bluuebunny/crossref_metadata_2025 huggingface dataset:
FRI383 Androgen Receptor Signaling Regulates Follicular Growth And Steroidogenesis In The Ovary In Interaction With Gonadotropins During Mini-puberty In Mice
Authors: Devillers Marie , François Charlotte M , Chester Mélanie , Corre Raphael , Cluzet Victoria , Giton Frank , Cohen-Tannoudji Joelle , Guigon Celine J
Published: October 2023

Disclosure: M. Devillers: None. C.M. François: None. M. Chester: None. R. Corre: None. V. Cluzet: None. F. Giton: None. J. Cohen-Tannoudji: None. C.J. Guigon: None.

Introduction: In females, androgens contribute to ovarian diseases such as polycystic ovary syndrome (PCOS), but their action is also crucial for ovarian physiology, i.e., follicular growth and estradiol (E2) synthesis during reproductive life, in interaction with the gonadotropins LH and FSH. However, it is unclear whether androgens already play a role in the ovary at mini-puberty, a phase of postnatal development with active follicular growth and high E2 levels. Hypothesis/question: Given their role in the adult ovary, we hypothesized that androgens may regulate early ovarian function at mini-puberty. Therefore, we analyzed their potential actions on the ovary and their possible interaction with gonadotropins during this period. Methods: We used the mouse as an experimental model to measure the intra-ovarian content and serum levels of testosterone by gas chromatography-mass spectrometry (GC-MS) at different prepubertal ages, including mini-puberty. We performed molecular-based studies (immunohistochemistry, RT-qPCR), morphometric studies and pharmacological approaches in vivo and in cultured ovaries. Main results: We found that mini-pubertal ovaries produce significant amounts of testosterone and display androgen receptor (AR) expression in growing follicles, both under the control of LH. By blocking AR signaling with flutamide either in vivo or in ovarian cultures, we found that this pathway may participate in the regulation of prepubertal E2 synthesis and follicular growth, possibly by regulating the expression of a number of key intra-ovarian regulators, including FSH receptor (Fshr), the aromatase enzyme converting androgens into estrogens (Cyp19a1) and the cell cycle inhibitor p27KIP1 (Cdkn1b). We further showed that AR may stimulate FSH-mediated regulation of Cyp19a1 through its action on Fshr mRNA abundance. Conclusion: This work supports the idea that AR signaling is already activated in mini-pubertal ovaries to regulate E2 synthesis and follicular growth, in interaction with LH and FSH signaling. This early physiological action of androgens may contribute to the implementation of early ovarian function with possible impacts on reproductive function.

Presentation: Friday, June 16, 2023
FRI404 CNS Manifestations Are Linked With Hot Flashes: Analysis Of Real World Data From A Social Network
Authors: Shaklai Sigal , Greenman Yona , Yom-Tov Elad
Published: October 2023

Disclosure: S. Shaklai: None. Y. Greenman: None. E. Yom-Tov: None.

Background: Hot flashes, a hallmark of the menopausal transition, frequently coincides with CNS manifestations of disturbed sleep, cognition, and mood. How these relate is an active area of research. Objective: To evaluate the association of hot flashes with specific CNS manifestations, as expressed by women on one of the largest social media platforms (Reddit). Methods: We downloaded 4772 posts from Reddit’s Menopause group. 586 randomly sampled posts were labelled for their relevancy to menopause. Relevant posts were further labelled for mentions of hot flashes, cognition, reports of adverse mood, sleep problems and reported age. A random forest model for identifying relevant posts from words and bigrams of the posts was trained using the labelled samples and its performance evaluated using 10-fold cross-validation. The model reached an Area Under Curve (AUC) of 0.77. The model was used to filter the remaining posts by selecting posts classified as having a 75% or more likelihood of being about menopause\perimenopause. This resulted in 3546 posts from 1854 users. Models for the remaining labels were trained, reaching AUCs of 0.70 to 0.79. The models were applied to the unlabeled posts. Labels with a prediction in the range of 33-66% were removed to keep only those for which models provided strong indications. Posts were aggregated by user and the average score for each predicted label was computed. Main Outcome Measures: The ratio of women reporting one of three outcomes; disturbances in cognition, mood, or sleep, from all women with or without hot flashes. Results: The average stated age was 44.3 years (range: 21-59, N=165). In the whole cohort, hot flashes were reported in 32%, adverse mood in 40%, impaired sleep in18% and cognitive disruption in 15% of women. In women with hot flashes, adverse mood occurred in 46.9%, impaired sleep in 27.2%, and cognitive disruption in 25.3%. In women without hot flashes adverse mood occurred in 4.3%, impaired sleep in 0.7% and cognitive disruption in 0.7%. Results are statistically significant (chi2 test) at P<10^(-10). Conclusions: Hot flashes, which occurred in a third of the women, were individually associated with disturbances in mood, sleep and cognition. Adverse mood was highly prevalent and should be actively sought and addressed.

Presentation: Friday, June 16, 2023
FRI407 Identification Of AIPB Expression For Early Breast Cancer Prediction
Authors: Doetch Nicole Elizabeth , Bose Himangshu S
Published: October 2023

Disclosure: N.E. Doetch: None. H.S. Bose: None.

The incidence of developing invasive breast cancer in women is about 14% during their lifetime and accounts for over 16% of all female cancers. Breast cancer is categorized based on the presence and absence of receptors including Estrogen Receptor (ER+/-), Progesterone Receptor (PR+/-), and Human Epidermal Growth Factor 2 Receptor (HER2+/-). Patients with Estrogen Receptor (ER+) and Progesterone Receptor (PR+) can participate in treatment catered to targeting both hormonally regulated receptors. Estradiol or estrogen are required and promote the growth of 80% of hormone receptor positive breast cancers which is regulated by Aromatase, a rate-limiting enzyme catalyzing the conversion of testosterone to estradiol. By decreasing estradiol synthesis, reduction in the progression of ER+/PR+ breast cancer is attainable.The expression of aromatase is increased in the ovaries of pre-menopausal women with substantial increase in peripheral and breast tissue in post-menopausal women contributing to tumor growth. “Aromatase Interacting Partner in Breast” (AIPB) has an inhibitory effect on aromatase causing a reduction in estradiol synthesis. AIPB is stimulated by detectable estrogen levels but remains unaffected by cAMP and inactivated cycloheximide. Expressed levels of AIPB were similar in unaffected breast tissue and WT MCF-12A breast cells. Western blot with tumorigenic human breast tissues showed decreased AIPB expression in ER+/PR+/HER2- tumors. We created conditional overexpression of AIPB under Tetracycline control that synthesized 3.52 pg/mL of estradiol. This was a 3-fold reduction in comparison to unaffected breast tissue and WT MCF-12A suggesting a leaky expression in tumorigenic breast cells. Findings led to hypothesis that AIPB stabilization is essential in promoting AIPB-Aromatase interaction resulting in decreased estradiol synthesis. The standard treatment for ER+/PR+ tumors, Tamoxifen, was incubated with MCF-12A cells overexpressing AIPB at varying Tamoxifen concentrations for different timed intervals and compared to untreated MCF-12A cells overexpressing AIPB and WT MCF-12A cells. Results yielded that AIPB expression in cells treated with Tamoxifen were substantially increased and no significant AIPB expression in untreated cells. MCF-12A-AIPB cells underwent incubation with Tamoxifen for 24h, soluble complex isolation, and a density gradient centrifugation. Western blotting with the CT antibody yielded one region in the density gradient fractionation in treated cells as compared to no complex formation in untreated cells. Therefore, AIPB confirmed crucial role in the pathophysiology of breast tumor development and maintenance of proper estradiol levels during post-menopause and tumorigenesis. The findings emphasize ability for future advancements in the early prediction of breast cancer with the identification of AIPB expression.

Presentation: Friday, June 16, 2023
FRI426 Raised Thyroid Stimulating Hormone In Girls With Polycystic Ovary SyndromeEffects Of Randomized Interventions
Authors: Ibanez Lourdes , Garcia-Beltran Cristina , Bassols Judit , Carreras-Badosa Gemma , Lopez-Bermejo Abel , de Zegher Francis Edouard
Published: October 2023

Disclosure: L. Ibanez: None. C. Garcia-Beltran: None. J. Bassols: None. G. Carreras-Badosa: None. A. Lopez-Bermejo: None. F.E. de Zegher: None.

Introduction: Polycystic ovary syndrome (PCOS) in women associates with raised levels of circulating thyroid stimulating hormone (TSH) and with high rates of gestational complications. A low range of preconception TSH is followed by low rates of gestational complications. It is unknown whether TSH levels are elevated in adolescents with PCOS and, if so, whether traditional or exploratory treatments can lower them into safe preconception range. We investigated TSH in non-obese adolescents with PCOS, including the effects of randomized interventions. Methods: Morning TSH was a safety marker in randomized pilot studies comparing the effects of an oral contraceptive (OC) versus those of a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET, aiming at a reduction of ectopic fat without necessarily lowering body weight) in non-obese adolescents with PCOS. A post-hoc analysis compared: TSH levels in PCOS (N= 62) vs controls; TSH changes on treatment (1 year); TSH levels post treatment (1 year). Results: Mean TSH levels were higher in PCOS patients than in control girls (P<0.01). On-treatment TSH levels diverged (P<0.001), remaining elevated on OC, and descending swiftly on SPIOMET, well into safe preconception range. Post-treatment TSH levels were stable in both subgroups. On-treatment changes of circulating TSH associated to those of liver fat (R= 0.307, P= 0.017). Conclusion: The endocrine signature of early PCOS is herewith extended to include modestly raised levels of circulating TSH; the normalizing effects of SPIOMET intervention in non-obese adolescents with PCOS are herewith extended to include on- and post-treatment TSH.

Presentation: Friday, June 16, 2023
FRI432 An Interesting Case Of Primary Hypogonadism In A Patient With Multiple Sclerosis
Authors: Ahsun Sana , Lekprasert Patamaporn , Win Kay K
Published: October 2023

Disclosure: S. Ahsun: None. P. Lekprasert: None. K.K. Win: None.

Introduction: As per the recent data there is an association between low levels of testosterone in men and the risk for multiple sclerosis (MS). Most recent practice involves checking testosterone levels for male patients with newly developed MS and treating with testosterone supplementation if levels are low. CASE PRESENTATION: A 65-year-old male with medical history of multiple sclerosis, prediabetes, hypogonadism, squamous cell carcinoma of left ear, thyroid cancer (unknown type) status post total thyroidectomy and radioiodine therapy; presented to our endocrine office for an initial visit. Patient had been following with Endocrinologist at different state in the past and did not have much of his prior records since that practice closed. He has been on 150 mcg of levothyroxine and his TSH was stable at 1.2 (0.4-4.5 mIU/L). He also had a history of hypogonadism and had been on testosterone supplementation since the age around 50. Patient did not know the underlying cause for his hypogonadism. He has 3 biological children and the youngest one is 26 years old. He had been off of testosterone therapy for 3 months prior to our initial visit. We did some workup which showed total testosterone level of <20 (250-1100 ng/dL). Free testosterone 2.2 (46-224 pg/mL). FSH and LH levels were elevated at 27.1 (1.6-8 mIU/mL) and 17.3 (1.6-15.2 mIU/mL). Prolactin level was 5.1 (5.2-26.5) ng/mL. These labs were consistent with Primary hypogonadism. Repeat testing was done and the patient had redemonstration of very low testosterone levels. Further checking of the karyotype analysis revealed normal male karyotype testing. His physical exam showed normal sized testicles at 20 cc and no gynecomastia. Body hair distribution was normal but there was decreased shaving frequency with decreased muscle strength. Patient never had any chemotherapy or the radiation therapy to the pelvic area. No known history of chronic infection or trauma. Currently, he is on Ocrelizumab for Multiple Sclerosis. His testosterone level is now in the normal range with the testosterone therapy after the work up. CONCLUSION: As per the above case, our patient has an interesting presentation of primary hypogonadism with multiple sclerosis. He has no known reason for his primary testicular failure. We know that testosterone deficiency has been linked to development of MS and MS can lead to secondary hypogonadism. But Primary hypogonadism has not yet been seen with MS although autoimmunity can be postulated to lead to primary testicular failure in these patients, but more studies and investigation will need to be done to establish this cause and effect relationship.

REFERENCE: Chitnis T. The role of testosterone in MS risk and course. Mult Scler. 2018 Jan;24(1):36-41. doi: 10.1177/1352458517737395. PMID: 29307293

Presentation: Friday, June 16, 2023
FRI435 A Grave Case Of Gynecomastia
Authors: Seltzer Sean , Williams Ashley , Kader Tina
Published: October 2023

Disclosure: S. Seltzer: None. A. illiams: None. T. Kader: None.

Background: Gynecomastia is a common endocrinology referral. Our team saw a patient in the clinic with an unusual presentation.

Clinical Case: A 28 year old male presented with worsening painful gynecomastia affecting one breast initially but eventually progressing to both breasts. His secondary concern was a 40lb weight loss and new onset tremor. He declined hypogonadal symptoms, palpitations, or new testicular growth. Exam revealed a resting pulse of 120 b.p.m., a palpable goiter, visible tremor, hyperdynamic heart sounds and bilateral tender gynecomastia. Labs revealed normal FSH, LH and hCG, high total testosterone (TT), thyroxine (T4) and triiodothyronine (T3) with positive thyroid receptor antibodies. Methimazole and beta blockade were started. He did develop an episode of atrial fibrillation requiring admission. Due to medication intolerance and patient preference the decision was made for total thyroidectomy. Three months post-surgery there was complete resolution of hyperthyroidism and gynecomastia.The differential for true gynecomastia is broad. The initial diagnostic approach includes a thorough history and physical exam followed by measuring serum testosterone (T), LH, hCG and estradiol (E2). Increased LH and low T indicates hypogonadism. Normal values may suggest an idiopathic cause. Elevated hCG warrants testicular imaging and if negative, chest and abdominal imaging to rule out extragonadal germ cell tumors. Elevated total T and LH should prompt measurement of TSH and T4 and if normal androgen resistance should be suspected. Elevated E2 and low/low normal LH should prompt testicular imaging and if normal an adrenal CT to rule out an adrenal neoplasm. If LH and T are low, prolactin should be measured as well as dedicated pituitary imaging.Any state which induces an increased E to T ratio may cause gynecomastia. The true pathophysiology in hyperthyroidism driving the increased sex hormone binding globulin (SHBG) production is unknown. It is postulated that this increase is driven by increased transcription and translation of hepatocyte nuclear factor-4ɑ secondary to elevated T41. SHBG more readily binds androgens than estrogens leading to a relative decrease in free T (FT). The lower FT levels result in negative feedback to the pituitary gland which causes increases in LH resulting in production of androgens, estradiol and peripheral aromatases. The increase in peripheral aromatization of testosterone leads to further elevation of the free estrogen levels.

Conclusion: Hyperthyroidism should always be in the differential of gynecomastia as in our case the presentation may be atypical.

References: Selva DM, Hammond GL. Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α. Journal of Molecular Endocrinology. 2009;43(1):19-27. doi:10.1677/jme-09-0025

Presentation: Friday, June 16, 2023
FRI437 Regenerative Treatment With Platelet-rich Plasma In Patients With Refractory Erectile Dysfunction: The Predictive Value Of Mean Platelet Volume
Authors: Francomano Davide , Iuliano Stefano , Condorelli Rosita Angela , Cannarella Rossella , La Vignera Sandro , Calogero Aldo E , Greco Emanuela A , Antonini Gabriele , Aversa Antonio
Published: October 2023

Disclosure: D. Francomano: None. S. Iuliano: None. R.A. Condorelli: None. R. Cannarella: None. S. La Vignera: None. A.E. Calogero: None. E.A. Greco: None. G. Antonini: None. A. Aversa: None.

Objective: Refractory erectile dysfunction (ED) is a common disorder in men regardless of the presence of late-onset hypogonadism. Being rich in growth factors, chemokines, and angiogenic factors, platelet-derived biomaterials contained in platelet-rich plasma (PRP) are particularly useful as some of the major therapeutic regenerative agents. PRP plays a crucial role in nerve cell regeneration, axon myelinization, progenitor cell homing and migration, and anti-fibrosis and anti-apoptosis of damaged cavernous nerve, and vascular corporal tissues (J Endocrinol 2001;170:395). Based on these findings, this study aimed to evaluate whether the mean platelet volume (MPV) may predict the efficacy of PRP before its intracavernous injection in patients with ED poorly responsive to phosphodiesterase type 5 inhibitors (PDE5i) and normal testosterone levels. Methods: 150 ED patients [age: 51±16.7 years; mean international index of erectile function (IIEF)-5: 12±2.6; mean peak systolic velocity (PSV): 32±5.5 cm/sec; and MPV=9.3±1.1 fl) underwent a single-shot treatment of PRP for their inability to respond to oral PDE5i. All patients were evaluated at baseline for MPV, at baseline and 1 month after intracavernous PRP injection for IIEF5, and dynamic penile duplex ultrasound (d-PDU) according to our previously published procedure (Andrology, 2021; 9:1457). Results: All patients had a significant improvement in ED symptoms (IIEF5: 12±2.6 vs. 19±3.0; p<0.0001) and a significant improvement in d-PDU (PSV: 32±5.5 vs. 42±7.6 cm/sec; p<0.0001). ROC curve analysis showed a significant accuracy (72.1%, C.I. 64.0 - 80.2, p<0.0001) for MPV in identifying clinically PRP-responsive patients with favorable outcomes (≧ +4 points in the IIEF5 score). In particular, an MPV <8.95 was recognized as the best threshold with a sensitivity of 90% and a specificity of 54.1%. Conclusion: This study provides the first evidence that the efficacy of a single PRP injection correlates with baseline MPV in patients with ED and poor response to PDE5i. An MPV value of less than 8.95 fl. identifies patients with a lower response to treatment who could benefit from re-treatments with more PRP injections.

Presentation: Friday, June 16, 2023
OR19-03 SIK2 Regulates Granulosa Cell Response to Exogenous Gonadotropins
Authors: Hayes Emily , Lakomy Oliwia , Hassan Mariam , Filzen Rachael , Esquivel Miriam Rodriguez , Foretz Marc , Stocco Carlos Oscar
Published: October 2023

Disclosure: E. Hayes: None. O. Lakomy: None. M. Hassan: None. R. Filzen: None. M. Rodriguez Esquivel: None. M. Foretz: None. C.O. Stocco: Grant Recipient; Self; NIH R01HD097202.

Forty percent of cases of infertility are attributed to ovulatory defects. Successful ovulation requires the coordinated development of the ovarian follicle, the functional unit of the ovary that is composed of the oocyte surrounded by steroidogenic granulosa cells. However, the mechanisms that govern follicle development remain incompletely understood. Previously, our group showed that loss of salt-inducible kinase 2 (SIK2) in a murine knockout model resulted in a significantly increased number of ovulated oocytes in response to an ovarian hyperstimulation protocol. Here, we aimed to further characterize the reproductive phenotype of SIK2 knockout mice, as well as to understand the role of SIK2 in granulosa cells by creating and characterizing a granulosa cell-specific knockdown of SIK2 using the Cre-Lox system. Loss of SIK2 resulted in no changes in the number of litters or litter size as well as a normal estrus cycle. Interestingly, granulosa cell-specific knockdown of SIK2 resulted in a significantly increased number of ovulated oocytes in response to ovarian hyperstimulation. However, SIK2 knockout mice do not ovulate more oocytes under physiologic conditions. Furthermore, knockdown of SIK2 in granulosa cells resulted in significantly increased Cyp19a1 gene expression and serum estradiol concentration. The data reveal that SIK2 plays an important role in the regulation of the response of granulosa cells to gonadotropins. These data support the potential of SIK2 as a pharmacologic target for improving oocyte yield for women receiving gonadotropins during in vitro fertilization as a treatment to trigger follicular maturation and ovulation. SIK2-regulated mechanisms could reveal new targets for the development of innovative methods of contraception.

Presentation Date: Saturday, June 17, 2023
SAT354 Molecular and Histological Characterization of a Guinea Pig Model of Mild Hyperandrogenemia
Authors: Tanori Rosalia N , Barboza Sagrero Juriana E , Noll-Bader Kayla , Chandu Sarpana , Chappell Patrick E , Bishop Cecily Vauna
Published: October 2023

Disclosure: R.N. Tanori: None. J.E. Barboza Sagrero: None. K. Noll-Bader: None. S. Chandu: None. P.E. Chappell: None. C.V. Bishop: Consulting Fee; Self; Oviva, Oxford Pharmaceuticals Inc.

There are several rodent models for polycystic ovarian syndrome (PCOS), but unlike primates, most rodents will not form a long-lived corpus luteum (CL) unless they experience cervico-vaginal stimulation/mating. Our research group has begun to determine if guinea pigs (Cavia porcellus), rodents with long-lived CL, are a suitable model for mild hyperandrogenemia, a risk factor for PCOS. The objective of this analysis was to determine the relative abundance of each follicle type within a cross-section of 20-week old guinea pig ovarian tissue from control and T-treated females after 3 months of androgen exposure. Ovarian tissues were collected from six guinea pigs treated with cholesterol implants (vehicle, n=4) or testosterone implants (n=3), which elevated androgen levels ∼2-fold above control females. Tissues were embedded in paraffin wax and cut into serial sections (5 μm) and placed onto glass slides (1 section/slide) for hematoxylin and eosin staining to identify follicle morphology within the ovarian tissue. Every fifth section was stained and analyzed using an ECHO Revolve microscope and follicles counted using ImageJ. Follicles of interest were primordial, primary, multi-layer, antral, and corpus luteum, and counts were normalized to ovarian area. All follicle types were found in all the ovaries imaged, as well as some corpora lutea. Multilayer follicles were significantly reduced by chronic exposure to mild hyperandrogenemia (p=0.01). These should provide needed baseline analyses for future experiments employing guinea pigs as a model of PCOS. In addition to histological analysis, we have begun quantifying gene expression changes for hormones and receptors throughout the reproductive axis. Preliminary studies using qPCR illustrate significantly elevated expression levels of hypothalamic kiss1, pituitary gnrhr, and ovarian fshr in T-treated females. No discernable differences were observed between treatment groups for kiss1r, gnrh, or fshb. Ongoing studies will explore differences in estrogen and androgen receptor expression throughout the reproductive axis, as well as any changes in metabolic regulators in liver and skeletal muscle that are associated with mild hyperandrogenemia in these animals.

Presentation Date: Saturday, June 17, 2023
FRI172 Assessment Of Plasma Dexamethasone Levels After 1-mg Dexamethasone Suppression Test In Adults With Obesity
Authors: Paopongpaiboon Pimonrat , Santisitthanon Prangareeya , Houngngam Natnicha , Snabboon Thiti , Boonchaya-anant Patchaya
Published: October 2023

Disclosure: P. Paopongpaiboon: None. P. Santisitthanon: None. N. Houngngam: None. T. Snabboon: None. P. Boonchaya-anant: None.

Background: The 1-mg overnight dexamethasone suppression test is the most frequently used screening test for Cushing’s syndrome. It has been proposed that obese patients may have insufficient plasma dexamethasone levels for the test which may result in false positives. We sought to compare the plasma dexamethasone levels after 1-mg DST in healthy obese participants and in normal-weight participants. Methods: A total of 30 normal-weight participants (BMI ≤ 25 kg/m2) and 62 obese participants (BMI >25 kg/m2) were enrolled in the study. Obese patients were further divided into class 1 (25 - 29.9 kg/m2) and class 2 (>30 kg/m2). After a standard overnight 1-mg dexamethasone suppression test, blood samples were obtained for serum cortisol and plasma dexamethasone levels. Plasma dexamethasone levels were quantified using liquid chromatography - mass spectrometry (LC-MS/MS). Results: No significant difference in plasma dexamethasone levels were found between obese and normal-weight participants (3.31 ± 1.35 vs 2.82 ± 1.11 nmol/L, mean ± SD; P=0.09 respectively). There were also no correlations found between sex, BMI, body surface area (BSA) and plasma dexamethasone levels. There was also no significant difference in the proportion of participants who achieved a plasma dexamethasone level > 3.3 nmol/L in comparison between obesity class 1, obesity class 2, and normal-weight groups. Conclusion: We did not find a difference in plasma dexamethasone levels after 1-mg DST between obese and normal-weight participants. Our results suggest that BMI does not affect plasma dexamethasone levels and routine dexamethasone measurement may not help to identify false-positives using the 1-mg DST.

Presentation: Friday, June 16, 2023
SAT368 Severe Hyperandrogenism in a Young Woman with Elevated BMI: A Case Study of The Role of Weight Loss in The Management of PCOS
Authors: Ortega Susel Rodriguez , Bass Ilana R
Published: October 2023

Disclosure: S. Rodriguez Ortega: None. I.R. Bass: None.

Background: Increased adiposity enhances the phenotypic expression and severity of hyperandrogenism in women with Polycystic Ovarian Syndrome (PCOS). Weight loss has been associated with improved endocrine features in women with PCOS and elevated Body Mass Index (BMI). Bariatric surgery can be an effective means of significant weight loss and restoration of the hypothalamic pituitary axis. Case Presentation: A 21-year-old Hispanic nulligravid woman presented with history of oligomenorrhea, weight gain and hirsutism. Her symptoms started after menarche at 15 years old with irregular periods, hair growth on her face and neck, and rapid weight gain. She was evaluated by an endocrinologist and was found to have an elevated total testosterone level by LC/MS on several different occasions: 309ng/dl, 259ng/dl and 229 ng/dl, as well as elevated androstenedione 346 ng/dl (41-262ng/dl). She was treated with metformin and oral contraceptive pill for two years and then referred for second opinion. On our physical exam, she had a BMI of 44.60 kg/ m2, a deep voice, Ferriman Gallwey score of 12 and acanthosis nigricans. OCPs were held for three months for accurate testing and work up revealed total testosterone 164.7 ng/dl (10.0-55.0 ng/dl), sex hormone binding globulin 25.4 nmol/L (24.6-112.0 nmol/L), bioavailable testosterone 84.3ng/dL (51.4%), DHEAs 375 µg/dl (110-431.7 µg/dl), and androstenedione 264 ng/dl (41-262 ng/dl). Other causes of hyperandrogenism such as hyperprolactinemia, hypothyroidism and congenital adrenal hyperplasia were ruled out. MRI pituitary from outside facility was reviewed and was normal. MRI abdomen and pelvis with/without contrast was performed, which demonstrated normal adrenal glands and an 8.1 cm midline pelvic cyst, containing a 0.7 cm enhancing solid nodule. She was referred for surgery for concern for possible virilizing tumor. The cyst was surgically removed and intra-operative ovarian exploration and cytopathology from pelvic washing were negative. She was referred for bariatric surgery and underwent a sleeve gastrectomy. After 6 weeks, she lost 30lbs, BMI improved to 37.1 kg/ m2 and her menses resumed. Repeat labs showed improvement in her androgens: total testosterone 64.8ng/dl, SHBG 104nmol/L, androstenedione 127ng/dl. After 8 months, she lost 110lbs and has dramatic improvement in her hirsutism and clearance of her acanthosis nigricans. Conclusion: Sustained lifestyle changes and weight loss are a mainstay in the treatment of patients with PCOS and obesity. Bariatric surgery results in durable weight loss and restores the normal physiological balance of sex hormones and improves signs and symptoms of hyperandrogenism.

Presentation Date: Saturday, June 17, 2023
SAT369 Rare Cause of Hyperandrogenism and Elevated 17 OH Progesterone Levels - Ovarian Steroid Cell Tumor (NOS)
Authors: Shafi Amtul , Surrey Garnet Meier
Published: October 2023

Disclosure: A. Shafi: None. G. Meier Surrey: None.

Background:There are several causes of hyperandrogenism. We report a rare cause of hyperandrogenism and elevated 17 OH progesterone levels due to ovarian steroid cell tumor

Clinical Case: A 21 yr old female presented to our clinic for evaluation of secondary amenorrhea and hirsutism for 2 years. She also endorsed deepening of voice and possible clitoromegaly. On physical exam she had hirsutism, acne with mild clitoromegaly. Labs were pertinent for normal TSH, Ft4, prolactin, DHEAS, am cortisol 14.85 ug/dl, ACTH 16 pg/ml (6-50), IGF-1 303 ng/ml (830-456), but elevated total and free testosterone 394.5 ng/dl (10-75), 70.5 pg/ml (0.2-5) respectively, elevated 17 OH progesterone 842 ng/dl (23-431 ng/dl depending on the menstrual phase). Due to testosterone >3x ULN, and significant symptoms of hirsutism/hyperandrogenism there was a concern for androgen producing tumor and therefore CT abdomen and Pelvis was obtained which showed “heterogeneously enhancing right adnexal mass measuring 6 x 5.1 x 5.4 cm causing leftward displacement of the uterus and left ovary. Right ovary was not identified and is likely inseparable from the right adnexal mass”. She underwent a laparoscopic Right salpingo oophorectomy with pelvic washings, peritoneal biopsies and omental biopsy. Pathology of ovary showed a steroid cell tumor, NOS. Pt seen 2 months post surgery pt reported that her menstrual cycles had become regular, however she continued to have acne and hirsutism for which she was referred to Dermatology. Post surgery 17 OH progesterone levels had normalized. Conclusion:Steroid cell tumors of the ovary are extremely rare, accounting for only 0.1% of all ovarian tumors. The clinical presentation may take many forms, including abdominal pain, distention, irregular menstrual cycles, and hirsutism. Labs can show elevated 17 OH progesterone levels. Therefore among other etiologies clinicians should also consider Ovarian Steroid cell tumor (NOS) as a possible cause for hypernadorgenism and elevated 17 OH progesterone levels

Presentation Date: Saturday, June 17, 2023
SAT376 Luteinizing Hormone Secretion in Hyperandrogenic Girls Taking Spironolactone or Metformin
Authors: Burt Solorzano Christine Michele , Gilrain Melissa , Kim Su Hee , McCartney Christopher Rolland
Published: October 2023

Disclosure: C.M. Burt Solorzano: None. M. Gilrain: None. S.H. Kim: None. C.R. McCartney: None.

Peri-pubertal hyperandrogenism (HA) typically relates to excess adrenal and/or ovarian androgen production in response to adrenocorticotropin (ACTH) and/or luteinizing hormone (LH), respectively. Spironolactone and metformin are commonly used medications to treat adolescent androgen excess. We examined how end-organ responsiveness and LH pulse patterns are affected by these medications in adolescents with HA. We studied free testosterone (T) levels (including baseline and peaks after ACTH and recombinant human chorionic gonadotropin [r-hCG] stimulation), oral glucose tolerance testing (OGTT), and 12-hr overnight LH secretion (sampled q 10 min) in post-menarcheal girls with HA before and after 3-months of either spironolactone (100 mg BID) or metformin (500 mg BID). Free T was calculated using total T (LC-MS/MS) and sex hormone binding globulin (SHBG).To date, 3 girls (aged 12-18) have been studied using spironolactone and 4 girls (aged 14-17) using metformin. (1 girl was studied twice, once with each medication.) After spironolactone treatment, free T changed by -19% (-58 to +37) (median [range]) unstimulated, by -53% (-62 to -15) after ACTH, and by -54% (-66 to +12) after r-hCG. Peak insulin level during OGTT changed by +28% (+16 to +98). Overnight LH pulse frequency changed by -64% (-89 to -10) and LH mean by -74% (-89 to -17). Two subjects in the spironolactone group demonstrated luteal LH patterns despite serum progesterone concentrations < 0.7 ng/mL. In the metformin group, free T changed by +35% (-32 to +125) unstimulated, by 36% (-54 to +66) after ACTH, and by 21% (-41 to +105) after r-hCG. Peak insulin level during OGTT changed by -47% (-74 to +102). LH pulse frequency changed by +10% (-29 to +22) and LH mean by +1% (-2 to +74). To summarize findings to date, mean LH and LH pulse frequency decreased in all three subjects taking spironolactone, including marked reductions in two subjects who demonstrated luteal LH patterns. While free T levels decreased in some of these girls, this seems unlikely to account for such marked changes in LH secretion. And despite similar decreases in T and also decreases in peak insulin in some girls taking metformin, LH pulse frequency did not change markedly. LH pulse patterns in two girls taking spironolactone suggest a progesterone-like effect on LH pulsatility. Spironolactone can cause irregular uterine bleeding, and canrenone (the major metabolite of spironolactone) binds to uterine progesterone receptors competitively (Fernandez MD, Br J Clin Pharm 1983). However, to our knowledge, this is the first report of LH pulse changes in HA girls using spironolactone. Further studies are needed to confirm this finding.

Presentation Date: Saturday, June 17, 2023
SAT382 Lean Mass and Associated Factors in Women with PCOS with Different Phenotypes
Authors: Fighera Tayane Muniz , dos Santos Betania Rodrigues , Spritzer Poli Mara
Published: October 2023

Disclosure: T.M. Fighera: None. B.R. Santos: None. P.M. Spritzer: None.

Introduction: Obesity, insulin resistance and hyperandrogenism are common findings in women with PCOS. These abnormalities have been associated with muscle mass changes reported in previous studies, with conflicting results comparing women with PCOS versus non-PCOS controls. The aim of the present study was to evaluate clinical and laboratory variables related to lean body mass according to PCOS phenotype. METHODS: In this case-control study, we analyzed 133 women of reproductive age, recruited through public advertisement at the outpatient clinic of a University Hospital. Inclusion criteria were body mass index (BMI) ranging from 18.5 to 39.9 kg/m², age between 17 and 35 years and no intake of drugs known to interfere with hormone levels for at least 3 months before the study. Women with diabetes, thyroid dysfunction, liver or renal disease were excluded. PCOS was defined according to the Rotterdam Consensus. The study protocol was approved by the local Ethics Committee, and written informed consent was obtained from all participants. Blood pressure, BMI, body composition by dual-energy X-ray absorptiometry (DXA), and laboratory measurements for metabolic and hormonal variables were performed in all subjects. Creatinine values were used as an indirect marker of lean mass. RESULTS: Median age was 28 years (23-31), and the median BMI was 27.9kg/m² (24.1-33.7), with higher BMI in women with the AB phenotype of PCOS (n=59) compared to ovulatory (C phenotype) PCOS (n=23) and controls (n=51) (p=0.005). Women with the AB phenotype of PCOS presented higher Ferriman-Gallway score (p<0.001), systolic (p=0.001) and diastolic blood pressure (p=0.002), insulin levels (p=0.006), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p=0.008), metabolic syndrome prevalence (p<0.001), testosterone (p=0.008), free androgen index (FAI) (p<0.001), fat mass index (FMI) (0.015), and android-to-gynoid (AG) fat ratio (p=0.036) compared to controls. Appendicular lean mass index (ALMI) was higher in the AB phenotype than controls [7.01 (6.33-8.02) vs 6.69 (5.94-7.09), p= 0.024] and the C phenotype [6.60 (6.16-7.22), p=0.022]. A positive correlation was observed between ALMI and creatinine, even after adjustment to BMI, in women with AB phenotype (rho=0.319, p=0.023), but not with ovulatory PCOS (rho=0.293, p=0.238) or controls (rho=0.277, p=0.097). In a multivariate linear regression model, creatinine, HOMA-IR, and FMI were positively associated with ALMI, explaining 38.4% of the variation in lean mass. CONCLUSIONS: The present results suggest that the higher lean mass observed in women with the AB phenotype of PCOS is associated with hyperinsulinemia and higher fat mass. Sources of research support: INCT/CNPq and FAPERGS

Presentation Date: Saturday, June 17, 2023
SAT384 Is This A Case of Androgen-Secreting Endometrial Cancer in A Postmenopausal Woman?
Authors: Taqi Vian , Rimal Priya , Gilden Janice L
Published: October 2023

Disclosure: V. Taqi: None. P. rimal: None. J.L. Gilden: None.

Background: Hirsutism (HIR) is a common disorder of women of reproductive age, often due to polycystic ovary syndrome (PCOS). During post menopause (PM), there is usually diminishment of androgenizing hormone levels and symptoms associated with PCOS. However, rapidly progressive HIR and symptoms of virilization in PM women should always raise the question of androgen-secreting tumors, whether of ovarian or adrenal origin. Other rare causes include ovarian hyperthecosis and Leydig cell hyperplasia. We present a rare case of hyperandrogenism with endometrial carcinoma, associated with increasing hirsutism and normal ovarian imaging and pathology. Clinical case: A 56-year-old woman G3P3 PM for 2 yrs, with Type 2 Diabetes, obesity, HTN, hypercholesterolemia, IBS, Factor S Leiden, menarche at age 12-13 yrs, and PCOS s/p laser HIR removal, and previous regular menses, was referred to endocrine clinic for increasing HIR with diffuse hair loss for 6 months and suprapubic/abdominal discomfort. She also had prior corneal melanoma treated with radiation and cardiac ablation for arrhythmia. Her paternal grandmother had uterine cancer. Physical Exam: VS BP=121/78; HR=66; BMI=31 Kg/m²: (Ferriman-Gallwey score 16/36) with HIR on face, abdomen, chest and back, but no other virilization or cushingoid signs. Initial labs: elevated total and free testosterone (59 ng/dl, n<45), (9.3 pg/ml, n<6.4) respectively, unconjugated DHEA (55 ng/dL, n 77-85) low DHEA-S (29 mcg/dl, n 35- 430 mcg/dl) 17-OHP (50 ng/dL, repeat 44 (n≤ 45) with normal prolactin (5.4 ng/mL, n 0.7-31.6) ACTH (7 pg/mL, n 0-47), salivary cortisol <0.03 mcg/dL, FSH (50.3 mIU/mL ;n=5.9-72.8), LH (29.7 mIU/ml, n 1.1-52.4), estradiol (21.71 pg/mL (n <11-32.2). CT abdomen-hepatic steatosis, normal adrenals. US- heterogenous mass uterine fundus 1.1 x 1.0 x 1.0 cm with subendometrial calcifications, subcm follicles in ovaries. MRI-hypoechoic 0.7X0.8X0.7 cm uterine lesion, normal ovaries; Endometrial biopsy-disordered proliferative endometrium. Hysteroscopy with biopsy confirmed grade I endometrial adenocarcinoma. A total laparoscopic abdominal hysterectomy with bilateral oophorectomy (TAH/BSO) was performed. Pathology-endometrial carcinoma, endometroid type F1GO stage 1A with positive estrogen and progesterone receptors, normal ovaries. By 3 months postop, the HIR significantly decreased with normalized total and free testosterone levels (14 ng/dl), (1.8 pg/ml). Conclusion: This is a rare case of hyperandrogenism associated with endometrial cancer in a postmenopausal woman causing hirsutism with the resolution of symptoms and normalization of androgen levels following TAH/BSO. Clinicians should be aware to thoroughly evaluate postmenopausal women who develop sudden increasing signs of androgenization, particularly if it is of recent onset, and consider other rare diagnoses.

Presentation Date: Saturday, June 17, 2023
THU570 Isoform Specific Gene Regulation By Progesterone Receptors Drives Expansion Of Breast Cancer Stem Cell Expansion In 3D Cell Culture Models
Authors: Gillis Noelle E , Ha Truong Thu , Lange Carol A
Published: October 2023

Disclosure: N.E. Gillis: None. T.H. Truong: None. C.A. Lange: None.

Exposure to progesterone is a risk factor for breast cancer, and numerous PGR polymorphisms are linked to breast, endometrial, and ovarian cancer. Two progesterone receptor (PR) isoforms are expressed from PGR in breast tissues: full-length PR-B and truncated PR-A. In normal breast epithelia, PR isoforms are equally expressed and mostly function as A:B heterodimers. An imbalance of this ratio, and thus a predominance of homodimers, is frequent in ER+ breast cancer. Luminal A-type estrogen receptor positive (ER+) tumors often exhibit an elevated PR-A:PR-B ratio that predicts resistance to tamoxifen. It has recently been shown that PRs promote endocrine resistance and drive expansion of breast cancer stem-like cell (CSC) populations. However, the isoform-specific molecular mechanisms of PR action in ER+ breast cancers remain undefined. The goal of our current work is to map the progesterone-driven gene expression in CSC cells through transcriptomic profiling of T47D cells grown in spheroid-culture conditions that express exclusively PR-A or PR-B. This transcriptomic data has been integrated with phenotypic studies of T47D and MCF7 cells that express a single isoform of PR. Our data shows PR-A is a regulator of the cell cycle and of senescence, while PR-B mediates cell metabolism and intracellular signaling. We further integrated our cell line data with transcriptomes from patient tumors that have been classified based on their PR-A:PR-B ratio and their response to treatment with anti-progestins. Our results are a first step towards re-defining the role of PRs in gene regulation within the CSC population.

Presentation Date: Thursday, June 15, 2023
THU571 Mechanisms Of Estrogen-induced Skeletal Muscle Fibrosis In An Inguinal Hernia Humanized Aromatase Mouse Model
Authors: Potluri Tanvi , Zhao Hong , Yin Ping , Stulberg Jonah J , Lieber Richard L , Bulun Serdar E
Published: October 2023

Disclosure: T. Potluri: None. H. Zhao: None. P. Yin: None. J.J. Stulberg: None. R.L. Lieber: None. S.E. Bulun: None.

Mechanisms of Estrogen-Induced Skeletal Muscle Fibrosis in an Inguinal Hernia Humanized Aromatase Mouse Model Abdominal skeletal muscle weakening via fibrosis and atrophy leads to inguinal herniation. Despite the high prevalence and morbidity of inguinal herniation, the mechanisms and etiology are largely unknown. We developed a transgenic mouse model with the human aromatase gene (Aromhum), where all male mice develop spontaneous scrotal hernias at puberty. The lower abdominal muscles (LAM) in these mice can synthesize estradiol (E2), which activates the stromal fibroblasts, leading to fibrosis and herniation. Remarkably, the administration of Estrogen Receptor Alpha (ERα) antagonist Fulvestrant to the herniated mice reverses fibrosis and herniation. We use this novel model to uncover mechanisms of E2-induced skeletal muscle fibrosis and its subsequent reversal. Hernia-Associated Fibroblasts (HAFs) were isolated from LAM tissues and cultured under estrogen-replete (10nM E2) and deplete (10nM E2 + 100nM Fulvestrant) conditions. The cells were analyzed using ERα ChIP-seq, ATAC-seq, and RNA-seq to observe genetic, epigenetic, and transcriptomic changes (n = 10-15 mice/group in 3 technical replicates).Via RNA-seq, we identified 853 differentially expressed genes between E2 and E2+Fulvestrant treated fibroblasts. These genes were associated with the extracellular matrix, WNT signaling, TGFβ, and focal adhesions were enriched in our study. We further identified 657 E2-upregulated annotated genes common between ATAC-seq and ChIP-seq. Overall, 58 genes were identified across all three datasets, including known E2-responsive genes such as Pgr, as well as extracellular modulators such as Adamts3, Adamts6, Pcdh7, Ltbp1, Fbln5, and Fbln7. Furthermore, E2-ERα activation also directly induced the expression of other transcription regulators, such as Pbx1, Id2, Hlf, Zfp521, and Zfp618. Together, we identified the core E2-modulated genes in HAFs that lead to skeletal muscle fibrosis and reversal. To validate these findings, we performed RNAscope on human inguinal hernia tissues. We detected PBX1, PIEZO2, NRP2, LTBP1, NCAM1, and ADAMTS6 expression in the herniated fibrotic regions of the samples. In contrast, there is no expression of these genes in corresponding healthy muscle fibers.Using this Aromhum mouse model, we characterized, for the first time, characterize E2 mechanisms in skeletal muscle fibrosis and herniation. In addition, we provide an insight into the specific disease-causing fibroblast populations and markers that can form the source for future therapeutics to treat hernias and other fibrotic disorders.

Presentation Date: Thursday, June 15, 2023
FRI164 The Glucocorticoid Receptor is Required for Efficient Aldosterone-induced Transcription by the Mineralocorticoid Receptor
Authors: Johnson Thomas A , Fettweis Gregory , Wagh Kaustubh , Almeida-Prieto Brian , Hager Gordon L , Alvarez de la Rosa Diego
Published: October 2023

Disclosure: T.A. Johnson: None. G. Fettweis: None. K. Wagh: None. B. Almeida-Prieto: None. G.L. Hager: None. D. Alvarez de la Rosa: None.

The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There is evidence in the literature that the two receptors interact both functionally and physically, but the global role of this interdependence is poorly understood (1,2). Here, we analyze the impact of GR co-expression on MR genome-wide chromatin binding and transcriptional responses to aldosterone and glucocorticoids. Our data show that GR co-expression alters MR genome-wide binding in locus- and ligand-specific ways. MR binding to consensus hormone response elements is affected by GR. Additionally, gene responses by MR in the absence of GR are weak and show poor correlation with chromatin binding. In contrast, co-expression of GR greatly potentiates genome-wide MR-mediated transcription, particularly in response to aldosterone. These aldosterone-mediated transcriptional responses do not occur with GR alone. Finally, single molecule tracking of MR in live cells indicates that the presence of GR contributes to productive chromatin binding events. Together, our data indicate that co-expression of GR enables optimal aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids.

REFERENCES: (1) Mayumi Nishi et al., J Neuroscience. 2004 May 26; 24(21):4918 - 4927. (2) Liu et al., PNAS. Dec 1995; 92: 12480-12484.

Presentation Date: Friday, June 16, 2023