Metabolic effects of estradiol versus testosterone in complete androgen insensitivity syndrome.

PURPOSE: To study differences in metabolic outcomes between testosterone and estradiol replacement in probands with complete androgen insensitivity syndrome (CAIS). METHODS: In this multicentre, double-blind, randomized crossover trial, 26 women with CAIS were included of whom 17 completed the study. After a two-months run in phase with estradiol, probands either received transdermal estradiol followed by crossover to transdermal testosterone or vice versa. After six months, differences in lipids, fasting glucose, insulin, hematocrit, liver parameters and blood pressure between the treatment phases were investigated. RESULTS: Linear mixed models adjusted for period and sequence did not reveal major group differences according to treatment for the investigated outcomes. In each treatment group, there were however significant uniform changes in BMI and cholesterol. BMI increased significantly, following six months of estradiol ( + 2.7%; p = 0.036) as well as testosterone treatment ( + 2.8%; p = 0.036). There was also a significant increase in total ( + 10.4%; p = 0.001) and LDL-cholesterol ( + 29.2%; p = 0.049) and a decrease in HDL-cholesterol (-15.8%; p < 0.001) following six months of estradiol as well as six months of testosterone treatment (total cholesterol: + 14.6%; p = 0.008; LDL-cholesterol: + 39.1%; p = 0.005, HDL-cholesterol: -15.8%; p = 0.004). Other parameters remained unchanged. CONCLUSION: Transdermal estradiol as well as testosterone treatment in women with CAIS results in worsening in lipid profiles. Given the relatively small sample size, subtle group differences in other metabolic parameters may have remained undetected.

Pubertal development in 46,XY patients with NR5A1 mutations.

PURPOSE: Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age. METHODS: We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition. RESULTS: Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty. CONCLUSION: Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.

Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a multicentre, randomised, double-dummy, double-blind crossover trial.

BACKGROUND: Women with complete androgen insensitivity syndrome (CAIS) after gonadectomy have complained about reduced psychological wellbeing and sexual satisfaction. The aim of this study was to compare the effectiveness of hormone-replacement therapy with either androgen or oestrogen in women with 46,XY karyotype and CAIS after gonadectomy. METHODS: This national, multicentre, double-blind, randomised crossover trial was performed at three university medical centres and three specialised treatment institutions in Germany. Eligible participants were women aged 18-54 years with 46,XY karyotype, genetically diagnosed CAIS, and removed gonads. Participants were randomly assigned (14:12) by a central computer-based minimisation method to either oestradiol 1·5 mg/day for 6 months followed by crossover to testosterone 50 mg/day for 6 months (sequence A) or to testosterone 50 mg/day for 6 months followed by crossover to oestradiol 1·5 mg/day for 6 months (sequence B). Participants also received oestradiol or testosterone dummy to avoid identification of the active substance. All participants received oestradiol 1·5 mg/day during a 2 months' run-in phase. The primary outcome was mental health-related quality of life, as measured with the standardised German version of the SF-36 questionnaire. Secondary outcomes were psychological wellbeing, as measured with the Brief Symptom Inventory (BSI), sexual function, as measured with the Female Sexual Function Index (FSFI), and somatic effects, such as signs of virilisation and effects on metabolic blood values. The primary analysis included all patients who were available at least until visit 5, even if protocol violations occurred. The safety analysis included all patients who received at least oestradiol during the run-in phase. This trial is registered with the German Clinical Trials Register, number DRKS00003136, and with the European Clinical Trials Database, number 2010-021790-37. FINDINGS: We enrolled 26 patients into the study, with the first patient enrolled on Nov 7, 2011, and the last patient leaving the study on Jan 23, 2016. 14 patients were assigned to sequence A and 12 were assigned to sequence B. Ten participants were withdrawn from the study, two of whom attended at least five visits and so could be included in the primary analysis. Mental health-related quality of life did not differ between treatment groups (linear mixed model, p=0·794), nor did BSI scores for psychological wellbeing (global severity index, p=0·638; positive symptom distress index, p=0·378; positive symptom total, p=0·570). For the FSFI, testosterone was superior to oestradiol only in improving sexual desire (linear mixed model, p=0·018). No virilisation was observed, and gonadotrophin concentrations remained stable in both treatment groups. Oestradiol and testosterone concentrations changed substantially during the study in both treatment groups. 28 adverse events were reported for patients receiving oestradiol (23 grade 1 and five grade 2), and 38 adverse events were reported for patients receiving testosterone (34 grade 1, three grade 2, and one grade 3). One serious adverse event (fibrous mastopathy) and 20 adverse events (16 grade 1 and four grade 2) were reported during the run-in phase, and 12 adverse events during follow-up (nine grade 1 and three grade 2). INTERPRETATION: Testosterone was well tolerated and as safe as oestrogen for hormone-replacement therapy. Testosterone can be an alternative hormone substitution in CAIS, especially for woment with reduced sexual functioning. FUNDING: German Federal Ministry of Education and Research.

Quality of health care in adolescents and adults with disorders/differences of sex development (DSD) in six European countries (dsd-LIFE).

BACKGROUND: To investigate the association between the structural quality of care and patient satisfaction with care in individuals with disorders/ differences of sex development (DSD). METHODS: A multicenter cross-sectional comparative study was conducted in 14 clinics in six European countries. We assessed the level of structural quality of care in each center using a self-constructed measure (Center Score) and the level of participant satisfaction with care using the customer satisfaction questionnaire (CSQ-4) and an adopted version of the Youth Health Care - Satisfaction, Utilization & Needs (YHC-SUN-SF). Data were obtained from individuals with Turner Syndrome (261), Klinefelter Syndrome (173), 46, XX congenital adrenal hyperplasia (190) and XY-DSD (257). RESULTS: We found large variations between the scores for structural quality of care both within a diagnostic group and within a country; the overall association between participant satisfaction with the center score was significant. CONCLUSIONS: Comparative effectiveness research across Europe can lead to more insight on beneficial structures and processes and the overall strategy to care for people with rare diseases in general and specific conditions such as disorders/ differences of sex development. Appreciation of higher levels of structural quality of the centers in this study supports the concept of comprehensive care. TRIAL REGISTRATION: German Clinical Trials Register: Registration identification number: DRKS00006072 , date of registration April 17th, 2014. DRKS00006072 (German Clinical Trials Register).

Endoscopy and Laparoscopy in Disorders of Sex Development.

Endoscopy and laparoscopy are used for the assessment of disorders of sex development (DSD) and therapeutic interventions. Endoscopy (urethra-cystoscopy, vaginoscopy) is especially useful when vaginal or urethral surgery is planned. It is also valuable for the assessment of complications. Laparoscopy is used to identify sex ducts and gonads and to perform minimally invasive abdominal and pelvic surgery. This article reviews clinical indications, limitations, findings, and their reporting. It further discusses the impact of these findings on care in typical clinical situations.

Pubertal Development in17Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency
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BACKGROUND: 17ß-hydroxysteroid dehydrogenase (17ß-HSD) type 3 deficiency is an autosomal recessive disorder with diminished testosterone synthesis and consequently underandrogenisation. 46,XY patients with 17ß-HSD type 3 deficiency are often assigned a female sex at birth but have a high virilisation potential at the time of puberty. METHODS: We studied four 46,XY patients with 17ß-HSD type 3 deficiency at puberty with regard to the underlying mutations, the hormone values, and the clinical findings. RESULTS: Three patients were initially assigned a female sex and 1 was assigned a male sex. All had relevant mutations in the HSD17B3 gene. The 2 patients with deleterious mutations had lower testosterone values at the time of puberty than the patients with possible residual activity of 17ß-HSD type 3. One of the latter patients changed to male gender. CONCLUSION: All 4 patients with 17ß-HSD type 3 deficiency synthesized relevant amounts (>0.7 µg/L) of testosterone at puberty, which lead to variable androgenisation. In patients with presumable residual activity of the mutated enzyme, testosterone values in the male reference range can be achieved, thereby inducing male pubertal development. These patients should possibly be assigned a male sex. Any surgical intervention should be avoided until the patients are old enough to consider their options of medical and surgical intervention.
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46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome Sequencing.

BACKGROUND: 46,XY disorders of sex development (DSD) comprise a heterogeneous group of congenital conditions. Mutations in a variety of genes can affect gonadal development or androgen biosynthesis/action and thereby influence the development of the internal and external genital organs. OBJECTIVE: The objective of the study was to identify the genetic cause in two 46,XY sisters of a consanguineous family with DSD and gonadal tumor formation. METHODS: We used a next-generation sequencing approach by exome sequencing. Electrophysiological and high-resolution ultrasound examination of peripheral nerves as well as histopathological examination of the gonads were performed. RESULTS: We identified a novel homozygous R124Q mutation in the desert hedgehog gene (DHH), which alters a conserved residue among the three mammalian Hedgehog ligands sonic hedgehog, Indian hedgehog, and desert hedgehog. No other relevant mutations in DSD-related genes were encountered. The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in more dysgenetic parts of the gonad. In addition, both patients suffer from a polyneuropathy. High-resolution ultrasound revealed a structural change of peripheral nerve structure that fits well to a minifascicle formation of peripheral nerves. CONCLUSION: Mutations in DHH play a role in 46,XY gonadal dysgenesis and are associated with seminoma formation and a neuropathy with minifascicle formation. Gonadal dysgenesis in these cases may be due to impairment of Sertoli cell-Leydig cell interaction during gonadal development.

Sex hormone replacement in disorders of sex development.

People with disorders of sex development (DSD) may have impaired sex steroid production or their gonads removed before, during or after adolescence, thus requiring hormone replacement therapy (HRT) to induce puberty and/or maintain secondary sexual characteristics, to optimize bone health, and to promote physical and social well-being. Oestrogens are usually used for this purpose in persons reared as females (eventually combined with progestins if a uterus is present) and androgens in those reared as males. An alternative therapy for women with ascertained complete androgen insensitivity syndrome could be testosterone, because this is the main sex steroid hormone secreted by their gonads, but this approach remains to be better explored. Few sound evidence-based data are available to guide HRT administration at puberty and in adulthood in individuals with DSD, but recent data and new formulations may give better perspectives for the future.

Management of disorders of sex development.

The medical term disorders of sex development (DSDs) is used to describe individuals with an atypical composition of chromosomal, gonadal and phenotypic sex, which leads to differences in the development of the urogenital tract and reproductive system. A variety of genetic factors have been identified that affect sex development during gonadal differentiation or in specific disorders associated with altered androgen biosynthesis or action. The diagnosis of DSDs in individuals and the subsequent management of patients and their families requires a targeted and structured approach, involving a multidisciplinary team with effective communication between the disciplines. This approach includes distinct clinical, imaging, laboratory and genetic evaluations of patients with DSDs. Although treatment of patients with DSDs can include endocrine and surgical options, many patients have concerns that arise from past incorrect treatments that were founded on the traditional binary concept of the sexes. To dispel these concerns, it is necessary to create centres of expertise for DSDs that include physicians, surgeons, psychologists and specialists in diagnostic procedures to manage patients and their families. Additionally, the inclusion of trained peer support in the multidisciplinary DSD team seems to be integral to the supportive management of patients with DSDs. Most importantly, dealing with DSDs requires acceptance of the fact that deviation from the traditional definitions of gender is not necessarily pathologic.