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Laura Cucinella,1,2 Lara Tiranini,1,2 Chiara Cassani,1,3 Silvia Martella,4 Rossella E Nappi1,2 1Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; 2Research Centre for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy; 3Unit of Obstetrics and Gynecology, IRCCS San Matteo Foundation, Pavia, Italy; 4Unit of Preventive Gynecology, IRCCS European Institute of Oncology, Milan, ItalyCorrespondence: Rossella E Nappi, Research Centre for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Piazzale Golgi 2, Pavia, 27100, Italy, Tel +390382501561, Fax +390382516176, Email nappi@rossellanappi.comAbstract: Genitourinary syndrome of menopause (GSM) is a frequent consequence of iatrogenic menopause or anti-estrogenic adjuvant therapies in breast cancer survivors (BCSs). GSM may profoundly affect sexual health and quality of life, and a multidimensional unique model of care is needed to address the burden of this chronic heterogeneous condition. Severe symptoms may be insufficiently managed with non-hormonal traditional treatments, such as moisturizers and lubricants, recommended as the first-line approach by current guidelines, because concerns exist around the use of vaginal estrogens, particularly in women on aromatase inhibitors (AIs). Vaginal laser therapy has emerged as a promising alternative in women with GSM who are not suitable or do not respond to hormonal management, or are not willing to use pharmacological strategies. We aim to systematically review current evidence about vaginal laser efficacy and safety in BCSs and to highlight gaps in the literature. We analyzed results from 20 studies, including over 700 BCSs treated with either CO2 or erbium laser, with quite heterogeneous primary outcomes and duration of follow up (4 weeks– 24 months). Although evidence for laser efficacy in BCSs comes mostly from single-arm prospective studies, with only one randomized double-blind sham-controlled trial for CO2 laser and one randomized comparative trial of erbium laser and hyaluronic acid, available data are reassuring in the short term and indicate effectiveness of both CO2 and erbium lasers on the most common GSM symptoms. However, further studies are mandatory to establish long-term efficacy and safety in menopausal women, including BCSs.Keywords: genitourinary syndrome of menopause, GSM, vaginal laser, breast cancer, vulvovaginal atrophy, VVA

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Introduction: Vasomotor symptoms (VMS) affect the majority of menopausal women, with possible negative impact on several domains of quality of life (QoL). Although menopausal hormone therapy (MHT) represents an effective treatment, the risk-benefit profile is not favorable for every woman. Non-hormonal options are limited in number and efficacy., Areas Covered: Fezolinetant is a novel oral non-hormonal drug recently approved for treatment of moderate-severe VMS. It acts as an antagonist of neurokinin 3 receptor (NK3R), the main target of neurokinin B (a tachykinin over-expressed by kisspeptin/neurokinin B/dynorphin [KNDy] neurons after menopausal hypoestrogenism), involved in modulation of thermoregulatory hypothalamic center. In here, we report pharmacodynamics and pharmacokinetic properties of fezolinetant as well efficacy and safety data from available clinical trials., Expert Opinion: Fezolinetant has shown efficacy in reducing frequency and severity of VMS with a positive impact on sleep and health related QoL and acceptable safety and tolerability profile. Given the limited availability of effective non-hormonal options for VMS, fezolinetant could potentially represent a game-changer for care of menopausal women, especially when relative or absolute contraindications to MHT use are present. Further studies to gain more information about safety profile and potential extra-VMS benefits or disadvantages are warranted in real-life clinical practice.

The shift in paradigm from the belief that endometriosis exclusively affects women of reproductive age has brought attention to its manifestation in postmenopausal patients. Despite this emerging awareness, there remains a dearth of information in the literature regarding postmenopausal endometriosis, with uncertainties surrounding its prevalence, clinical significance, optimal management strategies, and prognosis. Clinical manifestations of endometriosis in menopausal patients lack specificity, with pain onset possible at any stage of life. The primary approach for symptomatic postmenopausal endometriosis continues to be surgical excision, serving both diagnostic and therapeutic purposes while mitigating the risk of coexisting malignancies. Managing the disease in postmenopausal women presents challenges due to possible contraindications for menopausal hormone therapy and the elevated risk of recurrence and malignant transformation. However, conclusive data regarding the appropriateness of menopausal hormone therapy in women with endometriosis or a history of the disease are lacking. Current recommendations lean towards prioritizing combined menopausal hormone therapy formulations or tibolone over estrogen-only therapies due to their potentially higher malignancy risk. The possible increased risk of osteoporosis and cardiovascular disease in postmenopausal women with endometriosis is likely linked to a history of surgical menopause at an earlier age, but more research is warranted. This narrative review summarizes the available literature and provides insights into the intricate connection between endometriosis and menopause, shedding light on pathogenesis, symptoms, oncologic risk, diagnosis, and treatment., Competing Interests: Declaration of competing interest Rossella E. Nappi had past financial relationships (lecturer, member of advisory boards and/or consultant) with Boehringer Ingelheim, Ely Lilly, Endoceutics, Exeltis, HRA Pharma, Palatin Technologies, Pfizer Inc., Procter & Gamble Co, TEVA Women's Health Inc. and Zambon SpA. At present, she has on-going relationship with Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Fidia, Gedeon Richter, Merck Sharpe & Dohme, Novo Nordisk, Organon & Co, Shionogi Limited, Theramex, Viatris, and Vichy Laboratories. None of these are relevant to the present work. All the other authors have nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea and chronic anovulation in adolescent girls and young women, diagnosed after excluding other organic causes. It is commonly associated with calorie restriction, excessive physical exercise, and psychosocial stress. These stressors alter the pulsatile secretion of gonadotropin-releasing hormone, leading to a chronic condition of hypoestrogenism and significant health consequences. Recent evidence has highlighted a genetic predisposition to FHA that could explain interindividual variability in stress response. Indeed, not all women experience FHA in response to stress. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been identified in women with FHA, suggesting that these mutations may contribute to an increased susceptibility of women to the trigger of stress exposure. FHA appears today as a complex disease resulting from the combination of genetic predisposition, environmental factors, and epigenetic changes. Furthermore, the genetic background of FHA allows for the hypothesis of a male counterpart. Despite the paucity of data, preliminary findings indicate that an equivalent condition of FHA exists in men, warranting further investigation. This narrative review aims to summarize the recent genetic evidence contributing to the pathophysiology of FHA and to raise awareness on a possible male counterpart., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Barbagallo, Bosoni, Perone, Cucinella, Dealberti, Cannarella, Calogero and Nappi.)

Competing Interests: Conflict of interest: L.C. has nothing to disclose. R.E.N. has on-going relationship with Abbott, Astellas, Bayer Pharma, Besins Healthcare, Fidia, Gedeon Richter, Merck & Co, Novo Nordisk, Organon & Co, Shionogi Limited, Theramex, Viatris, and Vichy Laboratories. None of these are relevant to the present work.

Genitourinary syndrome of menopause is a comprehensive term that groups genital, urinary and sexual signs and symptoms mainly due sex hormone deficiency and aging, with a crucial impact on quality of life of midlife women. While this broad definition captures the common underlying physiopathology and the frequent overlap of symptomatology, improving knowledge about different components of genitourinary syndrome of menopause may be relevant for individualized treatment, with possible implications for efficacy, compliance and satisfaction. This narrative review focuses on the vulvar component of genitourinary syndrome of menopause, highlighting anatomical and functional peculiarities of the vulva that are responsible for some of the self-reported symptoms, as well as specific signs at physical examination. Increasing evidence points towards a pivotal role of vulvar vestibular health in the occurrence of sexual pain, one of the most common and distressing symptoms of genitourinary syndrome of menopause, which should be evaluated with validated scales taking a biopsychosocial perspective. This is an essential step in the recognition of different phenotypes of genitourinary syndrome of menopause and in the assessment of the most effective diagnostic and therapeutic algorithm. Menopausal vulvar health deserves more research into tailored non-hormonal and hormonal treatment options., Competing Interests: Declaration of competing interest Rossella E. Nappi had past financial relationships (lecturer, member of advisory boards and/or consultant) with Boehringer Ingelheim, Ely Lilly, Endoceutics, HRA Pharma, Procter & Gamble Co, TEVA Women's Health Inc. and Zambon SpA. At present, she has on-going relationship with Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Exeltis, Fidia, Gedeon Richter Merck Sharpe & Dohme, Novo Nordisk, Palatin Technologies, Pfizer Inc., Shionogi Limited, Theramex, and Viatris. None of these are relevant to the present work. All the other authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Female sexual dysfunctions (FSDs) have received little attention in the context of thyroid diseases, despite the high prevalence of both conditions., Objectives: This review aims to update and summarize the state of knowledge on the association between thyroid diseases and FSDs and to investigate the complex mechanisms through which thyroid hormone imbalance can impact female sexual health in the context of the biopsychosocial model., Methods: A comprehensive literature search was performed through the PubMed, MEDLINE, and Scopus databases, using the following keywords: "female sexual function," "sexual dysfunction," "hypoactive sexual desire disorder," "thyroid disease," "thyroiditis," "hypothyroidism," and "hyperthyroidism.", Results: To date, well-designed studies that describe the relationship between FSDs and thyroid disorders are lacking. However, despite the limitations on available studies, current data indicate that sexual alterations are frequently associated with thyroid diseases in women. A complex interplay of direct and indirect hormonal and nonhormonal mechanisms has been hypothesized, including hormonal changes, neurotransmitter imbalance, reduced nitric oxide release, mood disorders, and other systemic consequences of both hypothyroidism and hyperthyroidism. Thyroid hormone receptors have also been identified in the genitourinary system., Conclusions: In a clinical setting, physicians should investigate the sexuality of patients consulting for thyroid disease. At the same time, an evaluation of thyroid function should be performed in patients presenting with FSD, especially after menopause, when the risk of thyroid diseases and FSDs increases strongly., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Psychological vulnerability is a relevant component of polycystic ovarian syndrome (PCOS), but it is still under-explored, especially during adolescence. The aim of this study was to describe a selection of psychometric characteristics in a clinical sample of Italian adolescents with PCOS. Moreover, we reported the associations of body image, eating attitudes, and mood with metabolic features., Methods: Our sample included 128 adolescent girls (age range: 14-19 years) with PCOS. Validated psychometric questionnaires were administered: State Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Body Attitude Test (BAT), Bulimia Investigation Test (BITE), Eating Attitudes Test (EAT), and Perceived Stress Scale (PSS)., Results: Anxiety was the most prevalent mood disorder (63.1% trait anxiety and 57% state anxiety). Our cohort also showed a high prevalence of depression (39.1%), body image dissatisfaction (49.2%), disordered eating (11.7%), and bulimic risk (41.4%). PCOS adolescents with obesity and insulin resistance (IR) had statistically significant higher body image distress compared to those with normal weight and without IR ( p < 0.001). The Sobel test for mediation showed that body image dissatisfaction mediates the relationship between state anxiety and bulimic risk (Z = 3.42, p < 0.001) and between depression and bulimic risk (Z = 4.59, p < 0.001)., Conclusions: A considerable number of patients with PCOS experience psychological disorders during adolescence. IR and obesity play a role in the distress associated with body image, further contributing to psychological vulnerability, especially in the bulimic domain. A comprehensive biopsychosocial approach in adolescents with PCOS represents the basis for effectively managing and preventing complications arising from both psychological and biological disorders in adulthood.

Background: Vulvovaginal atrophy (VVA) negatively affects the sexual well-being and quality of life of postmenopausal women, yet it is underreported and undertreated., Aim: The study sought to investigate the efficacy and safety of a nonablative, noncoagulative multipolar radiofrequency (RF) and pulsed electromagnetic field-based device (PEMF) in treatment of symptoms related to VVA., Methods: Seventy-six women ≥19 years of age with symptoms associated with VVA were enrolled into this prospective, randomized, sham-controlled, multicenter clinical study. Subjects were randomized to receive 3 RF + PEMF treatments (active group) or sham treatments (sham group) delivered to vaginal tissue at monthly intervals. The Vaginal Health Index (VHI), along with the Female Sexual Function Index (FSFI), subject sexual satisfaction and vaginal laxity (VL) score, treatment-associated pain, and adverse events were assessed at 4 follow-up (FU) visits between 1 and 12 months after treatment., Outcomes: Changes from baseline VHI, pH, FSFI, VL, and sexual satisfaction scores between the active and sham groups were compared before and after treatment., Results: Mean VHI scores in the active group were significantly better compared with the sham group after treatment at all but the last FU visit (P < .001). A greater decrease in pH (active over sham) was seen at 1 and 4 months after treatment (P < .05). FSFI improvement was shown in the active group; however, it was not significantly better than sham improvement at all FU visits. Subject sexual satisfaction in the active group showed better improvement over sham at all FU visits (P < .05), while VL evaluations saw greater improvement in the active group at 4, 6, and 12 months posttreatment (P < .05). Treatment satisfaction was greater in the active group and pain was minimal in both groups. No serious adverse effects were reported., Clinical Implications: As a noninvasive alternative to traditional surgical and topical procedures, 3 sessions of noninvasive combination RF/PEMF safely demonstrated improvement in symptoms related to VVA., Strengths and Limitations: This study was strengthened by the randomized, sham-controlled design; large sample size; and extended FU period. The study assessments were decreased at later FU visits due to the global COVID pandemic, and this was a key limitation to the study., Conclusion: Nonablative, noncoagulative multipolar RF/PEMF therapy was safe, improved symptoms associated with VVA, and improved female sexual function while yielding high subject satisfaction., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Nigella sativa L. is an herb that is commonly used in cooking and in traditional medicine, particularly in Arab countries, the Indian subcontinent, and some areas of eastern Europe. Nigella sativa is also called "black cumin" or "black seeds", as the seeds are the most-used part of the plant. They contain the main bioactive component thymoquinone (TQ), which is responsible for the pleiotropic pharmacological properties of the seeds, including anti-oxidant, anti-inflammatory, anti-hypertensive, anti-hepatotoxic, hypoglycemic, and lipid-lowering properties. In this narrative review, both the potential mechanisms of action of Nigella sativa and the fundamental role played by pharmaceutical technology in optimizing preparations based on this herb in terms of yield, quality, and effectiveness have been outlined. Moreover, an analysis of the market of products containing Nigella sativa was carried out based on the current literature with an international perspective, along with a specific focus on Italy.

Women may experience changes in sexuality across menopause, because at this step in life hormone deficiency interacts with several determinants in a bio-psycho-social perspective. Healthcare providers should inform women about menopause impact on sexuality and be proactive during consultation in disclosing sexual concerns that would require a targeted assessment. Sexual symptoms become more frequent as women age, but they do not always translate into sexual dysfunction diagnosis, for which distress is required. It is important to recognize conditions that may increase the risk of dysfunctional response to menopause challenges in order to promote sexual longevity through counselling and specific management. In this review, we report key elements for a comprehensive assessment of sexual health around menopause, with a focus on genitourinary syndrome of menopause (GSM) and hypoactive sexual desire disorder (HSDD), representing well identified clinical conditions affecting sexuality at midlife and beyond. We also address the issue of contraception across the menopausal transition, highlighting risks and benefits, and possible implications on sexual function., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: We investigated the attitudes to change the frequency of menstrual bleeding by using combined hormonal contraception (CHC). Personality characteristics were also explored., Methods: We conducted a cross-sectional study in two university hospitals in northern Italy. Current, past and never CHC users ( n  = 545; age 18-44 years) completed a self-administered semi-structured questionnaire and the Ten-Item Personality Inventory (TIPI)., Results: Forty-five percent of responders ( n  = 301) would prefer to change their bleeding frequency by using CHC. A flexible regimen was the preferred choice ( n  = 80; 33%) followed by extended regimens to bleed every 3 months ( n  = 54; 22%) or to never bleed ( n  = 43; 18%). The main positive reasons were to avoid dysmenorrhea (43%) and have more freedom in sexual (36%) and active (35%) life, whereas the main reason for a negative attitude was 'menstrual rhythm is natural' (59%). Age had a significant influence on women's willingness to change menstrual frequency by using CHC [>39 years (57%), 30-39 years (31%) and <30 years (46%)] (χ 2 : 9.1; p  = 0.01). Never users significantly reported a more negative attitude (71%) in comparison with past (51%) and current users (49%) (χ 2 : 18.7; p  = 0.001). Personality traits played a role, with higher scores of openness ( p  = 0.005) and extraversion ( p  = 0.001) in women with a positive attitude., Conclusions: Almost half of our study sample reported a preference for changing their menstrual pattern by using CHC. Flexibility was the preferred choice across age and use of CHC. Personality characteristics (openness and extroversion) might influence attitudes toward CHC-induced menstrual bleeding changes.

The huge impact of climate change on humankind is multidimensional, and includes direct and indirect challenges to the physical, psychological and socio-cultural wellbeing. Women may be more vulnerable to climate-sensitive diseases, but little attention has been paid to specific needs and challenges associated with the menopause transition. The increase in average and extreme temperatures may modulate the manifestation of vasomotor symptoms; in particular, environmental temperature and seasonality may affect hot flushes and night sweats. However, more research is needed to define the impact of climate-related factors among the determinants influencing the individual experience of menopause. In addition, increased exposure to environmental pollution and toxins may also have a role in the modulation of ovarian aging mechanisms, possibly influencing timing of menopause. Finally, both air pollution and menopause transition are associated with unfavorable modifications of cardio-metabolic, bone and cognitive health, and account should be taken of these in the evaluation of the individual woman's health vulnerabilities. Overall, the evidence reported in this narrative review supports the need for specific strategies aimed at reducing the burden of climate and environmental change on menopausal women. Healthcare providers should promote behavioral measures that reduce anthropogenic climate change and at the same time have a beneficial role on several domains of physical and psychological wellbeing. From this perspective, menopause represents a golden moment to implement virtuous behaviors that will benefit at the same time women's longevity and the planet., Competing Interests: Declaration of competing interest Rossella E. Nappi had past financial relationships (lecturer, member of advisory boards and/or consultant) with Boehringer Ingelheim, Ely Lilly, Endoceutics, Gedeon Richter, HRA Pharma, Procter & Gamble Co, TEVA Women's Health Inc. and Zambon SpA. At present, she has on-going relationship with Astellas, Bayer HealthCare AG, Exeltis, Fidia, Merck Sharpe & Dohme, Novo Nordisk, Palatin Technologies, Pfizer Inc., Shionogi Limited, Theramex, and Viatris. None of these are relevant to the present work. All the other authors have nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Estrogen fluctuations modulate pain threshold and play a pivotal role in the central and peripheral pathogenesis of menstrually related migraine (MRM). Estrogen-withdrawal during the perimenstrual phase of a spontaneous menstrual cycle or the hormone-free interval (HFI) of hormonal treatments seems to be the culprit., Area Covered: The authors report the most relevant data on risks, benefits, and limitations of exogenous estrogens as a treatment for MRM considering gynecological comorbidities associated with chronic pelvic pain that may be effectively managed by the use of combined hormonal contraception (CHC). Given that migraine and CHC are both currently known as independent risk factors for stroke, levels of evidence contraindicate CHC in women with migraine with aura, whereas quality of evidence is low in women with migraine without aura, including MRM. Continuous/extended/flexible CHC regimens, shorter HFI, or estrogens supplementation during the HFI/perimenstrual spontaneous phase may be beneficial in women with MRM., Expert Opinion: Safety is a main issue, and it is mandatory to investigate the impact of CHC containing natural estrogens, instead of ethinylestradiol, on clinical pattern of MRM and cardiovascular associated risk. Reproductive characteristics may be relevant and should be considered in a multidisciplinary approach to increase the power of endocrine management in MRM.

Introduction: Female sexual dysfunctions (FSDs) are common in women of any age and have a huge impact on quality of life and relationships. They have a multifaceted etiology limiting the development of pharmacotherapies with a high rate of effectiveness. Safety issues are also a concern., Areas Covered: The authors report the most recent advances in pharmacotherapy for premenopausal and postmenopausal women with a main focus on hypoactive sexual desire disorders (HSDD) and associated sexual symptoms. Good levels of evidence have emerged for psychoactive agents, such as flibanserin and bremelanotide, as well as hormonal compounds (transdermal testosterone). The authors also report briefly on intravaginal DHEA (prasterone), local estrogen therapy (LET), and ospemifene to manage effectively vulvovaginal atrophy/genitourinary syndrome of menopause (VVA/GSM). In addition, they discuss promising therapeutic options highlighting the main reasons that hamper the availability of new labeled products. Finally, they include the importance of the multimodal approach to address FSDs., Expert Opinion: Approved pharmacotherapies for FSD are limited. Validated multidimensional instruments and adequate objective measures of physical and mental responses to sexual external and internal incentives are mandatory to identify women suitable to chronic or on-demand treatments and to assess their pattern of response in research and practice.

Introduction: Female sexual function relies on a complex interplay of physical, psychosocial, and neurobiological factors. Over the last decades, increasing attention has been paid to the influence of personality traits on general health and many aspects of quality of life, including sexuality., Objective: To assess whether dimensions of the personality are related to the domains of sexual function (desire, arousal, lubrication, orgasm, satisfaction, and pain) in symptomatic postmenopausal women. Mood was also investigated to explore its association with female sexual dysfunction (FSD)., Methods: Validated questionnaires to assess sexual function [the Female Sexual Functioning Index (FSFI)], mood [the State-Anxiety Inventory (STAI), and Zung Self Rating Depression Scale (SDS)], and personality traits [the Tridimensional Personality Questionnaire (TPQ)] were filled in by 130 early postmenopausal women experiencing hot flushes (≥30/week)., Results: 61.5 % (n = 80) of the women had an FSFI total score lower than 26.55, the standard cut-off for FSD. A clinical state of anxiety was present in 53.8 % (n = 70), whereas only 12.3 % (n = 16) showed clinically relevant depressive symptoms. According to the FSFI cut-off score, women with sexual disorders had statistically significantly higher levels of anxiety, depression (p < 0.001 for both), and harm avoidance (HA) (p = 0.004) than women without such disorders. Significantly higher levels of anxiety were found in women in the lower quartile (LQ) of the distribution of the total FSFI score than in women in both the interquartile range (IQR) and in the upper quartile (UQ) (p < 0.05). Moreover, women in the UQ had a lower grade of depression and HA than others (p < 0.05). The Sobel test showed that the personality trait HA significantly mediated the relationship between anxiety and FSFI total score (Z = -2.19, p < 0.05) and between depression and FSFI total score (Z = -2.35, p < 0.05)., Conclusions: The present data suggest the personality trait HA is relevant to sexual function and mediates the impact of mood on FSD in symptomatic menopausal women. In clinical practice, the use of validated psychometric tools for mood screening is useful to establish appropriate diagnosis and treatment of sexual disorders in menopausal women. Moreover, the assessment of personality traits could provide additional information that directs clinicians towards an increasingly tailored and multidimensional treatment of FSD., Competing Interests: Declaration of competing interest Rossella E. Nappi had past financial relationships (lecturer, member of advisory boards and/or consultant) with Boehringer Ingelheim, Ely Lilly, Endoceutics, Palatin Technologies, Procter & Gamble Co, TEVA Women's Health Inc. and Zambon SpA. At present, she has on-going relationship with Astellas, Bayer HealthCare AG, Exceltis, Fidia, Gedeon Richter, HRA Pharma, Merck Sharpe & Dohme, Novo Nordisk, Pfizer Inc., Shionogi Limited and Theramex. None of these are relevant to the present work. All the other authors have nothing to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Biological and psycho-relational factors contribute equally to the development of sexual symptoms and associated distress, a key element to diagnose female sexual dysfunctions (FSDs) in menopausal women. Consultation at midlife represents an optimal time to discuss sexual life, and healthcare providers have to be proactive in rising the conversation, as patients may not report their sexual concerns spontaneously. An accurate sexual history is essential to characterize the primary symptom, determine the impact on patient's quality of life and identify risk and precipitating factors. Among FSDs, hypoactive sexual desire disorder is very frequent at midlife together with genitourinary syndrome of menopause, a chronic condition negatively affecting the full sexual response. A multidimensional approach targeted to the patient's characteristics, goals and expectations is mandatory and should start from educative counselling and correction of modifiable risk factors. When specific treatments are required, they should include non-pharmacological and pharmacological options, often prescribed in combination to address concomitantly the biological and psychosocial components of FSDs.

A multitude of biopsychosocial factors influences sexual health at midlife, a common concern in daily practice along with vaginal and pelvic health. Health-care providers (HCPs) need to be proactive in dealing with possible symptoms because in most cases early management prevents distress and improves quality of life. Female sexual dysfunctions (FSDs) may have a complex etiology but sexual history is not difficult implementing basic knowledge of risk factors and some skills helping women to cope with hormonal and age-related changes. This work summarizes key points to approach sexual symptoms in midlife women, providing principles to diagnose and manage hypoactive sexual desire disorder (HSDD) and genitourinary syndrome of menopause (GSM)/vulvovaginal atrophy (VVA), as well as manage contraceptive needs., Competing Interests: Declaration of competing interest This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. R.E.N. had past financial relationships (lecturer, member of advisory boards, and/or consultant) with Boehringer Ingelheim, Eli Lilly, Endoceutics, Gedeon Richter, HRA Pharma, Merck Sharpe & Dohme, Procter & Gamble Co, TEVA Women's Health Inc, and Zambon SpA. At present, she has ongoing relationships with Abbott, Astellas, Bayer HealthCare AG, Exceltis, Fidia, Gedeon Richter, Novo Nordisk, Organon & Co, Palatin Technologies, Pfizer Inc, Shionogi Limited, and Theramex. L.C. declare no competing interests for this work., (Copyright © 2021. Published by Elsevier Ltd.)

Premature ovarian insufficiency (POI) has a strong genetic component, but, in most cases, the etiology remains unidentified. PSMC3IP is an autosomal recessive gene for POI and ovarian dysgenesis, and so far, biallelic mutations in this gene have been described in only four independent families, with all affected members showing primary amenorrhea. Here, we report on the first family with recessive variants in the PSMC3IP gene and POI in a patient with secondary amenorrhea. Whole-exome sequencing (WES) was performed on a 29-year-old woman with secondary amenorrhea and POI; she was found to carry compound heterozygous variants in the PSMC3IP gene: c.206&#95;208delAGA and c.189 G > T. Her younger sister, who also presented with a suspect of POI due to infertility and very low levels of anti-müllerian hormone (AMH), was found to carry the same PSMC3IP variants. Our case report shows the importance to include PSMC3IP in designed POI NGS panels or in WES/WGS studies in patients with either primary or secondary amenorrhea., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Female sexual dysfunction (FSD) comprises multiple overlapping sexual disorders with a multifaceted cause within the frame of the biopsychosocial model. Health care providers can screen for FSD according to their level of expertise and deliver at least basic counseling before eventually referring to sexual medicine specialists for specific care. The therapeutic algorithm comprises a multidisciplinary approach, including pharmacologic and nonpharmacologic management. Flibanserin and bremelanotide are psychoactive agents indicated for the treatment of generalized acquired hypoactive sexual desire disorder (HSDD) in premenopausal women, whereas transdermal testosterone is effective on HSDD in postmenopausal women. Menopause hormone therapy (systemic and local) is the mainstay for individualized management of women at midlife., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Menopause represents an endocrine challenge to urogenital health, as oestrogens deprivation and androgens decline significantly contributes to age-related involution of vulvovaginal tissues and lower urinary tract. Genitourinary syndrome of menopause (GSM) is a clinical entity including the chronic and progressive condition of vulvovaginal atrophy (VVA) and encompassing both anatomical and functional consequences of menopause. The term GSM describes genital, sexual and urinary symptoms with a detrimental impact on quality of life (QOL). Several treatment options are available, but many barriers are still present to adequately diagnose and treat GSM. This review aims to present current evidences about epidemiology, aetiology, diagnosis and treatment of GSM, with a focus on prescription medications [low-dose local oestrogen therapy (LET), prasterone (DHEA) and the SERM ospemifene] for urogenital symptoms in healthy postmenopausal women and in special populations, including women with premature ovarian insufficiency (POI) and breast cancer survivors (BCS)., Competing Interests: Declaration of competing interest The present work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. R.E.N. had past financial relationships (lecturer, member of advisory boards, and/or consultant) with Boehringer Ingelheim, Eli Lilly, Endoceutics, Gedeon Richter, HRA Pharma, Merck Sharpe & Dohme, Procter & Gamble Co, TEVA Women's Health Inc, and Zambon SpA. At present, she has on-going relationships with Abbott, Astellas, Bayer HealthCare AG, Exceltis, Fidia, Gedeon Richter, Novo Nordisk, Organon & Co, Palatin Technologies, Pfizer Inc, Shionogi Limited, and Theramex. L.C. declare no competing interests for the present work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: we aimed to explore the use of an estro-androgenic symptom questionnaire in women (EASQ-W), including items typically associated with menopausal hypoestrogenism and some others possibly related to androgen insufficiency that may be relevant to further characterize women reporting VVA/GSM at midlife., Methods: web-based survey involving a representative sample of 1505 Italian women (age range: 40-65 years). The responders completed a structured, online questionnaire, reporting symptoms (yes/no option) and rating them (from 1 to 10), if present during the past 4 weeks. A factor analysis methodology (principal component analysis and K-MEANS clustering algorithm) was used to segment women. Statistically significant differences between groups were determined at the 95 % level of confidence., Results: more than half of our study sample were aged 50-65 years (n = 901; 59.9 %) and 55 % were postmenopausal women (PMW). We obtained 8 principal domains of the EASQ-W with PMW reporting significantly more severe symptoms in the majority of domains related to well-being at mid-life. The K-MEANS clustering algorithm identified 4 clusters of women characterized by different symptoms: vasomotor (VMS; n = 341), sexual (SEX; n = 301), poorly symptomatic (LOWSYMPT; n = 766), sexual and anatomic, mainly at genital level (SEX + ANAT; n = 97), independently from the menopausal status. The cluster SEX + ANAT was the one reporting overall more symptoms in each of the other principal domains. Some symptoms (impression of being diminished in height, deterioration in work performance, more memory lapses/confusion than before, more wrinkles/signs of aging in the mirror, put on more tummy than usual) and the entire urological (UROL) cluster were significantly more reported by women in the cluster SEX + ANAT. Even when only severe symptoms were analysed, women in the SEX + ANAT cluster were the ones more symptomatic. The SEX only cluster identified younger women, with significantly less day and night hot flushes and sweats and less vaginal dryness and low lubrication associated with sexual pain as compared to SEX + ANAT., Conclusion: our results provide insight into the constellation of symptoms associated with VVA/GSM by identifying women with distinct clusters of complaints that may require a tailored diagnostic and therapeutic approach across age and menopause., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Vaginal health is an essential component of active and healthy aging in women at midlife and beyond. As a consequence of hormonal deprivation and senescence, the anatomy and function of urogenital tissues are significantly affected and vulvovaginal atrophy (VVA) may occur. In a high proportion of postmenopausal women, progressive and chronic VVA symptoms have a strong impact on sexual function and quality of life. The new definition of genitourinary syndrome of menopause (GSM) comprises genital symptoms (dryness, burning, itching, irritation, bleeding), sexual symptoms (dyspareunia and other sexual dysfunctions) and urinary symptoms (dysuria, frequency, urgency, recurrent urinary infections). Many variables (age, sexual activity and partnership status) influence the clinical impact VVA/GSM symptoms and attitudes of elderly women to consult for receiving effective treatments. Psychosocial factors play a critical role in sexual functioning, but the integrity of the urogenital system is as well important affecting many domains of postmenopausal women's health, including sexual function. Several international surveys have extensively documented the need to improve VVA/GSM management because of the strong impact on women's daily life and on couple's intimacy. Health care providers (HCPs) need to be proactive in the early recognition of VVA/GSM in order to preserve urogenital and sexual longevity, by using hormonal and non-hormonal strategies. The clinical diagnosis is based on genital examination to identify objective signs and on the use of subjective scales to rate most bothersome symptoms (MBS), especially vaginal dryness. Recent studies point to the importance of addressing VVA/GSM as a potential early marker of poor general health in analogy with vasomotor symptoms. Therefore, a standard of VVA/GSM care in elderly women is desirable to enhance physical, emotional and mental well-being.

Background: Menstrually-related headache and headaches associated with oestrogen withdrawal are common conditions, whose pathophysiology has not been completely elucidated. In this study we evaluated the influence of combined hormonal contraceptives (CHC) on pain threshold in women presenting migraine attacks during hormone-free interval., Findings: Eleven women with migraine attacks recurring exclusively during the oestrogen-withdrawal period were studied with the nociceptive flexion reflex, a neurophysiological assessment of the pain control systems, during the third week of active treatment and during the hormone-free interval. During the hormone-free interval, nociceptive withdrawal reflex threshold was significantly lower (12.8 ± 8.0 mA) as compared to the third week of hormonal treatment (15.6 ± 6.6 mA) (p = 0.02). No change was observed in the pain perceived and in the temporal summation., Conclusions: Oestrogen withdrawal may mediate an increased sensitivity to somatosensory stimuli in women with migraine attacks recurring during the hormone-free interval.

Female sexual dysfunction (FSD) and quality of life (QOL) are both multidimensional and have a bidirectional relationship across the reproductive life span and beyond. Methodological difficulties exist in estimating the real prevalence of FSD because it is hard to determine the level of distress associated with sexual symptoms in a large-scale survey. Approximately 40-50% of all women report at least one sexual symptom, and some conditions associated with hormonal changes at menopause, such as vulvovaginal atrophy (VVA) and hypoactive sexual desire disorder (HSDD), have a significant impact on sexual function and QOL. Sexual distress peaks at midlife, declines with age and is strongly partner-related. Many postmenopausal women are still sexually active, especially if they are in a stable partnership. Even though sexual functioning is impaired, a variety of psychosocial factors may maintain sexual satisfaction. That being so, health care providers (HCPs) should proactively address sexual symptoms at midlife and in older women, from a balanced perspective. Adequate counselling should be offered. Women with distressing symptoms may benefit from tailored hormonal and non-hormonal therapies, whereas women without distress related to their sexual experiences should not receive any specific treatment., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: 'Female sexual dysfunction' (FSD) is an umbrella term comprising a range of common disorders, including hypoactive sexual desire, reduced subjective and/or physical genital arousal (poor sensation, vasocongestion, lubrication), sexual pain and inability to achieve orgasm/satisfaction, which are multidimensional by nature and often coexisting. Psychological and contextual factors have a significant influence on organic components of sexual response and behavior and a tailored medical approach to sexual symptoms is inevitably limited., Areas Covered: The paper reports the most recent advances in pharmacotherapy for women taking into account the biopsychosocial model. Hormone therapy, including estrogens, testosterone, tibolone and dehydroepiandrosterone, are discussed in term of efficacy and safety in postmenopausal women both for female sexual interest/arousal disorder (FSIAD) and genito-pelvic pain/penetration disorder. Ospemifene, a selective estrogen receptor modulator, approved to treat dyspareunia at menopause, is also discussed. Data on psychoactive agents for treatment of FSIAD in premenopausal women are discussed, including the potential use of on-demand combined hormonal (testosterone) and non-hormonal (buspirone or sildenafil) treatments to address possible neurophysiological profiles of women., Expert Opinion: We are still waiting for an approved pharmacotherapy for FSD. This is not the result of gender inequality in sexual medicine, but it reflects the need of balancing benefits and risks in order to provide effective and safe treatments to women of any age.