Low LH Levels Research Articles

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

Effect of Choline Inositol and Metformin Combination Versus Metformin Alone on Ovarian Activities in PCOS Iraqi Women: A Cross Sectional Study

Abstract: Polycystic ovary syndrome (PCOS) is a predominant endocrine sickness disturbing females. It is marked via unequal menstrual cycles, hyper-androgenism, and polycystic ovarian morphology. Furthermore, PCOS is linked to several health issues, including insulin resistance and metabolic syndrome. PCOS management encompasses a range of strategies and treatments. Medications acting on hormones, including insulin sensitizers such as inositol and metformin, are commonly used to treat PCOS symptoms. Also choline is other potential therapies that could improve reproductive health. It has been suggested to be beneficial in various aspects of fertility, including endocrine disorders like polycystic ovarian syndrome (PCOS). Aim of the study: The current study aims to determine the effect of choline inositol and metformin combination versus metformin alone on ovarian. Materials and methods: This study was performed at the Maternity and Paediatrics Teaching Hospital in ALdiwaniyah Province, Iraq. The study involved a total of (150) patients at (18- <40) years. A gynecologist uses Rotterdam criteria and ultrasound ovarian morphology in the selection of PCOS patients. The study consisted of several groups: G1 is a thirty women had received oral Metformin 500 mg bid during meal for last three months and served as metformin group. G2 is a thirty women had received choline inositol supplement 500/500 mg per- oral twice daily for last three months and served as the choline inositol supplement group. G3 is a thirty women had received choline inositol and metformin combination, they received with the same above dose for last three months and served as the choline inositol and metformin combination group . G4 is a thirty women who have not received any treatment for PCOS and served as new diagnosis PCOS group. Finally G5 is a thirty healthy women control group (control group). Characteristics included body mass index, type of period (regular, irregular ,amenorrhea ) were evaluated for all the participants. Furthermore, follicle and ovary volume were measured for all women .Additionally, serum hormonal levels [prolactin, (FSH), (LH), (TSH)], test were done. Results: There was no important alteration in the mean age, TSH and prolactin among the five groups. The results showed that metformin had significantly lowered in BMI but the addition choline inositol to metformin showed more significantly lowering in BMI but new PCOS group had higher significant BMI than other groups followed by choline inositol group. Rate of amenorrhea and rate of cycle irregularity stayed considerably upper in metformin grouping paralleled to choline inositol and choline inositol + metformin combination groups but this rate was more significantly higher in new PCOS compared to other groups. Metformin had significantly higher LH level compared to other groups but choline inositol + metformin and choline inositol groups had significantly lower LH level and there were no significance in the mean of LH between Choline inositol + metformin and choline inositol groups. Moreover, choline inositol + metformin group showed more significant FSH normal followed by metformin and new PCOS then by choline inositol and lastly control group. Choline inositol followed by metformin showed a significance in the mean of follicle and ovary volume but when adding choline inositol to metformin it showed more significant improvement in follicle and ovary volume ,so positive pregnancy was only seen in choline inositol + metformin as compared to other groups.

GnRH agonist-only trigger, compared to dual trigger, reduces oocyte retrieval rate in high responders without affecting cumulative live birth rate.

This study compared, in high responders undergoing IVF treatment, GnRH agonist-only trigger and dual trigger on oocyte retrieval rate and cumulative live birth rate (LBR). The aim was to determine if the GnRH agonist-only triggers had provided outcomes comparable to dual trigger, while minimizing the risk of ovarian hyperstimulation syndrome (OHSS). A retrospective, matched case-control study was conducted at Taichung Veterans General Hospital, Taiwan, including women who underwent IVF/ICSI between January 1, 2014, and December 31, 2022. Inclusion criteria were: GnRH antagonist protocol and estrogen level >3,000 pg/ml on trigger day. Exclusion criteria were: immune/metabolic diseases, donated oocytes, and mixed stimulation cycles. Propensity score matching was applied to balance age, AMH level, and oocyte number between the GnRH agonist-only and dual trigger groups. Outcomes were analyzed for patients who had complete treatment cycles, focusing on oocyte retrieval rate and cumulative LBR. We analyzed 116 cycles in the agonist-only group, and 232 cycles in the dual trigger group. No inter-group difference was found in their age, BMI, and AMH levels. The dual trigger group had a higher oocyte retrieval rate (93% vs. 80%; p <0.05), while fertilization rates, blastocyst formation rates, and cumulative LBR were comparable. Notably, no OHSS cases had been reported in the GnRH agonist-only group, compared with 7 cases in the dual trigger group. GnRH agonist-only triggers resulted in a lower oocyte retrieval rate compared to dual triggers but did not significantly affect cumulative LBR in high responders. This approach effectively reduces OHSS risk without compromising pregnancy outcomes, making it a preferable option in freeze-all strategies, despite a longer oocyte pick-up duration and a medium cost. GnRH agonist-only trigger, however, may not be suitable for fresh embryo transfers or patients with low serum LH levels on trigger day.

Risk factors for poor oocyte yield and oocyte immaturity after GnRH agonist triggering.

What are the potential risk factors for poor oocyte recuperation rate (ORR) and oocyte immaturity after GnRH agonist (GnRHa) ovulation triggering? Lower ovarian reserve and LH levels after GnRHa triggering are risk factors of poor ORR. Higher BMI and anti-Müllerian hormone (AMH) levels are risk factors of poor oocyte maturation rate (OMR). The use of GnRHa to trigger ovulation is increasing. However, some patients may have a suboptimal response after GnRHa triggering. This suboptimal response can refer to any negative endpoint, such as suboptimal oocyte recovery, oocyte immaturity, or empty follicle syndrome. For some authors, a suboptimal response to GnRHa triggering refers to a suboptimal LH and/or progesterone level following triggering. Several studies have investigated a combination of demographic, clinical, and endocrine characteristics at different stages of the treatment process that may affect the efficacy of the GnRHa trigger and thus be involved in a poor endocrine response or efficiency but no consensus exists. Bicentric retrospective cohort study between 2015 and 2021 (N = 1747). All patients aged 18-43 years who underwent controlled ovarian hyperstimulation and ovulation triggering by GnRHa alone (triptorelin 0.2 mg) for ICSI or oocyte cryopreservation were included. The ORR was defined as the ratio of the total number of retrieved oocytes to the number of follicles >12 mm on the day of triggering. The OMR was defined as the ratio of the number of mature oocytes to the number of retrieved oocytes. A logistic regression model with a backward selection method was used for the analysis of risk factors. Odds ratios (OR) are displayed with their two-sided 95% confidence interval. In the multivariate analysis, initial antral follicular count and LH level 12-h post-triggering were negatively associated with poor ORR (i.e. below the 10th percentile) (OR: 0.61 [95% CI: 0.42-0.88]; P = 0.008 and OR: 0.86 [95% CI: 0.76-0.97]; P = 0.02, respectively). A nonlinear relationship was found between LH level 12-h post-triggering and poor ORR, but no LH threshold was found. A total of 25.3% of patients suffered from oocyte immaturity (i.e. OMR < 75%). In the multivariate analysis, BMI and AMH levels were negatively associated with an OMR < 75% (OR: 4.34 [95% CI: 1.96-9.6]; P < 0.001 and OR: 1.22 [95% CI: 1.03-1.12]; P = 0.015, respectively). Antigonadotrophic pretreatment decreased the risk of OMR < 75% compared to no pretreatment (OR: 0.72 [95% CI: 0.57-0.91]; P = 0.02). Our study is limited by its retrospective design and by the exclusion of patients who had hCG retriggers. However, this occurred in only six cycles. We were also not able to collect information on the duration of pretreatment and the duration of wash out period. In clinical practice, to avoid poor ORR, GnRHa trigger alone should not be considered in patients with higher BMI and/or low ovarian reserve, balanced by the risk of ovarian hyperstimulation syndrome. In the case of a low 12-h post-triggering LH level, practicians must be aware of the risk of poor ORR, and hCG retriggering could be considered. None. N/A.

Pretreatment with oral contraceptive pills in women with PCOS scheduled for IVF: a randomized clinical trial

Abstract STUDY QUESTION What is the effect of pretreatment with oral contraceptive pills (OCPs) on oocyte and embryo quality and pregnancy rates in women with polycystic ovary syndrome (PCOS) scheduled for IVF/ICSI cycles? SUMMARY ANSWER In women with PCOS who underwent a first or second IVF/ICSI cycle with a GnRH antagonist protocol and were randomized to start ovarian stimulation immediately, the quality of cleavage-stage embryos was non-inferior to pretreatment with OCP. WHAT IS KNOWN ALREADY PCOS in Asian populations is characterized by high levels of circulating LH in the early follicular phase. Previous studies indicated that inappropriately high LH levels might affect oocyte maturation and fertilization rates, and impaired embryo quality, consequently resulting in higher rates of impaired pregnancy and miscarriage in women with PCOS. OCPs are frequently used as pretreatment to lower LH levels in PCOS patients. STUDY DESIGN, SIZE, DURATION We performed a randomized controlled trial. After informed consent, women diagnosed with PCOS scheduled for their first or second IVF/ICSI cycle with a GnRH antagonist protocol were randomized to receive OCPs (OCP group) or start ovarian stimulation immediately, regardless of the day of the menstrual cycle (non-OCP group). Using a non-inferiority hypothesis, the sample size was calculated at 242 women. The study lasted from 7 February 2018 to 31 August 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 242 infertility patients with PCOS undergoing the first or second cycle of IVF or ICSI were enrolled and randomized into two groups. In the OCP group, recombinant FSH was started on Day 7 of the washout period after pretreatment with OCP. In the non-OCP group, recombinant FSH was started immediately regardless of the day of the menstrual cycle. All participants received standardized GnRH antagonist ovarian stimulation. The freeze-all strategy was applied to all participants. The primary outcome was the number of good-quality embryos on Day 3 after insemination. Secondary outcomes included the rates of blastocyst formation, implantation, clinical pregnancy, and live birth from the first frozen/warmed embryo transfer cycles and cumulative live birth rates. MAIN RESULTS AND THE ROLE OF CHANCE We randomized 242 women to receive OCP (n = 121) or start immediately with ovarian stimulation (n = 121). The number of good-quality embryos on Day 3 in the OCP group was non-inferior to the non-OCP group (OCP group versus non-OCP group, 6.58 ± 4.93 versus 7.18 ± 4.39, AD −0.61, 95% CI: −1.86 to 0.65, P = 0.34). The rates of blastocyst formation (55.4% versus 52.9%, relative risk (RR) 1.11, 95% CI: 0.96 to 1.28, P = 0.17), implantation (63.0% versus 65.5%, RR 0.90, 95% CI: 0.53 to 1.53, P = 0.79), clinical pregnancy (67.9% versus 68.8%, RR 0.96, 95% CI: 0.54 to 1.71, P = 1.0), and live birth rate (52.8% versus 55.1%, RR 0.92, 95% CI: 0.53 to 1.56, P = 0.79) of the first frozen/warmed embryo transfer cycles were all comparable between the OCP and non-OCP group, respectively. Cumulative live birth rates were also similar in the OCP and non-OCP groups (78.3% versus 83.5%, respectively RR 0.71, 95% CI: 0.36 to 1.42, P = 0.39). LIMITATIONS, REASONS FOR CAUTION Only patients with PCOS in Southern China were recruited. Therefore, caution is necessary when generalizing our results to all such patients with PCOS. Also, since a freeze-only strategy was used, the results of this study are only applicable when infertile women with PCOS undergo the freeze-only method. The obvious treatment difference between the two groups meant that the study was designed as an open-label study for women and doctors. The study had a randomized controlled design that minimized bias. WIDER IMPLICATIONS OF THE FINDINGS Pretreatment with OCPs to lower LH levels in patients with PCOS before ovarian stimulation in IVF or ICSI cycles may not improve the quality of cleavage-stage embryos. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the National Key Research and Development Program of China (No. 2023YFC2705503). This study was supported in part by the Investigator-Initiated Studies Program (grant from MSD and Organon). BWM reports consultancy, travel support, and research funding from Merck. He reports consultancy from Organon and Norgine, and also reports holding stock from ObsEva. No conflicts of interest are declared for the other authors. TRIAL REGISTRATION NUMBER Chinese Clinical Trial Registry (No. chiCTR1800014822). URL: https://www.chictr.org.cn/showproj.html?proj=25280 TRIAL REGISTRATION DATE 7 February 2018. DATE OF FIRST PATIENT’S ENROLLMENT 22 February 2018.

Hyperuricemia and testosterone deficiency: An underestimated correlation

Hyperuricemia and testosterone deficiency (TD) are two relatively common conditions in clinical practice. We conducted the present study on 9573 men to evaluate the association between the two conditions and establish a hypothetic explanation. Compared with the normal group, the hyperuricemia group has lower testosterone level (14.79 ± 5.55 vs. 17.12 ± 6.24, p &lt; 0.001) and lower LH level (5.57 ± 3.31 vs. 5.75 ± 3.21, p = 0.003). There is a weak negative correlation between testosterone and serum uric acid (SUA) after adjusting for confounding factors (Spearman's Rho = -0.2, p &lt; 0.001). On linear regression, serum uric acid corresponds to testosterone with the formula: Testosterone = -0.015 x SUA + 22.37. We hypothesize that the mechanism underlying testosterone deficiency in hyperuricemia patients is due to an inhibition of LH release of the pituitary. Further studies are needed to examine this hypothesis.

Analysis of genotype and phenotype in congenital hypogonadotropic hypogonadism with reversible gonadotropin deficiency: A case report

The case involved a 32-year-old male patient who experienced delayed puberty until the age of 18. He exhibited low levels of LH, FSH, and testosterone. Chromosome karyotyping revealed a 46XY genotype, while whole exon sequencing identified a missense mutation (c.337T&gt;C) in the PROKR2 gene. Pituitary MRI did not indicate the presence of any masses, leading to a clinical diagnosis of Congenital Hypogonadotropic Hypogonadism (CHH). The patient underwent hormone replacement therapy with HCG for 3 years, followed by long-term testosterone treatment. Interestingly, the patient demonstrated spontaneous sperm production without the need for gonadotropin therapy. His wife conceived naturally on four occasions, resulting in two miscarriages and two successful deliveries, indicating a reversal of the patient’s gonadal function. Bioinformatics analysis and analysis based on the guidelines provided by the American College of Medical Genetics and Genomics (ACMG) confirmed that the missense mutation c.337T&gt;C in the PROKR2 gene was a potential pathogenic variant. However, our study indicated that this specific mutation in the PROKR2 gene could not solely account for the observed reversal of gonadal function in this patient.

Serum LH level prior to progestin administration is significant on pregnancy and live birth in programmed frozen-thawed embryo transfer cycles.

To evaluate the impact of serum LH levels prior to progestin administration on the outcomes of programmed frozen-thawed embryo transfer (FET) cycles. Retrospective cohort study was conducted to compare the treatment outcomes between four groups based on the 25 percentiles of serum LH levels before progestin administration in 596 cycles of 518 patients undergoing artificial endometrial preparation protocols for FET. Primary outcome measures were ongoing and live birth rates. Secondary outcome measures were the pregnancy rates, clinical pregnancy rates, and pregnancy loss rates. The trends in clinical pregnancy (CPR) and live birth rates (LBR) increased from the first to the fourth quartile (Q1 to Q4) of serum LH levels prior to progestin administration (37,0% to 48,3%, p = 0.042, and 22.6% to 39.5%, respectively, p = 0.003). Pregnancy loss rates (PLR) were higher in group Q1, although the difference was not statistically significant. Based on a multivariate logistic regression analysis, a low serum LH level before progestin initiation was found to be the most significant predictor associated with a negative effect on live birth (OR: 0,421, 95% CI 0,178 - 0,994, p=0,048). The day of estrogen initiation was significantly correlated with serum LH levels and quartiles of serum LH levels before progestin administration (r=0,200, p=0,015 and r=0,215, p=0,009, respectively). The serum LH level prior to progestin administration significantly affects pregnancy and live birth rates in patients undergoing an artificial endometrial preparation protocol for FET. LH monitoring should be incorporated into the follow-up, in addition to assessing endometrial thickness and morphology in artificial FET cycles.

OR09-01 Mini-Puberty Could Be A Key Phase Regulating Reproductive Function In Female Mice

Abstract Disclosure: M. Chester: None. M. Devillers: None. L. Naule: None. F. Souaré: None. R. Corre: None. D. Quintas: None. C. Petrovic: None. J. Cohen-Tannoudji: None. S. Mhaouty-Kodja: None. C.J. Guigon: None. After birth, there is a transient activation of the hypothalamic-pituitary-ovary (HPO) axis, with high secretion of LH and FSH acting on the ovary to promote the secretion of sex steroids and in particular that of estradiol (E2). This period, called mini-puberty, occurs between 10-17 days postnatal (dpn) in mice. During reproductive life, E2 plays an important role on the HPO axis by regulating GnRH pulsatility and, thus, the cyclic fluctuations of gonadotropin hormone levels required for follicular development and ovulation. E2 acts on hypothalamic kisspeptin neurons of the arcuate (ARC) and the anteroventral periventricular nucleus (AVPV), which project to GnRH neurons and regulate their activity by negative and positive feedbacks, respectively. The possibility that E2 contributes, during mini-puberty, to the maturation of hypothalamic structures involved in puberty onset and reproductive function, has never been investigated. The aim of this study was to elucidate the putative roles of mini-puberty on reproduction. We developed a mouse model injected with a GnRH receptor antagonist (GonadoSTOP mice) suppressing LH and FSH surges to cause a 50% decrease in E2 levels during mini-puberty. Our results show that GonadoSTOP mice exhibited later first diestrus 2 (D2) (31.0 dpn versus 29.9 dpn in CTR; n=55-56 mice/group; P=0.0285), suggesting a possible delay in the timing of puberty. During reproductive life, GonadoSTOP mice spent a longer % of time in D2 than control mice, with no alteration in total estrous cycle time (64.4% versus 56% in CTR; n=18-19 mice/group; P=0.0350). Immunohistochemical analysis of kisspeptin neurons in ARC and AVPV of ovariectomized and hormonally-primed mice showed that their numbers were significantly lower in AVPV from GonadoSTOP mice than in control mice (n=5-6 brains/group; P=0.038). In fertility studies, we observed no difference in the time to conception or % of pregnant mice between the two groups at early reproductive life (3, 4 and 5 months). Contrary to these results, at the time of reproductive decline in control mice (11 months), a substantial % of GonadoSTOP mice could still be pregnant (47% versus 18% of CTR mice; P=0.0017). At this age, GonadoSTOP mice had lower LH levels than control mice (P=0.0074), but similar levels to young control mice at 4 months (P&amp;gt;0.05). RT-qPCR analyses of markers reflecting ovarian activity (Cyp19a1, Inhbb, Amh, Gdf9) at 4 and 11 months revealed that ovarian aging occurred similarly in both groups, suggesting that reproductive longevity in GonadoSTOP mice does not have an ovarian origin. Taken together these data suggest that transient and sustained activation of the HPO axis at mini-puberty may regulate key aspects of reproductive function with long-term impact on fertility, possibly by acting on the hypothalamus. Presentation: Friday, June 16, 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

Gonadotropin Levels and Underlying Diseases in Adolescent With Secondary Amenorrhea.

To provide characteristics and hormonal profiles of secondary amenorrhea cases in adolescent patients treated at Hasan Sadikin General Hospital in Bandung. The study was retrospective in nature and involved the analysis of medical records from 2017 to 2022 for 44 adolescent patients aged 10-18 who had secondary amenorrhea. There were 44 adolescents included in this study after excluded 69 adults from 113 secondary amenorrhea cases. The majority of patients were 14-17 years old (38.63%), in senior high school (45.45%), had started menarche at 11 years old (45.45%), had normal nutritional status (65.91%), and had normal stature (65.91%). The underlying diseases found in most patients were systemic lupus erythematosus (SLE) and tuberculosis. Among the patients, 29 had FSH, LH, and estradiol levels measured. The results of hormonal assays showed a wide range of abnormal serum levels, with normal to low concentrations of FSH and low levels of LH and estradiol. The median (interquartile range) results for FSH, LH, and estradiol were 4.57 (0.64, 90.65), 1.635 (0.06, 55.76), and 24.3 (0.2, 154.71), respectively. Positive significant correlation between FSH and LH (p < 0.01) was found in children with secondary amenorrhea. Hormonal assay for FSH, LH, and Estradiol showed a wide range of abnormal serum level. Normal to low concentration levels of FSH and low LH and estradiol. The majority of secondary amenorrhea patients are associated with autoimmune disease and infection.

P-617 Combined oral contraceptive pill (COCP) pre-treatment and progestin-primed ovarian stimulation (PPOS) protocol: a detrimental combination for the oocyte yield in egg donation programs

Abstract Study question Could the use of combined oral contraceptive pill (COCP) pre-treatment before controlled ovarian hyperstimulation (COH) have a negative effect on oocyte yield in normo-responders patients? Summary answer When COH with progestin-primed ovarian stimulation (PPOS) protocol in normo-responders patients is performed, the COCP pre-treatment could have a detrimental effect on oocyte yield. What is known already COCP pre-treatment is widely used to schedule the start of COH and to organize the working week, but its usefulness and efficiency are still not clear. Most of studies on IVF outcomes have shown no effect of COCP on oocyte yield. For oocyte donation only few studies were carried out showing controversial effects on oocyte yield, but all considered short antagonist or long agonist protocols and no one PPOS protocol. COCP leads to long lasting pituitary suppression and lower LH level in follicular phase that could reduce the ability to effectively respond to GnRH-agonist trigger leading to poor oocyte yield. Study design, size, duration The egg donation cycles carried out from January to September 2022 in Next Fertility Valencia were retrospectively analyzed. Two analyses were conducted. Analysis A, comparative retrospective cohort study of 397 COH cycles: 290 with COCP and 107 without COCP. Analysis B, comparative retrospective paired study of 90 COH cycles: 45 with COCP and 45 without COCP, in which, to attempt to eliminate possible bias due to interpersonal differences, every patient was her own control. Participants/materials, setting, methods All donors underwent to COH with FSH monotherapy, PPOS protocol for pituitary suppression and a GnRH-agonist triggering. The oocyte yield was analyzed focusing on: the number of oocytes retrieved, mature (MII) oocytes and useful oocytes (good mature oocytes used for ICSI), the appropriate response to the GnRH-agonist trigger, the stimulation days, the total gonadotropins dose used and the cancellation rate (for low response or low LH level in follicular phase the first day of COH). Main results and the role of chance In both analyses, the data showed no differences in terms of stimulation days, total FSH dose, number of follicles ≥ 15 mm on the trigger day regardless of use of COCP. After conducting the analysis based on the administration or not of COCP, in the Analysis A a higher number of total oocytes retrieved, mature oocytes and useful oocytes were found in the group that did not used COCP. A significant difference in a nominal variable (Pearson's chi-square test) was observed, consisting of a higher proportion of cancellations due to low LH level (&amp;lt; 2,5 mUI/ml) in the group that used COCP (COCP no: 0.7% vs. COCP yes: 3.7% ). While, in the Analysis B (analysis of variance of one factor, Anova test), the variables total oocytes retrieved, total MII oocytes and total useful oocytes showed significant differences consisting of a higher number of oocytes in the group that did not received COCP. These results have statistical significance both before removing the cases in which the values were 0 due to a cancellation (p &amp;lt; 0.01), and after removing the cancelled cases (p &amp;lt; 0.05). Limitations, reasons for caution The main limitation lies in the retrospective nature of the study. However, since each patient is her own control (Paired study), it gives an added value. Wider implications of the findings COCP before COH in PPOS cycles could have detrimental effects on oocyte yield, reducing the efficacy and efficiency of egg donation programs. This could be extended to social freezing programs in normo-responders patients, in which the probability of future pregnancy is closely linked to the number of good oocytes vitrified. Trial registration number Not Applicable

McCune-Albright Syndrome: A-rare-case report

McCune-Albright syndrome (MAS) is a rare genetic disordered originally recognized by the triad of polyostotic fibrous dysplasia, precocious puberty, and cafe-au-late spots. We report a case of 2 years-11-month-old girl who came with complaints of menstruation 5 days ago. Breasts appear enlarged. On physical examination, it appears that the café au lait region of the abdomen and left femur resembles the "coast of Maine". There was an increase in the levels of FT4, estradiol, and alkaline phosphatase, and low TSHs, LH, and FSH levels. The radiological examination of the bones of the left hand corresponded to the bone age of 6 years. Bone survey photo showing multiple lytic and blastic lesions in the proximal 1/3 of the left femur. We are monitoring this patient, and planning to administer Tamoxifen and Zoledronic acid. Tamoxifen (an estrogen agonist/antagonist) or Letrozole (an aromatase inhibitor) have been used for the management of precocious puberty and rapid bone maturation. Despite differing in presentation, all patients with precocious puberty were successfully treated with Tamoxifen and/or Letrozole, to emphasize the significant progress of bone age. A systematic approach to diagnosis and management is essential to optimize outcomes for patients with MAS, especially with fibrous dysplasia. No medical therapy is able to change the course of the disease in fibrous dysplasia. However, screening and treatment for endocrinopathy can reduce some bone morbidities.

A mouse model mimicking gender-affirming treatment with pubertal suppression followed by testosterone in transmasculine youth.

Can mice serve as a translational model to examine the reproductive consequences of pubertal suppression with GnRH agonist (GnRHa) followed by testosterone (T) administration, a typical therapy in peripubertal transmasculine youth? An implanted depot with 3.6 mg of GnRHa followed by T enanthate at 0.45 mg weekly can be used in peripubertal female mice for investigating the impact of gender-affirming hormone therapy in transmasculine youth. There is limited knowledge available in transgender medicine to provide evidence-based fertility care, with the current guidelines being based on the assumption of fertility loss. We recently successfully developed a mouse model to investigate the reproductive consequences of T therapy given to transgender men. On the other hand, to our knowledge, there is no mouse model to assess the reproductive outcomes in peripubertal transmasculine youth. A total of 80 C57BL/6N female mice were used in this study, with n = 7 mice in each experimental group. We first assessed the effectiveness of GnRHa in arresting pubertal development in the female mice. In this experiment, 26-day-old female mice were subcutaneously implanted with a GnRHa (3.6 mg) depot. Controls underwent a sham surgery. Animals were euthanized at 3, 9, 21 and 28 days after the day of surgery. In the second experiment, we induced a transmasculine youth mouse model. C57BL/6N female mice were subcutaneously implanted with a 3.6 mg GnRHa depot on postnatal day 26 for 21 days and this was followed by weekly injections of 0.45 mg T enanthate for 6 weeks. The control for the GnRH treatment was sham surgery and the control for T treatment was sesame oil vehicle injections. Animals were sacrificed 0.5 weeks after the last injection. The data collected included the day of the vaginal opening and first estrus, daily vaginal cytology, weekly and terminal reproductive hormones levels, body/organ weights, ovarian follicular distribution and corpora lutea (CL) counts. GnRHa implanted animals remained in persistent diestrus and had reduced levels of FSH (P = 0.0013), LH (P = 0.0082) and estradiol (P = 0.0155), decreased uterine (P < 0.0001) and ovarian weights (P = 0.0002), and a lack of CL at 21 days after GnRHa implantation. T-only and GnRHa+T-treated animals were acyclic throughout the treatment period, had sustained elevated levels of T, suppressed LH levels (P < 0.0001), and an absence of CL compared to controls (P < 0.0001). Paired ovarian weights were reduced in the T-only and GnRHa+T groups compared with the control and GnRHa-only groups. N/A. Although it is an appropriate tool to provide relevant findings, precaution is needed to extrapolate mouse model results to mirror human reproductive physiology. To our knowledge, this study describes the first mouse model mimicking gender-affirming hormone therapy in peripubertal transmasculine youth. This model provides a tool for researchers studying the effects of GnRHa-T therapy on other aspects of reproduction, other organ systems and transgenerational effects. The model is supported by GnRHa suppressing puberty and maintaining acyclicity during T treatment, lower LH levels and absence of CL. The results also suggest GnRHa+T therapy in peripubertal female mice does not affect ovarian reserve, since the number of primordial follicles was not affected by treatment. This work was supported by the Michigan Institute for Clinical and Health Research grants KL2 TR 002241 and UL1 TR 002240 (C.D.C.); National Institutes of Health grants F30-HD100163 and T32-HD079342 (H.M.K.); University of Michigan Office of Research funding U058227 (A.S.); American Society for Reproductive Medicine/Society for Reproductive Endocrinology and Infertility grant (M.B.M.); and National Institutes of Health R01-HD098233 (M.B.M.). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core Facility was supported by the Eunice Kennedy Shriver NICHD/NIH grants P50-HD028934 and R24-HD102061. The authors declare that they have no competing interests.

State of sexual development in children with congenital epidermolysis bullosa

Purpose of the study. Assess the state of sexual development in children with CEB.Methods and materials. The study included 50 children aged 8.11 to 17.80 years with CEB who were treated at the National Medical Research Centre for Children’s Health (Moscow, Russia) from December 2020 to April 2022. Anthropometric parameters, the stage of sexual development on the Tanner scale, bone age, the level of pituitary (FSH, LH) and sex (estradiol, testosterone) hormones, additional hormonal parameters (cortisol, DHEA-sulfate, 17OHP, ACTH, prolactin, TSH, T3, T4, insulin), ultrasound of the pelvic organs for girls and ultrasound of the scrotum organs in boys, the results of a psychological and pedagogical examination (questionnaire according to S. Bem, ‘drawing of a person’ by K. Machover, D. Wechsler’s test) were assessed in all patients. The data are presented using median (Me), quartiles of 25 and 75% [Q25; Q75] and standard error (SE). Due to the small number of observations, nonparametric statistical criteria were used to assess the significance of the differences in the obtained indicators.Results. According to the results of the study, a statistically significant relationship was established between the occurrence of deviations in sexual development in children with CEB and the clinical form of the disease (p &lt; 0,001). The severity of clinical manifestations of CEB according to the EBDASI scale was significantly higher in children in the group with deviations in sexual development (p = 0,000) compared with the group of children with normal sexual development. Anthropometric indicators of BAZ and HAZ in the group of children with deviations in sexual development were statistically significantly reduced (p = 0.000, p = 0.000, respectively) compared with children with normal sexual development, which means a significantly higher incidence of malnutrition in this cohort of patients. Basal levels of FSH and LH (p = 0,000, p = 0,001, respectively), estradiol and testosterone (p = 0,002, p = 0,000, respectively) were significantly lower in children with abnormalities in sexual development compared with children with normal sexual development. A statistically significant relationship was revealed in the studied groups with the stage of sexual development according to Tanner scale (p = 0,032). Among all patients with CEB (n = 50), delay puberty was diagnosed in 7 patients (14%), while all patients suffered from RDEB and had low basal LH levels, reduced estradiol and testosterone values, which allowed them to be diagnosed with hypogonadotropic hypogonadism (HH).Conclusions. In patients with CEB with the most severe degree of clinical manifestations, accompanied by decompensated malnutrition of multifactorial genesis, there are deviations in sexual development and upon reaching the age of 13 years, girls and boys develop transient (symptomatic).

Metabolic syndrome with involvement of the male reproductive system

Metabolic syndrome is an endocrine disorder that involves systemic alterations of intermediate metabolism, cardiovascular, hormonal, and reproductive systems. It is characterized by central obesity, elevated blood pressure, insulin resistance, and dyslipidemia, which lead to the development of type 2 diabetes mellitus, cardiovascular and renal diseases. At the clinical level, the central axis of patients with metabolic syndrome focuses on the prevention of cardiorenometabolic comorbidities, however, it's not common that the physician addresses the issue of male reproduction and its implications. Currently there is increasing evidence that patients with metabolic syndrome have low levels of testosterone, GnRH, FSH and LH and high levels of estrogen which impacts sperm quality, fertility, and sexual health, which can undoubtedly be reversible upon remission of the metabolic syndrome. This review addresses clinically how metabolic syndrome impacts the male reproductive system, addressing male fertility, testicular endocrine function, and sexual health.

Study of LHCGR gene variants in a sample of colombian women with polycystic ovarian syndrome: A pilot study

PurposeTo evaluate the association between polymorphisms of the LHCGR gene and PCOS in a sample from Colombian women. MethodsWe included 49 Colombian women with PCOS and 49 healthy women. Genotype distributions between groups were compared, and phenotype-genotype association analysis was performed in the PCOS group. Identification of five SNP’s in the LHCGR gene was carried out through the iPLEX and MassARRAY system (Agena Bioscience). ResultsOur results showed that the rs7371084 variant was negatively associated with PCOS under the codominant, dominant, and overdominant models. Women with the TC + TT genotypes in rs2293275 had shorter menstrual cycles (p = 0.026), and women with the CT + CC genotypes in rs6732721 showed a decrease in the number of antral follicles (p = 0.038).Within the endocrine parameters, we identified associations between GA + GG genotypes in rs13405728 and CT + CC genotypes in rs6732721, and the decrease in LH levels (p = 0.013; p = 0.04, respectively). Women with TC + TT genotypes in rs2293275 had increased DHEAS (p = 0.047) and androstenedione (p = 0.045) levels. Regarding metabolic parameters, we identified associations between GA + GG genotypes in rs13405728 and CT + CC genotypes in rs6732721, and an increase in fasting glucose levels (p = 0.028; p = 0.017, respectively). ConclusionWe found that the rs7371084 variant was negatively associated with PCOS. Also, we identify associations between combined genotypes of the LHCGR gene and the phenotypic traits of PCOS, such as shorter menstrual cycle length, fewer follicles, lower LH levels, and increased DHEAS, androstenedione, and fasting glucose levels. The results of this pilot study provide a basis to clarify the genetics and pathophysiology of PCOS in the Colombian population. Future large-scale studies are recommended for this population.

P-664 The effect of LH levels on the day of trigger on the oocyte retrieval and maturation rates in GnRH-antagonist cycles with an agonist trigger

Abstract Study question Are LH levels on day of trigger correlated with the number of oocytes retrieved and oocyte maturation rate in GnRH-antagonist cycles with an agonist trigger? Summary answer Low LH levels on the day of trigger were associated with a lower oocyte retrieval rate yet no correlation with oocyte maturation rates was found. What is known already The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. GnRHa trigger offers important advantages including the prevention of ovarian hyperstimulation syndrome (OHSS) with the elicitation of an endogenous LH and FSH surge. Therefore, we sought to evaluate whether LH levels on the day of the trigger are associated with the efficacy of the trigger in eliciting endogenous LH surge and thereby influencing oocyte retrieval and oocyte maturation rates. Study design, size, duration This retrospective single center study included all GnRH antagonist cycles triggered with GnRHa trigger (Decapeptyl 0.2mg) performed at our IVF unit between July 2013 and December 2020. We studied the association between LH levels on the day of trigger and the number of oocytes retrieved. Additionally, we studied the effect of LH levels on oocyte maturation rates. Participants/materials, setting, methods All GnRH antagonist cycles triggered with GnRHa trigger were included. Data was acquired through individual review of medical records. Linear regression was used to study the correlation between LH levels and oocyte retrieval and maturation rates. Moreover, LH levels on day of trigger were divided ≤1 IU/L and &amp;gt; 1 IU/L to further investigate this correlation. The ratio between Basal LH and LH on day of trigger was investigated as well. Main results and the role of chance There were 211 GnRH antagonist cycles triggered with GnRH agonist trigger during the study period. The mean age of patients in the study group was 30.1±4.8 y/o, mean basal LH levels were - 6.8±3.4 IU/L, mean Basal FSH levels were - 6.7±1.9IU/L and the mean total dose of gonadotropin administered was 1633.4±680.6 Units. The mean E2 levels were 11,444±7018.5 pmol/L and the mean number of oocytes retrieved was 19.8±10.2. A correlation was found between lower LH levels on the day of trigger and the number of oocytes retrieved (p &amp;lt; 0.001). No correlation was found between LH levels on the day of trigger and oocyte maturation rates (p = 0.82). The ratio between Basal LH and LH on day of trigger was not found to be a significant factor influencing either the number of oocytes retrieved or oocyte maturation rate. When dividing the group by LH on day of trigger to below and above 1, a borderline difference was found relating to oocyte retrieval rate between the two groups (p = 0.06). Limitations, reasons for caution The retrospective nature of the study is the main limitation. Patients receiving GnRHa trigger are mainly a selective population of either high responders or patients for fertility preservation stimulated to retrieve many oocytes, therefore findings may not be applicable to normal or poor responders. Wider implications of the findings Low LH levels on day of trigger were found associated with lower oocyte retrieval rates. GnRHa has become an alternative to standard hCG triggering in certain situations. These are preliminary findings of an ongoing study designed to investigate the efficacy of GnRHa trigger according to cycle parameters including LH levels. Trial registration number not applicable

Leydig Cell Hypoplasia and Pituitary Stalk Agenesis: Genetic Link or Coincidence

Leydig cell hypoplasia illustrates a rare category of 46, XY DSD "disorders of sex development". We report a case of a patient assigned to the female sex carrying a DSD with 46 XY karyotype on Leydig cell hypoplasia associated with pituitary stalk agenesis. This association has not been described yet in the literature. The patient was first admitted at the age of five for failure to thrive (FTT) with an abnormality of sexual development. The FTT was related to complete GH deficiency on pituitary stalk agenesis. Upon investigation, the patient was diagnosed as carrying a DSD 46, XY. The endocrine evaluation revealed low testosterone, FSH, and LH levels with a negative HCG test. The abdominopelvic ultrasound objectified two testicles in the inguinal folds. ²After discussing the case in a multidisciplinary consultation meeting, and taking into account the wishes of the family and the psychiatric expertise, the selected sex that was assigned to the patient was female. At the age of 19, the patient underwent a bilateral gonadectomy and the anatomopathological examination confirmed the diagnosis of Leydig cell hypoplasia. Leydig cell hypoplasia is a rare autosomal recessive syndrome, diagnosed by clinical, biological, radiological, histological, and genetic evidence. Its association with pituitary stalk agenesis has not been described in the literature. This syndrome is characterized by the inability of the chorionic gonadotropin luteinizing hormone receptor in Leydig cells to respond to luteinizing hormone, thereby causing feminization of a male fetus. The treatment has three components: hormonal treatment, surgical treatment, and psychological care.