Elevated FSH Research Articles

6597 An Unusual Case of Klinefelter Syndrome with Both Primary and Superimposed Secondary Hypogonadism

Abstract Disclosure: A. Krueger: None. E. Pelley: None. Introduction: Klinefelter syndrome (KS) (47, XXY) is a sex-chromosome disorder that is a common cause of infertility and hypogonadism in men. Clinical phenotype includes tall stature, delayed or incomplete puberty, small testes (<4ml), gynecomastia, and oligo or azoospermia. The extra X chromosome leads to fibrosis and hyalinization of seminiferous tubules resulting in impaired sperm production. Leydig cells also function abnormally and fail to stimulate with LH. Common biochemical evaluation results in low serum testosterone, elevated FSH and LH concentrations, and azoospermia. Case Report: 37-year-old male presented with long standing history of low libido and a perception that he had never fully progressed through puberty. Physical exam was notable for a height of 6’ 4”, obesity, fine pubic and axillary hair, and testes <4mL bilaterally. Initial biochemical work up revealed low serum total testosterone 43 (ref 300-1080 ng/dL), low free testosterone 8.1 (ref 47-244 pg/mL), inappropriately normal LH 10.8 (ref 0.6-12.1 mlU/mL), and elevated FSH 28.3 (ref 1.0-12.0 mlU/mL). Patient was referred to Endocrinology. Labs were repeated with consistent results in addition to chromosome analysis which confirmed diagnosis of Klinefelter syndrome with (47, XXY) karyotype. Due to inappropriately normal LH and mixed picture of primary and superimposed secondary hypogonadism, an MRI of the pituitary was obtained and revealed an 8mm x7mm x 14mm pituitary macroadenoma. Evaluation for pituitary hypersecretion and other deficiencies was unremarkable. Conclusion: Data from the Danish National registry shows that only 25% of Klinefelter patients are correctly diagnosed. Klinefelter syndrome should be considered in the differential for the evaluation of hypogonadism and infertility. Diagnosis can be made by karyotyping. The degree of impaired spermatogenesis and testosterone production in Klinefelter syndrome can be variable. Biochemical evaluation should be interpreted in conjunction with clinical context. Patients with known causes of primary hypogonadism who demonstrate an inappropriate gonadotropin response require evaluation for causes of secondary hypogonadism. In this case, the inappropriately normal LH was the sole clue leading to the identification of his pituitary macroadenoma. Presentation: 6/1/2024

8577 Gonadal function throughout life in XX and XY patients with a germline WT1 variant - lessons from a cohort of 80 patients

Abstract Disclosure: M. Carré Lecoindre: None. D. Mallet: None. C. Dossier: None. M. Glenisson: None. M. Grapin: None. A. Brac de la Perriere: None. Z. Chakhtoura: None. C. Bouvattier: None. M. Houang: None. C. Pienkowski: None. N. Zaegel: None. R. Rayneau,MD and PhD: None. T. Blanc: None. L. Martinerie: None. The WT1 gene is involved in tissue homeostasis, tumorigenesis, as well as embryonic development of kidneys, bipotential gonads and ovarian determinism. Germline WT1 variants are known to generate kidney and gonadal developmental diseases associated with differences in genital development (DSD). However, the state of gonadal function, its evolution over time, and the impact of WT1 variants on pubertal development and fertility potential in patients have never been studied. A French national, retrospective, multi-center, observational study evaluated gonadal function over time in patients with a germline variant of the WT1 gene, according to XX or XY karyotype and genotype. Among the 80 patients included - the largest cohort to date - 30% had a XX karyotype, 95% of whom were assigned female at birth. Importantly, 40% of them had uterine malformation, which was not known to be associated with WT1 anomalies. Patients with a XY karyotype presented with DSD (59%), typical female genitalia (15%) or typical male genitalia with or without bilateral cryptorchidism (27%). Thirty percent of XX and 87% of XY patients had gonadal dysgenesis defined as gonads with a dysplastic and/or dysmorphic appearance on histology, surgery and/or imaging or biological hormonal markers compatible with gonadal insufficiency. However only 3 patients (4%) developed gonadal tumors to date. Spontaneous puberty was observed in 94% of XX and 60% of XY patients. However, 67% had impaired gonadal function - defined as AMH and/or inhibin B below the threshold for age and/or elevated FSH and/or LH above 10 UI/L - at the age of 12.6 years and 83% at the age of 16.2 years, considering all karyotypes and genotypes. Hormonal treatment had to be initiated in 57% of XY patients with a median age at 14.4 years old. No difference was seen between patients with or without renal failure (p-value = 0,37), nor regarding the timing of renal insufficiency. In addition, increased FSH, LH and decreased AMH or inhibin B plasma levels were observed independently from gonadotoxic treatment exposure in most patients. None of the patient has had children to date.In conclusion, most XX and XY patients with a germline variant of WT1 gene are affected by early gonadal insufficiency of variable severity with potential impact on puberty and fertility. Even though dialysis, immunosuppressors, gonadotoxic chemotherapies, local radiotherapy and gonadal surgery are known to impair gonadal function, the gonadal disease linked to WT1 variants is the principal factor of gonadal impairment. For these reasons, regular follow-up by an endocrinologist appears essential for both XY and XX patients, providing clear information about gonadal function and fertility. Presentation: 6/1/2024

Male factor infertility and implication of fertility treatment in low resource settings

Introduction: The prevalence of infertility has increased worldwide. The etiological factors are also changing in trend and prominence. Male infertility is driving the epidemic in many regions of the world. Therefore, the aim of this study was to explore male factor infertility in the Gambia. Methodology: The design was a longitudinal descriptive study of subfertile couples at a specialist tertiary hospital in Banjul, the Gambia, from August 2022 to May 2023. Data were extracted from patients folders and entered into a computer database. Descriptive statistics were used to analyze the data and results expressed in tables, graphs, and percentages. Results: Total number of subfertile couples analyzed was 152: male factor 69 (45.4%), ovulation disorder 34 (22.4%), tubal factor 20 (13.2%), uterine factor 8 (5.3%), and unexplained 21 (13.8%). The median age of male folk was 50 years, with an age range of 31 to 64 years. The rates of asthenoteratozospermia, oligospermia, and azospermia were 37.8%, 36.2%, and 26%, respectively. In azoospermic males, over 75% had elevated FSH (12–44 miu/mL). Conclusions: The prevalence of male infertility is at 45.4%, which is 3-fold and 2-fold higher than tubal and ovarian factors, respectively. Male infertility is a problem with obvious implications. The predominant types of male infertility we observed in this study will almost always require multidisciplinary care and ICSI.

Meta-Analytical and Meta-Regression Evaluation of Subclinical Hyperthyroidism's Effect on Male Reproductive Health: Hormonal and Seminal Perspectives.

Subclinical hyperthyroidism (SCH) is a subtle thyroid dysfunction marked by decreased serum thyroid-stimulating hormone (TSH) levels while maintaining a normal thyroid hormone profile. Despite its mild nature, SCH can significantly impact various physiological functions, including male reproductive health. However, the effects of SCH on reproductive hormones and semen quality are less understood compared to overt thyroid disorders. This study employed extensive search methods across various databases from January 2000 to February 2024 to explore the relationship between SCH and Hormonal and Seminal Perspectives. Effect sizes, estimated using the standardized mean difference (SMD) and pooled with a Random-effect model, provided significant insights from 748 participants. Included studies adhered to the following criteria: Patients (male individuals with SCH), Intervention (assessment of reproductive hormones and semen quality), Comparison (SCH patients versus healthy controls), and Outcome (changes in reproductive factors). Significant alterations in reproductive hormones were observed in SCH patients, including reduced LH levels (SMD = - 0.20; p = 0.007), elevated FSH levels (SMD = 0.25; p = 0.002), and stable testosterone levels (SMD = - 0.05; p = 0.50). Regarding thyroid profile, SCH was associated with increased FT3 (SMD = 0.15; p < 0.001) and FT4 (SMD = 0.08; p = 0.002) levels, along with decreased TSH levels (SMD = - 2.00; p < 0.001). Adverse effects on semen quality were also observed. These findings underscore the need to incorporate thyroid health assessments in the evaluation of male infertility, recognizing the impact of minor thyroid hormone deviations on reproductive outcomes.

Expanding the Clinical Features of Schimke Immuno-Osseous Dysplasia: A New Patient with a Novel Variant and Novel Clinical Findings.

Schimke Immuno-Osseous Dysplasia (SIOD) (MIM:242900) is an ultra-rare autosomal recessive pan-ethnic pleiotropic disease. Typical findings of this syndrome are steroid-resistant nephrotic syndrome, cellular immunodeficiency and spondyloepiphyseal dysplasia and facial dysmorphism. Biallelic variants in the SMARCAL1 gene cause SIOD. The five-and-half-year-old female patient was evaluated because of short stature, dysmorphism, hypercalcemia, hypophosphatemia and elevated FSH levels. Karyotype analysis and array-CGH testing were normal. Clinical Exome Sequencing was performed via next-generation sequencing to analyze genes associated with hypophosphatemia. No pathogenic variant was detected. The subsequent detection of proteinuria during her follow-up for cross-fused ectopic left kidney ultimately facilitated the diagnosis of SIOD, although no obvious spondyloepiphyseal dysplasia was detected. Re-analysis of CES revealed a novel homozygous c.2422_2427+9delinsA pathogenic variant in the SMARCAL1. One hundred twenty-five SIOD cases from 38 literature reporting SMARCAL1 gene pathogenic variants were reviewed to investigate whether hypercalcemia, hypophosphatemia and elevated FSH levels had been previously reported in SIOD patients. This review revealed that this was the first time these findings had been reported in a SIOD patient. This report expands not only the phenotypic but also genotypic spectrum of SIOD.

Evaluation and diagnostic approach in patient with Perrault Syndrome

HIGHLIGHTS 1. The rare hereditary condition Perrault Syndrome is characterized by sensorineural hearing loss (SNHL) and ovarian dysfunction2. Cyclic estrogens and progesterone may be given to adolescents with amenorrhea to induce withdrawal bleeding and mimic the menstrual cycle. ABSTRACT Objectives: A multidisciplinary team, which included a reproductive endocrinologist and an otolaryngologist, identified Perrault Syndrome in a patient with secondary amenorrhea and bilateral sensorineural hearing loss. Case Report: A 16-year-old female presented to the obstetrics and gynecology clinic at a type B hospital with primary amenorrhea for one year. Menarche occurred at age 13, followed by regular menstrual cycles for two years, after which menstruation gradually ceased. She denied dysmenorrhea, constipation, leukorrhea, genital pruritus, growth retardation, and weight loss. The patient expressed concern about potential future infertility. At age 9, she was diagnosed with a viral infection by an ENT specialist due to bilateral hearing loss, leading to emotional disturbances. There was no history of prior medication, family illness, or chronic infections. Born at term via spontaneous vaginal delivery, the patient weighed 3,000 grams. Laboratory tests revealed normal T3 (1.51 ng/dl), FT4 (1.16 ng/dl), prolactin (18.25 ng/ml), estrogen (11 pg/ml), and progesterone (0.1 pg/ml) levels, but elevated FSH (66.46 mIU/ml) and LH (29.97 mIU/ml) levels. Symptomatic treatment included bone conduction hearing aids and estrogen replacement therapy. Conclusion: Perrault Syndrome, a rare hereditary condition, manifests as sensorineural hearing loss (SNHL) and ovarian dysfunction, including primary ovarian insufficiency (POI) and gonadal dysgenesis, in individuals with a 46, XX karyotype. Molecular diagnosis remains challenging. Consultation with a pediatric endocrinologist can guide cyclic estrogen and progesterone therapy to induce withdrawal bleeding in adolescents with amenorrhea. Women at risk of ovarian failure should consider donor eggs or oocyte cryopreservation. Avoiding aminoglycosides and excessive noise is crucial for managing hearing loss.

Reproductive Health Assessment and Reports of Fertility Counseling in Pediatric and Adolescent Patients with Sickle Cell Disease After Hematopoietic Cell Transplantation

Conditioning regimens for hematopoietic cell transplant (HCT) in patients with sickle cell disease (SCD) place patients at risk for reproductive health issues. The purpose of this study was to assess reproductive health and reports of fertility counseling in patients with SCD who received a transplant. This was a secondary analysis of gonadal hormone production, future infertility risk assessment, and parent-proxy/patient reports of fertility counseling in SCD transplant recipients who are currently pubertal and were enrolled in the Atlanta sites of the Sickle Cell Transplant Evaluation of Long-term and Late Effects Registry (STELLAR) between May 2017 and October 2023. Clinical information was abstracted from medical records and reproductive health survey data from the STELLAR database. Descriptive statistics were reported as median (interquartile range [IQR]) or percentages. There were 20 females and 12 males in the study population. Females were median (IQR) 19.6 (9.4) years old and males 20.8 (11.4) years old at the time of the study. Transplants most commonly occurred in the decade 2010 to 2019 at 10.7 (4.8) years old for females and 11.1 (4.1) years old for males. Most participants received bone marrow stem cells (95.0% females, 100.0% males) from matched sibling donors (90.0% females, 100.0% males). Participants received one of seven HCT conditioning regimens with cyclophosphamide equivalent doses ranging from 3388 to 9706 mg/m2. The majority of females (90.0%) had diminished ovarian reserve with low anti-Mullerian hormone levels, and 61.1% had premature ovarian insufficiency with two follicle-stimulating hormone levels (FSH) ≥40 mIU/mL post-HCT. All males had normal testosterone levels, but 63.6% had elevated FSH levels suggestive of impaired spermatogenesis post-HCT. Parent proxies (for patients <18 years old) and patients ≥18 years old completed surveys 9.0 years (5.2) and 7.9 years (9.3) since HCT in females and males respectively. Twenty-five percent of parent proxies and 45% of patients reported that they had not been informed by a healthcare provider of the risk of infertility post-transplant. There are high rates of gonadal dysfunction post-HCT, but many parent proxies and patients do not recall being told of the risk for future infertility. More effective methods of education are warranted to ensure SCD patients and their families clearly understand the risk for reproductive health issues post-HCT.

Are Young People with Turner Syndrome Who Have Undergone Treatment with Growth and Sex Hormones at Higher Risk of Metabolic Syndrome and Its Complications?

Metabolic syndrome (MetS), characterized by visceral obesity, glucose abnormalities, hypertension and dyslipidemia, poses a significant risk of diabetes and cardiovascular disease. Turner syndrome (TS), resulting from X chromosome abnormalities, carries health complications. Despite growing evidence of an increased risk of MetS in women with TS, its prevalence and risk factors remain under investigation. These considerations are further complicated by the varying timing and dosages of treatment with growth hormone and sex hormones. We conducted a cross-sectional study comparing 44 individuals with TS with 52 age-matched control subjects. Growth hormone treatment in the study group was administered for varying lengths of time, depending on clinical response. We collected anthropometric, metabolic, endocrine and body composition data. Statistical analyses included logistic regression. Baseline characteristics, including age, BMI and height, were comparable between the TS and control groups. Hormonally, individuals with TS showed lower levels of testosterone, DHEA-S, and cortisol, as well as elevated FSH. Lipid profiles indicated an atherogenic profile, and the body composition analysis showed increased visceral adipose tissue in those with TS. Other metabolic abnormalities were common in individuals with TS too, including hypertension and impaired fasting glucose levels. The risk of MetS components was assessed in subgroups according to karyotypes: monosomy 45X0 vs. other mosaic karyotypes. Logistic regression analysis showed a significant association between increased visceral adipose tissue in subjects with TS. Those with metabolic complications tended to have less muscle strength compared to those without these complications in both the study and control groups. This study highlights the unique metabolic and cardiovascular risk profile of individuals with TS, characterized by atherogenic lipids, higher levels of visceral adipose tissue and increased metabolic abnormalities. These findings underscore the importance of monitoring metabolic health in individuals with TS, regardless of age, BMI or karyotype, and suggest the potential benefits of lifestyle modification, building more muscle strength, and weight control strategies. Further research is needed to better understand and address the metabolic challenges faced by women with TS.

Gonadotropin elevation is ootoxic to ovulatory oocytes and inhibits oocyte maturation, and activin decoy receptor ActRIIB:Fc therapeutically restores maturation

BackgroundElevated FSH often occurs in women of advanced maternal age (AMA, age ≥ 35) and in infertility patients undergoing controlled ovarian stimulation (COS). There is controversy on whether high endogenous FSH contributes to infertility and whether high exogenous FSH adversely impacts patient pregnancy rates.MethodsThe senescence-accelerated mouse-prone-8 (SAMP8) model of female reproductive aging was employed to assess the separate impacts of age and high FSH activity on the percentages (%) of viable and mature ovulated oocytes recovered after gonadotropin treatment. Young and midlife mice were treated with the FSH analog equine chorionic gonadotropin (eCG) to model both endogenous FSH elevation and exogenous FSH elevation. Previously we showed the activin inhibitor ActRIIB:Fc increases oocyte quality by preventing chromosome and spindle misalignments. Therefore, ActRIIB:Fc treatment was performed in an effort to increase % oocyte viability and % oocyte maturation.ResultsThe high FSH activity of eCG is ootoxic to ovulatory oocytes, with greater decreases in % viable oocytes in midlife than young mice. High FSH activity of eCG potently inhibits oocyte maturation, decreasing the % of mature oocytes to similar degrees in young and midlife mice. ActRIIB:Fc treatment does not prevent eCG ootoxicity, but it restores most oocyte maturation impeded by eCG.ConclusionsFSH ootoxicity to ovulatory oocytes and FSH maturation inhibition pose a paradox given the well-known pro-growth and pro-maturation activities of FSH in the earlier stages of oocyte growth. We propose the FOOT Hypothesis (“FSH OoToxicity Hypothesis), that FSH ootoxicity to ovulatory oocytes comprises a new driver of infertility and low pregnancy success rates in DOR women attempting spontaneous pregnancy and in COS/IUI patients, especially AMA women. We speculate that endogenous FSH elevation also contributes to reduced fecundity in these DOR and COS/IUI patients.Restoration of oocyte maturation by ActRIB:Fc suggests that activin suppresses oocyte maturation in vivo. This contrasts with prior studies showing activin A promotes oocyte maturation in vitro. Improved oocyte maturation with agents that decrease endogenous activin activity with high specificity may have therapeutic benefit for COS/IVF patients, COS/IUI patients, and DOR patients attempting spontaneous pregnancies.

ASSOCIATION BETWEEN FEMALE HORMONES (FSH, LH, AND ESTROGEN) AS WELL AS HYPERLIPIDEMIA AND OBESITY IN AL- NAJAF HOLY CITY

An excessively high level of lipids, or fat, in the blood is called hyperlipidemia. The levels of hormones in females were examined, along with their correlation with elevated body fat and impact on cardiovascular conditions. The information was gathered in Najaf City between November 1, 2023, and December 20, 2023. The results of this study showed that the concentrations for a hormone that promotes follicle development within samples had increased by 58%. LH increased in 50% of the samples that were analyzed. Better pubertal development has been associated with elevated FSH levels in the blood. Improved metabolism has been associated with an increase in blood FSH. Moreover, nonlinear correlations were found between adiposity measures and serum FSH levels.

PRIMARY OVARIAN INSUFFICIENCY, A CHALLENGING DIAGNOSIS. A CASE SERIES

INTRODUCTION&#x0D; Primary ovarian insufficiency is rare, affecting 1-2% of those under 40 with only 0.1% of cases below 30 years. Etiology is mainly idiopathic, however chromosomal defects, autoimmune processes, and iatrogenic causes are associated. Symptoms are those of menopause but of intermittent durations and severities; and management targets the symptoms and complication prevention.&#x0D; CASE PRESENTATION&#x0D; We present two 18-year-old patients of African and Indian descent with an eight and five-month history of amenorrhea respectively with otherwise unremarkable history and physical exams. Investigation showed elevated FSH levels of 45.07 and 88.73 mIU/ml done four weeks apart in the first patient and 68.69 in the second patient. All other parameters were normal.&#x0D; DISCUSSION&#x0D; Aetiology is mainly idiopathic. 10-12% of diagnosed patients have chromosomal abnormalities such as Turner’s syndrome, fragile X syndrome, and genetic permutations of FMR 1 gene. Autoimmune causes are mainly autoimmune adrenal diseases. Autoimmune thyroiditis, Dermatomyosistis and Diabetes Mellitus type 1 also show association. Mumps Oophritis is the main infectious cause. Laparoscopic surgical procedures that involve the ovaries or affect their blood supply, pelvic radiotherapy, and chemotherapy all comprise the iatrogenic causes. Lifestyle and environmental factors such as smoking and heavy metals exposure also contribute.&#x0D; Diagnosis is by serum FSH levels of above 25 IU/l in two separate readings four weeks apart with a four-month history of amenorrhea occurring before 40 Years. Both patients were under 30 and met the criteria.&#x0D; Management involves hormone replacement therapy for symptoms, prevention and treatment of osteoporosis, oocyte donation for infertility, and counseling for both the psychological impact of the disease and the numerous complications living with the disease.&#x0D; CONCLUSION&#x0D; Multidisciplinary care is necessary for management of this rare and challenging illness

High FSH levels impair VEGF secretion of human, frozen-thawed ovarian cortical tissue in vitro

Cryopreservation and reimplantation of human ovarian tissue restore the ovarian hormonal function and fertility due to the preservation of follicles. As the success depends on proper angiogenesis, different approaches aim to support this process. In mice, pretreatment of ovarian tissue with FSH shows increased follicular numbers probably due to the supported angiogenesis by an increased vascular endothelial factor (VEGF) expression. However, in human tissue it remains completely unclear, which effect the hormonal status of the patient has at the time point of reimplantation. Frozen-thawed human ovarian cortical tissue was cultured for 48 h with 0, 1 or 10 ng/mL recombinant human FSH. VEGF-A expression was assessed by ELISA and immunohistofluorescence (IHF) analysis. By IHF, HIF-1α and FSHR expression dependency on culture and FSH concentration was analyzed. Follicles at all stages expressed VEGF-A, which increases during folliculogenesis. Frozen-thawed human ovarian cortical tissue secreted a not statistically different amount of VEGF-A, when cultured in presence of 1 ng/mL FSH (17.5 mIU/mL). However, the presence of 10 ng/mL FSH (175 mIU/mL) significantly decreased VEGF-A expression and secretion. The high FSH concentration increased especially the VEGF-A expression of already growing follicles. The presence of pre-menopausal concentrations of FSH had no significant effect on VEGF-A expression, whereas the presence of elevated FSH levels decreased cortical VEGF-A expression. A hormonal pre-treatment of women with elevated FSH concentrations prior to reimplantation might be considered to support angiogenesis. Here, we show that VEGF-A expression by follicles is affected by FSH dependent on the concentration.

Investigation of the molecular genetic causes of non-syndromic primary ovarian ınsufficiency by next generation sequencing analysis.

The aim of this study is to investigate the molecular genetic causes of non-syndromic primary ovarian insufficiency (POI) cases with the gene panel basedon next generation sequencing analysis and to establish the relationship between genotype and phenotype. Twenty three cases aged 14-40 years followed up with POI were included. Patients with a karyotype of 46, XX, primary or secondary amenorrhea before the age of 40, with elevated FSH (>40 IU/mL) and low AMH levels (<0.03 ng/mL) were included in the study. Molecular genetic analyzes were performed by the next generation sequencing analysis method targeted with the TruSight TM Exome panel. Median age of the cases was 17.8 (14.0-24.3) years, and 12 (52%) cases admitted before the age of 18. Fifteen (65%) patients had consanguineous parents. In2 (8.6%) cases, variants detected were in genes that have been previously proven to cause POI. One was homozygous variant in FIGLA gene and the other was homozygous variant in PSMC3IP gene. Heterozygous variants were detected in PROK2, WDR11 and CHD7 associated with hypogonadotropic hypogonadism, but these variants are insufficient to contribute to the POI phenotype. Genetic panels based on next generation sequencing analysis technologies can be used to determine the molecular genetic diagnosis of POI, which has a highly heterogeneous genetic basis.

Reproductive health in Turner's syndrome: from puberty to pregnancy.

Turner syndrome (TS) is a genetic pathology that affects about 1/2500 newborn females. Turner's syndrome is characterized by highly variable genetic anomalies that consist in a partial or complete deletion of the X sexual chromosome; it can be present as a monosomy or as a mosaicism with two o three different cellular lines. 50% of the patients with Turner's syndrome has a 45 XO karyotype while the remaining cases have karyotypes with mosaicism or X isochromosome or with partial or whole Y chromosome. This pathology is characterized by multiple anomalies that involve physical and cognitive development and in particular endocrine, cardiovascular, reproductive, auditive and visual systems. Integrity of the X chromosome in essential for fertility. In TS is accelerated germ cells apoptosis. About 30% of TS girls have some pubertal development, 10-20% undergo menarche and 2-8% go through spontaneous pregnancy. Women with TS should be informed about the risk of premature menopause and should be referred, if possible, to a specialist evaluation with a doctor expert in assisted reproductive techniques. In adolescents and in adults, Premature Ovarian Insufficiency (POI) can be evaluated clinically and biochemically with the classic combination of amenorrhea and elevated FSH concentrations (hypergonadotropic hypogonadism). However, in postpubertal adolescents and adult women, reproductive hormones may remain within the normal range before POI is clinically evident, despite significant depletion of the ovarian reserve. Today, reproductive medicine offers the opportunity of fertility preservation in women with premature ovarian insufficiency (POI). Two techniques have been suggested such as ovarian cortex cryopreservation and oocytes cryopreservation.

FRI310 Massive Gonadotropin-Secreting Adenoma In A Young Man: A Challenging Differential Diagnosis Of A Sellar Mass

Abstract Disclosure: C. Nava Suarez: None. J. Prater: None. N. Blocher: None. S. Sathi: None. Introduction: Gonadotropin-secreting adenomas are usually nonfunctioning representing 90% of silent pituitary masses. However, functioning gonadotropin-secreting adenomas (FGA) are rare, with unknown incidence given their infrequent recognition. FGA usually presents with high FSH and variable sex hormone levels. Usually misdiagnosed, these tumors present with late mass effect symptoms. Neuroimaging usually shows a sellar mass with extrasellar extension and compression of nearby structures. We present a case of a man with a massive FGA with craniopharyngioma features on imaging. Case: A 33-year-old male with left eye blindness for 3 years presented for evaluation of acute headache and right eye blurriness but no other symptoms. Ophthalmologic evaluation demonstrated left optic atrophy, right optic disc edema, and temporal field cut from optic chiasm involvement. Hormonal workup showed a markedly elevated FSH at 36.8 mIU/ml (&amp;lt;12 mIU/ml), normal total testosterone at 835 ng/dL (250-1000 ng/dL), and mildly elevated prolactin at 28.6 ng/dL (&amp;lt;29.4 ng/dL), all other pituitary hormones were normal. Brain MRI demonstrated a multilobulated, heterogeneously enhancing solid-cystic mass in the sellar and suprasellar area. It was T1 iso-hypointense, T2/FLAIR isointense, and had a few calcifications. There was mass effect on the optic chiasm, left frontal and temporal lobes, and left lateral ventricle causing obstructive hydrocephalus. Craniopharyngioma was the initial diagnosis given radiographic features. The patient required an extended left frontotemporal craniotomy for tumor debulking. Pathology reported pituitary macroadenoma with positive FSH immunostaining. He is planned for radiation therapy given the presence of residual tumor. Discussion: This case illustrates the late presentation of gonadotrophin pituitary adenoma. Up to 90% of silent pituitary adenomas stain for FSH or LH, but are not clinically active. A minority of these secrete functioning hormones which can result in clinically relevant effects with FSH elevation more commonly seen than LH elevation. In our case one would have expected low testosterone in the setting of high FSH as seen in primary hypogonadism, but testosterone levels can range from low to high in FGA. Men usually complain of erectile dysfunction and decreased libido. Our case is particularly interesting because of the imaging features (mixed cystic-solid components with calcifications) suggestive of craniopharyngioma. Radiologic features have over 90% accuracy in distinguishing craniopharyngioma from pituitary adenomas. An accurate pre-operatively diagnosis is important as it may affect the surgical approach and prognosis. Clinicians should have a high level of suspicion for FGA in patients with neurological and visual symptoms, especially when associated with sexual dysfunction, although the last is not always present. Presentation: Friday, June 16, 2023

THU618 Adrenal Cell Carcinoma Presenting With Post-menopausal Bleeding And IGF-2 Induced Hypoglycaemia

Abstract Disclosure: E.M. Lonergan: None. L.J. Tan: None. E. Ali: None. C.M. Joyce: None. N. Conlon: None. A. O'Sullivan: None. D.J. O'Halloran: None. Background: Non-islet cell tumour hypoglycaemia (NICTH) as a result of IGF-2 secretion is rare with a few case reports associated with adrenal tumours. Clinical Case: We present the case of a 59-year-old female initially presenting to gynaecology services with post-menopausal bleeding due to endometrial hyperplasia. Serum testosterone, oestradiol and adrenal androgens were found to be elevated and LH and FSH suppressed. A subsequent CT adrenals demonstrated a 12.8 x 13.2 x 10.6cm left adrenal mass and she failed a 1mg overnight dexamethasone suppression test. In the interim, while undergoing evaluation, the patient presented to A+E Department with point-of-care confirmed hypoglycaemia with a capillary blood glucose of 1.6mmol/L and neuroglycopaenic symptoms. There was no history of diabetes mellitus, prolonged fasting, access to sulphonylureas or insulin. During a supervised fast, symptomatic hypoglycaemia occurred within 5 hours at 2.0mmol/L fulfilling Whipple’s triad. Results of samples taken during hypoglycaemia revealed an elevated IGF-2 : IGF-1 ratio of 60.7 (normal &amp;lt;10) with a low paired C-peptide, insulin and pro-insulin, consistent with a suspected IGF-2-secreting tumour. Hypoglycaemia was successfully managed with low glycaemic index foods and clinical nutrition input. Radical surgical excision was undertaken including left adrenalectomy, nephrectomy, partial pancreatectomy and splenectomy. Post-operative pathology revealed an adrenocortical carcinoma (ACC) measuring 16.4cm in maximum dimension; Ki67 12%; Weiss score 5; lymph nodes negative. Tissue has been stained for IGF-2-IR. Post-operative IGF-2 : IGF-1 ratio normalised to 3.4. The patient is under active follow up with 3-monthly surveillance CT-TAP and has declined Mitotane therapy at present. Conclusion: This is a rare case of ACC secreting multiple hormones, resulting in post-menopausal bleeding and IGF-2 mediated hypoglycaemia. Presentation: Thursday, June 15, 2023

FRI244 Autoimmune Polyglandular Syndrome Type 2 And Peripartum Cardiomyopathy: A Case Report

Abstract Disclosure: A.G. Jimenez: None. J.D. Christensen: None. P. Surampudi: None. S. Phatak: None. J. Yoon: None. Background: Peripartum cardiomyopathy (PPCM) is a diagnosis of exclusion with evolving understanding of pathophysiology. There is limited consideration of the autoimmune processes contributing to PPCM. Case Presentation: A 20-year-old female had a recent delivery complicated by placenta previa, hemorrhage requiring transfusion, and pelvic infection. She presented 2 weeks postpartum with altered mental status and abdominal pain, found to be in septic shock, acute respiratory failure, acute liver injury initially thought to be secondary to retained products of conception. Subsequently, she was diagnosed with moderate-to-severe PPCM as she developed signs of heart failure, low ejection fraction &amp;lt;35%, mild ventricular dilatation, cardiogenic shock, hemorrhagic pericardial effusion with tamponade. She had no other prior cardiovascular history. She was briefly started on bromocriptine for treatment of suspected prolactin-mediated PPCM, in addition to digoxin, as her blood pressure was unable to sustain other treatments for PPCM. However, she hemodynamically decompensated and required persistent pressor support, leading to evaluation for other causes. Due to her prior history of hypothyroidism, an adrenal evaluation with a cosyntropin stimulation test was done. It demonstrated an undetectable cortisol at 0, 30, 60 minutes, with an elevated ACTH (1256, n=7-63 ng/dL), consistent with primary adrenal insufficiency (PAI). Workup for PAI did not reveal any infectious, infiltrative, vascular, pharmacological, or neoplastic etiology. Lab workup for concomitant hypophysitis was significant for low IGF-1 (Z-score -5.8, n= -2.0 to +2.0), but otherwise had expected elevated prolactin (121 ng/mL, n=5.2-26.5 ng/mL), suppressed LH (0.3 mIU/mL) and FSH (2.4 mIU/mL), and normal TSH (3.87 mIU/mL, n=0.27-4.20 mIU/mL) on levothyroxine 100 mcg. She had normal parathyroid hormone and hemoglobin A1c levels with no history of chronic candidiasis. Further workup showed positive antibodies to adrenal 21-hydroxylase enzyme, thyroid peroxidase, and glutamic acid decarboxylase 65, suggestive of autoimmune polyglandular syndrome (APS) type 2. She was started on glucocorticoids and mineralocorticoids for adrenal insufficiency resulting in a significant clinical improvement. She was subsequently discharged in stable condition. Conclusion: Due to increased rates of mortality in PPCM (4-11%), thought should be given to nontraditional etiologies of cardiac failure. Although rare, adrenal insufficiency must be considered in those with moderate-to-severe PPCM who continue to decompensate despite treatments. Untreated adrenal insufficiency can result in fatal consequences if not immediately treated. APS type 2 should be considered even in those without any confirmed family history of autoimmune disease. Those with autoimmune tendencies may be at higher risk of PPCM. Presentation: Friday, June 16, 2023

SAT437 Immunotherapy Induced Pituitary Apoplexy

Abstract Disclosure: A. Uddin: None. M.J. Gardner: None. A. Akofu: None. N. Sheung: None. S. Dejhansathit: None. N. Akabogu: None. F. Marium: None. We present a case of a 42 year old male with past history of metastatic melanoma s/p 3 cycles of ipilimumab and nivolumab immunotherapy that originally was referred to endocrinology due to elevated prolactin of 40 and MRI finding of questionable 6 mm pituitary adenoma. There was not a clear other cause of prolactin elevation. Other notable labs in pituitary hormonal evaluation were elevated FSH of 24 and LH 16 with normal testosterone 663. TSH of 4.3 and FT4 of 1.22. After the 4th cycle of ipilimumab and nivolumab he had a severe headache that was unremitting, he called his oncology nurse line which instructed him to hydrate. He presented for admission to the hospital after coming confused, unsteady on his feet and his headache had already improved. Labs demonstrated severe hyponatremia at 111 with serum osm of 238 and urine osmolality of 504 and specific gravity of 1.012. Brain MRI demonstrated a 1.2 cm pituitary lesion compared to less than 1 month prior, consistent with hypophysitis. Repeat pituitary labs showed hypogonadotropic hypogonadism with total testosterone of 39 and inappropriately normal FSH of 7 and LH of 2, central hypothyroidism with TSH 0.232, FT4 0.70, FT3 1.8, secondary adrenal insufficiency with cosyntropin stimulation test up to cortisol of 16 for partial response and ACTH of 17. Hyponatremia was managed inpatient and he was discharged on appropriate hormone replacement. Subsequent brain MRI with normal pituitary finding without enhancing lesions. Repeat hormonal testing showed persistent hormonal deficiencies with undetectable cortisol and ACTH despite holding hydrocortisone therapies. Prolactin was also tested in the 4-10 range on repeat testing. He continued on nivolumab monotherapy with oncology. This case report details a clear case of immunotherapy treatment leading to destruction of prolactinoma and presentation of pituitary apoplexy given the short time line of 1 month and cycle of therapy between radiographic and hormonal assessment. We hope this case helps bring awareness to the evolving list of conditions to survey for with immunotherapy and suggests a role of identifying prolactinomas biochemically and or radiographically to affect management. It may even suggest a role in treatment for medically refractory pituitary adenomas. Presentation: Saturday, June 17, 2023

THU098 Gonadotropin Secreting Pituitary Tumor Presenting As Primary Hypogonadism

Abstract Disclosure: J.N. Shapiro: None. T.X. Lu: None. J. Eapen: None. J.G. Karam: None. Gonadotroph adenomas are the most common subtype of nonfunctional pituitary adenomas, with 35 percent secreting enough LH or FSH to raise serum gonadotropin levels, but clinical syndromes due to hypersecretion of gonadotropins are rare. A low testosterone level with high FSH or LH can mislead to a diagnosis of concomitant primary hypogonadism rather than a secreting pituitary adenoma. We present a case of a patient with an FSH-secreting pituitary macroadenoma presenting with low testosterone levels. The patient is a 67-year-old man incidentally found to have a pituitary macroadenoma measuring 12 x 13 x 12 millimeters, impinging upon the optic chiasm on MRI of the brain obtained for headaches. Visual field tests revealed abnormalities compatible with glaucoma, but not chiasm compression. He has no symptoms of hormonal excess or deficit, although his wife reported decreased erectile function. Physical examination was unremarkable except for an atrophic left testicle. Pituitary hormone function tests (ACTH, AM cortisol, IGF-1, prolactin, thyroid function tests, and 24-hour urine free cortisol) were within normal range, except for an elevated FSH 14.8-18.1 mIU/mL and decreased testosterone in range of 185-256 ng/dL, with normal LH at 7.0 mIU/mL, for which he was referred for urology for evaluation of primary hypogonadism. The patient underwent transsphenoidal resection of the pituitary adenoma. Postoperative pathology revealed a pituitary adenoma, gonadotroph cell type, with immunohistochemical staining scattered positive FSH, and rare positive LH. Postoperative MRI showed post-surgical changes with no residual nodular enhancement. Following surgery, the patient suffered from severe clinical hypogonadism with episodes of profuse diaphoresis and extreme fatigue. Postoperative laboratory values revealed panhypopituitarism with undetectable testosterone level, and low LH and FSH levels. The patient was successfully treated with hydrocortisone, levothyroxine, and testosterone, with resolution of his symptoms. Our patient presented with a pituitary macroadenoma, low testosterone, and high FSH suggestive initially of primary hypogonadism, but found ultimately to have an FSH-secreting adenoma. He likely had underlying hypogonadism, primary or secondary, and although his adenoma secreted FSH, it was not enough to maintain testosterone level in normal range, possibly in part due to biologically inactive FSH molecules or to primary testicular failure. The extremely low testosterone levels postoperatively suggest that his testicular function was mostly stimulated by the adenoma secreted FSH and was therefore drastically lost after surgery. This case increases awareness to consider a gonadotropin-secreting tumor in the differential diagnosis of a pituitary adenoma with high FSH or LH, even when testosterone level is unexpectedly low. Presentation: Thursday, June 15, 2023

FRI311 GnRH Agonist Induced Pituitary Apoplexy In A Patient With Gonadotropinoma

Abstract Disclosure: I. Madahar: None. S. Khan: None. L. Hergenroeder: None. B. Skaff: None. A. Haider: None. Introduction: GnRH therapy is commonly employed in patients with advanced prostate cancer. It acts as an agonist that binds to pituitary GnRH receptors. It acts via desensitization, downregulating FSH and LH production, and ultimately decreasing testicular steroidogenesis. Initial administration leads to transient stimulation of the pituitary which leads to elevated FSH and LH levels and increased production of estrogen and testosterone with eventual downregulation of the overall pathway. Case description: 80-year-old male with a past history of atrial fibrillation and OA was diagnosed with prostate cancer. Prostate adenocarcinoma Gleason score 7 (4+3) grade 3 was diagnosed by needle core biopsy five months prior to presentation. CT chest, abdomen, pelvis, and bone scan did not show evidence of metastatic disease. A week prior to starting Lupron therapy he was started on bicalutamide therapy. He received a dose of leuprolide (Elligard) as part of his chemoradiation therapy for his cancer. The patient went golfing after the treatment and within four hours he started noticing headaches and retroorbital pain. Headaches were sharp in quality, intensity 9 out of 10, and associated with nausea and vomiting. He later developed right-sided ptosis and double vision which progressively worsened after the next few hours. An initial CT scan of the head showed an enlarging pituitary mass which was followed MRI of the brain with and without contrast showed an enlarged pituitary mass and right cavernous sinus effacement of the optic chiasm. Anterior pituitary hormone functions were ordered, and the patient was started on stress-dose steroids. Transsphenoidal pituitary resection was done which the patient tolerated well pathology showed pituitary adenoma with pituitary apoplexy and the immunoprofile was compatible with gonadotroph adenoma. The adenoma cells were positive for synaptophysin, cam 5.2, GATA3, and FSH. A repeat MRI of the Sella three months after surgery showed a 9 mm nodule in the right aspect of the Sella. Anterior pituitary hormone levels done prior to surgery showed an IGF- 1 level of 204 ng/ml (Z score 1.5 SD). TSH and free T4 were in the normal range. Hydrocortisone was tapered and stopped 6 weeks after transsphenoidal surgery. Discussion: Lupron levels reach maximum concentration four hours after intramuscular administration. Initial pituitary stimulation by leuprolide administration causes the increased metabolic activity of the underlying adenoma which outgrows its blood supply, thus developing ischemic necrosis and subsequent hemorrhage. The majority of pituitary apoplexy develops in patients with previous undiagnosed pituitary adenomas. Should patients get central imaging to screen for pituitary macroadenoma before Lupron treatments to prevent this potentially life-threatening complication? Presentation: Friday, June 16, 2023