Low FSH Research Articles

8230 Adrenal Crisis, Unrevealing the Impact of Immigration on Central Adrenal Insufficiency

Abstract Disclosure: D.H. Sacoto: None. K. Madani: None. D. Patel: None. A. De Rosairo: None. G. Rai: None. R. Belokovskaya: None. A.A. Franco-Akel: None. Introduction: Even though patients with secondary adrenal insufficiency (AI) may go through life without an episode of adrenal crisis, there is a 50% chance of developing it. Around 90% have a known precipitating, with infections and surgery being frequent causes. However, emotional stress is unrecognized. With the recent increase in worldwide immigration, it is important to recognize these as potential triggers in those with AI. Here, we present a case of adrenal crisis triggered by immigration. Case presentation: A 41-year-old female diagnosed eighteen years ago with Sheehan syndrome, with unknown replacement therapy status, is brought to ED for altered mental status. One week before, she crossed the Mexican-US border as an illegal immigrant and was hospitalized in Arizona after developing mutism and mood lability. She was initiated and discharged on hormone replacement therapy. She arrived in New York confused with flat affect and impaired recent memory. She was hypotensive (BP: 92/64 mmHg), hyponatremic (Na: 133 mEq/L), and anemic (Hb: 10.6 g/dL). She had an inappropriate normal ACTH of 25 pg/mL (7.2-63.3 pg/mL). MRI findings confirmed empty sella, suggestive of central AI. Additional studies revealed central hypothyroidism (low normal TSH (1.36 uIU/mL), low-normal Free T4 (1.4 ng/dL), gonadotroph dysfunction with low FSH (2.7 IU/L), and low estrogen levels (20 pg/mL) for her age, and low normal prolactin (4.6 ng/mL). After initiating a stress dose of IV hydrocortisone and IV levothyroxine, her affect, memory, mental status, and vital signs (BP: 128/80 mmHg) improved. She was educated regarding the need for maintenance doses as an outpatient. At the one-month follow-up, she continued with a positive response. Discussion: Patients with chronic AI are unable to produce sufficient cortisol and are at risk of acute adrenal crisis when under stress. Stressful situations, including accidents, job interviews, or death in the family, have been described. However, with almost doubling the number of people entering the US without prior authorization between 2022 and 2023, immigration, which poses physical and emotional stress, certainty will become a matter of importance for those with AI. Guidelines to manage cortisol replacement in times of fever, infections, trauma, surgery, or severe pain are available. However, it is more difficult to define how emotional and psychological challenges affect the stress response, mainly because each challenge is unique. Therefore, it is important to advocate for policies to provide medical alert bracelets to immigrants with known AI in addition to providing education about emergency injection kits in cases of impending crisis. Presentation: 6/3/2024

6963 A Rare Case Presentation of Untreated Congenital Adrenal Hyperplasia with Bilateral Giant Myelolipoma

Abstract Disclosure: F. Omran: None. S. Bromley: None. M. Ilahi: None. M. Zena: None. W. Al-Refaie: None. J. Delto: None. A. Singh,: None. Background: Adrenal myelolipoma is a rare benign neoplasm predominantly composed of mature adipose tissue and intermixed myeloid tissue, often associated with conditions like Congenital Adrenal Hyperplasia. The etiology of this neoplasm is not definitively known although there are numerous hypotheses, including research suggesting that excess ACTH could be responsible for the pathogenesis. Clinical Case: A 40-year-old female with a history of congenital adrenal hyperplasia noncompliant with treatment. She presented with cholelithiasis (s/p laparoscopic cholecystectomy), abdominal imaging revealed incidental finding of a large right retroperitoneal mass. She was noted to have generalized excessive hirsutism in male distribution, small breasts, enlarged clitoris, male body habitus, and amenorrhea after stopping steroids years prior. Laboratory workup showed the following hormonal abnormalities: elevated ACTH (1080 pg/ml), elevated testosterone (243 ng/dl) and free testosterone (31.3 pg/ml), elevated androstenedione (23.431 ng/ml), and low LH (<0.02 miu/ml), low FSH (<0.02 miu/ml). CT abdomen showed right lobulated retroperitoneal mass of 4x14.3x20cm with internal fat and soft tissue components, left lobulated retroperitoneal mass of 13.7x4.7x7.5cm with soft tissue and fat components. CT guided-biopsy showed pathology consistent with adrenal myelolipoma: fatty areas with interspersed hematopoietic tissue components, peripheral rim of normal adrenal cortical tissue. Given the large size of the mass and compressive effects on surrounding organs, patient underwent exploratory laparotomy with resection of right retroperitoneal mass, nephrectomy, and adrenalectomy. Discharged on hydrocortisone and fludrocortisone, instructed to follow up by endocrinologist, always wear medical alert bracelet, and provided with hydrocortisone emergency kit. Conclusion: This case serves as a classic presentation of a rare disease state. Adrenal myelolipomas, a rare benign adrenal neoplasm, have been found in several disorders associated with chronic ACTH hypersecretion including congenital adrenal hyperplasia. Most CAH patients with myelolipomas have untreated or poorly treated CAH. Adrenal myelolipomas that are asymptomatic and <5cm in size are usually monitored if one is certain there is no occult malignancy. If these tumors are symptomatic or >7cm, patients should undergo surgical excision. These patients should be followed by endocrinology. Importantly, further guidelines should be further developed for management. Presentation: 6/3/2024

6917 Multiple Red Herrings Complicating the Diagnosis of Cyclic Cushing’s Syndrome

Abstract Disclosure: A. Grover: None. R. McGlotten: None. L.K. Nieman: None. Introduction: Cyclic Cushing’s syndrome (CCS) is a rare disorder characterized by intermittent hypercortisolemia. It may be caused by pituitary tumor (Cushing disease), ectopic ACTH tumor secretion (EAS), or primary adrenal disease. We present a case of CCS with multiple red herrings complicating the diagnosis. Case: A 57-year-old Cushingoid appearing woman presented elsewhere with weight gain, brain fog, weakness, hypertension, worsening diabetes, and OSA. Screening tests showed more than three episodes of hypercortisolism with interval eucortisolism: salivary and 24-urine cortisol (UFC) ranged from 0.06-0.34 µg/dL (reference range, RR, ≤0.09 µg/dL) and 59.7-137.1 µg/24 h (RR 4-50 µg/24 h) respectively. The patient was symptomatic throughout. Differential diagnosis was CCS vs a physiologic non-neoplastic condition. As she had no clear etiology for the latter, further testing was performed. ACTH was indeterminate (23-27 pg/mL, RR <46). Pituitary MRI showed a left 7 mm lesion. Inferior petrosal sinus sampling (IPSS) with Corticotropin Releasing Hormone (CRH) administration showed peripheral baseline ACTH levels of 9.0 and 10.0 pg/mL, suggesting that she had cycled out of a hypercortisolemic phase. The left petrosal baseline values were low (9 pg/mL,16 pg/mL), suggesting poor catheterization, which was confirmed by a low prolactin-normalized ACTH ratio. The petrosal levels were lower than expected (maximum 767 pg/ml), due to suppression of normal corticotropes vs poor tumor response. However, a central:peripheral step-up was consistent with Cushing's disease (CD) or pseudo-CS. She was referred to us for re-evaluation. A low FSH, LH, low normal TSH, and UFC of 160 µg/24h supported a diagnosis of CS. ACTH was 14.6 pg/mL. Pituitary MRI showed a 1.3 cm x 0.8 cm mass extending into the left cavernous sinus. She did not suppress cortisol during a dexamethasone suppression test (DST). After CRH administration ACTH levels doubled. Based on the macroadenoma and CRH response, CD was established; IPSS was not repeated. After transsphenoidal hypophysectomy, pathology revealed ACTH positive adenoma. Post-operative adrenal insufficiency required hydrocortisone replacement. Conclusion: CCS can pose a diagnostic challenge due to unpredictable duration and frequency of hypercortisolism. Intermittently elevated cortisol levels with CS symptoms should raise suspicion for CCS. In our case, low peripheral ACTH levels further suggested this possibility. DST may give spurious results in CCS owing to spontaneous falls or rises in cortisol at the time of testing. Prolonged hypercortisolism is required in all patients to ensure suppression of normal corticotropes, which if not complete, may confound results in patients with EAS. Finally, inadequate catheterization may affect accuracy of lateralization in any patient with CS and is ideally evaluated both by venography and prolactin measurement. Presentation: 6/1/2024

8696 Whole Exome Sequence Analysis in a Naïve Cohort of Congenital Hypopituitarism in a Single Center

Abstract Disclosure: F.Q. Aratani: None. D.P. Di Matteo: None. I.P. de Magalhães: None. P. Frudit: None. L.S. Motomia: None. S.K. Beeby: None. L.R. Barros: None. D.D. Bissegatto: None. L.R. Carvalho: None. Background: Deficiency of one or more pituitary hormones is defined as hypopituitarism. In the literature, molecular diagnosis (MD) is defined in 12% by the Sanger sequencing and large scale sequencing increased this number to 15%. Aim: To perform whole exome sequencing (WES) in a cohort of patients with congenital hypopituitarism (CH) naïve to MD approach. Patients: Nine patients with CH followed in a single Brazilian tertiary center were included. Methods: Libraries were prepared with kits from Agilent and sequenced on Hi-Seq (Illumina). The variants were called following GATK best practices, using the Haplotypecaller and genome version hg38. They were classified in the Franklin by genoox (https://franklin.genoox.com/clinical-db/home). WES that did not pass the platform's initial quality control and variants that did not reach an adequate confidence level (low/medium confidence: VAF < 50%) were excluded. The remaining variants were classified according to ACMG criteria. Results: Three among 9 patients presented allelic variants and aredescribed here. Case 1: A 22-year-old female presented height of 143 cm (-3,13 SDS) at the first visit without signs of puberty, had delayed bone age (DBA), hypoplastic adenohypophysis, interrupted pituitary stalk (IPS) and ectopic neurohypophysis (ENH) at the magnetic resonance imaging (MRI). Hormonal profile showed low E2, GH, FSH and LH. Twoheterozygous missense variants in the ALMS1 gene (c.5450G>A : p.Arg1817GIn; and ALMS1:c.4225G>C: p.Ala1409Pro) were seen in the exome; both classified as VUS according to ACMG criteria. This allelic variant is related to Alstrom Syndrome. Case 2: A 7-year-old female presented with short stature and was diagnosed with GH followed by LH/FSH, TSH and ACTH deficiencies. At MRI presented IPS and ENH. A heterozygous variant in the PROK2 gene c.364C>T p.R122 with a premature stop codon and truncated protein was present and classified as probably pathogenic according to ACMG criteria. This variant was already described with hypogonadotropic hypogonadism (HH) with or without anosmia. Case3: A 15-year-old male was referred with growth hormone deficiency (GHD), DBA, and HH. Growth hormone replacement was started followed by testosterone. Despite delayed puberty, the testes were normal in size. WES showed a variant c.629G>A:p.Trp210*, in hemizygosity in IGSF1 gene and was classified as probably pathogenic according to ACMG criteria. Loss-of-function mutations in IGSF1 may cause an X-linked syndrome of central hypothyroidism, macroorchidism and delayed puberty (delayed rise of testosterone, but normal timing of testicular growth). Conclusion: WES in a cohort of patients with congenital hypopituitarism naïve to molecular diagnosis revealed 33% (3/9) with positive genetic findings, two of them with clinical significance and family segregation according to the genetic inheritance. Presentation: 6/3/2024

6977 Unraveling Secondary Adrenal Insufficiency and an Invasive Pituitary Macroadenoma in a COVID-19 Positive Patient

Abstract Disclosure: F. El Sayed: None. A.A. Banka: None. Invasive pituitary macroadenomas extend into the extrasellar region and invade surrounding dural, periosteal, or mucosal tissues, often exceeding 1 centimeter and potentially compressing adjacent structures. Nonfunctioning pituitary adenomas (NFPAs), as they enlarge, can cause visual field impairment and ophthalmoplegia, with the decision for surgical intervention influenced by the degree of optic chiasm compression. NFPAs are sometimes associated with impaired endocrine function, particularly secondary adrenal insufficiency (sAI), which, warrants specific clinical attention. Management involves a combination of surgical interventions, such as transsphenoidal surgery, and medical approaches, including tailored hormone therapy or radiation therapy based on the tumor's characteristics. Clinical case: A 51-year-old female with a history of Sjogren's disease presented with a one-week duration of nausea, vomiting, diarrhea, and fatigue. Upon admission, she tested positive for COVID-19. Her vital signs indicated hypotension with a blood pressure in the 80s/40s range, a heart rate in the 90s, and she was afebrile on room air. Laboratory findings revealed significant hyponatremia (Na+ 118), K+ 4.3, HCO3- 19, and glucose 80. Workup for hyponatremia included a cortisol stimulation test, revealing secondary adrenal insufficiency with baseline cortisol of 3.5 ug/dl, 10.7ug/dl after 30 minutes, and 12.7ug/dl after 60 minutes. The patient denied exogenous steroid use, hypothyroid symptoms, polyuria, or polydipsia, and reported no headaches or visual symptoms. Endocrine evaluation showed hypogonadism despite post-menopausal status, with low estrone, estradiol, LH, and FSH levels. She was initiated on Cortef (hydrocortisone) with symptomatic improvement. Further investigation through an MRI revealed a large lobulated sellar mass measuring 3.2 x 2.8 x 3.5 cm compressing the optic chiasm and partially encasing the right internal carotid artery, leading to peripheral visual defects confirmed on perimetry. Following endoscopic endonasal pituitary macroadenoma resection, there was no evidence of interval growth on a one-year follow-up MRI scan. Discussion: The presented case highlights the importance of considering invasive pituitary macroadenomas in the differential diagnosis of patients with hyponatremia, particularly when accompanied by suggestive symptoms and an atypical cortisol response. The coexistence of COVID-19 adds a layer of complexity to the clinical scenario, necessitating a comprehensive approach to both infectious and endocrine management. Timely recognition, appropriate endocrine assessment, and targeted interventions, such as hydrocortisone replacement and surgical resection, are crucial for optimizing outcomes in patients with this intricate interplay of pituitary pathology and infectious states Presentation: 6/1/2024

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

Basal FSH values are positively associated with aneuploidy incidence in pre-advanced maternal age (AMA) but not in AMA patients.

To assess the impact of maternal age on the association between maternal basal FSH and aneuploidy. A retrospective study including data from 1749 blastocysts diagnosed as euploid or aneuploid by PGT-A (preimplantation genetic testing for aneuploidy). Aneuploidy incidence was compared between embryos from mothers with high vs. low basal FSH levels (above and below the group median, respectively) in total, pre-AMA (advanced maternal age; < 35years, 198 embryos) and AMA (≥ 35years, 1551 embryos) patient groups, separately. To control for the interference of potentially confounding variables, the association between aneuploidy and high basal FSH levels was assessed by multivariate logistic analysis in overall, pre-AMA and AMA patient groups. Overall, aneuploidy rate was 9% higher (p = 0.02) in embryos from patients with high basal FSH (63.7%) compared to those with low basal FSH (58.4%). In the pre-AMA subgroup, aneuploidy incidence was 35% higher (p = 0.04) in embryos from patients with high basal FSH (53.5%) compared to those with low basal FSH (39.4%). Differently, aneuploidy occurrence did not vary between embryos from AMA patients with low (61.0%) and high (64.8%) basal FSH (p = 0.12). The multivariate analysis revealed that, in pre-AMA embryos, the association between aneuploidy occurrence and high basal FSH is independent of potential confounding variables (p = 0.04). Maternal basal FSH values are associated with embryo aneuploidy in pre-AMA but not in AMA patients. The present findings suggest that basal FSH is a useful parameter to assess aneuploidy risk in pre-AMA patients and reinforce the hypothesis that excessive FSH signalling can predispose to oocyte meiotic errors.

Impact of Hysteroscopic Polypectomy on IVF Outcomes in Women with Unexplained Infertility.

Objective: To assess the effect of hysteroscopic polypectomy on the in vitro fertilization (IVF) results in infertile women with at least one prior negative IVF outcome. Methods: This retrospective cohort study included women who had attended the "2nd Department of Obstetrics and Gynecology of the National and Kapodistrian University of Athens" and "Iaso" Maternity Hospital from October 2019 to January 2023 for infertility treatment. The medical records of 345 women aged 18-45 years old without abnormal findings in hysterosalpingography (HSG) and with at least one previous failed IVF procedure were analyzed. The male factor was excluded, as well as a prior hysteroscopic removal of polyps. In 67 women, polyps were suspected during initial two-dimensional ultrasound (2D-US) examination. The final sample of the study comprised 40 patients, in which endometrial polyps were removed by hysteroscopy with the use of resectoscope. All patients underwent ovarian stimulation and IVF in the consecutive cycle using a short GnRh antagonist protocol. Main Results: After hysteroscopic polypectomy, 29 (72.5%) out of 40 patients had a positive pregnancy result: 26 (65%) clinical and 3 (7.5%) biochemical pregnancies were documented. There was a statistically significant difference between the number of clinical pregnancies before and after polypectomy (p < 0.001), as well as between the total number of pregnancies (p < 0.001). Secondary Results: Women with positive outcome were significantly younger and had significantly lower FSH levels (p < 0.007). They also had significantly higher AMH (p < 0.009) and peak estradiol levels (p < 0.013) and yielded more M II oocytes (p < 0.009) and embryos (p < 0.002). Conclusions: Hysteroscopic polypectomy in women with a suspected endometrial polyp using 2D ultrasound and a history of prior failed IVF attempt improves IVF outcomes in terms of the clinical and total number of pregnancies.

O-059 ART in PCOS

Abstract Polycystic Ovarian Syndrome affects an estimated 8 – 13% of women of reproductive age (WHO). It is the commonest cause of anovulation and infertility. The high AMH, LH, Insulin resistance and hyperandrogenism seen in PCOS women contributes to infertility along with poor oocyte quality and reduced endometrial receptivity. ART procedures are recommended as the third line of treatment after ovulation induction, IUI or ovarian drilling. Prior to IVF, metabolic assessment and lifestyle adjustments with weight management must be done. Adjuvant agents such as metformin melatonin, myoinositol and Vitamin-D have been tried to improve IVF outcomes. Mild stimulation is an option in patients as high risk for ovarian hyperstimulation syndrome (OHSS). Conventional stimulation with low dose FSH, GnRH antagonist down regulation, agonist trigger with freezing of all embryos, significantly reduces risk of OHSS without compromising cumulative live birth rates. Adjustments for stimulation protocols may need to be made for BMI, insulin resistance and AMH. In vitro maturation can be considered in patients with prior severe OHSS, though the results may be inferior. ART in PCOS patients is challenging and even after pregnancy is achieved, there may be a higher risk of adverse obstetric outcomes.

P-664 Insulin-like peptide 3 as a potential biomarker in predicting IVF success and ovarian reserve in women with unexplained infertility and diminishing ovarian reserve

Abstract Study question Could insulin-like peptide 3 (INSL3) predict ovarian reserve and in vitro fertilization (IVF) success in women with unexplained infertility (UI) and diminishing ovarian reserve (DOR)? Summary answer In women with DOR, reduced intrafollicular and serum INSL3 levels correspond with low AMH and high FSH levels, similar to established ovarian reserve markers. What is known already INSL3, belonging to the insulin-like peptide family, is produced by theca interna cells within antral follicles and the corpora lutea. It is hypothesized that INSL3 is integral to the initial development and function of antral follicles, specifically through its regulatory effect on androgen biosynthesis in the thecal cells of these follicles. Moreover, INSL3 is implicated in the modulation of the ovarian microenvironment, which is essential for facilitating the maturation of oocytes. Study design, size, duration This research was carried out at the IVF centers of two tertiary university hospitals, assessing 49 infertile women with either UI (n = 24) or DOR (n = 25) during IVF treatment. A control group (n = 26) comprised women with normal ovarian reserve undergoing IVF due to male or tubal factors. Outcome parameters are ovarian reserve markers (serum FSH, estradiol, AMH, INSL3 concentration and antral follicle count [AFC]), positive pregnancy rate and live birth rate (LBR) (gestational age ≥28 weeks). Participants/materials, setting, methods Women aged between 20-40 with a body mass index (BMI)&amp;lt;30 kg/m² were included. Serum FSH, estradiol, AMH, INSL3 levels and AFC were evaluated on menstrual cycle days 2 or 3, and INSL3 in follicular fluid from dominant follicles (&amp;gt;14 mm) were evaluated during oocyte retrieval. Exclusions included endocrine abnormalities (e.g., polycystic ovary syndrome, hyperprolactinemia, hypo and hyperthyroidism) cycle cancellation due to lack of a viable embryo, uncorrected Mullerian anomalies, recurrent miscarriage history and hydrosalpinx presence. Main results and the role of chance The mean age in the study groups was 28.41±3.5 (UI), 32.40±4.21 (DOR), and 29.65±3.91 (control). In the DOR group, female age (p = 0.001), BMI (p = 0.049), duration of infertility (p = 0.006), previous IVF attempts (p &amp;lt; 0.001), basal FSH (p &amp;lt; 0.001), and basal estradiol (p &amp;lt; 0.001) were higher, while AMH (p &amp;lt; 0.001), AFC (p &amp;lt; 0.001), and follicular fluid INSL3 (p &amp;lt; 0.001) were lower. Serum INSL3 in DOR was lower but not statistically significant. No correlation was found between serum INLS, follicular fluid INSL3, ovarian reserve markers, positive pregnancy rates, miscarriage, and LBR. DOR group had longer stimulation durations (p = 0.017), but lower max estradiol (p &amp;lt; 0.001), fewer oocytes (p &amp;lt; 0.001), mature follicles (p &amp;lt; 0.001), and PN (p &amp;lt; 0.001). Pregnancy rates were 54.1% (UI), 24% (DOR), and 53.84% (control); LBRs were 54.1% (UI), 20% (DOR), and 42.3% (control), with significant differences in pregnancy tests (p = 0.04) and LBR (p = 0.03), both lower in DOR. Univariate analysis identified duration of infertility (p = 0.019) and basal FSH (p = 0.009) as significant LBR predictors. Multivariable analysis confirmed basal FSH (p = 0.033) as significant, with increased duration of infertility and basal FSH level reducing LBR probability. Limitations, reasons for caution The limited sample size of our study potentially undermines the robustness of circulating INSL3 as a predictive biomarker for DOR, evidenced by the non-significant decrease in serum INSL3 levels in the DOR group. Moreover, the lack of INSL3 level assessment during oocyte retrieval further constrains our findings. Wider implications of the findings Our research explored INSL3 as a viable biomarker for predicting ovarian reserve and IVF success in UI and DOR cases. Reduced INSL3 levels in circulation and follicular fluid in DOR patients could be beneficial in clinical practice. Trial registration number not applicable

Association of Vitamin-D insufficiency and infertility: A Literature Review

Vitamin D receptors are present in both male and female central neural system and reproductive system hence Vitamin D sufficiency or insufficiency affects fertility. The present review aims to determine a correlation between Vitamin D insufficiency and infertility. Regarding female infertility, it was found that Vitamin D insufficiency is associated with increased issues during conception and higher miscarriage rate. Furthermore, Vitamin D insufficiency is associated with lower FSH levels affecting follicle formation, maturation and ovulation. Regarding male infertility, Vitamin D and its Receptor have been identified in the prostate, seminal vesicles, epididymis, germ cells, spermatogonia, spermatocytes and Sertoli cells. The prevalence of Vitamin D insufficiency is higher among men with lower sperm count and lower motility. However, the relation between Vitamin D and testosterone levels remain unclear. The present review stresses the effects of Vitamin D insufficiency in both male and female infertility.

SAT597 Pituitary Abscess Growing Serratia Marcescens With Associated Clivus Osteomyelitis

Abstract Disclosure: S. Brown: None. J. Milosavljevic: None. J. Chai: None. B.Y. Wong: None. Background: Pituitary abscesses are a rare etiology for pituitary lesions (0.2%-1.1%). Up to 60% of abscesses do not have an obvious source of infection. Pituitary abscesses can develop from the spread of local infection (usually the sphenoid sinus or cavernous sinus). Commonly isolated organisms of pituitary abscesses are gram positive cocci (Staphylococcus and Streptococcus) or gram negative bacilli (E. coli, Neisseria, and Corynebacterium). We present a case of a pituitary abscess growing Serratia marcescens with associated clivus osteomyelitis. Clinical Case: A 26-year-old woman with a history of recurrent left ear infections presented with right eye pain, sixth cranial nerve palsy and headaches. Brain MRI revealed 1.2 x 0.9 x 1.2 cm septated, cystic-appearing, rim-enhancing lesion originating from the sella, exerting mild pressure on the optic chiasm and infiltrating the right cavernous sinus. Contrast-enhanced CT scan revealed sclerotic and erosive changes concerning for clivus osteomyelitis and petrous apicitis. Hormonal evaluation demonstrated panhypopituitarism with undetectable cortisol (&amp;lt;1.0 µg/dL, n = 4-20 µg/dL), low ACTH (2.8 pg/mL, n = 7.2-63.3pg/mL), low-normal FT4 (0.6 ng/dL, n = 0.6-1.5ng/dL), low-normal TSH (0.32 µU/mL, n = 0.3-4.2µU/mL), undetectable estradiol (&amp;lt;25 pg/mL, n = 10-400pg/mL), low FSH (4.1 mIU/mL, n = &amp;lt;20 mIU/mL), low LH (0.5 mIU/mL, n = &amp;lt;10 mIU/mL), elevated prolactin (79 ng/mL, n&amp;lt;25ng/mL), and normal IGF-1 (192 ng/mL, n = 63-373ng/mL). Blood cultures, HIV testing, hepatitis serologies, Aspergillus galactomannan and cryptococcal antigen were negative. Replacement with hydrocortisone and levothyroxine was initiated, as well as empiric treatment with ceftriaxone, vancomycin, and metronidazole. Patient then underwent trans-sphenoidal evacuation of the sellar abscess. Specimen cultures grew Serratia marcescens. Post-operatively, she developed arginine vasopressin (AVP) deficiency and was started on desmopressin. Her symptoms and sixth nerve palsy resolved after surgery, and she was discharged with hormone replacements and a 6-week course of ceftriaxone. Conclusion: While other Enterobacteriaceae have previously been isolated from pituitary abscesses (including E. coli, Citrobacter, Salmonella, Proteus and Klebsiella), our case demonstrates, to the best of our knowledge, the first case of Serratia isolated from a pituitary abscess. Serratia is considered to be an opportunistic pathogen, although this patient had no identifiable risk factors for immunosuppression. Also, pituitary abscesses commonly spread from local infections. However, the source of infection in this case is likely the clivus osteomyelitis, which to the best of our knowledge, also has never been reported. In summary, this case differs from other reported cases due to the pituitary abscess growing Serratia with a potential source from the clivus osteomyelitis. Presentation: Saturday, June 17, 2023

FRI330 A Rare Case Of Hypogonadotropic Hypogonadism In A Patient With Disseminated Tberculosis And Tuberculoma Involving Tuberculum Sellae

Abstract Disclosure: J.S. Genkil: None. S. Ahsun: None. N. Mohan: None. C. Anastasopoulou: None. Introduction: Central nervous system (CNS) tuberculosis accounts for 1-10% of all tuberculosis (TB) infections and has been known to lead to irreversible consequences. CNS TB may present variably as meningeal tuberculosis, tuberculoma, tuberculous abscess, hydrocephalus, ventricular involvement or cerebritis. Tuberculomas involving the sellar region are amongst the rarest of presentations. We describe a unique case of hypogonadotropic hypogonadism with CNS tuberculoma. Case: A 46-year-old male with depression, alcohol use, tobacco smoking, and daily K2 spice use presented to the hospital with multiple days of upper extremity weakness, seizures, and slurred speech. Head CT was done that showed a soft tissue density with mild hypoattenuation on the right frontal region. MRI of the brain showed 3 round 4-5mm lesions with rim enhancement in the frontal lobes. Chest CT showed apical lung lesion. It was believed that patient had a malignant process with metastasis to the brain. During his course, it was discovered that he had TB exposure from his mother several months ago. Despite multiple negative AFB sputum samples, left lung biopsy confirmed TB diagnosis. He was subsequently diagnosed with tubercular meningitis with tuberculomas, one of them involving tuberculum sellae. The patient was started on antitubercular treatment with isoniazid, rifampin, pyrazinamide, streptomycin, and dexamethasone. Lab revealed normal thyroid studies, but very low total testosterone&amp;lt;20 ng/dl (Normal 220-872 ng/dl), with low FSH=2.6 IU/L (Normal 1-12 IU/L) and LH=0.8 IU/ml (Normal 0.6-12.1 IU/ml), with normal prolactin=7.9 ug/L (Normal 3.5-19.4 ug/L). To treat hypogonadotropic hypogonadism, the patient was started on weekly testosterone supplementation with testosterone cypionate 50 mg subcutaneous injections. Ultimately the patient was discharged to a full-time nursing facility and made significant clinical and functional improvement. Discussion: TB of the CNS is among the least common of extra pulmonary tuberculosis yet is associated with the most devastating manifestations making it a feared complication of TB. These lesions are associated with high rates of morbidity and mortality despite appropriate therapy so prompt diagnosis is key. CNS tuberculomas may present isolated or in combination with pulmonary TB. They are unique as they may masquerade as other intracranial space occupying lesions such as tumors or hematomas, further complicating diagnosis. In particular, sellar and suprasellar region tuberculomas are rare and can present with varied amount of hypopituitarism. In the patient’s case, he developed hypogonadotropic hypogonadism which was successfully treated with testosterone replacement. Hypogonadotropic hypogonadism can only be recognized if there is a high index of suspicion and can result in improvement of the quality of life with preservation of sexual function. Presentation: Friday, June 16, 2023

THU131 Functional Hypogonadotropic Hypogonadism And Failure To Thrive In A Poorly Controlled Type 1 Diabetes Patient

Abstract Disclosure: P. Rakhra: None. V. Wright: None. I. Athanassaki: None. Background: Multiple reports exist of obese males with type 2 diabetes linked to hypogonadotropic hypogonadism. We report a rare case of poorly controlled type 1 diabetes leading to functional hypogonadotropic hypogonadism as well as failure to thrive. Clinical Case: A 16-year-old Caucasian male with type 1 diabetes, antibody positive, diagnosed at 3 years of age presented in severe diabetic ketoacidosis. Patient had been lost to follow-up and had not had a clinic visit in over three years. He had reportedly been using a family member’s Tresiba and over the counter Humulin in the interim. Upon presentation, his hemoglobin A1c was found to be 11.8%. It was last documented at greater than 14%. He was also at less than the first percentile for height and weight, with a BMI of 16 kg/m2. His mid-parental height was 68.5 inches (25 – 50th percentile). His physical exam was remarkable for Tanner III pubic hair with 12 cc testicular volume bilaterally. Biochemical analysis revealed LH was in pubertal range of 0.5 mIU/mL (0.2 – 2.3 mIU/mL), low FSH &amp;lt;0.7 mIU/mL (0.7 – 6.2 mIU/mL), and low testosterone 7.7 ng/dL (200 – 1036 ng/dL). IGF-1 was low at 49 ng/mL (230 – 769 ng/mL) and low IGF-BP3 at 2.6 mg/L (3.1 – 8.9 mg/L). Bone age per the standards of Greulich and Pyle was delayed at 14 years with a predicted adult height of 68 inches. Associated conditions known to cause failure to thrive in patients with diabetes, such as adrenal insufficiency, hyperthyroidism, and celiac disease were ruled out. ACTH stimulation test revealed cortisol peak of 24.6 ug/dL (&amp;gt;18.0 ug/dL). TSH was normal 2.474 mIU/mL (0.5 – 3.4 mIU/mL) and normal Free T4 0.8 ng/dL (0.8 – 2 ng/dL). Mauriac syndrome was considered however, patient lacked any Cushingoid features, did not have hepatomegaly on exam, and had normal liver function tests. A brain/pituitary MRI was performed prior to discharge and was found to be normal, ruling out concerns for a central lesion causing delayed puberty. Patient was able to gain weight during the admission with intensive insulin management. However, he remains less than the first percentile for height and weight. A growth hormone stimulation test (with clonidine and arginine) was performed outpatient. Patient was primed with estrace prior to the test and results revealed a peak of 15.0 ng/mL (&amp;gt;10 ng/mL) ruling out concerns for growth hormone deficiency. Conclusion: We report this case to highlight that although uncommon in the developed world, delayed puberty and growth failure are known but rare complications of poorly controlled type 1 diabetes. Presentation: Thursday, June 15, 2023

SAT627 Is Cyberknife Stereotactic Radiosurgery Effective For Treating Cushing’s Disease?

Abstract Disclosure: G. Wintermyer: None. E. Villanueva: None. Patients with pituitary adenoma can often present with endocrine abnormalities. Transsphenoidal surgery(TSS) is the “gold standard” treatment. In patients with recurrent or post-surgery remaining adenoma, stereotactic radiosurgery with CyberKnife (CKRS) has demonstrated to be a good adjuvant therapy. Occasionally patients develop hypopituitarism and adrenal insufficiency (AI) post CKRS. Here is a patient with ACTH-secreting pituitary adenoma with Cushing’s disease who developed remission afterCKRS:52-year-old-male with PMHx of T2DM, hypothyroidism, HTN presented to hospital complaining of fatigue, ataxia, 40-lbs weight loss over four months and mood changes. Due to ataxia, CT of the head was done which revealed an Empty Sella. During the workup, ACTH and cortisol were detected 131 pg/mL and 37.5 ug/dL respectively. After ruling out life-threatening medical conditions, he was discharged with endocrinology referral for Empty Sella syndrome (ESS) and elevated ACTH. During endocrinology evaluation, patient was sent for testosterone, LH, FSH, ACTH, AM cortisol, prolactin and DHEAS tests. Results were as follows: elevated ACTH (91 pg/mL) and Cortisol (33.5ug/dL), elevated DHEAS (401 ug/dL) and prolactin (15 NG/dL), low testosterone (72 NG/dL), within appropriately low LH and FSH. Later, PM Salivary cortisol level, Dexamethasone suppression test(DST), and urine free cortisol (UFC) level were tested. He had pituitary MRI concurrently. Salivary cortisol and UFC were high. There was no suppression of cortisol level after DST. Pituitary MRI demonstrated pituitary tumor. He was diagnosed with Cushing’s disease and was referred to neurosurgery for pituitary tumor TSS. Patient was started on Ketoconazole prior to surgery. Pathology confirmed ACTH-secreting pituitary adenoma. After surgery, Cortisol level normalized, and the patient regained his energy. Post-surgery MRI showed complete resection of adenoma. Ketoconazole was discontinued post-operatively. Two years later, during routine workup, there were elevations in 24-hour and PM salivary cortisol levels. The patient was asymptomatic. He failed his DST. Repeat pituitary MRI showed small hypo enhancement at the bottom of Sella suspicious for pituitary adenoma recurrence. The patient underwent CKRS. Cortisol level and pituitary axis activity remained normal since CKRS. No change was noted in the six-month and one-year surveillance MRI. Even though TSS is a “gold standard” treatment for pituitary adenoma, the likelihood of remaining residues or recurrence of the tumor is high. Frequent pituitary hormone checks can detect recurrence of adenoma before emerging symptoms. CKRS should be considered as a therapeutic option for recurrent adenoma. Clinicians should frequently check patients for hypopituitarism and AI post-CKRS. Clinicians should also recognize that ESS may contribute to MRI-negative Cushing’s disease. 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

THU200 Three Cases Of Prepubertal Vaginal Bleeding

Abstract Disclosure: H. Doi: None. M. Igarashi: None. T. Kashima: None. N. Ujita: None. H. Konno: None. A. Fujioka: None. H. Miyagi: None. K. Yoshii: None. Y. Naiki: None. R. Horikawa: None. Introduction: Children with prepubertal vaginal bleeding (PVB) are usually referred to pediatric endocrinologists, because precocious puberty is one of the important causes of PVB. However, the diagnosis remains challenging due to a wide variety of causative diseases beyond endocrinological disorders. We present three illustrative cases of children with PVB in our institution. Case presentations: Case 1. A 2-year-old girl had suppressed serum LH and FSH levels and elevated estradiol level. She had café-au-lait spots with jagged “coast of Maine” borders on her left chest and back. Her bone X ray showed multiple fibrous dysplasia. The diagnosis of McCune-Albright syndrome was made by a triad of skin, bone and hyperfunctioning endocrinopathy. Case 2. A 5-year-old girl had low serum LH, FSH, and estradiol levels. Her pelvic MRI showed a mass in her vagina and contrast enhancement of the vaginal membrane. Although some malignant tumor had been suspected, vaginal observation using cystoscopy revealed a foreign body of a sponge that seemed to be part of a toy. Her vaginal bleeding disappeared after removal. Our multidisciplinary team concluded that this case was not child abuse. Case 3. A 4-year-old girl had been misdiagnosed as central precocious puberty due to slightly elevated gonadotropin levels. She was referred to our hospital because gonadal suppression therapy with leuprorelin didn’t stop her PVB. Although the observation of her urethra, bladder, vagina, and uterus using cystoscopy revealed no abnormal findings, a small fistula on the membrane of her vaginal opening was noted. Finally, the diagnosis of von Willebrand’s disease type I was made by low level of von Willebrand factor. We speculated that her repeated bleeding was triggered by minor trauma with the background of bleeding tendency. When severe bleeding occurs or is expected to occur, factor VIII containing von Willebrand factor should be administered. Discussion: There are various etiologies of PVB. Detailed history taking and physical examination are quite important, but might be difficult for young pediatric patients. Neoplasms and sexual abuse must be ruled out. In case of suspicion of abuse, the patient’s safety should be guaranteed. Inspection using cystoscopy under general anesthesia is a useful option in recurrent PVB cases. It is critical to make the correct diagnosis because the treatments can be totally different. Conclusion: In PVB cases we need to perform detailed assessments including careful history taking, physical examination and necessary testing considering a broad range of possible diseases. Presentation: Thursday, June 15, 2023

FRI382 High Androgen And Progesterone Metabolite Concentrations In Naturally Matured Follicles Are Concurrent With High Serum Anti-Müllerian Hormone Concentrations

Abstract Disclosure: T. Du Toit: None. M. Von Wolff: None. A.C. Swart: None. M. Groessl: None. C.E. Flueck: None. Infertility in women is routinely evaluated with the assessment of circulating steroid levels. Profiling steroid levels in follicular fluid (FF) would provide a focused evaluation of the ovarian endocrine milieu and is therefore better suited to identify key hormones potentially involved in dysfunctional follicular growth. The anti-Müllerian hormone (AMH) level in serum is a well-established clinical marker to estimate the ovarian reserve in assisted reproductive technology, while the AMH level in FF serves as a new prognostic marker for oocyte developmental potential. However, AMH-linked changes in the follicular steroid milieu have not been fully explored. We conducted an AMH-dependent analysis of the FF endocrine milieu. Hormones were quantified using LC-MS (n=42) and ELISA (n=4) in FF of 83 women undergoing natural cycle in vitro fertilisation. Patients were age-matched and classified into 4 statistically different (p&amp;lt;0.0001) groups according to serum AMH levels: group A (&amp;lt;1.1 pmol/L, n=20); group B (1 - 7.14 pmol/L, n=21); group C (7.14 - 35.5 pmol/L, n=21); and group D (&amp;gt;35.5 pmol/L, n=21). Group D was designated as our polycystic ovary syndrome (PCOS)-like group, as high serum AMH is a marker for PCOS. We characterised androgen and progesterone metabolic pathways in FF. Androstenedione (A4) and testosterone (T) levels differed significantly between the groups (p&amp;lt;0.01) and were highest in group D at 60 nmol/L and 4.7 nmol/L, respectively. The levels of 11-ketoandrostenedione (11KA4) and 11β-hydroxyandrosterone (adrenal-origin) also differed between the groups (p&amp;lt;0.05), with higher 11KA4 levels (±2.7-fold) quantified in group D. In parallel with serum AMH, FF AMH differed between the groups (p&amp;lt;0.0001), together with luteinizing hormone/FSH, A4/dehydroepiandrosterone, estradiol(E2)/T and E2/A4 ratios. In comparison to groups A, B and C combined, the PCOS-like group D showed significantly increased downstream progesterone metabolite levels –11α-hydroxyprogesterone [OHP4], 17α,20α-diOHP4, 16α-OHP4 and 5α-pregnanolone, with lower FSH levels. Our results show that the follicular milieu is significantly different when high AMH levels are measured compared to when AMH levels are low, marked by: (i) higher progesterone metabolite levels in follicles and (ii) higher A4 and T levels, concomitant with unchanged E2 levels suggesting that androgens were not fully converted to estrogens in these follicles. Our study furthermore corroborates other studies reporting an intrafollicular hyperandrogenic state in women with increased circulatory AMH levels. In summary, our study not only provides data based on a broad steroid profile that the follicular androgen endocrine milieu is affected in women with high serum AMH levels, but it also provides a model for the premature progesterone increase in PCOS women which leads to a reduction in the embryo implantation rate. Presentation: Friday, June 16, 2023

Response to Controlled Ovarian Stimulation Is Not Impaired in Young Patients with a Sarcoma: Results from a Monocentric Case-Control Study.

Sarcomas are relatively common in the young and their treatment can impair fertility. Fertility preservation can be achieved via the cryopreservation of gametes after controlled ovarian stimulation before cancer treatment. A reduced response to hormonal stimulation in patients suffering from certain types of malignancy is reported. The purpose of this study was to assess the performance of oocyte cryopreservation in patients with sarcoma by comparing their outcomes with those of a population without cancer. Patients were matched by age with control women undergoing hormonal stimulation for isolated male factor infertility. The population included 84 women with a sarcoma and 355 controls. In the final analysis, 37 patients with sarcoma were matched in a 1:3 ratio with 109 healthy controls. Patients with sarcoma were generally younger and were stimulated with lower FSH doses. They did not perform worse than controls during stimulation, with an average retrieval of 10.6 oocytes vs. 8.1 in the controls. Linear regression on the number of retrieved mature oocytes confirmed that patients with sarcoma performed comparably to controls. In conclusion, patients with sarcoma can expect retrieval outcomes comparable to those of patients without cancer.

Ovarian Response can be Predicted in Women with PCOS who have Ovulation Induction with Letrozole

To compare the clinical, metabolic, and hormonal characteristics of patients with and without selected dominant follicles in infertile women with PCOS who used letrozole for ovulation induction. A descriptive cohort study. Department of Obstetrics and Gynaecology of Bagcilar Research and Training Hospital, Istanbul, Turkey, from October 2019 to November 2021. Eighty-eight female patients with PCOS, who underwent ovulation induction by giving 5mg/day letrozole, were screened for demographic characteristics, laboratory values, and dominant follicle development. Those who were given letrozole as the first treatment agent, those who took clomiphene citrate (CC) and started letrozole the following month, and those who were treated with letrozole and given letrozole again were recorded separately. Seventy-five patients responded to letrozole and developed a dominant follicle; 13 patients did not develop a dominant follicle. Threshold values were determined for statistically significant parameters between patients with and without dominant follicles. Follicle development occurred in 85.2% of the women. A statistically significant variable in clinical and metabolic values, between ovulating and non-ovulating groups could not be found. There was a significant difference between the two groups for the serum AMH value, total testosterone value, and FSH level. The authors found that follicle response was higher in those with AMH values less than 11.89ng/mL, FSH levels higher than 6.25Iu/L, and total testosterone less than 0.96ng/mL. In this study, the pregnancy rate was found to be lower than in the literature(11%). Among the women with PCOS who had ovulation induction with letrozole, follicle development was higher in women with lower FSH, androgen and AMH values. Letrozole, Aromatase inhibitor, Androgens, Ovulation induction, AMH.