Fertility and pregnancy outcomes in women with Turner syndrome: A single centre experience.

OBJECTIVE: Many women with Turner syndrome (TS) will consider fertility options and pregnancy. We wished to examine the fertility and pregnancy outcomes in women with TS undergoing oocyte donation (OD) treatment or spontaneous pregnancy in a large single-centre cohort. General population reference data or data from those with idiopathic premature ovarian insufficiency were used as comparators. DESIGN: A retrospective single-centre cross-sectional study. PATIENTS AND MEASUREMENTS: Seventy-four women with TS underwent OD treatment with a total of 105 pregnancies, and 31 women with TS had 71 spontaneous conceptions. Fertility outcomes included clinical pregnancy and live birth rate. Pregnancy outcomes included miscarriage rate, prevalence of hypertension, gestational diabetes, lower segment caesarean section (LSCS), small for gestational age (SGA), prematurity and vertical transmission of TS. RESULTS: In those with TS, OD pregnancies were associated with increased rates of LSCS and SGA compared to spontaneous pregnancies; LSCS (OR: 4.19, 95% CI: 1.6-10.8, p = .003) and SGA (OR: 2.92, 95% CI: 1.02-8.38, p = .04). There were no recorded cardiac events but 5 (17.2%) cases of vertical transmissions of TS in daughters were identified. OD in those with TS was associated with a lower live birth rate per cycle started (OR: 0.53, 95% CI: 0.34-0.84, p = .008) and a higher rate of miscarriage compared to women with POI (40% vs. 26.2%, p = .04). CONCLUSIONS: We show that pregnancy in women with TS, whether OD or spontaneously conceived, carries obstetric risks, and therefore, women with TS, considering pregnancy, should receive comprehensive pre-pregnancy counselling and optimal obstetric care.

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.

PURPOSE: XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. METHODS: We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS. RESULTS: Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10-10). Five variants are de novo (P value = 1.5 × 10-5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. CONCLUSION: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.

Relationship and sexual experiences in women with early-onset oestrogen deficiency: Comparison between women with Turner syndrome and premature ovarian insufficiency.

OBJECTIVE: 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). DESIGN: Cross-sectional observational study. PATIENTS: 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). MEASUREMENTS: A self-reporting questionnaire was used to collect data on relationship and sexual experiences. RESULTS: 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). CONCLUSIONS: 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.

A critical assessment of case reports describing absent uterus in subjects with oestrogen deficiency.

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.

Reduced uterine volume after induction of puberty in women with hypogonadism.

OBJECTIVE: 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. DESIGN: This is a single-centre, retrospective, cross-sectional study of women who underwent pubertal induction compared with a reference group. PATIENTS: 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. MEASUREMENTS: 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. RESULTS: 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 FCR >1, 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. CONCLUSION: 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.

Establishing reproductive potential and advances in fertility preservation techniques for XY individuals with differences in sex development.

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, 17ß-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.

Fracture rate in women with oestrogen deficiency - Comparison of Turner syndrome and premature ovarian insufficiency.

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.

Bone mineral density in complete androgen insensitivity syndrome and the timing of gonadectomy.

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% confidence interval); T-score -1.34 (-1.55 to -1.13; P<.001) at the lumbar spine and -0.3 (-0.49 to -0.12; P=.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<.001), but was normal at the hip; T-score -0.04 (-0.35 to 0.28; P=.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 (1.7-12.8) 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.

The Turner syndrome life course project: Karyotype-phenotype analyses across the lifespan.

INTRODUCTION: Turner syndrome (TS) 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 AND METHODS: Karyotypes were available in 656 women with TS. 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 comorbidities, initiation of formal treatment was recorded. RESULTS: 45,X/46,XX had considerably lower frequency of comorbidities 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 comorbidity 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 comorbidities.

Experience in optimizing fertility outcomes in men with congenital adrenal hyperplasia due to 21 hydroxylase deficiency.

OBJECTIVE: Men with congenital adrenal hyperplasia (CAH) have impaired fertility. We aimed to assess fertility outcomes and the importance of hypogonadotropic hypogonadism, testicular failure and the presence of testicular adrenal rest tumours (TART). DESIGN: Retrospective analysis of men attending an adult CAH clinic in a tertiary centre. PATIENTS: Fifty men with CAH due to 21 hydroxylase deficiency were identified of whom 35 were salt wasting and 15 were non-salt-wasting. MEASUREMENTS: Review of fertility history and parameters including luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione, 17-hydroxyprogesterone (17-OHP), semen analysis and the presence of testicular adrenal rest tissue (TART) on ultrasound. RESULTS: TART were detected by ultrasound in 21 (47%), and their presence was associated with an elevated FSH (P = 0·01). Severe oligospermia was present in 11 of 23 (48%), and this was associated with an elevated FSH (P = 0·02), suppressed LH (P < 0·01) and TART (P = 0·03) when compared to those with a sperm count >5 × 10(6) per ml. Of those that desired fertility, 10 of 17 (59%) required treatment intensification and four underwent in vitro fertilization. Intensification resulted in a rise in median LH (0·6-4·3 IU/l; P = 0·01). Live birth rate was 15 of 17 (88%) with a median (range) time to conception of 8 (0-38) months. CONCLUSIONS: Suppressed LH is a marker for subfertility and is often reversible. Testicular failure is closely associated with TART formation. If TART are detected, sperm cryopreservation should be offered given the risk of progression to irreversible testicular failure. Male fertility in CAH can be improved by intensified treatment and assisted reproductive technology.

Characterization of Turner Syndrome-associated diabetes mellitus.

CONTEXT: Diabetes mellitus (DM) risk factors in Turner Syndrome (TS) may include autoimmunity, obesity, beta-cell dysfunction, genetic predisposition and insulin resistance (IR). OBJECTIVE: Evaluate glucose tolerance and DM risk factors in adults with TS. DESIGN: A single centre study with two phases. To determine the prevalence of DM and to assess diabetes risk markers comparing women with TS with and without impaired glucose tolerance (IGT). SETTING: Tertiary referral center, University College Hospitals. PATIENTS: 106 Women with TS (age range 18-70 years) undergoing annual health surveillance. INTERVENTIONS: Participants underwent oral glucose tolerance tests (OGTT), with additional samples for autoimmunity and genetic analysis. MAIN OUTCOME MEASURE: Glucose tolerance, insulin, autoimmune and single nucleotide polymorphism (SNP) profile. RESULTS: OGTT screening showed that those without a previous DM diagnosis, 72.7% had normal glucose tolerance, 19.5% had IGT, and 7.6% were newly diagnosed with DM. OGTT identified more cases of DM than HbAc1 sampling alone. Women with IGT or DM were older, with higher body mass index and IR. No association was found between autoimmune markers GAD, IA-2 and ZnT8, risk karyotypes or selected SNPs and DM. In DM cases, GAD positivity was associated with requirement for insulin therapy. The median age of onset of the diagnosis of DM was 36 years (range 11-56). CONCLUSIONS: In the spectrum of DM subtypes, TS-associated DM lies between type 1 and type 2 DM with features of both. Key factors include weight and IR. Assessing C-peptide or GAD antibodies may aid future insulin requirement.

A conserved NR5A1-responsive enhancer regulates SRY in testis-determination.

The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of SRY is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer is required for appropriate SRY expression to initiate testis-determination in humans. Comparative sequence analysis of SRY 5' regions in mammals identified an evolutionary conserved SF-1/NR5A1-binding motif within a 250 bp region of open chromatin located 5 kilobases upstream of the SRY transcription start site. Genomic analysis of 46,XY individuals with disrupted testis-determination, including a large multigenerational family, identified unique single-base substitutions of highly conserved residues within the SF-1/NR5A1-binding element. In silico modelling and in vitro assays demonstrate the enhancer properties of the NR5A1 motif. Deletion of this hemizygous element by genome-editing, in a novel in vitro cellular model recapitulating human Sertoli cell formation, resulted in a significant reduction in expression of SRY. Therefore, human NR5A1 acts as a regulatory switch between testis and ovary development by upregulating SRY expression, a role that may predate the eutherian radiation. We show that disruption of an enhancer can phenocopy variants in the coding regions of SRY that cause human testis dysgenesis. Since disease causing variants in enhancers are currently rare, the regulation of gene expression in testis-determination offers a paradigm to define enhancer activity in a key developmental process.

Evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome.

PURPOSE: To evaluate the magnetic resonance (MR) imaging appearance of the testes in women with complete androgen insensitivity syndrome (CAIS), including any benign or malignant changes. MATERIALS AND METHODS: This was a retrospective review of the testicular MR images and histologic reports from 25 patients with CAIS who chose to retain their testes beyond age 16 years and who were imaged between January 2004 and December 2010. Ethical approval was obtained, and informed consent was obtained from each subject to review the medical records, images, and histologic slides and reports. Imaging and histologic findings were compared. RESULTS: Twelve patients (mean age, 24 years; age range, 18-39 years) retained their testes and 13 (mean age, 22 years; age range, 17-37 years) eventually underwent gonadectomy. Review of the MR images showed that testicular parenchyma was heterogeneous in 30 of 46 testes (65%). The most common changes on MR images included simple-looking paratesticular cysts (34 of 46 testes, 74%) and low-signal-intensity, well-defined Sertoli cell adenomas (26 of 46 testes, 56%). Correlation of the histologic and MR imaging findings showed that MR imaging could correctly depict the presence or absence of Sertoli cell adenomas in 19 of 23 testes (83%). Paratesticular cysts were correctly detected in 22 of 23 testes (96%). Microscopic examination showed that the testes were composed of atrophic seminiferous tubules, whereas germ cells were found in 13 of 26 testes (50%). All paratesticular cysts were confirmed to be benign; however, a focus of intratubular germ cell neoplasia was found in a Sertoli cell adenoma. Premalignant foci were detected in three patients, two with intratubular germ cell neoplasia and one with sex cord tumor with annular tubules. No invasive cancers were found. CONCLUSION: MR imaging is accurate in the detection of testicular changes, including paratesticular cysts and Sertoli cell adenomas. Although these changes are usually benign, Sertoli adenomas can sometimes harbor premalignant lesions. MR imaging cannot depict premalignant changes; therefore, the standard of care for patients with CAIS should remain gonadectomy after puberty.

Analysis of genetic variability in Turner syndrome linked to long-term clinical features.

Background: Women with Turner syndrome (TS) (45,X and related karyotypes) have an increased prevalence of conditions such as diabetes mellitus, obesity, hypothyroidism, autoimmunity, hypertension, and congenital cardiovascular anomalies (CCA). Whilst the risk of developing these co-morbidities may be partly related to haploinsufficiency of key genes on the X chromosome, other mechanisms may be involved. Improving our understanding of underlying processes is important to develop personalized approaches to management. Objective: We investigated whether: 1) global genetic variability differs in women with TS, which might contribute to co-morbidities; 2) common variants in X genes - on the background of haploinsufficiency - are associated with phenotype (a "two-hit" hypothesis); 3) the previously reported association of autosomal TIMP3 variants with CCA can be replicated. Methods: Whole exome sequencing was undertaken in leukocyte DNA from 134 adult women with TS and compared to 46,XX controls (n=23), 46,XX women with primary ovarian insufficiency (n=101), and 46,XY controls (n=11). 1) Variability in autosomal and X chromosome genes was analyzed for all individuals; 2) the relation between common X chromosome variants and the long-term phenotypes listed above was investigated in a subgroup of women with monosomy X; 3) TIMP3 variance was investigated in relation to CCA. Results: Standard filtering identified 6,457,085 autosomal variants and 126,335 X chromosome variants for the entire cohort, whereas a somatic variant pipeline identified 16,223 autosomal and 477 X chromosome changes. 1) Overall exome variability of autosomal genes was similar in women with TS and control/comparison groups, whereas X chromosome variants were proportionate to the complement of X chromosome material; 2) when adjusted for multiple comparisons, no X chromosome gene/variants were strongly enriched in monosomy X women with key phenotypes compared to monosomy X women without these conditions, although several variants of interest emerged; 3) an association between TIMP3 22:32857305:C-T and CCA was found (CCA 13.6%; non-CCA 3.4%, p<0.02). Conclusions: Women with TS do not have an excess of genetic variability in exome analysis. No obvious X-chromosome variants driving phenotype were found, but several possible genes/variants of interest emerged. A reported association between autosomal TIMP3 variance and congenital cardiac anomalies was replicated.

Quantification of the adverse effect of ethinylestradiol containing oral contraceptive pills when used in conjunction with growth hormone replacement in routine practice.

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.

Timing of gonadectomy in adult women with complete androgen insensitivity syndrome (CAIS): patient preferences and clinical evidence.

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.

Premature ovarian insufficiency.

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.

Management of a Girl With Delayed Puberty and Elevated Gonadotropins.

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.

ZSWIM7 Is Associated With Human Female Meiosis and Familial Primary Ovarian Insufficiency.

BACKGROUND: Primary 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. OBJECTIVE: We aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree. METHODS: Genome 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. RESULTS: Only 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 CONCLUSIONS: Disruption 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.