Primary Gonadal Failure Research Articles

A novel homozygote nonsense variant of MSH4 leads to primary ovarian insufficiency and non-obstructive azoospermia.

Both non-obstructive azoospermia (NOA) and primary ovarian insufficiency (POI) are pathological conditions characterized by premature and frequently complete gametogenesis failure. Considering that the conserved meiosis I steps are the same between oogenesis and spermatogenesis, inherited defects in meiosis I may result in common causes for both POI and NOA. The present research is a retrospective investigation on an Iranian family with four siblings of both genders who were affected by primary gonadal failure. Proband, an individual with NOA, was subjected to clinical examination, hormonal assessment, and genetic consultation. After reviewing the medical history of other infertile members of the family, patients with NOA went through genetic investigations including karyotyping and assessment of Y chromosome microdeletions, followed by Whole exome sequencing (WES) on the proband. After analyzing WES data, the candidate variant was validated using Sanger sequencing and traced in the family. WES analysis of the proband uncovered a novel homozygote nonsense variant, namely c.118C>T in MSH4. This variant resulted in the occurrence of a premature stop codon in residue 40 of MSH4. Notably, the variant was absent in all public exome databases and in the exome data of 400 fertile Iranian individuals. Additionally, the variant was found to co-segregate with infertility in the family. It was also observed that all affected members had homozygous mutations, while their parents were heterozygous and the fertile sister had no mutant allele, corresponding to autosomal recessive inheritance. In addition, we conducted a review of variants reported so far in MSH4, as well as available clinical features related to these variants. The results show that the testicular sperm retrieval and ovarian stimulation cycles have not been successful yet. Overall, the results of this study indicate that the identification of pathogenic variants in this gene will be beneficial in selecting proper therapeutic strategies. Also, the findings of this study demonstrate that clinicians should obtain the history of other family members of the opposite sex when diagnosing for POI and/or NOA.

Development of Economic Learning Innovation Using Lectora Inspire Media on Demand and Supply Materials for Class X Muhammadiyah Senior High School 2 of Kertosono

Hypogonadism in female is one of the causes of menstrual irregularities and infertility. This clinical syndrome is characterized by decreased sex steroid secretion either due to primary gonadal failure or secondarily due to central hypothalamic-pituitary causes. In our study, it is found that patients with diabetes have primary ovarian failure with low estradiol and high FSH, LH values. [Learning media, Lectora Inspire, Computer Hardware]

How to manage puberty and prevent fertility disorders in men with CAH?

Gonadal dysfunction is an adverse outcome in patients with congenital adrenal hyperplasia (CAH), which may become apparent already during puberty. In males, gonadal dysfunction can be caused by primary gonadal failure due to testicular adrenal rest tumours (TART), and by secondary gonadal failure due to poor hormonal control. Yearly evaluation for TART using ultrasonography is recommended from the start of puberty or even earlier when poor hormonal control is present. We recommend yearly evaluation of gonadal function by measuring LH, FSH, testosterone, and inhibin B. When TART is present, cryopreservation of semen should be considered as soon as possible.

Generation of Primordial Germ Cell-like Cells from iPSCs Derived from Turner Syndrome Patients

Turner syndrome (TS) is a genetic disorder in females with X Chromosome monosomy associated with highly variable clinical features, including premature primary gonadal failure leading to ovarian dysfunction and infertility. The mechanism of development of primordial germ cells (PGCs) and their connection with ovarian failure in TS is poorly understood. An in vitro model of PGCs from TS would be beneficial for investigating genetic and epigenetic factors that influence germ cell specification. Here we investigated the potential of reprogramming peripheral mononuclear blood cells from TS women (PBMCs-TS) into iPSCs following in vitro differentiation in hPGCLCs. All hiPSCs-TS lines demonstrated pluripotency state and were capable of differentiation into three embryonic layers (ectoderm, endoderm, and mesoderm). The PGCLCs-TS recapitulated the initial germline development period regarding transcripts and protein marks, including the epigenetic profile. Overall, our results highlighted the feasibility of producing in vitro models to help the understanding of the mechanisms associated with germ cell formation in TS.

Serum prokineticin-2 in prepubertal and adult Klinefelter individuals.

The prokineticin-2 (PROK2) is a small peptide belonging to the prokineticin family. In humans and rodents this chemokine is primarily involved in the control of central and peripheral reproductive processes. Klinefelter's syndrome (KS) is the first cause of male genetic infertility, due to an extra X chromosome, which may occur with a classical karyotype (47, XXY) or mosaic forms (46, XY/47, XXY). In affected subjects, pubertal maturation usually begins at an adequate chronological age, but when development is almost complete, they display a primary gonadal failure, with early spermatogenesis damage, and later onset of testosterone insufficiency. Thus, the main aim of the present study was to investigate the serum levels of PROK2 in prepubertal and adult KS patients, comparing them with healthy subjects. We showed for the first time the presence of PROK2 in the children serum but with significant changes in KS individuals. Indeed, compared with healthy subjects characterized by PROK2 serum elevation during the growth, KS individuals showed constant serum levels during the sexual maturation phase (higher during the prepubertal phase but lower during the adult age). In conclusion, these data indicate that in KS individuals PROK2 may be considered a biomarker for investigating the SK infertility process.

Sphingosine 1- Phosphate Lyase Insufficiency Syndrome (SPLIS); A Role in Multiple Endocrinopathies

Sphingosine 1-phosphate lyase insufficiency syndrome (SPLIS) was described in 2017 as a novel condition affecting sphingolipid metabolism. There is a multisystemic phenotype including nephrotic syndrome and primary adrenal insufficiency (PAI) and to a lesser extent ichthyosis, neurological disease and lymphopenia. A proportion of patients also presented with hypothyroidism and hypogonadism. To interrogate the endocrine aspect of the syndrome we reviewed clinical data within our patient cohort with SPLIS and those within the wider literature. To date there have been 45 patients identified with SPLIS with significant associated mortality (n=23/45, 51%; 4 of these in utero). There is no clear genotype-phenotype correlation. Whilst nephrotic syndrome is most prevalent (n=34/45; 76%), a significant proportion of patients (n=27/45, 60%) also presented with glucocorticoid deficiency, some with additional mineralocorticoid deficiency (n=7/27). Five further patients were noted to have adrenal calcifications though biochemistry was not undertaken. Most patients presented with PAI in the first 2 years of life (n=21/27), with the oldest presentation being 11 years of age. Adrenal calcifications are a common finding in those who had documented imaging (n=13/15, 87%). Primary gonadal failure has been reported in 8 male cases, all with concomitant PAI. Presenting features included microphallus (n=7/8) and cryptorchidism (n=8/8), indicating reduced in utero androgen exposure. All who had biochemical evaluation demonstrated raised basal LH and FSH/ exaggerated response to LHRH stimulation, a lack of testosterone response to HCG stimulation and low antimullerian hormone (AMH) levels. To date there are no reports of pubertal delay in female patients, and those of age within our cohort have normal ovarian reserve as evidenced by AMH levels (n=2). Primary hypothyroidism, with mildly raised TSH and low Free T4 is reported in 12 patients. Most did not have goiters and had concomitant PAI and nephrotic syndrome (n=11/12). SPLIS is unique amongst sphingolipid disorders in presenting with significant endocrinopathy. This may be the consequence of the particular sphingolipid signature of the disease and the pathogenic mechanisms need to be explored further. It is clear that endocrine dysfunction needs to be considered at diagnosis and surveillance undertaken to detect evolving disease which could have a significant impact on morbidity and mortality.

Endocrine Complications in Children and Adolescents With Non-Central Nervous System Solid Tumors.

BackgroundDue to remarkable progress in cancer treatment, endocrine complications are now the major medical issues facing childhood cancer survivors. Although non-central nervous system solid tumors (NCSTs) account for approximately 40% of all pediatric cancers, there have been few studies on endocrine complications associated with NCSTs. This study investigated endocrinopathies following the treatment of pediatric NCSTs.Design and settingRetrospective study in a single academic center.MethodsThis study analyzed 253 survivors of childhood NCSTs who were diagnosed between January of 2000 and December of 2018. The medical charts were reviewed regarding the frequency of endocrinopathies and treatment modalities. The hazard ratios were assessed by multivariable Cox regression analysis. The final height-SDS were analyzed by multivariable linear regression analysis.ResultsThere were 76 patients (30%) that developed at least one endocrine complication. Forty-four patients (17.4%) experienced endocrine complications within five years of their cancer diagnosis. The most common endocrine complication was growth failure (n = 35), followed by obesity (n = 18), and primary gonadal failure (n = 16). High cumulative doses of alkylating agents increased the risk of developing at least one endocrine complication. Hematopoietic stem cell transplantation was an important risk factor for primary gonadal failure.ConclusionsThis study described the comprehensive endocrine outcomes, including growth failure, obesity, primary gonadal failure, primary hypothyroidism, dyslipidemia, and osteoporosis, following the treatment of childhood NCSTs. As endocrinopathies occurred within five years of primary tumor diagnosis, surveillance for endocrine dysfunction is required for early intervention and management.

Rare missense variant in MSH4 associated with primary gonadal failure in both 46, XX and 46, XY individuals.

Can whole-exome sequencing (WES) reveal a shared pathogenic variant responsible for primary gonadal failure in both male and female patients from a consanguineous family? Patients with primary ovarian insufficiency (POI) and non-obstructive azoospermia (NOA) were homozygous for the rare missense variant p. S754L located in the highly conserved MSH4 MutS signature motif of the ATPase domain. An oligozoospermic patient was heterozygous for the variant. MSH4 is a meiosis-specific protein expressed at a certain level in the testes and ovaries. Along with its heterodimer partner MSH5, it is responsible for double-strand Holliday junction recognition and stabilization, to ensure accurate chromosome segregation during meiosis. Knockout male and female mice for Msh4 and Msh5 are reportedly infertile due to meiotic arrest. In humans, MSH4 is associated with male and female gonadal failure, with distinct variations in the MutS domain V. This was a retrospective genetics study of a consanguineous family with multiple cases of gonadal failure in both genders. The subject family was recruited in Iran, in 2018. The proband who is affected by POI, an NOA brother, a fertile sister and their parents were subjected to WES. The discovered variant was validated in these individuals, and the rest of the family was also genotyped by Sanger sequencing. The variant was not detected in 800 healthy Iranian individuals from the Iranome database nor in 30 sporadic NOA and 30 sporadic POI patients. Suggested effect in aberrant splicing was studied by RT-PCR. Moreover, protein homology modeling was used to further investigate the amino acid substitution in silico. The discovered variant is very rare and has never been reported in the homozygous state. It occurs in the ATPase domain at Serine 754, the first residue within the highly conserved MutS signature motif, substituting it with a Leucine. All variant effect prediction tools indicated this variant as deleterious. Since the substitution occurs immediately before the Walker B motif at position 755, further investigations based on protein homology were conducted. Considering the modeling results, the nature of the substituted amino acid residue and the distances between p. S754L variation and the residues of the Walker B motif suggested the possibility of conformational changes affecting the ATPase activity of the protein. We have submitted dbSNP entry rs377712900 to ClinVar under SCV001169709, SCV001169708 and SCV001142647 for oligozoospermia, NOA and POI, respectively. Studies in model organisms can shed more light on the role of this variant as our results were obtained by variant effect prediction tools and protein homology modeling. Identification of variants in meiotic genes should improve genetic counseling for both male and female infertility. Also, as two of our NOA patients underwent testicular sperm extraction (TESE) with no success, ruling out the existence of pathogenic variants in meiotic genes in such patients prior to TESE could prove useful. This study was financially supported by Royan Institute in Tehran, Iran, and Institut Pasteur in Paris, France. The authors declare no competing interests. N/A.

MANAGEMENT OF ENDOCRINE DISEASE: Gonadal dysfunction in congenital adrenal hyperplasia.

Gonadal dysfunction is an adverse outcome in patients with congenital adrenal hyperplasia (CAH), which may become apparent already during puberty. Clinical consequences of gonadal dysfunction include menstrual disturbances in females and hypogonadism and impaired fertility in males and females. In males, gonadal dysfunction can be caused by primary gonadal failure due to testicular adrenal rest tumours (TART), and by secondary gonadal failure due to poor hormonal control. In females, gonadal dysfunction can result from an overproduction of adrenal androgens including 11-oxygenated C-19 androgens and progestins, and rarely from ovarian adrenal rest tumours. In all patients with CAH, optimal hormonal control is the key for adequate gonadal function. Therefore, regular measurements of adrenal steroids and/or their metabolites should be performed. In addition, markers of the hypothalamus-pituitary-gonadal axis need to be assessed. In females, the regularity of the menstrual cycle should be evaluated. In males, regular evaluation for TART using ultrasonography is recommended from the start of puberty or even earlier when poor hormonal control is present. When TART is present, counselling on cryopreservation of semen should be offered.

Wolfram syndrome: clinical and genetic profiling of a cohort from a tertiary care centre with characterization of the primary gonadal failure.

Wolfram syndrome (WFS) is a rare, monogenic neurodegenerative syndrome characterised by insulin requiring non-autoimmune diabetes mellitus (DM) and optic atrophy which are usually the earliest and commonest manifestations. However, there are other features which are under-recognized, adding to morbidity and premature mortality in these patients. Five patients (three males, two females) with genetically confirmed WFS at a single tertiary care centre were prospectively followed up. Their symptomatology, clinical profile, genetic analysis and radiology were analyzed. Multidisciplinary approach was used for comprehensive clinical care of this cohort. Patients with primary gonadal failure were subjected to biopsy and immunohistochemistry (IHC) for wolframin was performed. DM was the earliest presenting manifestation at 6.2 ± 1.3 years followed by optic atrophy at 10.4 ± 2.3 years, diabetes insipidus at 12 ± 2.1 years and deafness at 12.8 ± 2.1 years. All patients were autoantibody negative with low C-peptide(<0.6 ng/ml). Hypoglycemic episodes were frequent (upto 60%) but there was no instance of diabetic ketoacidosis. Optic atrophy was present alongwith proliferative diabetic retinopathy and cataract in 40%. Uncommon manifestations included neuropsychiatric features, parasuicide, cystopathy, brainstem atrophy and hypergonadotropic hypogonadism only in adult males (n = 2). Testicular biopsy revealed partly hyalinised seminiferous tubules and prominence of Leydig cells. IHC confirmed the presence of mutated wolframin, which was not significantly different from normal testis specimen on protein quantification. WFS requires a multidisciplinary approach with special emphasis on early diagnosis and management of other endocrine and non-endocrine features so as to improve long-term outcomes. Gonadal functions need periodic assessment, especially in adult males.

A case of acute hypogonadism following taipan (Oxyuranus scutellatus) envenomation

A previously well man developed acute, marked tender bilateral gynaecomastia two months after confirmed taipan (Oxyuranus scutellatus) envenomation. He had had laboratory evidence of thrombotic microangiopathy (TMA) including microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury. Scrotal ultrasound revealed bilateral testicular atrophy, his serum testosterone was repeatedly low, while his luteinising and follicle stimulating hormone were elevated. It is hypothesised that TMA-related testicular ischaemia was responsible for his primary gonadal failure and dramatic clinical presentation.

Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: 6 years of follow-up.

Background Testicular adrenal rest tumors (TARTs) leading to primary gonadal failure are the main etiology of infertility in congenital adrenal hyperplasia (CAH). We aimed at identifying the evolution of TART and related findings in young CAH patients. Methods Twelve male patients (3-23 years old) with 21-hydroxilase deficiency (11 with classic salt-wasting form) were included. Testicular ultrasonography (US) was performed in two moments, by a single blinded specialist in pediatric diagnostic imaging. Tumor progression was classified according to the Response Evaluation Criteria in Solid Tumors (RECIST). The clinical and laboratory data were retrieved from medical records. Serum 17-OH-progesterone (17OHP) and androstenedione concentrations were evaluated during the whole period of follow-up, from the CAH diagnosis. A logistic regression model with repeated measures was developed for the analysis. Results The prevalence of TART was 41.6% (n = 5) in the initial US evaluation and 66.6% (n = 8) after 6 years of follow-up. Tumor progression was detected in 4 of the 5 patients, and 1 presented with a stable tumor. Three patients presented with new tumors in the second evaluation. Most of the patients (n = 11) were pubertal, including a 7-year-old child with TART who presented with central precocious puberty. At regression analysis, it was observed that an inadequate hormonal control led to a 16 times greater chance of a patient to present with TART (OR = 16.08; confidence interval [CI] 95% = 2.38-108.81; p = 0.004). Conclusions We found a high prevalence of progressive TART in young pubertal subjects. US testicular screening should help in improving therapeutic optimization in CAH patients to reduce future impairment in fertility.

Disorders of Puberty: Pharmacotherapeutic Strategies for Management.

During puberty, with activation of the hypothalamic pituitary axis that has been quiescent since the neonatal period, linear growth accelerates, secondary sexual characteristics develop, and adult fertility potential and bone mass are achieved, together with psychosocial and emotional maturation.Disordered pubertal onset and progress, either early or late, presents frequently for endocrine care. Where a disorder is found, due either to a central hypothalamic pituitary cause or to primary gonadal failure, pharmacotherapeutic interventions are required to alter the trajectory of disturbed pubertal onset or progress and for maintenance of adolescent and adult sex hormone status. This paper describes pharmacologic interventions used for pubertal disorders but is not intended to address the diagnostic cascade in detail.

Characterization of the CYP11A1 Nonsynonymous Variant p.E314K in Children Presenting With Adrenal Insufficiency.

Cholesterol side-chain cleavage enzyme (P450scc), encoded by CYP11A1, catalyzes the first step of steroidogenesis. Complete P450scc deficiency leads to primary adrenal insufficiency (PAI) and 46,XY disordered sexual development. Partial impairment can cause variable adrenal and gonadal dysfunction. Our aim was to evaluate the effects of the CYP11A1 variant p.E314K, identified in patients with PAI, specifically on P450scc enzyme stability and function. We studied four boys from two unrelated families presenting with PAI during childhood (3.6 to 9 years old). All patients were compound heterozygous for c.940G>A (p.E314K), a CYP11A1 nonsynonymous variant likely to be pathogenic by some but not all in silico prediction models, and c.835delA (p.I79Yfs*10), a known pathogenic variant. HEK293T cells were transfected with wild type (WT) and p.E314K mutant vectors, and a cycloheximide chase assay was performed to analyze protein stability. Pregnenolone production was assayed from cells expressing WT and p.E314K-F2 fusion proteins. Two boys experienced spontaneous puberty but then developed evidence of primary gonadal failure at 14 and 18 years old. Two boys had testicular adrenal rest tumor (TART), detected by ultrasound at ages 8.6 and 16 years. Compared with WT, mutant protein synthesis was reduced (P = 0.0006) with increased protein turnover, and mutant P450scc half-life was decreased by ~50%. p.E314K mutant P450scc retained 60% of WT enzymatic activity (P = 0.007). The CYP11A1 p.E314K variant impairs P450scc stability and is a possible cause of PAI in childhood. Pathogenic CYP11A1 variants potentially affect both adrenal and gonadal function, and male patients may develop TART.

Endocrine and Metabolic Disturbances in Survivors of Hematopoietic Stem Cell Transplantation in Childhood and Adolescence

Background/Aims: The objective was to evaluate endocrine complications in survivors of hematopoietic stem cell transplantation (HSCT) performed during childhood. Methods: Endocrine dysfunction and metabolic syndrome parameters were assessed by chart review of 178 childhood HSCT survivors (median age at evaluation, 15.5 [range: 3.8–29.8] years; median follow-up, 8.5 [range: 2–23.4] years). Results: The following statistically significant associations were identified (p < 0.05 for all): growth hormone deficiency (17.4%) was associated with cranial/craniospinal irradiation, total body irradiation (TBI), allogeneic HSCT, and longer follow-up. Short adult stature (23.3% of patients who had attained adult height) was associated with cranial/craniospinal irradiation and, in females, with younger age at HSCT. Primary gonadal failure was more prevalent in females (52.6 vs. 24.1%), and was associated with TBI in males and with a primary diagnosis of hematological malignancy in females. Hypothyroidism (25.2%) was associated with previous neck/mediastinal irradiation. Metabolic disturbances included obesity (3.9%), type 2 diabetes (2.2%), impaired glucose tolerance (2.8%), and dyslipidemia (18.5%). Dyslipidemia was associated with a primary diagnosis of hematological malignancy, TBI, and a positive family history of dyslipidemia. Endocrine dysfunction was less frequent in patients who had received fludarabine. Conclusions: Patients after HSCT require long-term surveillance for the detection of endocrine and metabolic disorders. Nonmyeloablative conditioning regimens may reduce the incidence of these complications.

Outcome of linear growth and onset of menarche following therapy in children with Turner syndrome followed up at a tertiary care referral centre: An interim report from Sri Lanka

Introduction: Short stature and primary gonadal failure are characteristic features of Turner Syndrome (TS). Both these aspects need to be addressed in the care of these patients for a satisfactory outcome. This is the first report from Sri Lanka documenting the short term outcome on linear growth and puberty following treatment with growth hormone (GH) and hormone replacement therapy (HRT). Method: A prospective analysis was done on 20 patients from a cohort of patients with TS followed up at the University Paediatric Unit at the Lady Ridgeway Hospital, Colombo. An interviewer-administered questionnaire was used to record the relevant information including details and outcome of treatment with GH and HRT. Ethics Review Committee of the Faculty of Medicine, University of Colombo approved the study. Results: Thirteen (65%) patients had a 45, X karyotype. Their mean (SD) age at presentation was 10.06 (2.83) years with a range of 3.16 to 13.58 years. Their heights at presentation were all th percentile on the TS specific growth chart and ranged from 84.0 to 129.8 cm with a mean (SD) of 113.6 (12.13) cm. Growth hormone (n=20) and HRT (n=14) were started at mean (SD) ages of 10.19 (2.72) and 13.41 (1.13) years respectively. Time to menarche after HRT in 9 patients ranged from 0.42 to 2 years with a mean (SD) of 1.26 (0.46) years. The gain in height with GH alone (n=12) was 3.5 to 26.4 cm and at the time of reporting at a mean (SD) age of 13.89 (2.86) years the heights of 7 patients were ≥75 th percentile on the TS specific growth chart. Conclusion: A satisfactory response to GH therapy was observed despite the mean (SD) age of presentation being 10.06 (2.83) years and thus initiating definitive therapy at a mean (SD) age of 10.19 (2.72) years. Sri Lanka Journal of Child Health , 2017; 46 : 55-58

Gonadal function is associated with cardiometabolic health in pre-pubertal boys with Klinefelter syndrome.

The most common sex chromosome aneuploidy, Klinefelter syndrome (KS), is associated with primary gonadal failure and increased morbidity and mortality from cardiometabolic disorders in adulthood. Children with KS also have a high prevalence of metabolic syndrome (MetS) features. To assess the relationship of gonadal and cardiometabolic function in children with KS, we evaluated serum hormones [gonadotropins, inhibin B (INHB), anti-mullerian hormone (AMH), total testosterone (TT)], and features of MetS (waist circumference, fasting lipid panel, fasting blood glucose (FBG), and blood pressure) in 93 pre-pubertal boys with KS age 4-12years (mean 7.7±2.5years). The cohort was grouped by age and tanner stage, and biomarkers were compared to normal ranges. A total of 80% of this pre-pubertal cohort had ≥1 feature of metabolic syndrome (MetS) and 11% had ≥3 features of MetS. Risk of MetS was independent of age and body mass index. Sertoli cell dysfunction was common with 18% having an INHB below the normal range. A low INHB was associated with higher FBG, triglycerides, LDL, and lower HDL (p<0.05). An INHB <50ng/dL yielded a sensitivity of 83% and a specificity of 79% for having ≥3 features of MetS. INHB and AMH positively correlated with each other (p<0.001), and high AMH was protective of MetS. TT was below the lower limit of normal in 49% of subjects, with mean values significantly lower than expected (3.3ng/dL vs. 4.9ng/dL, p<0.0001), however, no convincing relationship between TT and MetS was seen. In conclusion, gonadal and cardiometabolic dysfunction are prevalent in pre-pubertal boys with KS. Although the relationship of testosterone deficiency and MetS is well-known, this study is the first to report an association between impaired Sertoli cell function and cardiometabolic risk.

Estradiol: micrograms or milligrams

SummaryEstrogen is used to induce puberty in peripubertal girls with hypogonadism. Although both synthetic and natural forms are available, along with different routes of administration, in the UK oral ethinyl estradiol and the low-dose oral contraceptive pill are commonly used as hormone replacement therapy for practical reasons. We present five peripubertal girls (aged 12.5–14.9 years) with hypogonadism (two with primary hypogonadism due to Turner syndrome and three with central (secondary) hypogonadism as part of multiple pituitary hormone deficiency) who for a variety of reasons have received milligram doses of estradiol (E2) in error for between 6 weeks and 6 months, instead of the expected microgram doses of ethinyl estradiol. Although there are no direct comparisons in peripubertal girls between synthetic and natural estrogens, all girls had vaginal bleeding whilst receiving the milligram doses and have ended up with reduced final heights, below the 9th centile in 1 and below the 2nd centile in 4. Whilst reduction in final height may be part of the underlying condition (especially in Turner syndrome) the two girls with height predictions performed prior to receiving the estrogen overdose have not achieved their predicted height. Estrogen is one of the few drugs which is available in both milligram and microgram formulations. Clinicians need to be alert to the possibility of patients receiving the wrong formulation and dosage in error.Learning pointsGirls with primary and secondary gonadal failure require assistance with pubertal induction.Although several different formulations and route of administration are available, for practical reasons, the majority of girls in the UK receive oral ethinyl estradiol.Estrogen preparations are available in both milligram and microgram formulations, with potential for receiving the wrong dose.Girls receiving milligram rather than microgram preparations all had vaginal bleeding and a short final height.

Primordial germ cells (PGCs) derived from patients with turner syndrome and Klinefelter syndrome offer insight to the mechanism of premature gonadal failure

Premature primary gonadal failure is the hallmark of Turner (TS) and Klinefelter syndromes (KS). However, the mechanism of germ cell exhaustion in these patients is unknown. We aim to investigate this mechanism by examining primordial germ cells (PGCs) generated from patients with these syndromes.

Insulinoma Presenting with Long-Standing Depression, Primary Hypogonadism, and Sertoli Cell Only Syndrome

The aim was to report an unusual case of insulinoma presenting with long-standing depression and primary testicular failure. We describe a 34-year-old male with clinical, laboratory, and radiologic data consistent with islet cell tumor and seminiferous tubule failure primary hypogonadism. The literature is reviewed relative to the component of this syndrome, and a possible association is discussed. The subject was investigated for a long-standing history of depression requiring medical attention because of mental confusion and slurred speech and was found to have an insulinoma. He was diagnosed with primary gonadal failure and physical examination showed no evidence of dysmorphic features. Chromosomal analysis revealed normal 46 XY and testicular biopsy showed Sertoli cell only syndrome (SCOS). Biochemistry revealed endogenous hyperinsulinism and histology confirmed an islet cell tumor. He remained euglycemic postoperatively and on followup. From this report, we emphasize drawing clinicians' attention to the possibility of an association between insulinoma and primary testicular failure and suggest consideration of this diagnosis in patients with hypergonadotropic hypogonadism who may present with infertility.