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The natural lifespan of the ovary is occasionally interrupted by pathological processes; some are known, but many are unknown. Premature ovarian insufficiency (POI) can be a devastating diagnosis for an adolescent or for someone who has yet to start a family. Common causes of POI include genetic and chromosomal defects, autoimmune damage, and cancer treatments. Knowledge of the pathogenesis of this condition and an awareness of contemporary hormone replacement and fertility options are required to design a multidisciplinary therapeutic approach comprising reproductive medicine, endocrinology, clinical psychology, and assisted fertility expertise.

A girl presenting with delayed puberty and elevated gonadotropins may have a range of conditions such as Turner syndrome (TS), primary ovarian insufficiency (POI), and 46,XY disorders of sexual development (DSD). An organized and measured approach to investigation can help reach a timely diagnosis. Management of young people often requires specialist multidisciplinary input to address the endocrine and nonendocrine features of these complex conditions, as well as the psychological challenges posed by their diagnosis. Next-generation sequencing within the research setting has revealed several genetic causes of POI and 46,XY DSD, which may further facilitate an individualized approach to care of these young people in the future. Pubertal induction is required in many and the timing of this may need to be balanced with other issues specific to the condition (eg, allowing time for information-sharing in 46,XY DSD, optimizing growth in TS). Shared decision-making and sign-posting to relevant support groups from the outset can help empower young people and their families to manage these conditions. We describe 3 clinical vignettes of girls presenting with delayed puberty and hypergonadotropic amenorrhea and discuss their clinical management in the context of current literature and guidelines.

Age at first date and sexual intercourse have been observed to be delayed in women with Turner syndrome (TS), with delayed puberty being the main factor. We sought to assess relationship and sexual experiences comparing women with TS and premature ovarian insufficiency (POI).Cross-sectional observational study.302 women with TS and 53 women with karyotypically normal POI (median age 33.0 [15.0-78.4] and 26.3 [17.8-52.3], respectively).A self-reporting questionnaire was used to collect data on relationship and sexual experiences.Women with TS were older than women with POI (P = .002). Compared to women with POI, a smaller proportion of women with TS had ever had vaginal sexual intercourse (VSI) (40 [78.4%] vs 169 [58.1%], respectively, P = .006) and women with TS exhibited a delay in the median age at first relationship and VSI (POI 19.3 ± 0.4 vs TS 22.2 ± 1.1, P = .001). Start of oestrogen replacement therapy at ≤ 14 years of age compared with 14 years did not result in earlier relationship and sexual debut. After adjusting for age and diagnosis, induction of puberty, as opposed to spontaneous puberty, was associated with a delay in the median age at first relationship and VSI and a reduced probability of having VSI (Hazard ratio = 0.44 [95% confidence interval: 0.32-0.60], P = .001).Turner syndrome and induction of puberty are associated with a reduced likelihood and a delay in relationship and sexual experiences. Women needing puberty induction and women with TS more than POI have a delayed mean age at first VSI compared to the general population.

The natural lifespan of the ovary is occasionally interrupted by pathological processes, some known but many unknown. Premature ovarian insufficiency (POI) may be caused by genetic and chromosomal defects, autoimmune damage, and cancer treatments. POI can be a devastating diagnosis for a teenager or for someone who has yet to start a family. Knowledge of the pathogenesis of the condition, as well as treatment options in terms of hormones and assisted fertility require a multidisciplinary team comprising reproductive medicine, endocrinology, clinical psychology, and specialists in assisted conception. Premature ovarian failure is a complex condition that requires specialist services. The diagnostic work-up is aimed at determined the aetiology where possible and is followed by a screen for syndromic conditions. Oestrogen replacement and fertility options need to be reassessed at intervals and clinicians have to be vigilant for psychological sequelae.

Objective Women with early-onset oestrogen deficiency are at risk of reduced bone mineral density (BMD). We sought to assess fracture history and BMD in women with Turner syndrome (TS) and premature ovarian insufficiency (POI). Design A cross-sectional observational study. Patients Two hundred and sixty seven women with TS (median age 34.3 years) and 67 women with POI (median age 28.1 years). Measurements A questionnaire was used to collect data on fracture history, co-morbidities and drug history including age at first oestrogen exposure. Clinical data included height, weight, serum vitamin D and hip and spine T-scores, which were adjusted for height and age. Fractures were subdivided into major osteoporotic fractures (MOF) and 'other' fracture types. Results Overall fracture rate was similar in women with TS and POI (82 [30.5%] vs 22 [32.8%] respectively, P = .74). Compared to women with POI, those with TS had more fractures at MOF sites (30.2% vs 52.7%, P = .012) and fewer phalangeal fractures (27.9% vs 9.8%, P = .005). There was no difference in BMD between women who sustained a fracture compared to those who did not. Women with TS who fractured were more likely to suffer from hearing impairment compared to those with no fracture (62.2% vs 48.1%, P = .045). Conclusions TS is not associated with an overall excess risk of bone fracture. The higher rate of fractures at MOF sites in women with TS may be secondary to hearing impairment, thin cortical bone and abnormal bone remodelling.

Objective To study the effects of increasingly prosperous diet content on clinical features of polycystic ovary syndrome (PCOS). Design A cross-sectional cohort study of 711 women with PCOS from a heterogeneous population spanning a wide spectrum of socioeconomic strata. Setting Independent hospital. Patient(s) A total of 711 women with PCOS in whom the diagnosis was based on Rotterdam criteria. Results were compared with a locally recruited reference group. Intervention(s) Clinical assessment of women with PCOS. Main Outcome Measure(s) Clinical characteristics were assessed with particular reference to diet composition. Four diet groups were identified: simple rice with vegetables, vegetarian with mixed carbohydrates, nonvegetarian with mixed carbohydrates, and an urban diet of processed foods. Result(s) Women with PCOS showed the characteristic features of raised LH and androstenedione concentrations and increased ovarian volume and antral follicle count. There was a notable association between an increasingly affluent diet, the presence of hirsutism, raised body mass index, insulin resistance, and higher serum antimullerian hormone concentrations. The positive association between antimullerian hormone and body mass index is an unusual feature possibly explained by the wide spectrum of lifestyles in this cohort. Conclusion(s) Urbanization of women in India is associated with increasingly severe phenotype of PCOS, which is likely to have implications on fertility outcomes.

Study Objective To summarize the self-reported sexual experiences of women with vaginal agenesis before treatment and discuss the clinical implications. Design A retrospective review of pretreatment baseline sexuality data and medical records of women with vaginal agenesis seeking vaginal construction. Setting A specialist multidisciplinary center for women with genital differences associated with diverse sex development. Participants One hundred thirty-seven women with untreated vaginal agenesis associated with Mayer-Rokitansky-Kuster-Hauser Syndrome and complete androgen insensitivity syndrome aged 15 to 41 years (mean age, 20 years). Interventions Gynecological examination and completion of questionnaires. Main Outcome Measures (1) Sexual Experiences Questionnaire; (2) Multidimensional Sexuality Questionnaire; (3) Vaginal Self-Perceptions; and (4) vaginal length. Results A sizable proportion of women reported having had sexually intimate experiences before any medical intervention on the vagina. Vaginal length, which ranged from dimple to 7 cm and averaged 2.7 cm for the cohort, was unrelated to the range of sexual experiences. Most women perceived their vagina as being too small, but less than half believed that a sexual partner would notice this. Two-thirds of the cohort subsequently completed the dilation program, which was not predicted by pretreatment vaginal length or sexual experience. Conclusion Contrary to the assumption that a vagina of certain dimensions is a prerequisite for women to “have sex,” many women with Mayer-Rokitansky-Kuster-Hauser syndrome and complete androgen insensitivity syndrome reported having experienced genital and nongenital sexual activities with no medical interventions. It is recommended that treatment providers affirm women's capacity for sexual intimacy, relationships, and enjoyment before they introduce the topic of vaginal construction as a non-urgent choice.

Objective: The dual diagnosis of hypoplastic uterus in association with ovarian dysgenesis is regularly reported but the pathogenesis of the association is unclear. The uterus, however, may be invisible to all imaging modalities without at least six months of exogenous oestrogen exposure in complete ovarian failure. We assessed all available case reports in this category to estimate whether the apparent association between primary ovarian insufficiency or Turner syndrome and Mullerian agenesis can be largely accounted for by oestrogen deficiency. Design: A literature review of all cases in which an association between ovarian insufficiency or Turner syndrome and hypoplastic uterus has been reported. Patients: PubMed was searched for all case reports associated with relevant key terms. In total, 22 publications with a total of 25 patients were identified and reviewed; 14 subjects had the normal female karyotype (46,XX), and 11 subjects had Turner Syndrome. Measurements: Proportion of subjects who had been exposed to adequate oestrogen prior to the absent uterine diagnosis. Results: A diagnosis of absent uterus was made prior to exposure to exogenous oestrogen in 22/25 (88%) of subjects with primary hypogonadism including 14/14 females with normal karyotype and 8/11 females with Turner syndrome. Conclusions: Oestrogen deficiency is a possible explanation for most subjects being reported as having Mullerian agenesis in association with Turner syndrome or primary ovarian insufficiency. In the presence of oestrogen deficiency, no conclusion can be made about the status of the uterus until adequate exposure to exogenous oestrogen has been completed and we suggest reassessment of the uterus when full adult dose has been reached towards the end of induction of puberty.

BackgroundPrimary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. A genetic cause for POI can be found in up to 30% of women, elucidating key roles for these genes in human ovary development.ObjectiveWe aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree.MethodsGenome sequencing and variant filtering using an autosomal recessive model was performed in the 2 affected sisters and their unaffected family members. Quantitative reverse transcriptase PCR (qRT-PCR) and RNA sequencing were used to study the expression of key genes at critical stages of human fetal gonad development (Carnegie Stage 22/23, 9 weeks post conception (wpc), 11 wpc, 15/16 wpc, 19/20 wpc) and in adult tissue.ResultsOnly 1 homozygous variant cosegregating with the POI phenotype was found: a single nucleotide substitution in zinc finger SWIM-type containing 7 (ZSWIM7), NM_001042697.2: c.173C > G; resulting in predicted loss-of-function p.(Ser58*). qRT-PCR demonstrated higher expression of ZSWIM7 in the 15/16 wpc ovary compared with testis, corresponding to peak meiosis in the fetal ovary. RNA sequencing of fetal gonad samples showed that ZSWIM7 has a similar temporal expression profile in the developing ovary to other homologous recombination genes.Main conclusionsDisruption of ZSWIM7 is associated with POI in humans. ZSWIM7 is likely to be important for human homologous recombination; these findings expand the range of genes associated with POI in women.

Objective To review the treatment choices of women with complete androgen insensitivity syndrome (CAIS) at a single tertiary centre. Design Retrospective review. Patients Women with CAIS identified from our database. Results The study group comprised 141 women with CAIS. Eleven percent (16/141) of women had gonads in situ, 3 of whom were under workup for gonadectomy. The age of gonadectomy in the remainder 125 women was 17 (0.1–53) years. The most common form of HRT was oral oestrogen or transdermal oestrogen in 80% (113/141). 13/141 (9%) women used vaginal oestrogens alone or together with other forms of HRT. Testosterone preparations had been used by 17% (24/141) of women and were currently used in 10% (14/141). Of those who had used testosterone, 42% (10/24) had chosen not to continue after a therapeutic trial. Conclusions In a clinic offering individualised multidisciplinary care for women with CAIS, we found that the majority of women chose oestrogen-based treatment while a significant minority used testosterone.

Introduction Turner Syndrome is associated with a variety of morbidities affecting nearly every body system, some of which increase in prevalence in adult life. The severity of clinical features in TS is roughly in parallel with the magnitude of the deficit of X chromosome material. The aim of this study was to extend the established karyotype phenotype relationships using data from a large adult cohort. Materials & Methods Karyotypes were available in 656 (78.1%), 611 of whom could be classified into five major groups within the cohort: 45,X; 45,X mosaicism (45,X/46,XX); isochromosome X (isochromosome Xq); mosaicism 45,X/46,XY and ring X. Continuous variables such as blood pressure and biochemical markers from clinic data were binarised allocating those in the upper quartile to represent at- risk individuals. With the exception of bone mineral density T- score for which the lower quartile was allocated as at risk. For co-morbidities, initiation of formal treatment was recorded. Results 45,X/46,XX had considerably lower incidences of co-morbidities compared to 45,X. The isochromosome group experienced similar outcomes to 45,X. Novel associations were found between the XY mosaic karyotype group and a decreased prevalence of thyroid disease and severe hearing loss. A previously unreported increased incidence of metabolic syndrome was noted within the ring chromosome subgroup. Conclusions Karyotype may play an important factor against stratifying risk of co-morbidity in TS and should be taken into consideration when managing adults with TS. Further investigations of the isochromosome (Xq) and ring groups are necessary to further clarify their associations with co-morbidities. This article is protected by copyright. All rights reserved.

Objective Low bone mineral density (BMD) has been reported in complete androgen insensitivity syndrome (CAIS), but the impact of timing of gonadectomy is not known. We aimed to assess the relationship between age of gonadectomy and BMD in women with CAIS. Design Retrospective analysis of pre- and post-gonadectomy parameters in women with CAIS attending an adult Disorders of Sex Development (DSD) clinic in a tertiary centre. Patients One hundred and thirteen women with CAIS. Measurements Dual-energy x-ray absorptiometry (DXA) before and after gonadectomy; and pre-gonadectomy hormone profile. Results Mean BMD was reduced (95%CI); T-score -1.34 (-1.55 to -1.13; P < 0.001) at the lumbar spine and -0.3 (-0.49 to -0.12; P = 0.001) at the hip. There was no relationship between age of gonadectomy and BMD. Thirty-two subjects had BMD measured before or within 2 years of gonadectomy, and mean BMD was reduced (95%CI) at the lumbar spine; T-score: -1.05 (-1.54 to -0.57; P < 0.001), but was normal at the hip; T-score -0.04 (-0.35 to 0.28; P = 0.8). There was no relationship between BMD and history of hernia, testosterone, oestradiol or follicle stimulating hormone levels. Twelve subjects had DXA both before and after gonadectomy, and after 4.3 (1.7 to 12.8) years there was no change in BMD. Conclusions We found reduced BMD at the spine and hip in subjects with CAIS. We found no relationship between age of gonadectomy and BMD, and we also found no drop in BMD in subjects followed up after gonadectomy. This article is protected by copyright. All rights reserved.

Increasingly, mitochondria are being recognized as having an important role in fertility. Indeed in assisted reproductive technologies mitochondrial function is a key indicator of sperm and oocyte quality. Here, we review the literature regarding mitochondrial genetics and infertility. In many multisystem disorders caused by mitochondrial dysfunction death occurs prior to sexual maturity, or the clinical features are so severe that infertility may be underreported. Interestingly, many of the genes linked to mitochondrial dysfunction and infertility have roles in the maintenance of mitochondrial DNA or in mitochondrial translation. Studies on populations with genetically uncharacterized infertility have highlighted an association with mitochondrial DNA deletions, whether this is causative or indicative of poor functioning mitochondria requires further examination. Studies on the impact of mitochondrial DNA variants present conflicting data but highlight POLG as a particularly interesting candidate gene for both male and female infertility.

Adequate uterine growth is an essential component of pubertal induction with exogenous oestradiol in those with hypogonadism. Poor uterine development will render the individual vulnerable in the context of fertility. We assessed uterine size using ultrasound in those who had undergone pubertal induction treatment compared with a reference group who had experienced spontaneous puberty.This is a single-centre, retrospective, cross-sectional study of women who underwent pubertal induction compared with a reference group.Ninety-five women with hypogonadism who had previously undergone pubertal induction and were receiving maintenance oestrogen replacement as adults were recruited: 48 women with Turner syndrome, 32 with premature ovarian insufficiency and 15 with gonadotrophin deficiency. The reference group consisted of 35 nulliparous women attending with male factor subfertility with a normal pelvis on ultrasonography.Pelvic ultrasound was performed by a single observer. Uterine dimensions (total length, anterior-posterior (AP), transverse, uterine volume and fundal cervical AP ratio (FCR) measurements) were recorded. Clinical details were also recorded.Those with hypogonadism had significantly reduced uterine dimensions compared with the reference group (uterine length 64 mm vs 71 mm P = .05, uterine volume 28.9 mL vs 43.9 mL P = .05). All women in the reference group attained a mature uterine configuration with a FCR1, compared with 84% of those with hypogonadism (P = .01). A total of 24% and 48% of the diagnostic group had total uterine length and uterine volume measurements less than the 5th percentile of the reference group, respectively. In a subgroup of 22 women in whom serum oestradiol concentrations could be analysed, there was a positive correlation between this parameter and uterine volume.Despite standard oestrogen therapy, uterine growth is often compromised in those with hypogonadism. Uterine health has historically been overlooked in pubertal induction protocols; however, with increasing options for fertility treatment, adequate uterine development is crucial. Given the variation in uterine size witnessed, a more tailored approach to treatment with regular monitoring of uterine dimensions should be advocated.

Menopause and the years preceding it are associated with a wide variety of symptoms that are often missed in a routine consultation. Informed choice regarding hormone replacement therapy and lifestyle options can alleviate much of the burden of the menopause when this change in life has a major impact on well-being. Premature ovarian insufficiency is one of the most difficult conditions in reproductive medicine. It occurs in 1% of women. The impact of the diagnosis can dissipate with time assisted by full evaluation and discussion of the implications of POI. The role of the nurse includes assessment of symptoms, discussion of implications for fertility as well as assisted fertility treatment options and then to give guidance through choices of sex steroid replacement. Ongoing education is required in order to adapt the level of information and types of treatment according to life circumstances. Women with ovarian insufficiency frequently feel isolated or that there is insufficient time in a clinic visit for full discussion. Nursing input can overcome some of these limitations.

Background Discordance between gonadal type and gender identity has often led to an assumption of infertility in patients with differences in sex development (DSD). However, there is now greater recognition of fertility being an important issue for this group of patients. Currently, gonadal tissue that may have fertility potential is not being stored for individuals with DSD and, where gonadectomy forms part of management, is often discarded. The area of fertility preservation has been predominantly driven by oncofertility which is a field dedicated to preserving the fertility of patients undergoing gonadotoxic cancer treatment. The use of fertility preservation techniques could be expanded to include individuals with DSD where functioning gonads are present. Methods This is a systematic literature review evaluating original research articles and relevant reviews between 1974 and 2018 addressing DSD and fertility, in vitro maturation of sperm, and histological/ultrastructural assessment of gonadal tissue in complete and partial androgen insensitivity syndrome, 17β‐hydroxysteroid dehydrogenase type 3 and 5α‐reductase deficiency. Conclusion Successful clinical outcomes of ovarian tissue cryopreservation are paving the way for similar research being conducted using testicular tissue and sperm. There have been promising results from both animal and human studies leading to cryopreservation of testicular tissue now being offered to boys prior to cancer treatment. Although data are limited, there is evidence to suggest the presence of reproductive potential in the gonads of some individuals with DSD. Larger, more detailed studies are required, but if these continue to be encouraging, individuals with DSD should be given the same information, opportunities and access to fertility preservation as other patient groups.

Context Turner syndrome (TS) is often associated with delayed puberty. To induce puberty, estrogen is administered in incremental doses at an age determined by age of presentation. After puberty, various types of maintenance estrogen replacement therapy (ERT) are used. Objective We sought associations between age of induction of puberty and type of ERT on adult health outcomes. Design Health surveillance data included blood profiles, bone density, and blood pressure. We assessed interactions between these data and age at first estrogen exposure in women with primary amenorrhea. We also assessed these data according to ERT subgroups [combined oral contraceptive pill (OCP), oral estrogen (OE), and transdermal estradiol (TE)] using data from each of 6679 clinic visits, controlling for age, body mass index, and height. Setting Adult TS clinic at University College London Hospital. Patients Of 799 women with TS, 624 had primary amenorrhea and 599 had accurate maintenance ERT data. Main outcome measures Parameters of health surveillance derived from clinical guidelines. Results Estrogen start age was negatively correlated with adult bone density (spine: r = -0.20 and hip: r = -0.022; P ≤ 0.001). OCP users had higher blood pressure and an adverse lipid profile compared with other ERT subgroups. TE was associated with elevated liver enzymes and hemoglobin A1c compared with OE (P ≤ 0.01). Conclusions An earlier age of induction of puberty may be beneficial for adult bone density. Given the high prevalence of hypertension in TS, the use of OCP for ERT should be limited. OE may be a benefit for steatohepatitis.

Objective To study the safety and efficacy of ovarian stimulation and oocyte cryopreservation as a method of fertility preservation in women with Turner syndrome (TS). Design Retrospective cohort study. Setting Reproductive medicine clinic. Patient(s) Seven women with TS who attended the clinic between 2011 and 2017. Intervention(s) Ovarian stimulation and oocyte cryopreservation. Main Outcomes Measure(s) Number of oocytes cryopreserved, ovarian hyperstimulation syndrome. Result(s) The oocyte retrieval rates (mean ± SD, 9 ± 3.16) in women with TS were comparable to the published data from healthy women. The oocyte yield was higher than expected based on the low antimullerian hormone levels. There was no correlation between baseline antimullerian hormone or antral follicle count levels and the number of oocytes retrieved. Conclusion(s) Oocyte cryopreservation after ovarian stimulation appears to be safe and successful in women with mosaic TS who wish to consider fertility preservation.

Adrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood- and urine-derived cells through forced expression of Steroidogenic Factor-1 and activation of PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes and secreted steroid hormones in response to stimuli. hiSCs successfully engrafted into the mouse kidney capsule and underwent intra-adrenal differentiation. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications to study adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies.

Background Phaeochromocytomas and paragangliomas arise from the same chromaffin cell, but evidence suggests they do not represent a single clinical entity. The aim of this study was to compare clinical presentations, outcomes of surgical and oncological treatments and survival in patients with phaeochromocytomas and paragangliomas. Methods A retrospective review was undertaken of all patients treated for these conditions at our centre between 1983 and 2012. Results One hundred and six patients (88 adults, 18 children) with phaeochromocytoma (n = 83) or paraganglioma (n = 23) were studied. Catecholamine symptoms and incidentalomas were the main presentations in phaeochromocytoma patients (67% and 17%) respectively, but in those with paragangliomas pain (39%) was more common (P

Context and objectiveThe precise diagnosis of partially virilised women with 46,XY disorders of sex development (DSD) is often obscure. In practice, this group often comes under the poorly defined, clinically based label of partial androgen insensitivity syndrome (PAIS). In a previous study, we found that 5α-reductase 2 (SRD5A2) mutations occurred in 43% of women in this subgroup. We expand this work to include biochemical and genetic screening for 17β-hydroxysteroid dehydrogenase (HSD17B3) and androgen receptor (AR) mutations.MethodsAnalysis of serum androgens (androstenedione and testosterone) and genetic analyses for HSD17B3 and AR were performed in 42 women from 36 pedigrees with partially virilised 46,XY DSD in whom SRD5A2 deficiency had been excluded by urine steroid profiling.ResultsOut of 36 unrelated women, 14 (38%) were found to have HSD17B3 mutations and one (2.7%) to have an AR defect. Six novel pathogenic HSD17B3 mutations were identified: three splice site mutations and three missense changes. Seven patients with HSD17B3 deficiency tested before gonadectomy had basal testosterone/androstenedione (T/A) ratio ConclusionsHSD17B3 deficiency is prevalent in the adolescent and adult 46,XY female DSD population and is often associated with lesser degrees of virilisation compared with those with 5α-reductase deficiency. This diagnosis should be considered for individuals labelled as PAIS, particularly, but not exclusively, those who present with virilisation at puberty or primary amenorrhoea. Before gondadectomy, T/A ratio is useful to aid diagnosis, but after gonadectomy sequencing of HSD17B3 must be performed to confirm the diagnosis.

Treatment of congenital adrenal hyperplasia (CAH) in childhood focuses on growth and development and adult final height (FH) is a measure of effective treatment. We hypothesized that shorter adults will have more severe underlying disease and worse health outcomes.This was a cross-sectional analysis of 199 adults with CAH. FH and quality of life were expressed as z-scores adjusted for midparental target height or UK population height.FH correlated inversely with age (men, r = -0.38; women, r = -0.26, P.01). Men and women had z-scores adjusted for midparental target height of -2 and -1, respectively, and both groups had UK population height z-scores of -1 below the UK population (P.01). In women, FH was shorter in non-salt-wasting than salt-wasting classic CAH (P.05) and in moderately affected genotype group B women than either more severely affected groups null and A (P.01) or the mildest group C (P.001). Short stature and a higher prevalence of hypertension were observed in classic CAH patients diagnosed late (after 1 y) compared with those diagnosed early and in women treated with glucocorticoid only compared with those treated with both glucocorticoids and mineralocorticoids (P.05). FH did not associate with insulin sensitivity, lipid profile, adiposity, or quality of life.Adult CAH patients remain short, although height prognosis has improved over time. The shortest adults are those diagnosed late with moderate severity CAH and are at increased risk of adult hypertension; we hypothesize that these patients are exposed in childhood to high androgens and/or excessive glucocorticoids with potential programming of hypertension. Another possibility is inadequate mineralocorticoid treatment early in life in the late-diagnosed patient group. Prospective studies are now required to examine these hypotheses.

Background: Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes. Objectives: This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317. Design: This was a randomized, double-blind, placebo-controlled, single ascending dose study. Patients: Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo). Setting: The study was conducted in 17 adult endocrinology centers in North America and Europe. Main Outcome Measures: Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed. Results: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3–5.0 μg/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between −1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed. Conclusions: The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing.

OBJECTIVE: Adult women with complete androgen insensitivity syndrome (CAIS) are increasingly likely to defer or decline gonadectomy despite counselling about malignancy risk. The objectives of this study were to review the evidence on the risk of gonadal malignancy in adult women with CAIS and to explore women's reasons for deferring gonadectomy. STUDY DESIGN: A case series and literature review. PATIENTS: Sixteen women with CAIS over the age of 18 years who have elected to defer gonadectomy. RESULTS: Sixty-two relevant papers were identified. Of these, 14 confirmed that tumours had been reported in 98 adults. Taking into account the limitations of combining historic case series, this review estimates a risk of gonadal malignancy of 14% (range 0% and 22%) in adults with CAIS. The most common reasons women offered for deferring gonadectomy included inconvenience of surgery, concern about surgical risk and reluctance to take hormone replacement therapy. CONCLUSIONS: Perceived benefits for retaining gonads in women with CAIS are prompting more women to keep their gonads in situ. An accurate estimate for adult malignancy risk is unavailable, and the risks currently quoted may be falsely reassuring.

Summary Objective Oestrogen antagonizes the action of growth hormone (GH). For women with combined GH and oestrogen deficiency, transdermal oestradiol is more favourable in this regard compared to oral oestradiol. Oral contraceptive pills containing ethinylestradiol (EE) are commonly used in young women with GHD and there is little information on the impact of this form of oestrogen. Design A case note review of women with growth hormone deficiency (GHD) attending a tertiary endocrine clinic comparing the dose of GH and serum insulin-like growth factor 1 concentrations and the type of exogenous oestrogen. Methods All women with GHD between the ages of 18 and 47 attending University College London Hospitals (UCLH) were included and grouped according to type of oestrogen replacement. Weight, GH dose and serum IGF-I concentrations were recorded at 121 visits in 88 women. Results The daily dose of GH was significantly higher and the GH responsivity was significantly lower in the EE group compared to those taking no oestrogen and transdermal oestrogen. The additional cost of GH for women using EE compared to transdermal oestradiol was £6016 per patient per year. Effectiveness of GH improved in all women changing from EE to another form of oestrogen. Conclusion Use of oral contraceptive pills containing EE should be avoided in women receiving treatment with GH. Alternative options include oral or transdermal hormone replacement therapy (HRT) preparations for those that require oestrogen replacement or a progesterone-based regimen for contraceptive purposes.

Highlights ► Lin28 proteins regulate micro RNAs and are implicated in germ cell development. ► We assessed LIN28A and LIN28B in the early human ovary and testis. ► Expression of LIN28A increases in the developing ovary between 6 and 9 weeks conception. ► Expression of LIN28B was lower and did not change. ► Alterations in LIN28A were not found in women with primary ovarian insufficiency., Lin28 proteins are emerging as important regulators of microRNAs in endocrine systems. Lin28a regulates primordial germ cell development and puberty timing in mice, whereas the related protein LIN28B is associated with age at menarche in genome-wide association studies in humans. Here, we studied expression of LIN28A and LIN28B in early human gonad development. LIN28A increased in the developing ovary between 6 and 9 weeks post conception, but not in the developing testis. Immunohistochemistry demonstrated LIN28A in peripheral germ cells. LIN28B was expressed at lower levels in both tissues and did not increase with time. As disruption of Lin28a affects germ cell development in mice, LIN28A was considered a candidate gene for primary ovarian insufficiency (POI) in humans. However, no significant changes were found in 50 women studied. These findings show LIN28A is strongly expressed in germ cells during early human ovary development, but disruption of LIN28A is not a common cause of POI.

Objective Polycystic ovary syndrome (PCOS) is associated with dyslipidaemia and obesity. It is not clear whether the dyslipidaemia of PCOS is attributable to PCOS itself, obesity, or a combination of both. Our objective was to assess the importance of familial dyslipidaemia in PCOS by comparing fasting lipids between probands and their (affected and nonaffected) sisters. Design Retrospective data set analyses. Patients Family study; 157 probands, 214 sisters and 76 control women (normal ovaries and regular cycles). All probands had PCOS, defined by symptoms of anovulation and/or hyperandrogenism with polycystic ovaries on ultrasound. Affected or unaffected status of sisters was defined by ovarian morphology. Measurements Serum concentrations of triglycerides, total cholesterol, high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol. Results Triglyceride levels and body mass index (BMI) were higher and HDL cholesterol levels were lower in the probands than affected sisters, unaffected sisters and controls. These differences in lipid profiles between the groups disappeared after adjustment for BMI. No differences in lipids were seen between affected and unaffected sisters. Conclusions These data are consistent with heritability of lipid levels in sisters but strongly suggest that the predominant influence on the manifestation of dyslipidaemia in PCOS is body weight.

Objective To collect information on clinical concerns relating to adolescent girls with disorders of sex development (DSD) during the process of transition from paediatric-to-adult clinical services. Subjects and methods This was a prospective audit of the clinical indications for referral and on-going clinical needs for all girls aged 12–20 years seen in a specialist DSD clinic over a 6-month period. Clinical needs were classified according to level of urgency using a simple ‘traffic light’ classification: green for low, amber for moderate, and red for high. Results Fifty girls were seen during the study period and all were referred from paediatric services. Patients may have had one or more indication(s) for referral to the adult clinic and these were: urology/gynaecology (70%), endocrinology (42%) and psychology (14%). The most common indication for on-going clinical input was psychology, with 46% of patients requiring monitoring and intervention. Of the 14 patients (28%) classified red suggesting they had an urgent clinical need, psychology was a major factor in all but one patient. Conclusion Clinicians working with adolescents with DSD need to develop a co-ordinated programme for transitional care that recognises the importance of psychological input within the multi-disciplinary team.

Within endocrinology, the long-term management of Turner syndrome (TS) in adults is fast becoming a specialist subject in its own right. The complications of TS can affect every system in the body, and the main reason why it falls to endocrinologists to coordinate health care is that many features are clearly within the endocrine remit: hypothyroidism, diabetes, hypertension, osteoporosis, hypogonadism. Endocrinologists as general physicians can often cover surveillance of problems in other areas such as congenital heart disease, inflammatory bowel disease and deafness, calling upon specialist input only if the need arises. In this way, a simple 'one stop shop' can offer a well-woman service for women with TS in a cost-effective manner. Such a service requires a multidisciplinary approach.

Background: it is recognized that FMR1 premutation expansions are associated with premature ovarian failure (POF), but the role of smaller repeats at the boundary of premutation and normal is less clear. Methods: we have therefore investigated the incidence of these intermediate sized FMR1 CGG repeats (35–58 repeats) in a series of 366 women ascertained because of menopause before the age of 40. Results: we found no significant difference in the incidence of intermediates in cases compared with controls. Thus, we were unable to replicate previous studies showing a positive association, despite a significantly larger sample size. Conclusions: we therefore conclude that intermediate sized FMR1 CGG repeat alleles should not be considered a high-risk factor for POF based on current evidence

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.

Turner syndrome (TS) is a model for X chromosome influences on neurodevelopment because it is most commonly caused by absence of one X chromosome and associated with altered brain structure and function. However, all prior in vivo magnetic resonance imaging studies of the brain in TS have either used manual approaches or voxel-based morphometry (VBM) to measure cortical volume (CV). These methods, unlike surface-based morphometry (SBM), cannot measure the two neurobiologically distinct determinants of CV- cortical thickness (CT) and surface area (SA) - which have differing genetic determinants and may be independently altered. Therefore, in 24 adults with X monosomy and 19 healthy female controls, we used SBM to compare (i) lobar CV, CT and SA; (ii) an index of hemispheric gyrification; (iii) CT throughout the cortical sheet; and (iv) CT correlation between cortical regions. Compared to controls, females with TS had (i) significantly increased CT and decreased SA in parietal and occipital lobes (resulting in no significant difference in lobar CV); (ii) reduced hemispheric gyrification bilaterally; (iii) foci of significantly increased CT involving inferior temporal, lateral occipital, intraparietal sulcus (IPS), cingulate and orbitofrontal cortices; and (iv) significantly reduced CT correlation between the left IPS and cortical regions including supramarginal and lateral occipital gyri. Our findings suggest that females with TS have complex, sometimes "opposing", abnormalities in SA/gyrification (decreased) and CT (increased), which can result in no overall detectable differences in CV. Thus, haploinsufficiency of X chromosome genes, may differentially impact the distinct mechanisms shaping SA (e.g. cortical folding) and CT (e.g. dendritic arborization/pruning). CT disruptions are maximal within and between cortical regions previously implicated in the TS cognitive phenotype.