a bridge between sexual mental desire and genital arousal. Noradrenaline (NE) is mainly responsible for genital arousal and activates the sympathetic tone. Two other important excitatory systems are melanocortins and oxytocin. Melanocortins (MCs) drive DA to induce desire and arousal. Oxytocin (OT) plays a role in arousal but also in sexual bonding.

More specifically, DA activates neurons in the medial and ventral preoptic area that drives sexual motivation in response to sexual stimuli. It processes priming cues in the brain and predicts the strength of reward or pleasure. Therefore, DA amalgamates genital responses, appetitive behaviours, and somato-motor patterns into a behavioural response called sexual desire. In both men and women, the activation of mPOA occurs in response to visual sexual cues, while in subjects with HSDD it is not observed. In this context, bremelanotide is a treatment for HSDD. Bremelanotide is an analogue of alpha-melanocyte-stimulating hormone (α-MSH), a neuropeptide that binds to several melanocortin receptors (MCR). Melanocortin receptor subtype 4 (MC4R) is the most relevant: it is predominantly expressed in the hypothalamic mPOA and is important for female sexual function. It is observed that in absence of erotic cues, bremelanotide alone can activate mPOA as a pharmacological priming cue and facilitate components of desire as solicitations in female rats. More specifically, peripheral administration of bremelanotide activates presynaptic MC4Rs on mPOA neurons and induces a significant release of dopamine in mPOA (pfaus 2021). DA acts on DA type 1 receptor (D1R) of GABA neurons in mPOA with subsequent inhibition of GABA interneurons in the ventral tegmental area (VTA). The result is disinhibition of DA neurons in VTA that drives the mesolimbic system in response to sexual cues. In clinical trials, the administration of bremelanotide in women with HSDD increased desire and decreased distress with amelioration of symptoms of HSDD. DA works in concert with oxytocin in coordinating desire and genital blood flow. On one side, DA release in the mPOA affects GABA output leading to disinhibition of DA neurons in the VTA and subsequent stimulation of desire and attention through mesolimbic system. On the other side, DA release in mPOA modifies glutamate output in paraventricular nucleus (PVN) that results in OT release. OT effects are both central and peripheral. Through VTA, OT amplifies central dopaminergic effects on mesolimbic system (not only attention but also partner preference), while through spinal cord oxytocin prepares genital apparatus for arousal, erection, and orgasm.

Orgasm leads to pleasure and satiety obtained through some neural inhibitory systems. A mediator of reward is the proopiomelanocortin (POMC) system whose neurons project to hypothalamic, limbic, cortical, midbrain and brainstem regions, notably to the mPOA, PVN and VTA. Opioids (as beta-endorphin) disinhibit DA and OT release during sexual arousal and desire but play an inhibitory role at orgasm, when are released in massive quantities. This inhibition results in sensitization and reinforcement for conditioned release of DA and OT in subsequent presentation of sexual stimuli. Another inhibitory system is the serotonergic system, linked to satiety and refractoriness. Serotonin (5-HT) neurons have ascending projections to hypothalamic, limbic and cortical regions but also descending projections to brainstem and spinal cord. In the prefrontal cortex, 5-HT stimulates descending glutamate neurons that activate inhibitory GABA interneurons in the VTA, leading to the downregulation of mesolimbic DA as it occurs during orgasm. Flibanserin is a selective agonist and antagonist of serotonin receptors, more specifically it is agonist at 5-HT1A presynaptic autoreceptor (reduces serotonin release) and antagonist at 5-HT2A postsynaptic receptor (block serotonin action). The effect is an increased sexual desire, a decreased distress and a modest increase in sexually satisfying events through a biochemical decrease of 5-HT that induces an increase of DA and NA. Animal studies have shown that chronic flibanserin administration induces sexual desire typical of rat females primed with estrogens and progesterone. Clinical trial on humans observed the same effects of bremelanotide in increasing desire and reducing distress. Therefore, sexual inhibition could result from hyper-inhibition or hypo-excitation, both depending on genetic predisposition, epigenetic activation (sexual experiences), and drugs or states that modifies neurotransmitters and neuropeptides.

A brief focus on sexual pleasure

According to the World Health Organization (WHO), sexual health is a state of physical, emotional, mental and social well-being in relation to sexuality; it is not merely the absence of disease, dysfunction of infirmity. Sexual health requires a positive and respectful approach to sexuality and sexual relationships, as well as the possibility of having pleasurable and safe sexual experiences, free of coercion, discrimination and violence. In 2021, the World Association of Sexual Health (WAS) published the Declaration on Sexual Pleasure. According to the WAS declaration, sexual pleasure is the physical and/or psychological satisfaction and enjoyment derived from shared or solitary erotic experiences, including thoughts, fantasies, dreams, emotions, and feelings. Self-determination, consent, safety, privacy, confidence and the ability to communicate and negotiate sexual relations are key enabling factors for pleasure to contribute to sexual health and well-being; the experiences of sexual pleasure should not be obtained by violating other people’s human rights and well-being. Sexual pleasure should be integrated into education, health promotion and service delivery, research and advocacy worldwide. Sexual satisfaction has been studied extensively, while less research involved enjoyment. Studies show that enjoyment and also mutual pleasure are crucial components of sexual satisfaction. A recent systematic review and meta-analysis confirmed that incorporating sexual pleasure in sexual health interventions could have positive effects across different knowledge-based attitudes.

Online counselling and treatment

Elisa Maseroli from Florence (Italy) discussed how to treat vaginism in the COVID19 era, which has required healthcare and social systems, clinicians, and citizens to adjust to the digital era, triggering a forgotten need in the clinical sexology context. e-Health is the use of communication and information technologies for health (SMS, e-mail, video-call, apps, etc.) and the WHO deemed e-Health a priority target for the improvement of public and universal health. Social isolation may have a detrimental effect on sexuality, because of new family configurations and stressors (unemployment, domestic overload), discrepancies in sexual expressions, lack of privacy, forced separation of intimate partners, absence of usual erotic cues, high risk of sexual victimization. In the general US population, overall FSFI significantly worsened during the pandemic (27.2 vs 28.8, P=.002), with domain-specific decreases in arousal (4.41 vs 4.86, P=.0002), lubrication (4.90 vs 5.22, P=.004), and satisfaction (4.40 vs 4.70, P=.04). In a sample of women recently treated for vaginismus with vaginal dilators, it was observed that the patients sustained their sexual function during the pandemic: the total FSFI score and pain score improved, but it was observed an increased dissatisfaction and anorgasmia, which may be attributed to increased depressive symptoms. Vaginismus is the result of medical and psycho-relational contributors. Medical aspects are important in the etiology of vaginismus: pelvic floor muscle overreactivity is often documented by electromyography, and organic conditions are identified, as sexually transmitted diseases, vestibulodynia, vulvodynia, congenital abnormalities, scarring from trauma or radiations, vaginal atrophy, pelvic inflammatory disease, dermatologic conditions as lichen, cancer. Considering psycho-relational aspects, the painful and negative experiences are followed by catastrophizing thoughts, fear, avoidance and behavioural modification; women have separation anxiety and higher histrionic-hysterical symptoms and traits. Male partners demonstrated higher anxiety levels and less sexual satisfaction. Interestingly, it was observed that men with depressive temperament have a positive effect on sexual function of women with vaginismus. Therefore, vaginismus is a complex condition that requires a multimodal approach, as cognitive-behavioral therapy, mindfulness and relaxation training, pelvic floor physical therapy, intravaginal muscle relaxant suppositories, vaginal hormonal therapy, botulinum toxic injections, electromyographic biofeedback, electrical stimulation, manual tissue manipulation, stretching exercises, etc. In a recent meta-analysis of observational studies on interventions for vaginismus, it was observed that no method was superior to the others for the achievement of penetrative intercourse, with an overall success of 79% independently of the therapeutic approach. Botulinum neurotoxin injection in the pelvic floor muscle is the most employed pharmacological therapy for vaginismus: it reduces pain sensation by inhibiting neuropeptides release in the presynaptic neuron and has the potential to alleviate muscle tension. Pelvic floor physiotherapy has gained popularity: it includes education in the anatomy and physiology of the area, pelvic floor exercises (i.e. Kegel exercises), graduated desensitization guided by the therapist. These sessions may be remotely supervised by the physiotherapist.  Synchronic video calls or telephone calls, may be used to answer questions, and reinforce instructions for proper exercise. Internet-based guided treatment for vaginismus has been proposed in recent years and addresses some limitations of traditional psychological approaches, as limited availability, high threshold, and costs. It is readily available and easily accessible independently of time and place, it allows users to work at their own pace and to review materials, it is more likely to reach affected women earlier if compared to traditional mental health services, and it may reach women who might otherwise not seek out help. A protocol of internet-based guided treatment for vaginismus has been tested in a randomized clinical trial. The protocol intervention consisted in a cognitive-behavioral approach for 8-16 weeks, supported by an e-coach to reinforce treatment efforts, answer questions and motivate. Each session is completed in 45-60 minutes, is tailored on the specific need of the subject, and consists in general text-based information, interactive elements, quizzes, audio files, video clip and downloadable worksheets. It was observed that more participants in the intervention group had sexual intercourse compared to controls, but the difference was not statistically significant. However, the intervention group demonstrated a significant increase in intercourse penetration from baseline to 6 months, decrease in fear of coitus, and increased overall satisfaction. Therefore, telemedicine is a valid option in the treatment of vaginismus due to the following conditions: for providers the possibility to see more patients with a decreased risk of burn out, for patients the reduced costs of care and the flexibility and convenience of being seen remotely for follow-up visits. On the contrary, eHealth is not suitable in the following situations: first evaluation of vaginismus, necessity of physical examination, need of in-office procedures (i.e. dilators, injections), cognitive disorders, language barrier, lack of required technology to conduct a virtual visit. Moreover, both provider and patient must be aware of privacy issues, informed consent, avoid requesting images and videos involving exposure of women’s bodies, the possibility to lose the personal relationship with the doctor/patient. Internet-based trainings show promising results, but more high-quality research is needed in this field.

Trauma and sexual function

Bayerle-Eder from Wien (Austria) gave a talk on “hypothalamic-pituitary-adrenal (HPA) axis dysregulation and sexual function”. The HPA axis is the principal neuroendocrine system involved in the maintenance of homeostasis after stressful stimuli. Some conditions as trauma, sexual abuse, burn out, depression, life events can lead to dysregulation of the HPA system with an over-activation of the stress adaption response that contributes to FSD. It is demonstrated that childhood adversity (neglect, physical, emotional or sexual abuse) may predispose individuals to HPA dysregulation later in life, as observed in heathy subjects exposed to mild-to-moderate childhood adversity who had a blunted diurnal cortisol activity compared to controls. A similar pattern is seen in post-traumatic stress disorder (low basal cortisol and DHEA), sexual trauma, obesity, depression, chronic stress or pain, diabetes and immune disorders. In a recent study, it was observed that women with HSDD have lower cortisol and DHEA levels, a flatter diurnal cortisol slope, and a lower cortisol awakening response compared to controls, suggesting that persistently low sexual desire in women is associated with HPA axis dysregulation, with both cortisol and DHEA alterations potentially detrimental for sexual desire.

Limoncin from Rome (Italy) focused on “sexuality and post-traumatic stress disorder (PTSD)”, a psychiatric condition associated to the exposure to negative life experiences or trauma (child physical or sexual abuse, neglect, war, migration and natural catastrophes). The exposure to trauma does not always cause the development of PTSD. Gender, biological risk factors, family relationship, personal vulnerability are factors influencing the reaction to trauma, which may manifest through resilience, coping strategies, search for social supports, or may cause the development of psychiatric illnesses as PTSD, personality disorders, psychoses, all capable of affecting sexuality. In a study involving female military members and veterans, it was observed an association between suicidal ideation, PTSD, depression and FSD. More specifically, higher suicidal ideation was significantly correlated with lower arousal and lower sexual satisfaction. The same authors recently confirmed that higher PTSD severity was associated with lower lubrication and sexual arousal. In particular, depression severity mediated the relation between PTSD and sexual arousal, while lower romantic relationship satisfaction mediated the association between PTSD and lubrication. On the contrary, in a study involving a non-clinical sample of men and women, post-traumatic symptoms were also associated to hypersexual behavior. This relation between trauma and hypersexuality is direct and mediated by depression and guilt, and male gender is a relevant risk factor.

Castellini from Florence (Italy) discussed “sexuality after child sexual abuse (CSA)”, defined as forced and often traumatic sexual experiences prior to age 16, a developmental time when the individual is still forming a sense of the sexual self. The prevalence of sexual abuse in children is very high; in US it is estimated to be 16.7% in boy and 26.7% in girls. CSA may affect sexual well-being in adulthood, but literature is controversial. Some evidence reports that CSA is related to greater sexual dysfunction and lower sexual satisfaction (hypofunction), while other studies observe an association with sexual compulsivity and sexual risk behaviours (hyperfunction). A recent systematic review suggests that CSA is not unanimously related to all domains of sexual well-being, but rather other comorbidities or the characteristics of the sample must be considered. FSD associated to CSA are sex avoidance, vaginismus, and dysfunction in desire, arousal, lubrication and satisfaction. In a study involving women consulting for FSD, women reporting unwanted sexual experiences during childhood or adolescence had lower orgasm, lubrication and arousal with severe body uneasiness as mediator. Other studies suggest that emotion-oriented coping and optimism mediate some sexual health outcomes in women with CSA, while in a case-control study Alessandra Rellini observed that the lower sexual satisfaction of CSA survivors was only partially mediated by higher reports of negative affect prior to sexual stimuli. According to these results, it was shown that women with a history of CSA had a weaker vaginal response and sexual arousal compared to controls; moreover, they had a smaller decrease in cortisol during sexual arousal potentially due to an increase in basal cortisol in some survivors of CSA.

On the other side, CSA related hyperactive sexuality is associated to dysfunctional behaviours, such as younger age at first consensual intercourse, teenage pregnancies, large number of sexual partners, high frequency of unprotected sex, higher prevalence of sexually transmitted diseases, extramarital affairs and drug abuse. In a CSA survivor, hypoactive and hyperactive sexuality may coexist. Indeed, women who experiences CSA and subsequent traumatic sexualization may consider sex as necessary for affection, thus engaging in high-risk sexual activity. In a study on women with eating disorders, it was found that hypersexuality was associated with emotion dysregulation and impulsive eating disorders only in those patients reporting childhood traumatic experiences. Moreover, women reporting a tendency toward binge-eating episodes and dissociation during sexual experiences (linked to the emotional component of body image esteem) showed higher levels of cortisol in response to sexual stimuli. Sexual activity was associated with HPA activation in women with eating disorders reporting history of CSA. In women with a CSA history, the emotional involvement in the sexual relationship would result in activation of mechanisms of stress response. Considering the reward process, it was observed that hypersexuality in women with eating disorders was associated with high levels of ghrelin correlating with binge eating, emotional eating and hypersexuality only in women with CSA. Ghrelin is responsible of the reward value of stimulus, and it is also implicated in the stress response, suggesting the necessity to further explore this field of reward and stress response as overlapping conditions. In conclusion, not all women with a history of CSA develop sexual difficulties, thus not always the abuse is the cause of FSD. Treatment approaches for patients with CSA and sexual dysfunctions include:

expressive writing-based intervention, which improves both PTSD and sexual dysfunction; mindfulness based approach, which improves subjective levels of sexual arousal that favours the connection between mind and body; eye movement desensitization and reprocessing (EMDR), which aims to facilitate information processing of emotionally distressing traumatic events.


Recent research in the field of female sexual function focused on the contribution of life style habits as physical activity, the strength of the pelvic floor, vaginal treatments for sexual pain and the impact of oncological diseases and treatments as in breast cancer survivors.

Physical activity and female sexual dysfunction: a lot helps, but not too much

In a sample of women with FSD, Maseroli et al (Italy) reported that physical activity was associated with better sexual function (FSFI domains of desire, arousal, and lubrication) and clitoral vascularization, lower sexual distress, and reduced risk of HSDD and female genital arousal disorder (FGAD). The benefits of physical activity on sexuality were mediated by both psychological (reduced body image concerns, mental distress, sexual distress) and organic (lower BMI) determinants. Excessive physical activity (>6 hours/week) was related with a poor overall sexual function, a low arousal and sexual satisfaction and a higher histrionic/hysterical traits and body uneasiness compared to a sedentary lifestyle.

The strength of the pelvic floor muscles contributes to a better female sexual function

Zachariou et al (Greece) studied a group of healthy sexually-active nulliparous women evaluated for the pelvic floor muscles’ strength (PFMS) with both the Modified Oxford Grading Scale and the Peritron manometer. It was observed that women with a higher PFMS (>41.1 cm H2O at Peritron manometer) exhibited a better sexual function for FSFI total scores and all domains, while no statistical significant difference was observed for pain.

Transvaginal shockwave therapy (TVST) – a novel treatment for premenopause female sexual dysfunction

Kornya et al (Hungary) conducted a pilot study: 15 premenopausal women with FSD were treated with low-intensity extracorporeal shockwave therapy applied to vaginal wall, labia minora and labia majora through six treatment sessions of 20 minutes at rate of two sessions/week. The average FSFI total score improved from 12.7 at baseline to 21.1 and 24.9 at 4 and 12 weeks of follow up, respectively. The treatment proved safe and was well-tolerated.

Low-intensity shockwave for treatment of vestibulodynia, a randomized controlled therapy trial

In a double-blind, randomized, Gruenwald et al (Israel) conducted a sham-controlled prospective study involving 32 women with provoked vestibulodynia. Low-intensity shockwave therapy at the introitus performed twice a week for 6 weeks was effective in pain relief and improved sexual function. From baseline to 1- and 3-months post-treatment, visual-analogue scale score for dyspareunia decreased and total FSFI score significantly increased (from 17.9 to 20.9 and 22.5, respectively). Moreover, pain threshold and tolerance measured with an algometer showed improvement at 3 months post-treatment compared to baseline.

Use of platelet-rich plasma (PRP) for the treatment of dyspareunia in postmenopausal women

Romashchenko et (Kyiv) studied a sample of 52 postmenopausal women suffering from dyspareunia who received injections of autologous platelet-rich plasma (PRP) twice with an interval of 21-22 days in the regions of paraurethral area, vaginal introitus and vagina in association to psychotherapy. After PRP treatment, it was observed an improvement in genital blood flow and lubrication and a reduction in dyspareunia symptoms.

Sexuality in women after breast cancer: sexual experiences, emotions, and cognitions in a group of women under hormonal therapy

Nimbi et al (Italy) studied a group of 79 breast cancer survivors under anticancer hormonal treatment compared to a group of 103 healthy controls, exploring sexual experiences, emotions and cognition through validated questionnaires. Breast cancer survivors had a diminished or absent sexual activity, lower level of sexual functioning, higher levels of sexual and psychological distress and increased negative emotions related to sexuality. Therefore, the impact of cancer should be evaluated on a biopsychosocial level and healthcare providers should address even sexual needs of breast cancer survivors during the routine practice.

Selected references

  1. Arnow BA, Millheiser L, Garrett A, Lake Polan M, Glover GH, Hill KR, Lightbody A, Watson C, Banner L, Smart T, Buchanan T, Desmond JE. Women with hypoactive sexual desire disorder compared to normal females: a functional magnetic resonance imaging study. Neuroscience 2009;158:484-502. doi: 10.1016/j.neuroscience.2008.09.044.
  2. Basson R, O’Loughlin JI, Weinberg J, Young AH, Bodnar T, Brotto LA. Dehydroepiandrosterone and cortisol as markers of HPA axis dysregulation in women with low sexual desire. Psychoneuroendocrinology. 2019 Jun;104:259-268. doi: 10.1016/j.psyneuen.2019.03.001.
  3. Berghella AM, Contasta I, Marulli G, D’Innocenzo C, Garofalo F, Gizzi F, Bartolomucci M, Laglia G, Valeri M, Gizzi M, Friscioni M, Barone M, Del Beato T, Secinaro E, Pellegrini P. Ageing gender-specific “Biomarkers of Homeostasis”, to protect ourselves against the diseases of the old age. Immun Ageing 2014;11:3. doi: 10.1186/1742-4933-11-3.
  4. Bhambhvani HP, Chen T, Kasman AM, Wilson-King G, Enemchukwu E, Eisenberg ML. Female Sexual Function During the COVID-19 Pandemic in the United States. Sex Med 2021;9:100355. doi: 10.1016/j.esxm.2021.100355.
  5. Bicanic IA, Postma RM, Sinnema G, De Roos C, Olff M, Van Wesel F, Van de Putte EM. Salivary cortisol and dehydroepiandrosterone sulfate in adolescent rape victims with post traumatic stress disorder. Psychoneuroendocrinology 2013;38:408-15. doi: 10.1016/j.psyneuen.2012.06.015.
  6. Bigras N, Vaillancourt-Morel MP, Nolin MC, Bergeron S. Associations between Childhood Sexual Abuse and Sexual Well-being in Adulthood: A Systematic Literature Review. J Child Sex Abus 2021;30:332-352. doi: 10.1080/10538712.2020.1825148.
  7. Binder RL, Freedman MA, Sharma KB, Farage MA, Wang Y, Combs C, Moore D, Tiesman JP, Bascom CC, Isfort RJ, Warren R. Histological and Gene Expression Analysis of the Effects of Menopause Status and Hormone Therapy on the Vaginal Introitus and Labia Majora. J Clin Med Res 2019;11:745-759. doi: 10.14740/jocmr4006.
  8. Blais RK, Monteith LL, Kugler J. Sexual dysfunction is associated with suicidal ideation in female service members and veterans. J Affect Disord 2018;226:52-57. doi: 10.1016/j.jad.2017.08.079.
  9. Blais RK, Bird E, Sartin-Tarm A, Campbell SB, Lorenz T. Mechanisms of the association between PTSD and sexual arousal and lubrication functioning among trauma-exposed female service members/veterans. J Affect Disord 2022;301:352-359. doi: 10.1016/j.jad.2021.12.106.
  10. Bolmont M, Cacioppo JT, Cacioppo S. Love is in the gaze: an eye-tracking study of love and sexual desire. Psychol Sci 2014;25:1748-56. doi: 10.1177/0956797614539706.
  11. Brotman RM, Shardell MD, Gajer P, Fadrosh D, Chang K, Silver MI, Viscidi RP, Burke AE, Ravel J, Gravitt PE. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause. 2014;21:450-8.
  12. Brotto LA, Seal BN, Rellini A. Pilot study of a brief cognitive behavioral versus mindfulness-based intervention for women with sexual distress and a history of childhood sexual abuse. J Sex Marital Ther 2012;38:1-27. doi: 10.1080/0092623X.2011.569636.
  13. Carvalho J, Pascoal PM. Challenges in the Practice of Sexual Medicine in the Time of COVID-19 in Portugal. J Sex Med 2020;17:1212-1215. doi: 10.1016/j.jsxm.2020.05.024.
  14. Cassioli E, Rossi E, Squecco R, Baccari MC, Maggi M, Vignozzi L, Comeglio P, Gironi V, Lelli L, Rotella F, Monteleone AM, Ricca V, Castellini G. Reward and psychopathological correlates of eating disorders: The explanatory role of leptin. Psychiatry Res 2020;290:113071. doi: 10.1016/j.psychres.2020.113071.
  15. Castellini G, Lelli L, Lo Sauro C, Vignozzi L, Maggi M, Faravelli C, Ricca V. Childhood abuse, sexual function and cortisol levels in eating disorders. Psychother Psychosom 2012;81:380-2. doi: 10.1159/000337176.
  16. Castellini G, D’Anna G, Rossi E, Cassioli E, Appignanesi C, Monteleone AM, Rellini AH, Ricca V. Dysregulated Sexuality in Women with Eating Disorders: The Role of Childhood Traumatic Experiences. J Sex Marital Ther 2020;46:793-806. doi: 10.1080/0092623X.2020.1822484.
  17. Castellini G, Lo Sauro C, Ricca V, Rellini AH. Body Esteem as a Common Factor of a Tendency Toward Binge Eating and Sexual Dissatisfaction Among Women: The Role of Dissociation and Stress Response During Sex. J Sex Med 2017;14:1036-1045. doi: 10.1016/j.jsxm.2017.06.001.
  18. Cellai I, Di Stasi V, Comeglio P, Maseroli E, Todisco T, Corno C, Filippi S, Cipriani S, Sorbi F, Fambrini M, Petraglia F, Scavello I, Rastrelli G, Acciai G, Villanelli F, Danza G, Sarchielli E, Guarnieri G, Morelli A, Maggi M, Vignozzi L. Insight on the Intracrinology of Menopause: Androgen Production within the Human Vagina. Endocrinology 2021;162:bqaa219. doi: 10.1210/endocr/bqaa219.
  19. Chen R, Gillespie A, Zhao Y, Xi Y, Ren Y, McLean L. The Efficacy of Eye Movement Desensitization and Reprocessing in Children and Adults Who Have Experienced Complex Childhood Trauma: A Systematic Review of Randomized Controlled Trials. Front Psychol 2018;9:534. doi: 10.3389/fpsyg.2018.00534.
  20. Chiu GR, Lutfey KE, Litman HJ, Link CL, Hall SA, McKinlay JB. Prevalence and overlap of childhood and adult physical, sexual, and emotional abuse: a descriptive analysis of results from the Boston Area Community Health (BACH) survey. Violence Vict 2013;28:381-402. doi: 10.1891/0886-6708.11-043.
  21. Cipriani S, Maseroli E, Di Stasi V, Scavello I, Todisco T, Rastrelli G, Fambrini M, Sorbi F, Petraglia F, Jannini EA, Maggi M, Vignozzi L. Effects of testosterone treatment on clitoral haemodynamics in women with sexual dysfunction. J Endocrinol Invest 2021;44:2765-2776. doi: 10.1007/s40618-021-01598-1.
  22. Clayton AH, Althof SE, Kingsberg S, DeRogatis LR, Kroll R, Goldstein I, Kaminetsky J, Spana C, Lucas J, Jordan R, Portman DJ. Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Womens Health (Lond) 2016;12:325-37. doi: 10.2217/whe-2016-0018.
  23. Constantine GD, Bruyniks N, Princic N, Huse D, Palmer L, Lenhart G, Blumentals WA, Nappi RE. Incidence of genitourinary conditions in women with a diagnosis of vulvar/vaginal atrophy. Curr Med Res Opin 2014;30:143-8. doi: 10.1185/03007995.2013.850068.
  24. Davis SR, Robinson PJ, Jane F, White S, White M, Bell RJ. Intravaginal Testosterone Improves Sexual Satisfaction and Vaginal Symptoms Associated With Aromatase Inhibitors. J Clin Endocrinol Metab 2018;103:4146-4154. doi: 10.1210/jc.2018-01345.
  25. Dick B, Natale C, Reddy A, Akula KP, Yousif A, Hellstrom WJG. Application of Botulinum Neurotoxin in Female Sexual and Genitourinary Dysfunction: A Review of Current Practices. Sex Med Rev 2021;9:57-63. doi: 10.1016/j.sxmr.2020.01.003.
  26. Dooley AB, Houssaye N, Baum N. Use of Telemedicine for Sexual Medicine Patients. Sex Med Rev 2020;8:507-517. doi: 10.1016/j.sxmr.2020.06.001.
  27. Fontanesi L, Marchetti D, Limoncin E, Rossi R, Nimbi FM, Mollaioli D, Sansone A, Colonnello E, Simonelli C, Di Lorenzo G, Jannini EA, Ciocca G. Hypersexuality and Trauma: a mediation and moderation model from psychopathology to problematic sexual behavior. J Affect Disord 2021;281:631-637. doi: 10.1016/j.jad.2020.11.100.
  28. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 2018;14:576-590. doi: 10.1038/s41574-018-0059-4.
  29. Gelez H, Greggain-Mohr J, Pfaus JG, Allers KA, Giuliano F. Flibanserin treatment increases appetitive sexual motivation in the female rat. J Sex Med 2013;10:1231-9. doi: 10.1111/jsm.12094.
  30. Georgiadis JR, Kringelbach ML, Pfaus JG. Sex for fun: a synthesis of human and animal neurobiology. Nat Rev Urol 2012;9:486-98. doi: 10.1038/nrurol.2012.151.
  31. Gliniewicz K, Schneider GM, Ridenhour BJ, Williams CJ, Song Y, Farage MA, Miller K, Forney LJ. Comparison of the Vaginal Microbiomes of Premenopausal and Postmenopausal Women. Front Microbiol 2019;10:193. doi: 10.3389/fmicb.2019.00193.
  32. Graham MD, Gardner Gregory J, Hussain D, Brake WG, Pfaus JG. Ovarian steroids alter dopamine receptor populations in the medial preoptic area of female rats: implications for sexual motivation, desire, and behaviour. Eur J Neurosci 2015;42:3138-48. doi: 10.1111/ejn.13121.
  33. Gruenwald I, Gutzeit O, Petruseva A, Gartman I, Lowenstein L. Low-Intensity Shockwave for Treatment of Vestibulodynia: A Randomized Controlled Therapy Trial. J Sex Med 2021;18:347-352. doi: 10.1016/j.jsxm.2020.11.006.
  34. Gungor Ugurlucan F, Yasa C, Ates Tikiz M, Evruke I, Isik C, Dural O, Akhan SE. Effect of the COVID-19 pandemic and social distancing measures on the sexual functions of women treated for vaginismus (genitopelvic pain/penetration disorder). Int Urogynecol J 2021;32(5):1265-1271. doi: 10.1007/s00192-020-04667-w.
  35. Hull EM, Lorrain DS, Du J, Matuszewich L, Lumley LA, Putnam SK, Moses J. Hormone-neurotransmitter interactions in the control of sexual behavior. Behav Brain Res 1999;105:105-16. doi: 10.1016/s0166-4328(99)00086-8.
  36. Jannini EA, Buisson O, Rubio-Casillas A. Beyond the G-spot: clitourethrovaginal complex anatomy in female orgasm. Nat Rev Urol 2014;11(9):531-8. doi: 10.1038/nrurol.2014.193.
  37. Jessie V. Ford, Esther Corona-Vargas, Mariana Cruz, J. Dennis Fortenberry, Eszter Kismodi, Anne Philpott, Eusebio Rubio-Aurioles & Eli Coleman (2021). The World Association for Sexual Health’s Declaration on Sexual Pleasure: A Technical Guide, International Journal of Sexual Health, 33:4, 612-642, DOI: 10.1080/19317611.2021.2023718
  38. Komisaruk BR, Wise N, Frangos E, Liu WC, Allen K, Brody S. Women’s clitoris, vagina, and cervix mapped on the sensory cortex: fMRI evidence. J Sex Med 2011;8(10):2822-30. doi: 10.1111/j.1743-6109.2011.02388.x.
  39. Kuras YI, Assaf N, Thoma MV, Gianferante D, Hanlin L, Chen X, Fiksdal A, Rohleder N. Blunted Diurnal Cortisol Activity in Healthy Adults with Childhood Adversity. Front Hum Neurosci 2017;11:574. doi: 10.3389/fnhum.2017.00574.
  40. Lacelle C, Hébert M, Lavoie F, Vitaro F, Tremblay RE. Sexual health in women reporting a history of child sexual abuse. Child Abuse Negl 2012;36:247-59. doi: 10.1016/j.chiabu.2011.10.011.
  41. Leeners B, Kruger TH, Brody S, Schmidlin S, Naegeli E, Egli M. The quality of sexual experience in women correlates with post-orgasmic prolactin surges: results from an experimental prototype study. J Sex Med 2013;10:1313-9. doi: 10.1111/jsm.12097.
  42. Lindau ST, Gavrilova N. Sex, health, and years of sexually active life gained due to good health: evidence from two US population based cross sectional surveys of ageing. BMJ 2010;340:c810. doi: 10.1136/bmj.c810.
  43. Louar M, Morel-Journel N, Ruffion A, Carnicelli D, Neuville P. Female Sexual Function and Body Image After Urinary Diversion for Benign Conditions. J Sex Med 2022;19:263-269. doi: 10.1016/j.jsxm.2021.11.007.
  44. Maiorino MI, Bellastella G, Giugliano D, Esposito K. From inflammation to sexual dysfunctions: a journey through diabetes, obesity, and metabolic syndrome. J Endocrinol Invest 2018;41:1249-1258. doi: 10.1007/s40618-018-0872-6.
  45. Malik MO, Shah M, Irfan Ul Akbar Yousufzai M, Ullah N, Burgess JA, Goosens KA. Association of Acyl-Ghrelin With Posttraumatic Stress Disorder in Adolescents Who Experienced Severe Trauma. JAMA Netw Open 2020;3(8):e2013946. doi: 10.1001/jamanetworkopen.2020.13946.
  46. Maseroli E, Scavello I, Cipriani S, Palma M, Fambrini M, Corona G, Mannucci E, Maggi M, Vignozzi L. Psychobiological Correlates of Vaginismus: An Exploratory Analysis J Sex Med 2017;14:1392-1402. doi: 10.1016/j.jsxm.2017.09.015.
  47. Maseroli E, Scavello I, Rastrelli G, Limoncin E, Cipriani S, Corona G, Fambrini M, Magini A, Jannini EA, Maggi M, Vignozzi L. Outcome of Medical and Psychosexual Interventions for Vaginismus: A Systematic Review and Meta-Analysis. J Sex Med 2018;15:1752-1764. doi: 10.1016/j.jsxm.2018.10.003.
  48. Maseroli E, Scavello I, Campone B, Di Stasi V, Cipriani S, Felciai F, Camartini V, Magini A, Castellini G, Ricca V, Maggi M, Vignozzi L. Psychosexual Correlates of Unwanted Sexual Experiences in Women Consulting for Female Sexual Dysfunction According to Their Timing Across the Life Span. J Sex Med 2018;15:1739-1751. doi: 10.1016/j.jsxm.2018.10.004.
  49. Maseroli E, Vignozzi L. Testosterone and Vaginal Function. Sex Med Rev 2020;8:379-392. doi: 10.1016/j.sxmr.2020.03.003.
  50. Maseroli E, Cellai I, Filippi S, Comeglio P, Cipriani S, Rastrelli G, Rosi M, Sorbi F, Fambrini M, Petraglia F, Amoriello R, Ballerini C, Lombardelli L, Piccinni MP, Sarchielli E, Guarnieri G, Morelli A, Maggi M, Vignozzi L. Anti-inflammatory effects of androgens in the human vagina. J Mol Endocrinol 2020;65:109-124. doi: 10.1530/JME-20-0147.
  51. Maseroli E, Rastrelli G, Di Stasi V, Cipriani S, Scavello I, Todisco T, Gironi V, Castellini G, Ricca V, Sorbi F, Fambrini M, Petraglia F, Maggi M, Vignozzi L. Physical Activity and Female Sexual Dysfunction: A Lot Helps, But Not Too Much. J Sex Med 2021;18:1217-1229. doi: 10.1016/j.jsxm.2021.04.004.
  52. Melis MR, Argiolas A. Central control of penile erection: a re-visitation of the role of oxytocin and its interaction with dopamine and glutamic acid in male rats. Neurosci Biobehav Rev 2011;35:939-55. doi: 10.1016/j.neubiorev.2010.10.014.
  53. Meston CM, Lorenz TA, Stephenson KR. Effects of expressive writing on sexual dysfunction, depression, and PTSD in women with a history of childhood sexual abuse: results from a randomized clinical trial. J Sex Med 2013;10:2177-89. doi: 10.1111/jsm.12247.
  54. Mueck AO, Ruan X, Prasauskas V, Grob P, Ortmann O. Treatment of vaginal atrophy with estriol and lactobacilli combination: a clinical review. Climacteric 2018;21:140-147. doi: 10.1080/13697137.2017.1421923.
  55. Muhleisen AL, Herbst-Kralovetz MM. Menopause and the vaginal microbiome. Maturitas. 2016 Sep;91:42-50. doi: 10.1016/j.maturitas.2016.05.015.
  56. Nappi RE, Cucinella L, Martini E, Cassani C. The role of hormone therapy in urogenital health after menopause. Best Pract Res Clin Endocrinol Metab 2021;35:101595. doi: 10.1016/j.beem.2021.101595.
  57. Nimbi FM, Magno S, Agostini L, Di Micco A, Maggiore C, De Cesaris BM, Rossi R, Galizia R, Simonelli C, Tambelli R. Sexuality in breast cancer survivors: sexual experiences, emotions, and cognitions in a group of women under hormonal therapy. Breast Cancer 2022;29:419-428. doi: 10.1007/s12282-021-01320-2.
  58. Nunn KL, Forney LJ. Unraveling the Dynamics of the Human Vaginal Microbiome. Yale J Biol Med 2016;89:331-337.
  59. Pascoal PM, Narciso Ide S, Pereira NM. What is sexual satisfaction? Thematic analysis of lay people’s definitions. J Sex Res 2014;51:22-30. doi: 10.1080/00224499.2013.815149.
  60. Perelman MA. The sexual tipping point: a mind/body model for sexual medicine. J Sex Med 2009;6:629-32. doi: 10.1111/j.1743-6109.2008.01177.x
  61. Pfaus J, Giuliano F, Gelez H. Bremelanotide: an overview of preclinical CNS effects on female sexual function. J Sex Med 2007;4 Suppl 4:269-79. doi: 10.1111/j.1743-6109.2007.00610.x.
  62. Pfaus JG. Pathways of sexual desire. J Sex Med 2009;6:1506-1533. doi: 10.1111/j.1743-6109.2009.01309.x.
  63. Pfaus JG, Quintana GR, Mac Cionnaith C, Parada M. The whole versus the sum of some of the parts: toward resolving the apparent controversy of clitoral versus vaginal orgasms. Socioaffect Neurosci Psychol 2016;6:32578. doi: 10.3402/snp.v6.32578.
  64. Pfaus JG, Sadiq A, Spana C, Clayton AH. The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women. CNS Spectr 2021:1-9. doi: 10.1017/S109285292100002X.
  65. Pfaus JG, Tsarski K. A Case of Female Orgasm Without Genital Stimulation. Sex Med 2022;10:100496. doi: 10.1016/j.esxm.2022.100496.
  66. Pitchers KK, Coppens CM, Beloate LN, Fuller J, Van S, Frohmader KS, Laviolette SR, Lehman MN, Coolen LM. Endogenous opioid-induced neuroplasticity of dopaminergic neurons in the ventral tegmental area influences natural and opiate reward. J Neurosci 2014;34:8825-36. doi: 10.1523/JNEUROSCI.0133-14.2014.
  67. Qi W, Li H, Wang C, Li H, Fan A, Han C, Xue F. The effect of pathophysiological changes in the vaginal milieu on the signs and symptoms of genitourinary syndrome of menopause (GSM). Menopause 2020;28:102-108. doi: 10.1097/GME.0000000000001644.
  68. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, et al. Vaginal microbiome of reproductive-age women. PNAS 2011;108:4680-4687. doi: 10.1073/pnas.1002611107
  69. Reissing ED, Armstrong HL, Allen C. Pelvic floor physical therapy for lifelong vaginismus: a retrospective chart review and interview study. J Sex Marital Ther 2013;39:306-20. doi: 10.1080/0092623X.2012.697535.
  70. Rellini AH, Hamilton LD, Delville Y, Meston CM. The cortisol response during physiological sexual arousal in adult women with a history of childhood sexual abuse. J Trauma Stres 2009;22:557-65. doi: 10.1002/jts.20458.
  71. Rellini AH, Meston CM. Sexual self-schemas, sexual dysfunction, and the sexual responses of women with a history of childhood sexual abuse. Arch Sex Behav 2011;40:351-62. doi: 10.1007/s10508-010-9694-0.
  72. Salonia A, Giraldi A, Chivers ML, Georgiadis JR, Levin R, Maravilla KR, McCarthy MM. Physiology of women’s sexual function: basic knowledge and new findings. J Sex Med 2010;7:2637-60. doi: 10.1111/j.1743-6109.2010.01810.x.
  73. Senn TE, Carey MP, Vanable PA. Childhood and adolescent sexual abuse and subsequent sexual risk behavior: evidence from controlled studies, methodological critique, and suggestions for research. Clin Psychol Rev 2008;28:711-35. doi: 10.1016/j.cpr.2007.10.002.
  74. Simon JA, Thorp J, Millheiser L. Flibanserin for Premenopausal Hypoactive Sexual Desire Disorder: Pooled Analysis of Clinical Trials. J Womens Health (Larchmt) 2019;28:769-777. doi: 10.1089/jwh.2018.7516.
  75. Smith SB, Ravel J. The vaginal microbiota, host defence and reproductive physiology. J Physiol 2017;595:451-463. doi: 10.1113/JP271694.
  76. Sobel JD. Vulvovaginitis in healthy women. Compr Ther 1999;25:335-46. doi: 10.1007/BF02944280.
  77. Stahl SM, Sommer B, Allers KA. Multifunctional pharmacology of flibanserin: possible mechanism of therapeutic action in hypoactive sexual desire disorder. J Sex Med 2011;8:15-27. doi: 10.1111/j.1743-6109.2010.02032.x.
  78. Stulhofer A, Busko V, Brouillard P. Development and bicultural validation of the new sexual satisfaction scale. J Sex Res 2010;47:257-68. doi: 10.1080/00224490903100561.
  79. Szymański JK, Słabuszewska-Jóźwiak A, Jakiel G. Vaginal Aging-What We Know and What We Do Not Know. Int J Environ Res Public Health 2021;18:4935. doi: 10.3390/ijerph18094935.
  80. Turan Ş, Usta Sağlam NG, Bakay H, Gökler ME. Levels of Depression and Anxiety, Sexual Functions, and Affective Temperaments in Women With Lifelong Vaginismus and Their Male Partners. J Sex Med 2020;17:2434-2445. doi: 10.1016/j.jsxm.2020.08.018.
  81. Unlubilgin E, Tetik S, Aksoy I, Yuksel D, Tekin OM. Relationship Between Adult Separation Anxiety and Attachment Styles and Vaginismus. J Sex Med 2021;18:1752-1758. doi: 10.1016/j.jsxm.2021.07.005.
  82. Velten J, Milani S, Margraf J, Brotto LA. Visual Attention to Sexual Stimuli in Women With Clinical, Subclinical, and Normal Sexual Functioning: An Eye-Tracking Study. J Sex Med 2021;18:144-155. doi: 10.1016/j.jsxm.2020.10.005.
  83. Zaneva M, Philpott A, Singh A, Larsson G, Gonsalves L. What is the added value of incorporating pleasure in sexual health interventions? A systematic review and meta-analysis. PLoS One 2022;17:e0261034. doi: 10.1371/journal.pone.0261034.
  84. Zarski AC, Berking M, Ebert DD. Efficacy of Internet-Based Guided Treatment for Genito-Pelvic Pain/Penetration Disorder: Rationale, Treatment Protocol, and Design of a Randomized Controlled Trial. Front Psychiatry 2018;8:260. doi: 10.3389/fpsyt.2017.00260.