Standardised data collection for clinical follow-up and assessment of outcomes in differences of sex development (DSD): recommendations from the COST action DSDnet.

The treatment and care of individuals who have a difference of sex development (DSD) have been revised over the past two decades and new guidelines have been published. In order to study the impact of treatments and new forms of management in these rare and heterogeneous conditions, standardised assessment procedures across centres are needed. Diagnostic work-up and detailed genital phenotyping are crucial at first assessment. DSDs may affect general health, have associated features or lead to comorbidities which may only be observed through lifelong follow-up. The impact of medical treatments and surgical (non-) interventions warrants special attention in the context of critical review of current and future care. It is equally important to explore gender development early and refer to specialised services if needed. DSDs and the medical, psychological, cultural and familial ways of dealing with it may affect self-perception, self-esteem, and psychosexual function. Therefore, psychosocial support has become one of the cornerstones in the multidisciplinary management of DSD, but its impact remains to be assessed. Careful clinical evaluation and pooled data reporting in a global DSD registry will allow linking genetic, metabolomic, phenotypic and psychological data. For this purpose, our group of clinical experts and patient and parent representatives designed a template for structured longitudinal follow-up. In this paper, we explain the rationale behind the selection of the dataset. This tool provides guidance to professionals caring for individuals with a DSD and their families. At the same time, it collects the data needed for answering unsolved questions of patients, clinicians, and researchers. Ultimately, outcomes for defined subgroups of rare DSD conditions should be studied through large collaborative endeavours using a common protocol.

Caring for individuals with a difference of sex development (DSD): a Consensus Statement.

The term differences of sex development (DSDs; also known as disorders of sex development) refers to a heterogeneous group of congenital conditions affecting human sex determination and differentiation. Several reports highlighting suboptimal physical and psychosexual outcomes in individuals who have a DSD led to a radical revision of nomenclature and management a decade ago. Whereas the resulting recommendations for holistic, multidisciplinary care seem to have been implemented rapidly in specialized paediatric services around the world, adolescents often experience difficulties in finding access to expert adult care and gradually or abruptly cease medical follow-up. Many adults with a DSD have health-related questions that remain unanswered owing to a lack of evidence pertaining to the natural evolution of the various conditions in later life stages. This Consensus Statement, developed by a European multidisciplinary group of experts, including patient representatives, summarizes evidence-based and experience-based recommendations for lifelong care and data collection in individuals with a DSD across ages and highlights clinical research priorities. By doing so, we hope to contribute to improving understanding and management of these conditions by involved medical professionals. In addition, we hope to give impetus to multicentre studies that will shed light on outcomes and comorbidities of DSD conditions across the lifespan.

Changes in vaginal physiology of menopausal women with type 2 diabetes.

INTRODUCTION: Metabolic disorders, such as type 2 diabetes, have been associated with an increased risk of development of female sexual dysfunction (FSD). In experimental studies, vascular, neuronal, and hormonal responsiveness alteration at vaginal level were proposed as contributors to the onset of FSD in women with diabetes; however, conclusive data on humans are still lacking. AIMS: The study aimed to assess changes in vascularization, sex steroid receptors, nitric oxide synthase, and aquaporin-2 (AQP2) expression occurring at vaginal level in women with diabetes. METHODS: Vaginal biopsies were obtained from 21 postmenopausal women, 10 of whom were diagnosed as having type 2 diabetes mellitus. CD31, estrogen receptor-α (ERα) and androgen receptor (AR) expression and localization were analyzed by immunostaining. Expression of endothelial (eNOS) and neuronal (nNOS) nitric oxide synthase isoforms and AQP2 were also assessed in vaginal samples. MAIN OUTCOMES MEASURES: Changes in vaginal vascularization, sex steroids receptor, eNOS, nNOS and AQP2 expression. RESULTS: Vaginal samples from women with diabetes showed an increased microvessel density in the lamina propria, which were morphologically disrupted suggesting an angiogenic compensatory mechanism. While no differences were seen in ERα, AR expression was significantly reduced in the vaginal epithelium and lamina propria of women with diabetes. Similarly, the gene and protein expressions of both nNOS and eNOS were significantly reduced in patients with diabetes, while AQP2 mRNAs level did not significantly differ between the two groups. CONCLUSION: Diabetes greatly impacts vaginal physiology, being associated with alterations of the vaginal lamina propria vascular network, nitrergic signaling, and AR expression. These alterations may contribute to the increased risk of FSD development in women with diabetes.

Sexuality and psychopathological aspects in premenopausal women with metabolic syndrome.

INTRODUCTION: Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that have been suggested to impact female sexual function. AIMS: This study aims to assess the prevalence of female sexual dysfunction (FSD) in premenopausal women with MetS compared with healthy controls (HC). Psychopathological aspects and the relationship to FSD were also evaluated in both groups. METHODS: Two hundred four premenopausal women, of whom 98 had diagnosis of MetS, were asked to complete the Female Sexual Function Index (FSFI), the Female Sexual Distress Scale (FSDS), and the Middlesex Hospital Questionnaire (MHQ). Routine laboratory tests and anthropometric measurements were routinely performed. MAIN OUTCOME MEASURES: FSFI and FSDS questionnaires, prevalence of FSD, and MHQ scores. RESULTS: In the MetS group compared with the HC group, we found: a lower global FSFI score (P=0.005), higher prevalence of pathological scores compared with HC group, and lower scores in the desire, arousal, lubrication, and orgasm domains. An inverse correlation between the FSFI score and the number of risk factors for MetS was detected. MetS women reported significantly higher total scores in the somatization and depression domains when compared with the HC group. The logistic regression showed that high triglycerides (odds ratio [OR] 3.097; 95% confidence interval [CI] 1.272-7.542; P=0.026) and somatization (OR 7.068; CI 95% 2.291-21.812; P=0.001) are independently associated with FSD in premenopausal women. CONCLUSIONS: Our results indicate a higher prevalence of sexual dysfunction in MetS women. A number of risk factors for MetS are positively associated with FSD and higher triglycerides seem to be the strongest predictors of sexual dysfunction. Psychopathological dimensions such as somatization are strongly associated with sexual dysfunction.

Long-term influence of combined oral contraceptive use on the clinical course of relapsing-remitting multiple sclerosis.

OBJECTIVE: To assess the long-term effects of combined oral contraceptives (COCs) on the clinical course of relapsing-remitting multiple sclerosis (RRMS), focusing on disability progression and evolution to secondary-progressive multiple sclerosis (SPMS). DESIGN: Retrospective and exploratory study. SETTING: Academic medical center. PATIENT(S): A total of 174 women with clinically confirmed MS; of these, 33 had evolved to SPMS at the time of enrollment in the study, whereas 141 still had a relapsing-remitting form of disease. INTERVENTION(S): Women were interviewed to obtain gynecologic and obstetric history. MAIN OUTCOME MEASURE(S): Expanded Disability Status Scale (EDSS); Multiple Sclerosis Severity Score (MSSS); annualized relapse rate; evolution to SPMS. RESULT(S): Mean±SD duration of disease was 14.3±9.8 years. Compared with non-users of COCs, COC users had lower EDSS scores and MSSS only in the subset of the population with prior or current immunomodulatory treatment. Nonuse of COCs was a predictor of disease evolution in SPMS, whether treated or not with immunomodulatory drugs. The annualized relapse rate was not influenced by COC use. No differences in EDSS scores and evolution to SPMS depending on COC formulation were detected. CONCLUSION(S): Our results suggest that COC use is associated with a less severe disease and less severe evolution. Whether different doses or types of progestin may have different effects remains to be defined.

Advances in male hormonal contraception.

Contraception is a basic human right for its role on health, quality of life and wellbeing of the woman and of the society as a whole. Since the introduction of female hormonal contraception the responsibility of family planning has always been with women. Currently there are only a few contraceptive methods available for men, but recently, men have become more interested in supporting their partners actively. Over the last few decades different trials have been performed providing important advances in the development of a safe and effective hormonal contraceptive for men. This paper summarizes some of the most recent trials.

Safety of hormonal treatment in transgenders.

PURPOSE OF REVIEW: Discussion of short and long-term issues of cross-hormone treatment of transgender individuals in the light of recent literature. RECENT FINDINGS: Gender nonconformity has been depathologized and replaced by gender dysphoria in the Diagnostic and Statistical Manual of Mental Disorders version V.Safety of cross-sex hormone treatment is still a matter of debate, but the latest findings in literature are quite reassuring about short-term and long-term effects. No dramatic changes in recommendations for treatment have emerged in the past years, and for the most part, clinical work is based on Endocrine Society Clinical Guidelines published in 2009. SUMMARY: Most recent findings agreed on the importance of maintaining cross-sex hormone serum concentration within the physiological range, avoiding or limiting maximum peaks and troughs.Treatment must be highly individualized and transitioning patients need to be engaged in a 'clinical contract' with the physician in order to ensure compliance with prescribed treatments.Although overall mortality appears to be higher among transgender individuals, this in not attributed to hormonal treatment but to other causes mostly related to lifestyle habits.

Long-term cross-sex hormone treatment is safe in transsexual subjects.

The European Journal of Endocrinology recently published a paper (Asscheman et al.) presenting mortality data from more than a thousand transsexuals followed for a median time of 18 years and who had undergone previous or were currently on long term cross-sex hormonal treatment. Transsexualism is a rare condition and in scientific literature there are few reports on the long-term safety of different treatment protocols and on the physical and psychological outcomes of medical treatments. The safety of long-term high doses oestrogen or testosterone in subjects of the opposite sex has been debated and data on long term effects are scant at best. The Asscherman paper therefore represents a very important and reassuring reference for professionals working in this field suggesting that mortality is increased among transsexuals although due to causes unrelated to cross sex replacement therapy. These results will benefit the care and treatment of these subjects.

Opioid-induced hypogonadism: why and how to treat it.

BACKGROUND: Gonadal hormones are critical factors in modulating the experience of pain, as suggested by the several sex differences observed: women have a greater risk of many clinical pain conditions, and postoperative and procedural pain may be more severe in them than in men. A growing body of literature demonstrates the role of estrogen in the female pain experience, whereas less attention has been given to testosterone and its functions. Nevertheless, testosterone has an appreciable role in both women and men: adequate serum levels are required in males and females for libido and sexuality; cellular growth; maintenance of muscle mass and bone; healing; blood-brain barrier; and for central nervous system maintenance. Pain therapy, and particularly opioid therapy, has been shown to affect testosterone plasma levels. Thus, the chronic administration of pain killers, such as opioids, requires the physician to be aware of both the consequences that can develop due to long-term testosterone impairment and the available means to restore and maintain physiological testosterone levels. OBJECTIVE: The objective is to highlight to pain physicians that the endocrine changes occurring during chronic pain therapy can participate in the body dysfunctions often present in chronic pain patients and that there are possible hormone replacement methods that can be carried out in men and women to improve their quality of life. STUDY DESIGN: A comprehensive review of the literature. METHODS: A comprehensive review of the literature relating to opioid-induced hypogonadism, as well as other very common forms of hypogonadism, its endocrine effects, and possible therapeutic actions. The literature was collected from electronic and other sources. The reviewed literature included observational studies, case reports, systematic reviews, and guidelines. OUTCOME MEASURES: Evaluation of the endocrine changes described in chronic pain therapy was the primary outcome measure. The secondary outcome measures were functional improvement and adverse effects of hormone replacement. RESULTS: The results of the survey clearly show that sex hormone determination is very rare in pain centers. Given the complexity and widespread nature of pain therapy, there is a paucity of qualitative and quantitative literature regarding its endocrine consequences. The available evidence is weak for pain relief, but is consistent for many collateral effects, possibly deriving from pain therapy, such as fatigue, depression, and neurodegenerative diseases. LIMITATION: This is a narrative review without application of methodological quality assessment criteria. Even so, there is a paucity of literature concerning both controlled and observational literature for the endocrine effects of most analgesic drugs. CONCLUSION: Testosterone replacement suffers from old prejudices about its utility and safety. With this review we illustrate the available therapeutic choices able to maintain T concentration into physiological ranges and reduce nociception with a final goal of improving patients' quality of life.

Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic.

CONTEXT: The late presentation of steroid 5α-reductase-2 (SRD5A2) deficiency in females is poorly characterised. The ratios of 5α/5ß-reduced metabolites of adrenal steroids in a urine steroid profile (USP) can give an indication of SRD5A2 deficiency, although the diagnostic cut-off for 5α/5ß ratios are not clearly defined in genetically confirmed cases. OBJECTIVE: The aim of this study was to establish the frequency of SRD5A2 deficiency in an adult clinic for disorders of sexual development (DSD) focussing on 46XY partially virilised adult female subjects. We investigated the relationship between USP results and SRD5A2 genetic sequence and determined the cut-off for USP 5α/5ß-reduced steroid ratios compared with gene sequencing for the identification of SRD5A2 deficiency. METHODS: USP and SRD5A2 genetic analyses were performed in 23 adult females, aged 19-57 years, with 46XY DSD and in four males with confirmed SRD5A2 deficiency. 5α-Reductase activity was assessed using the USP ratio of androsterone to aetiocholanolone (A/Ae), 5α-tetrahydrocortisol (5α-THF)/tetrahydrocortisol (THF) and 5α-tetrahydrocorticosterone to tetrahydrocorticosterone (5α-THB/THB). RESULTS: The SRD5A2 gene mutations were found in 10/23 (43%) females and in all four males. Totally, four novel mutations were identified. All mutation-positive subjects had A/Ae and 5α-THB/THB ratios below the lower limit of normal (100% sensitivity) while the sensitivity of 5α-THF/THF ratio was 90%. CONCLUSION: SRD5A2 deficiency is more prevalent than expected in the adult female 46XY DSD population. The clinical spectrum of this disorder may extend to a more female phenotype than previously considered to include individuals with little or no virilisation.

Long-term health issues of women with XY karyotype.

46XY women is a label that gathers together a number of different conditions for which the natural history in to adult life is still only partially known. A common feature is the difficulty that many women encounter when approaching clinicians. In this review we assemble medical, surgical and psychological literature pertaining adult 46XY women together with our experience gained from an adult DSD clinic. There is increasing awareness for the need for multidisciplinary team involving endocrinologist, gynaecology, nurse specialist and particularly clinical psychologists. Management of adult women with a 46XY karyotype includes several aspects: revising the diagnosis in those with previously incomplete workup; exploring issues of disclosure of details of the diagnosis. Surgery needs to be discussed when the gonads are still in situ and when partial virilisation of genitalia have occurred. To maintain secondary sexual characteristics, for general well being and for bone health, most women require sex steroid replacement continuously until the approximately age of 50 and it is important that the treatment is tailored on individual basis. Women should have access to advice about fertility options involving egg donation and surrogacy.

The impairment of sexual function is less distressing for menopausal than for premenopausal women.

INTRODUCTION: Menopause requires psychological and physical adjustments because of the occurring significant hormonal changes. Sexuality is one of the aspects that undergoes the most profound modifications. Preliminary data suggest that sometimes women do not regard sexual changes as problematic and often readjust their life and relationship according to their new physical status. AIM: The aim of our study was to evaluate sexual function and the way women feel by comparing healthy postmenopausal and premenopausal women. METHODS: One hundred menopausal (M) and 100 premenopausal (pM) healthy women were asked to complete anonymous questionnaires to assess sexual function and stress related to sexual activity. MAIN OUTCOME MEASURES: Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS) were completed by M and pM women. Results. Medium FSFI score was 20.5 +/- 9.6 and 26.4 +/- 7.7 (P < 0.0005) and medium FSDS score was 12.1 +/- 11.7 (95% CI 9.7-14.4) and 11.3 +/- 10.2 (P = 0.917) for M and pM women, respectively. Twenty-five of the 69 M women and 20 of the 31 pM women with a pathological score in the FSFI questionnaire scored higher than 15 in the FSDS (P < 0.0005). The overall prevalence of sexual dysfunction was 20% and 25% (P = 0.5) in the M and pM women. CONCLUSIONS: Our data confirm that menopause is associated with changes in sexual function that may be compatible with sexual dysfunction. However, personal distress caused by these changes in sexual life appears to be lower among menopausal women (36.2%) as compared with premenopausal women (64.5%). These data suggest that medical treatment for sexual health in menopause must be highly personalized and carefully prescribed.

Testosterone decreases adiponectin levels in female to male transsexuals.

AIM: To evaluate the effect of testosterone (T) on adiponectin serum levels in transsexual female patients. METHODS: We measured adiponectin, leptin, luteinizing hormone and follicle stimulating hormone, T, estradiol, lipid profile, biochemical parameters and body composition in 16 transsexual female patients at baseline and after 6 months of T treatment (100 mg Testoviron Depot /10 days, i.m.). RESULTS: Adiponectin levels were 16.9 +/- 7.3 mg/mL at baseline and 13.5 +/- 7.4 mg/mL at month 6 of T treatment (P < 0.05). Leptin and high-density lipoprotein cholesterol decreased significantly, whereas body mass index, waist circumference and lean body mass increased significantly after 6 months of T treatment. No changes in insulin or Homeostasis Model Assessment were detected. CONCLUSION: T can significantly reduce adiponectin serum levels in transsexual female patients.