Gonadotropin Research Articles

Gestational Trophoblastic Tumours: Experience of the Oncology Department of the Moulay Ismail Military Hospital in Meknes (10 Cases)

Gestational trophoblastic tumors (GTTs) are the malignant forms of gestational trophoblastic diseases. They always follow a pregnancy, most often molar. The diagnosis of GTT is based on an abnormal course of HCG (chorionic gonadotropin hormone) and/or signs of ultrasound invasion and/or histological confirmation. We report a retrospective series of 10 cases of GTT collected at the Medical Oncology Department of the Moulay Ismail Military Hospital in Meknes over an 8-year period from January 2012 to January 2020. The analysis of our series led to the conclusion that: The average age of onsetis 42 years. 90% of our patients were pauciparic. The causal pregnancy was in 90% of the cases a molar pregnancy. The extension assessment was mainly based on the TAP CT identifying the lung as the main metastatic site in 40% of cases. 5 patients (50% of cases) underwent hysterectomy with post operative chemotherapy. 60% of our patients were classified as low risk according to the FIGO score and received methotrexate mono-chemotherapy. 4 patients were classified as high-risk and were treated with poly chemotherapy, the main protocol of which was EMA-CO. All our patients benefited from clinical and biological monitoring, before each chemotherapy session; then weekly and monthly after negativation, up to 12 months in case of good prognosis GTT, and up to 18 months in case of bad prognosis GTT. One case of MTX relapse (the case of IPTT) was reported and for which a 2nd line CMT with a favourable evolution was indicated. This study allowed us to analyze the cure rate, which was 100% for patients who were treated and had completed their monitoring.

6873 Expression of Constitutively Active YAP in Murine Gonadotrope Cells Leads to Morphological Alterations and Dysfunction of the Anterior Pituitary Gland

Abstract Disclosure: N. Jakuc: None. M. Bérubé: None. E. Corrêa Dos Santos: None. G. St-Jean: None. M. Paquet: None. U. Boehm: None. D.J. Bernard: None. D.T. Boerboom: None. A. Boyer: None. G. Zamberlam: None. The Hippo transcriptional coactivators, YAP and TAZ, are expressed in cells throughout the anterior pituitary gland in mice. Although the potential physiological roles of YAP and TAZ in gonadotrope cells was unknown, we recently reported that conditional deletion of YAP and TAZ in gonadotrope cells results in increased circulating levels of LH (in males and females) and FSH (males only), and female hyperfertility in mice. Here, to further study the effects of Hippo signaling in gonadotropes, we conditionally expressed a constitutively active YAP (5SA) in these cells using the Cre-lox system with one of two Cre-driver strains, steroidogenic factor-1 (SF-1)-Cre or GnRH receptor-IRES-Cre (GRIC). Such crosses generated two distinct mouse models, which are referred to herein as YAP5SA;SF1-Cre and YAP5SA;GRIC, respectively. Expression of total YAP (YAP5SA and endogenous Yap) and the classic YAP-TEAD target genes, Ctgf, Cyr61, and Ankrd1 was significantly increased in pituitaries of 6-week-old mutant males and females in both the YAP5SA;SF1-Cre and YAP5SA;GRIC models. Animals from both models also showed significantly reduced serum LH and FSH levels as well as lower body mass and gonadosomatic indices when compared to respective controls. Six-week-old male and female mutants from both models showed significant morphological alterations in the pituitary. YAP5SA;SF1-Cre mutants exhibited proliferation of poorly differentiated cells, with high cellular and nuclear atypia with several mitoses. Similarly, YAP5SA;GRIC pituitaries were characterized by an increased number of poorly differentiated cells as well as follicle or papillary-like structure formation and increased cell proliferation and necrosis. Together, these preliminary findings strongly suggest pituitary blastoma or choriocarcinoma, and confirmatory experiments are underway. In light of gross morphological changes that appeared to extend beyond gonadotropes, we performed qPCR analysis of other cell lineages in 6-week-old YAP5SA;GRIC mutants and corresponding controls. Gh, Prl, Tshb, and Pomc mRNA levels were decreased in pituitaries of mutant animals. In addition, GH and ACTH protein expression, as assessed by immunohistochemistry, was nearly undetectable in pituitaries in mutant animals, suggesting compromised presence or function of somatotropes and corticotropes. To better understand the onset of this pathology, we performed histopathological analysis of YAP5SA;GRIC mutants in early post-natal life. Although pituitaries from 1-day-old mutant animals seemed normal in comparison to controls, we found signs of cellular necrosis and vacuolar degeneration in 1-week-old mutants. Together, our results indicate that constitutively active YAP in murine gonadotropes leads to significant morphological and functional alterations throughout the pituitary. Presentation: 6/1/2024

6629 Pure Androgen Secreting Adrenal Adenoma In A Premenopausal Woman

Abstract Disclosure: S. Syed: None. Background: Pure androgen secreting adrenal adenomas are extremely rare; most of the reported cases occur in post-menopausal women, with significant virilization of acute onset and are usually malignant. Here we present a case of an androgen secreting adrenal adenoma found in a young female with regular menstrual cycles and hirsutism. Clinical Case: A 27-year-old female with no significant past medical history was referred to Endocrinology clinic for evaluation of elevated testosterone level noted on a routine OBGYN exam. Patient had miscarriage six months prior to initial endocrine clinic visit. She had a routine follow up visit with her gynecologist after miscarriage and noted to have mild male pattern hair growth on her chin, worse after stopping birth control pills two years ago. Patient had menarche at 14 years of age and had regular menstrual cycle until started birth control pills. The skin examination revealed coarse male pattern hair on chin. Scattered acne was present on back. No signs of hypercortisolism were present. Labs done at time of initial consultation showed unremarkable comprehensive metabolic panel, thyroid and gonadotropic hormones. Testosterone was elevated at 122ng/dl (0-75ng/dl). Pelvic ultrasound done in the year prior showed normal uterus and adnexal structures. Further work up showed elevated DHEAS 781 µg/dL (18-391 µg/dL) and normal 17 OH progesterone and androstenedione levels. MRI abdomen with and without contrast done at outside facility showed a 4 cm x 3.3 cm x 4.1 cm well-circumscribed round shaped, mildly heterogeneously enhancing mass arising from right adrenal gland, with restricting diffusion, no signal dropout in out-of-phase imaging. Normal ovaries were noted. Given the large size of lesion, adrenalectomy was recommended. Patient underwent laparoscopic right adrenalectomy. The histologic features on pathology specimen were consistent with an adrenal cortical adenoma. No evidence of malignancy was seen (based on modified Weiss criteria). 3 weeks post op labs showed Testosterone level reduced to 19 ng/dl (0-75ng/dl) and DHEAS 138 ug/dl (18-391 µg/dL). Patient is recovering from recent childbirth. Conclusion: In adults, pure androgen secreting adrenal tumors are extremely rare. Diagnosis of malignancy is made with histopathological examination and Weiss score calculation. Our patient has unique presentation of having mild hirsutism in setting of regular menstrual cycles with no other symptoms of virilization and is noted to have unexpectedly large adrenal adenoma. Given the size of adenoma, there was concern for adrenal cortical carcinoma, however histological examination was consistent with a benign lesion. Presentation: 6/1/2024

8574 Single cell multiomics suggests tumor cell energy metabolism heterogeneity in non-functioning gonadotroph pituitary adenomas

Abstract Disclosure: F.M. Ruf-Zamojski: None. Z. Zhang: None. W. Cheng: None. G.R. Smith: None. M. Zamojski: None. N. Mendelev: None. Y. Ge: None. D. Marrero-Rodríguez: None. K. Taniguchi-Ponciano: None. C.L. Andoniadou: None. E. Zaslavsky: None. X. Chen: None. O.G. Troyanskaya: None. M. Mercado: None. S.C. Sealfon: None. Pituitary adenomas cause hormonal dysregulation and severe morbidity. The absence of clear biomarkers for prognosis/treatment and the high risk of recurrence make management challenging. Non-functioning gonadotroph pituitary adenomas (NFPAs) represent proliferation of gonadotroph lineage cells without an increase in secretion of gonadotropins. Detection is often delayed until mass effects cause visual defects. Higher resolution molecular study may improve classification, diagnosis, treatment, and provide insight into adenoma biology. We analyzed four NFPAs using unbiased genome-wide same-cell single nucleus 10X Genomics multiome assay (transcriptome and chromatin accessibility) to define individual cell identity/states in comparison with normal gonadotrope cell references from twelve age/sex-matched human post-mortem pituitaries. In total, we generated high quality multiomics single-cell data for 33,832 adenoma cells and 5,451 normal gonadotropes. We identified tumor, immune, vascular, and proliferative cells confirming cellular heterogeneity. Multidimensional scaling analysis using Manhattan distances between cell types showed that NFPA gonadotropes were closer in gene expression to healthy gonadotropes among all pituitary cell types. In addition, we observed differences in the macrophage and endothelial cell populations between tumors and healthy pituitaries. Next, we studied gene regulatory circuitry (regulated gene, modulating transcription factor and its chromatin interaction site) using the new Control of Regulation Extracted from Multiomics Assays (CREMA, [1]) multiome analysis method which showed high variation between normal and tumor gonadotropes. Within each adenoma, the NFPA tumor cells encompassed two main subgroups of cells, one group (GT+ marker tumor cells) expressing established gonadotrope markers and another group not (GT- marker tumor cells). GT+ and GT- tumor cells formed a cluster distinct from healthy gonadotropes. GT+ and GT- tumor cells differed by their level of expression of mitochondrial genes, suggesting decreased aerobic capacity associated with the GT- tumor subgroup. Interestingly, differential analyses between the healthy and the NFPA gonadotropes from same-cell multiome data highlighted dissimilar gene expression and chromatin accessibility patterns.Our newly collected single cell data characterize the difference between NFPA tumor cells and normal gonadotrope cells. Our results suggest a Warburg-effect like difference in aerobic respiratory capacity among tumor cells within the same pituitary adenoma. Overall, this study brings new insights into the molecular characteristics of NFPAs, including tumor cell heterogeneity, and represents a new resource for the field. [1] PMID: 38084892. Presentation: 6/1/2024

Comparison of highly purified human menopausal gonadotropin and recombinant follicle stimulating hormone use in patients undergoing in vitro fertilization with progestin-primed ovarian stimulation protocol: a single center retrospective analysis.

Recently, progesterone has been used to prevent LH surge instead of GnRH analogues during ART treatments, which is known as progesterone-primed ovarian stimulation (PPOS) protocol. During ART treatment, highly purified human menopausal gonadotropin (HP-hMG) and recombinant follicle stimulating hormone (rFSH) are two of the agents used for stimulation of antral follicles. The aim of this study is to compare the efficacy and success of HP-hMG and rFSH agents in the ovarian stimulation step of the PPOS protocol, which has not been previously reported in the literature. This retrospective study was conducted at a university hospital with patients who underwent IVF treatment using PPOS protocols in between January 2019 and July 2021. For ovarian stimulation, rFSH was used in group I and HP-hMG was used in group II. Mature oocyte ratio was the primary outcome, and live birth rate was the secondary outcome. Mann-Whitney and Chi-square tests were used for statistical analysis. All p values below 0.05 were considered significant. Total numbers of follicles, oocytes, MII, and 2PN numbers obtained were similar between the two groups. The fertilization rates were 66.7% in the rFSH group and 64.3% in the HP-hMG group (p > 0.05). The pregnancy rates were 53.5% and 46.7% in the rFSH and HP-hMG groups, respectively. There was no statistically significant difference between pregnancy, abortus, and live birth rates. In this study, it is demonstrated that stimulation of oocytes with either rFSH or hMG in the PPOS protocol, which has been added to IVF treatment protocols in recent years, had no statistical difference regarding mature oocyte numbers and live birth rates between the two groups. These results are consistent with the previous literature which compared rFSH and hMG in GnRH agonist and antagonist protocols.

The impact of chronic stress on the hormonal state of women affected by hostilities and displaced women

During times of war, refugee women often have high levels of chronic stress due to factors such as war, displacement and uncertainty. The study focuses on examining the hormonal responses of female refugees experiencing chronic stress from war and displacement.The objective: to assess the impact of chronic stress caused by war and displacement on the hormonal balance of refugee women.Materials and methods. 60 women were examined, who were divided into groups: the 1st group included women who were affected by hostilities (20 persons), and the 2nd group included displaced women (20 individuals). In these 40 women the hormonal studies were conducted in the conditions of military aggression in Ukraine. The control group (3rd group) included healthy women who were examined in the pre-war period. All examined women were 20–25 years old with an average body weight of 55–60 kg. Concentrations of progesterone, estradiol, follicle-stimulating hormone (FSH) and luteinizing hormone, prolactin in the I and II phases of the menstrual cycle (MC), cortisol in the I phase of the MC were determined in blood serum using the enzyme immunoassay method. An analysis of the results of research on the role of the hypothalamic-pituitary-adrenal system in the regulation of the stress response was carried out.Results. In the examined women, various disorders of MC were observed, such as: menometrorrhagia, hypermenorrhea, acyclic uterine bleeding, oligomenorrhea, and amenorrhea. The most pronounced changes in menstrual function were observed in women who were affected by hostilities. Such significant disorders of MC in women of this group coincided with changes in indicators of gonadotropic hormones of the pituitary gland and sex hormones in the blood.A study of the psycho-emotional state of women who suffered from hostilities established that these women have a significant stressful effect of various risk factors on the body. Changes in the levels of cortisol, prolactin and other hormones were detected.Conclusions. Studies have shown that chronic stress affects the hormonal status of women affected by hostilities and of displaced women, including FSH, estradiol, and prolactin levels.A significant increase in the level of FSH in the follicular phase of the menstrual cycle and an increase in the level of estradiol in the luteal phase were determined, which may indicate a compensatory reaction of the body to stress. A significant increase in the level of prolactin was also found, which can cause disorders of menstrual function and affect the psycho-emotional state.

Investigation of the Effect of Nano-melatonin on Oxidative Stress in Sera of Patients with Polycystic Syndrome

Background: The association between polycystic ovary syndrome (PCOS) and oxidative stress in women, the possible causes of PCOS, insulin resistance (IR), obesity, and oxidative stress. Oxidants are chemical elements that tend to gain electrons, losing positive charge. The Oxidative Stress (OS) is defined as an imbalance between the formation and synthesis of free radicals and the antioxidant defense system, which results in oxidative damage. Objective: The purpose of this research is to investigate the effect of nano-melatonin on oxidative stress in the sera of patients with polycystic syndrome. Methods: The study includes 120 Iraqi women, divided into two groups: 60 PCOS patients and 60 healthy control patients. Sample Analysis Biochemistry analyses the hormonal profile and determines the hormonal levels (LH, FSH, Testosterone, and Prolactin) that were identified for all controls and patients. Hormones analysis was performed using the enzyme-linked fluorescent assay (ELFA) technique. Synthesized ML nanoparticles by ultrasonic sonication. Results: The results indicate that the mean of serum LH significantly increased (P<0.02) in PCOS BMI ≥ 25 patients G1 (6.19±3.13) mIU/mL compared with controls C1 (4.504±1.591) mIU/mL, while a nonsignificant difference (P>0.05) when compared the BMI<25 kg/m2 for G2 (5.55±1.93) with control group C2 (6.31±2.58) of luteinizing hormone in G1 and G2. Conclusions: An increased ratio of LH to FSH was shown to be characteristic of PCOS. For PCOS, high LH values are crucial. For the purpose of diagnosing PCOS, high LH values are crucial release of gonadotropin hormones (LH, FSH) from the pituitary. To higher the production of androgen in ovarian theca cells, The LH receptor is activated by the luteinizing hormone (LH). The nano Mel was higher in the inhibition of Oxidative stress two causes nano-melatonin high surface area and small size.

Characterization of gonadotropins and their receptors in a chondrichthyan, Scyliorhinus canicula, fills a gap in the understanding of their coevolution

In Gnathostomes, reproduction is mainly controlled by the hypothalamic-pituitary–gonadal (HPG) axis, with the involvement of the pituitary gonadotropic hormones (GTH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which activate their cognate receptors, FSHR and LHR, expressed in gonads. Each GTH consists of a common α subunit and of a specific FSHβ or LHβ subunit. Chondrichthyes (holocephalans and elasmobranchs) is a sister group of bony vertebrates. This position is highly favorable for the understanding of the evolution of endocrine regulations of reproduction among gnathostomes. Surprisingly, the characterization of gonadotropins and their receptors is still limited in chondrichthyes. In the present study, GTH and GTHR sequences have been identified from several chondrichthyan genomes, and their primary structures were analyzed relative to human orthologs. 3D models of GTH/GTHR interaction were built, highlighting the importance of the receptor hinge region for ligand recognition. Functional hormone-receptor interactions have been studied in HEK cells using the small-spotted catshark (Scyliorhinus canicula) recombinant proteins and showed that LHR was specifically activated by LH whereas FSHR was activated by both FSH and LH. Expression profiles of GTHs and their receptors were explored by real-time PCR, in situ hybridization and immunohistochemistry during spermatogenesis, along the male genital tract and other tissues, as well as in some female tissues for comparison. Tissue-expression analyses showed that the highest levels were observed for fshr transcripts in testis and ovary and for lhr in specific extragonadal tissues. The two receptors were expressed at all stages of spermatogenesis by both germ cells and somatic cells, including undifferentiated spermatogonia, spermatocytes, spermatids, somatic precursors and Sertoli cells; differentiated Leydig cells being absent in the testis of S. canicula. Receptors were also expressed by the lymphomyeloid epigonal tissue and the testicular tubules. These results, suggest a wide range of gonadotropin-regulated functions in Elasmobranchs, as well as functional redundancy during spermatogenesis. These extended functions are discussed in an evolutionary context in which the specificity of gonadotropin signaling must have contributed to the evolution of gonadal cells’ morphology and function.

Novel non-peptide uracil-derived human gonadotropin-releasing hormone receptor antagonists

Gonadotropin-releasing hormone (GnRH) is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). Traditionally, therapies targeting this receptor have relied on peptide modulators, which required subcutaneous or intramuscular injections. Due to the limitations of the parenteral administrations, there is a growing interest in developing oral small molecule modulators of GnRH1R as more convenient therapeutic alternatives.In this study, we examined the potential of chemically modifying elagolix, the first approved non-peptide, orally active GnRH1R antagonist, to increase its atropisomeric properties by introducing new moieties. We designed and synthesized the thio-uracil (1) and cytosine (2) derivatives of elagolix, both demonstrating GnRH1R antagonistic activities, with EC50 values of 39 and 110 nM, respectively. The atropisomers of 1 and 2 were efficiently separated using silica gel chromatography, and extensive NMR investigation, supported by Density Functional Theory (DFT) calculations, allowed us to define their conformations and rotational barriers. Docking and Molecular Dynamics (MD) studies revealed that 1 and 2 bind to GnRH1R with ΔG values comparable to elagolix, but through distinct binding modes. These results highlight the potential of non-peptide modulators to effectively modulate GnRH1R activity and pave the way for developing novel modulators.

TREATMENT OUTCOMES IN PCOS (POLYCYSTIC OVARIAN SYNDROME)-RELATED INFERTILITY

Polycystic ovarian syndrome (PCOS) is one of the underdiagnosed endocrine disorders found to be prevalent among females in the reproductive age group. PCOS effects on an average 8-13% of reproductive aged women, globally. This condition is responsible for causing distress physiologically and psychologically paving the way for a poor quality of life. One of the devastating complications of PCOS is infertility. At present, there is no treatment for PCOS but could be managed by alternate options such as lifestyle modification to in-vitro fertilization. The primary objective of this review article is to analyze the outcomes of certain pharmacological treatment options such as clomiphene citrate which is a selective estrogen receptor modulator, Letrozole an aromatase inhibitor, and gonadotropins for PCOS-related infertility. Clomiphene citrate binds to estrogen receptors indirectly increasing the gonadotropins. Studies confirm a 35-40% successful outcome. Letrozole similarly increases gonadotropins by indirectly decreasing estrogen. A notable increase in the successful outcome was observed with both clomiphene citrate and letrozole, with almost near similar results. The pregnancy outcome was approximately 40% with clomiphene citrate, while letrozole showed 50%. Notably, more side effects were observed in the administration of clomiphene citrate compared to letrozole. Human menopausal gonadotropin (hMG) and recombinant follicle-stimulating hormone (FSHr), that are gonadotropins, were used as they are directly responsible for the maturation of follicles and ovulation itself. The use of gonadotropins increased the pregnancy rate outcome to 20 -30 %, albeit with the risk of multiple births. Furthermore, we have discussed why letrozole and clomiphene citrate are used as the primary therapy compared to gonadotropins. Peer Review History: Received 22 May 2024; Reviewed 14 July 2024; Accepted 23 August; Available online 15 September 2024 Academic Editor: Dr. Rola Jadallah, Arab American University, Palestine, rola@aauj.edu Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. George Zhu, Tehran University of Medical Sciences, Tehran, Iran, sansan4240732@163.com Dr. Ogbonna B. Onyebuchi, Nnamdi Azikiwe University, Awka, Nigeria, summitpharm@yahoo.com

Low concentrations of the food contaminant Deoxynivalenol trigger apoptosis and impair GnRH-induced LH secretion in pituitary gonadotrope-like cells.

AbstractTheFusariummycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. Nearly all individuals are exposed to DON, due to it widespread presence in grains and grain-based products. Chronic DON poisoning is associated with growth retardation, immunotoxicity as well as impaired reproduction and fetal development. At the molecular level, DON alters intracellular signaling by activating mitogen-activated protein kinases (MAPKs) that modulate cell growth, differentiation, and apoptosis. Of note, these MAPKs are also critical mediators of gonadotrophin-releasing hormone (GnRH)-induced synthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by pituitary gonadotrope cells. So far, no research has explored the potential endocrine-disrupting effects of DON on pituitary gonadotropins production. Herein, we show the first evidence that DON affects LH production by the immortalized gonadotrope-like cell line LβT2 in a concentration-dependent manner. Taken together, our experiments demonstrated that low concentrations of DON affect GnRH-induced signaling through a mechanism that, at least in part, involves apoptosis and inhibition of GnRH-induced phosphorylation of ERK-MAPK. Consequently, DON also affects the GnRH-induced expression ofCgaandLhb, two critical genes for LH synthesis and secretion by gonadotrope cells in mammals. This research broadens our knowledge of the toxicity of DON and brings a new depth to the potential neuroendocrine implications for reproduction.Graphical abstract

HLA-DQB1 as a potential prognostic biomarker of hormonal therapy in patients with non-obstructive azoospermia

The gonadotropin treatment of infertile men may improve spermatogenesis and lead to sperm cell production, however, only a small fraction of treated patients positively responds to such therapy. To identify individual treatment prognostic biomarkers associated with responsiveness to gonadotropins, we compared the gene expression profiles of testicular oligobiopsies from 3 patients with non-obstructive azoospermia (NOA) who positively responded to therapy with a combination of human chorionic gonadotropin and recombinant follicle-stimulating hormone (hCG/rFSH) to those of 3 non-responders. We used Affymetrix Human Gene 1.0 ST microarrays. The results of the microarray evaluation were validated by the qPCR technique while gene variants of the HLA-DQB1 (major histocompatibility complex, class II, DQ beta 1) were subsequently sequenced. In our microarrays, we have identified most significantly 5 transcripts with different expression levels in responders versus non-responders groups. Our interest has been primarily focused on the transcript associated with the HLA-DQB1 gene. Because the expression of this gene was up-regulated in the non-responding patients and only patients with heterozygotic alleles of HLA-DQB1 turned out to be positive to gonadotropin therapy, we suggest that this gene may be a biomarker of potential significance for the gonadotropin treatment of male infertility. We also compared the testicular gene expression profile in one individual before and after gonadotropin treatment. In the re-biopsied sample, we have identified over 600 genes that showed differences in testicular expression; some of these genes are critical for spermiogenesis. Thus, we documented that the applied gonadotropins successfully stimulated the spermatogenetic wave in patients with NOA.

CORRELATION BETWEEN BMI AND GONADOTROPIN HORMONES IN THE FEMALE GENDER

Introduction: The pituitary gland affects growth and development. Its main function is in the activity of sexual/reproductive hormones and in the functioning of the glands (thyroid gland, adrenal glands and gonads). Gonadotropin hormones (gonadostimulins) are so named because they stimulate the function of the gonads - male and female sex glands (testicles and ovaries) in which sex cells - sperm and egg cells are created. Overweight is a state of metabolic disorders where excess body fat accumulates to the extent that it can negatively affect human health. Obesity as a BMI factor is related to the functioning of the thyroid gland with its hormones and the pituitary gland with gonadotropin hormones. Purpose of the study: This paper aims to present the correlation between BMI and gonadotropin hormones in reproductive and postmenopausal women. The aim of the paper will also consist in the status of gonadotropin hormones and the functional state of these hormones by comparing them with metabolic disorders such as BMI, obesity and the synthesis of follicle stimulating hormone and gonadotropin hormone. Material and method: A total of 20 patients will be included in the research, divided according to age group into two categories. The first group will include patients aged 10-40 years, the second group patients over 41 years old. Blood (serum) samples will be taken from patients for analyzing gonadotropin hormones: FSH, LH, PRL and thyroid hormones: TSH, FT4, FT3. They will be analyzed with the modern automatic fluorescent enzyme immunoassay method (Vidas-Biomerie). The BMI of the body will be measured with a metric formula where the weight of the patient (in kg) divided by the height of the patient (in m2) set to the square power will give us the measure of body index-BMI (%). SPSS – Software package version 20.0 Numerical series were analyzed using central tendency measures (average, median, minimum values, maximum values), as well as distribution measures (standard deviation); To determine the regularity of the frequency distribution of the examined variables, the Shapiro-Wilk W Test was used; Non-parametric tests for two independent parameters were used to test the significance and difference between some numerical parameters with irregular frequency distribution (Mann Whitney U test); To determine statistical significance, a two-way analysis was used with a significance level (means) of p<0.05. Results: The results of the research will give a real insight into the data of gonadotropic hormones FSH, LH, PRL and thyroid hormones TSH, FT4, FT3 of the female sex in the Tetova region. The results of the research will also provide information about the correlation of BMI and gonadotropin and thyroid hormones. Conclusion: From the analyzes performed on patients of different age groups we come to the conclusion that: • Gonadotropin hormonal disorders can lead to the phenomenon of metabolic diseases such as BMI. • These disorders can have consequences such as: polycystic ovary diseases in women, Hashimoto's genetic syndrome, Graves, infertility in women, etc.

Patterns of hormonal changes in hypophysitis by immune checkpoint inhibitor.

Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events, including endocrine dysfunctions, which can have serious consequences on patient health and quality of life. The clinical course and characteristics of immune-related hypophysitis (irH) are not well established. This study aimed to analyze the clinical course and characteristics of irH. This single-center, retrospective study analyzed data from electronic medical records of Asan Medical Center, spanning January 2017 through June 2021. It included adult patients with solid tumors who underwent thyroid and adrenal function tests, along with gonadotropin and/or growth hormone evaluations, following the initiation of ICI treatment within the same period. The study explored the clinical characteristics of ICI-treated patients with and without irH, the incidence of irH, the time to irH onset, and the associated hormonal changes. Twenty-one patients were included in this analysis. Clinical characteristics did not differ significantly between the irH (n = 13) and non-irH (n = 8) groups. Deficiency rates in the irH group were 23.1% for thyroid-stimulating hormone (n = 3), 76.9% for adrenocorticotropic hormone (n = 10), 61.5% for gonadotropin (n = 8), and 15.4% for growth hormone (n = 2). The overall incidence was 0.9 per person-year, with 6-month and 1-year cumulative incidences of 38.8% and 57.1%, respectively. The median time from ICI initiation to irH diagnosis was 7.7 months. Time to levothyroxine replacement was shorter in the irH group. The findings provide evidence that could facilitate the prediction of ICI-induced irH based on clinical course and characteristics.

Preclinical Evaluation of the effect of Pijusballi Rasa (PLRM) on steroidal and gonadotropin hormone profile on chronic administration to the male Sprague-Dawley rats

Preclinical Evaluation of the effect of Pijusballi Rasa (PLRM) on steroidal and gonadotropin hormone profile on chronic administration to the male Sprague-Dawley rats

Ameliorative Effect of Chitosan/Spirulina platensis Ethanolic Extract Nanoformulation against Cyclophosphamide-Induced Ovarian Toxicity: Role of PPAR-γ/Nrf-2/HO-1 and NF-kB/TNF-α Signaling Pathways.

Cyclophosphamide (CP) is an anticancer drug that causes infertility disorders. This study was designed to evaluate a nanoformulation of chitosan with an ethanolic extract from Spirulina platensis in terms of its protection against cyclophosphamide-induced ovarian toxicity. Nine groups of female Wistar rats were randomly assigned as follows: 1: control vehicle, 2: chitosan polymer, 3: telmisartan, 4: Spirulina platensis extract, 5: nanoformulation of the Spirulina platensis, and 6: single injection of CP; groups 7, 8, and 9 received the same treatments as those used in groups 3, 4, and 5, respectively, with a single dose of CP (200 mg/kg, I.P). The results displayed that the CP treatment decreased estradiol, progesterone, anti-mullerian hormone, and GSH content, and it downregulated PPAR-γ, Nrf-2, and HO-1 gene expression. In addition, the CP treatment caused an increase in the FSH, LH, and MDA levels. In the same manner, the protein expression of caspase-3, NF-kB, and TNF-α was upregulated in response to the CP treatment, while PPAR-γ was downregulated in comparison with the control. The rats treated with SPNPs exhibited a substantial reduction in the detrimental effects of oxidative stress and inflammation of the ovarian tissue. This study's conclusions showed that SPNPs counteracted the effects of CP, preventing the death of ovarian follicles and restoring the gonadotropin hormone balance and normal ovarian histological appearance.

ZEB1 Inhibits LHβ Subunit Transcription When Overexpressed, but Is Dispensable for LH Synthesis in Mice.

Luteinizing hormone (LH), a heterodimeric glycoprotein produced by pituitary gonadotrope cells, regulates gonadal function. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates LH synthesis and secretion. GnRH induces LHβ subunit (Lhb) expression via the transcription factor, early growth response 1 (EGR1), acting on the Lhb promoter. In contrast, overexpression of zinc finger E-box binding homeobox 1 (ZEB1) represses LH production in mice, but the underlying mechanism was not previously elucidated. Here, we observed that ZEB1 inhibited GnRH-stimulated but not basal Lhb mRNA expression in homologous murine LβT2 cells. Moreover, ZEB1 blocked GnRH and/or EGR1 induction of murine Lhb but not human LHB promoter-reporter activity in these cells. Using chimeric reporters, we mapped the species-specific ZEB1 sensitivity to sequence differences, including in Z- and E-boxes, in the proximal Lhb/LHB promoters, immediately upstream of the transcription start sites. ZEB1 bound to the murine Lhb promoter with higher affinity than to the human LHB promoter in this region. To examine ZEB1's physiological role in LH synthesis, we characterized gonadotrope-specific Zeb1 knockout mice. Loss of ZEB1 in gonadotropes did not affect LH production or secretion. Collectively, the data suggest that ZEB1, when overexpressed, can inhibit GnRH/EGR1 induction of murine Lhb transcription but does not play a necessary role in LH synthesis in mice.

Identification of Environmental Compounds That May Trigger Early Female Puberty by Activating Human GnRHR and KISS1R.

There has been an alarming trend toward earlier puberty in girls, suggesting the influence of an environmental factor(s). As the reactivation of the reproductive axis during puberty is thought to be mediated by the hypothalamic neuropeptides kisspeptin and gonadotropin-releasing hormone (GnRH), we asked whether an environmental compound might activate the kisspeptin (KISS1R) or GnRH receptor (GnRHR). We used GnRHR or KISS1R-expressing HEK293 cells to screen the Tox21 10K compound library, a compendium of pharmaceuticals and environmental compounds, for GnRHR and KISS1R activation. Agonists were identified using Ca2+ flux and phosphorylated extracellularly regulated kinase (p-ERK) detection assays. Follow-up studies included measurement of genes known to be upregulated upon receptor activation using relevant murine or human cell lines and molecular docking simulation. Musk ambrette was identified as a KISS1R agonist, and treatment with musk ambrette led to increased expression of Gnrh1 in murine and human hypothalamic cells and expansion of GnRH neuronal area in developing zebrafish larvae. Molecular docking demonstrated that musk ambrette interacts with the His309, Gln122, and Gln123 residues of the KISS1R. A group of cholinergic agonists with structures similar to methacholine was identified as GnRHR agonists. When applied to murine gonadotrope cells, these agonists upregulated Fos, Jun, and/or Egr1. Molecular docking revealed a potential interaction between GnRHR and 5 agonists, with Asn305 constituting the most conservative GnRHR binding site. In summary, using a Tox21 10K compound library screen combined with cellular, molecular, and structural biology techniques, we have identified novel environmental agents that may activate the human KISS1R or GnRHR.

An i-motif-regulated enhancer, eRNA and adjacent lncRNA affect Lhb expression through distinct mechanisms in a sex-specific context

Genome-wide studies have demonstrated regulatory roles for diverse non-coding elements, but their precise and interrelated functions have often remained enigmatic. Addressing the need for mechanistic insight, we studied their roles in expression of Lhb which encodes the pituitary gonadotropic hormone that controls reproduction. We identified a bi-directional enhancer in gonadotrope-specific open chromatin, whose functional eRNA (eRNA2) supports permissive chromatin at the Lhb locus. The central untranscribed region of the enhancer contains an iMotif (iM), and is bound by Hmgb2 which stabilizes the iM and directs transcription specifically towards the functional eRNA2. A distinct downstream lncRNA, associated with an inducible G-quadruplex (G4) and iM, also facilitates Lhb expression, following its splicing in situ. GnRH activates Lhb transcription and increased levels of all three RNAs, eRNA2 showing the highest response, while estradiol, which inhibits Lhb, repressed levels of eRNA2 and the lncRNA. The levels of these regulatory RNAs and Lhb mRNA correlate highly in female mice, though strikingly not in males, suggesting a female-specific function. Our findings, which shed new light on the workings of non-coding elements and non-canonical DNA structures, reveal novel mechanisms regulating transcription which have implications not only in the central control of reproduction but also for other inducible genes.

AB024. Preoperative and postoperative clinical manifestation, hormonal, and imaging profile of sellar region tumor in Dr. Saiful Anwar General Hospital, East Java: a 1-year cross-sectional study.

Due to their location, sellar region tumors can affect a patient's quality of life by mass compression effect and disrupting pituitary function. The treatment choice is determined by some factors, including the presence of mass effect and whether the tumor is secreting or non-secreting. This study assessed the preoperative and postoperative clinical manifestation, hormonal, and head magnetic resonance imaging (MRI) profile of sellar region tumor in Dr. Saiful Anwar General Hospital, East Java. This study used a descriptive, cross-sectional design. Data were taken from sellar region tumor registry of Dr. Saiful Anwar General Hospital from March 2023 to April 2024. Twenty-five patients were included in the study, with 18 (72%) women and 22 patients (88%) aged 41-60 years old. The most frequent neurological symptom was blurred vision (23 patients; 92%). Hormones checked were thyroid hormones [free T4 (FT4), T3, thyroid-stimulating hormone (TSH)], prolactin, cortisol, growth hormone, and gonadotropic hormone [testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH)], but not all patients were checked for all these hormones. Patients were further classified into having low, normal, or high level of the respective hormones, and patients mostly had normal levels. Pituitary macroadenoma was the frequently suspected tumor from head MRIs (11 patients; 44%). Eleven patients underwent tumor excision. Ten patients showed pituitary adenoma and one patient showed pituicytoma on histopathological examination. Mean levels of FT4, T3, and prolactin were decreased after surgery, but TSH and cortisol levels were increased. On postoperative head MRI, four patients showed reduced mass size and one patient showed no residual lesion. While pituitary macroadenoma was suspected in most head MRIs in this study, most of them were likely non-secreting. Therefore, surgical approach remained the mainstay of treatment. The need for medical management for hormonal disturbances was minimal. While postoperative data were incomplete, some findings from our patients showed that surgical approach could indeed reduce mass effect by improving bitemporal hemianopsia and pituitary deficit.