bluuebunny/crossref_metadata_2025_split huggingface dataset:
FRI375 Validation Of A Novel Mouse Placenta Explant Protocol For Screening Of Drugs Modulating Circadian Rhythms
Authors: Lee Jessica Sora , Hoffmann Hanne Mette 
Published: October 2023

Abstract
Disclosure: J.S. Lee: None. H.M. Hoffmann: None.
Introduction Pre-eclampsia is one of the leading causes of maternal, fetal, and neonatal morbidity and mortality, complicating about 4% of pregnancies. Recent work has identified PERIOD3 (PER3), a gene regulating 24-hour circadian rhythms, to be downregulated in the preeclamptic placenta. The role of circadian rhythms in the placenta largely remains unknown. Our goal is to establish an organotypic placental preparation to allow screening of drugs that regulate circadian rhythms. These studies are a first step towards understanding how circadian rhythm changes are caused in the placenta and will be the basis for future studies to understand how circadian rhythm disruption in the placenta cause pregnancy complications, such as preeclampsia.
Methods We established a novel organotypic placenta preparation allowing to study circadian rhythms in a LumiCycle using gestation day (GD) 14 and GD18 placental explants from the validated circadian reporter mouse Per2::Luciferase. Using H&E we validated the explants to be &gt;80% enriched in either decidua (DC) which is strictly of maternal origin, labyrinth (LB) which is strictly of fetal origin, and the junctional zone (JZ) which consists of binucleated cells fused of maternal and fetal cells.
Results Through H&E staining, we validated by distinct morphology that the DC is enriched with neutrophils; the JZ contains spongiotrophoblasts and glycogen trophoblasts; whereas the LB has anucleated red blood cells. We next established a protocol to record Per2::Luciferase circadian rhythms for &lt;6 days. We found that the Per2::Luciferase circadian rhythm shortens with increased gestational age, where the period in DC, LZ and LB in the GD14 placenta is ∼4h longer than in the GD18 placenta, showing an unexpected plasticity in circadian timekeeping in the placenta. Because PER3 is downregulated in the pre-eclamptic placenta, we asked if the explants would be useful for pharmacologically screenings. We applied PF670462 (1μM), which stabilizes PER1/2/3, or epidermal growth factor (EGF, 30ng/mL), a growth factor important in placental function and a PER2 enhancer. PF670462 lengthened Per2::Luciferase period in the DC and JZ, confirming the expected circadian rhythm stabilizing effect of PF670462. Surprisingly, EGF only modulated circadian rhythms in the GD14 placental, where EGF shortened Per2::Luciferase period in DC, and lengthen the period in the JZ and LB zones in the GD14 placenta. This data suggests EGF has gestational age and placenta zone specific effects.
Conclusion We validated a novel ex vivo placental preparation to study circadian rhythms at GD14 and GD18. We identified a placenta zone and gestation age specific effect of EGF, an effect future studies will further expand on. This model will be useful to complete pharmacological screenings of drugs that can restore circadian rhythms in the preeclamptic placenta.
Presentation: Friday, June 16, 2023
FRI384 Sterilization Of Female Dogs By A Neonatal Treatment Of Estrogen-Releasing Implants
Authors: Park Chan Jin , Lin Po-Ching , Zhou Sherry , Hess Rex A , Ko Chemyong 
Published: October 2023

Abstract
Disclosure: C. Park: None. P. Lin: None. S. Zhou: None. R.A. Hess: None. C. Ko: None.
Hypothalamic Kisspeptin neurons that control the GnRH neuron activity are known to be a core regulator of the reproductive axis. Loss of the Kisspeptin-1 gene in these neurons results in infertility. Recent reports showed that inhibition of Kisspeptin neuron development by daily injection of 17β-estradiol benzoate (EB, 0.5 mg/day), a long-lasting estrogen, to neonatal female rats for 10 days causes sterility. We aim to develop a single injection solution for achieving sterilization in female dogs by targeting developing Kisspeptin neurons. In this study, we tested a working hypothesis that, in female dogs, extended exposure to EB for 2 weeks after birth by slow-releasing implants will result in sterility. This hypothesis was proposed based on our proof-of-concept study in which neonatal treatment of female rats with implants that contained 0.3 mg EB decreased the number of Kisspeptin neurons, and made them infertile permanently. To test the hypothesis in dogs, pellets that contained 0.5 mg (n=3) or 1.0 mg EB (n=2) and were designed to release EB for 2-3 weeks were subcutaneously implanted in female beagle dogs on postnatal day 6 (PND6). Intact dogs (n=4) were used as controls. The indices for female fertility (estrous cyclicity, ovulation) were assessed by daily vulva examination (swelling, discharge) and monthly measurement of serum progesterone levels. In addition, when a dog exhibited signs of estrus, the dog was bred with fertility-proven male dogs. During the 3 years of the study period, control dogs showed a minimum of 3 reproductive cycles (estrus, ovulation), and successfully produced puppies each time. Treated dogs displayed dose-dependent fertility outcomes; none of the EB 1.0 mg-treated dogs exhibited estrus nor had elevated serum progesterone levels, while two dogs out of the three EB 0.5 mg-treated dogs remained infertile. The other dog of the EB 0.5 mg group showed estrus signs during the study period and produced a litter when bred with a proven male. In the second experiment, implants that contained 0.5 mg (n=2) or 1.0 mg EB (n=3) were injected into female puppies on PND1. They are currently 1-1.2 years of age, and none have shown estrus/ovulation signs so far. Our study demonstrates that neonatal treatment of EB by slow-releasing implants sterilizes female beagle dogs. During the study period, the complete blood cell count and serum chemistry of treated dogs were within the normal range. This study shows that the non-surgical solution using EB implants is a promising approach to replace the current practice of sterilizing pets with surgical methods. Supported by NSF SBIR grant (#2052603)
Presentation: Friday, June 16, 2023
FRI403 The Unintended Consequences Of Applying Topical Testosterone Directly To The Scrotum
Authors: Melendez-Rivera Juan Gabriel , Steven Scott James 
Published: October 2023

Abstract
Disclosure: J.G. Melendez-Rivera: None. S.J. Steven: None.
Background: Topical testosterone is commonly used to treat hypogonadism in men. A concern associated with its use is the unintentional transfer to partners and children by direct contact with the application site. While prior studies and case reports have demonstrated the effects of direct skin contact with traditional application sites including the axillary regions and the abdomen, scarce data is available regarding the effects of transfer from application to the scrotum. Clinical Case: A 44-year-old woman presented with gradually worsening hirsutism and deepening voice over the past two years along with sudden cessation of menses. Initial laboratory studies revealed elevated testosterone of 1,776 ng/dL [10-55 ng/dL], elevated free testosterone of 14.4 pg/mL [0-4.2 pg/mL], normal androstenedione of 80 ng/dL [41-262 ng/dL) and normal DHEA-S of 57.7 ug/dL [57.3-279.2 ug/dL]. Transvaginal ultrasound revealed no ovarian masses or hyperplasia and CT abdomen and pelvis with and without contrast revealed no adrenal masses or hyperplasia. Ovarian and adrenal vein sampling were unremarkable. Anabolic steroid panel demonstrated a significantly elevated testosterone-to-epitestosterone ratio of 83.5 [&lt;4] confirming an exogenous source of testosterone. Although the woman initially reported that her husband was applying topical testosterone, she reported that he was “obsessive” about being sure to wash the area of application prior to intimacy. Further questioning revealed that her husband was actually applying high concentration topical testosterone directly to his scrotum with sexual intercourse occurring up to five times daily. Conclusion: This case illustrates the dangers of applying topical testosterone directly to the scrotum. Prior studies have demonstrated that it may result in higher levels of serum testosterone in a shorter period of time which makes it seem like an attractive option for men desiring rapid resolution of their hypogonadal symptoms. Despite these perceived benefits, it can be detrimental to the health of their female partners who may experience extraordinarily elevated testosterone levels as a result of direct intravaginal absorption of topical testosterone.
Presentation: Friday, June 16, 2023
FRI412 A Case of 46,XX Gonadal Dysgenesis With Mayer-Rokitansky-Küster-Hauser Syndrome And Primary Hypothyroidism
Authors: Al Allawi Sarah , Osman Radwa 
Published: October 2023

Abstract
Disclosure: S. Al Allawi: None. R. Osman: None.
Introduction: The association between Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome and gonadal dysgenesis is rarely reported in the literature. Coexistence of hypothyroidism with this condition is scarce and clinical correlation remains unclear. We describe a case of this rare clinical entity in conjunction with primary hypothyroidism.
Clinical case: A 27-year-old Female with a medical history of primary hypothyroidism was referred to our clinic for evaluation of primary amenorrhea. She was born with a female phenotype. Growth was appropriate, but puberty was delayed with self-reported late pubarche at age 19. She never had a menstrual cycle, and had received hormonal replacement therapy (HRT) for a few months but failed to trigger menarche. However due to financial constraints, treatment was not continued. She was diagnosed with hypothyroidism since birth, for which she is currently maintained on levothyroxine 225 mcg daily.
On physical exam, blood pressure was 126/72 mmHg, pulse rate 83 BPM, height 5’9”, BMI 34 kg/m2. No facial dysmorphisms or skeletal deformity were apparent. She had normal pubic and axillary hair distribution, breast budding consistent with Tanner Stage II. Genital examination revealed normal external genitalia and a blind vaginal pouch.
Hormonal workup revealed hypergonadotrophic hypogonadism with estradiol &lt; 0.5 pg/mL and post-menopausal range follicle-stimulating hormone (FSH) 36.7 mIU/mL. Thyroid stimulating hormone (TSH) 2.19 uIU/ml (nl 0.45-4.5 uIU/mL) and anti-TPO antibodies 10 IU/mL (nl 0-34 IU/mL). Prior thyroid ultrasound reported a small thyroid gland. Fluorescence in situ hybridization (FISH) analysis revealed 46XX karyotype. Abdominal and pelvic ultrasound showed normal kidneys with a non-visualized uterus and ovaries. Pelvic MRI confirmed the absence of both and showed a blind end vaginal pouch, leading to the conclusion of the coexistence of gonadal dysgenesis with MRKH. She was then placed on transdermal estradioltherapy.
Conclusion: The association between gonadal dysgenesis (the most common cause of primary amenorrhea) and MRKH syndrome (the second most common cause) is infrequent. HRT remains the only therapeutic option. It aims to trigger the development of secondary sexual characteristics and prevent osteoporosis by allowing appropriate bone mineral accrual. Unfortunately, infertility remains the most significant consequential issue; hence the availability of good caring and psychological counseling should not be underestimated.
The co-existence of likely non-immune primary hypothyroidism is even less frequent. To our knowledge, our case is the second reported case of this trilogy. Given the paucity of data, the association of this condition with primary hypothyroidism cannot be well established and can be coincidental. More studies are needed to determine if this condition has a higher prevalence of hypothyroidism.
Presentation: Friday, June 16, 2023
FRI413 Hormonal Menstural Suppression For Menstrual Obstruction: A Retrospective Review Of Patients With Complex Obstructed Uterovaginal Anomalies Who Underwent Surgical Management In A Tertiary Referral Centre
Authors: Learner Hazel Isabella , Creighton Sarah M , Clarke Sophie A 
Published: October 2023

Abstract
Disclosure: H.I. Learner: None. S.M. Creighton: None. S.A. Clarke: None.
Aims: To describe the use of hormonal menstrual suppression in patients undergoing surgery for complex utero-vaginal anomalies with menstrual obstruction.
Background: Obstructed menstruation can present with painful primary amenorrhea or progressive dysmenorrhea due to unilateral obstructing duplication utero-vaginal anomalies. Menstrual suppression is essential to relieve pain during investigation and surgical planning. The off licence use of progestogens, hormonal contraception and GNRH analogues is common but there is little literature describing their best use in this context.
Methods: This was a retrospective case series review of patients undergoing surgical management of complex menstrual obstruction in a tertiary referral centre between 2016-2022. Data collected on age, diagnosis, symptoms, duration of symptoms, surgery, the type of endometrial suppression used and associated side effects.Patients with partial obstruction were excluded.
Results: Eighty-four patients were identified from the surgical database. The median age at time of surgery was 16 years (range 11-36). Unilateral obstruction was managed in 53/84 and complete obstruction in 31/84. Diagnoses included obstructed hemi-vagina (32/84), unicornuate uterus with functional uterine remnant (19/84), transverse vaginal septum (15/84), cervical/vaginal agenesis (9/84), and Mullerian agenesis with functional uterine remnant (5/84). Symptom duration information was available in 74/84 with a median of 10 months(0-252 months). Changes to endometrial suppression treatment were required in most patients, with 50/84 (40%) remaining on their original prescription. The average number of treatment regimes was 2 (0-7). Menstrual suppression at time of surgery was Norethisterone 35/84 (42%), Continuous combined oral contraceptive pill18/84 (21%), Medroxyprogesterone 11/84 (13%), GNRH 10/84 (12%), Desogestrel 6/84 (7%), and Depo-Provera 4/84 (5%). Tibolone was used as add-back in five patients on GNRHa for more than 6 months duration of use (4/5) or hypoestrogenic side-effects (1/5) .
Conclusion Menstrual suppression for pain relief is an essential component in management for complex uterovaginal anomalies. Suppression should be started at initial presentation but there is limited guidance for clinicians as to what and how to prescribe. Our study has demonstrated that this can lead to chaotic prescribing, unnecessary pain and multiple treatment changes.
Presentation: Friday, June 16, 2023
FRI431 Erythrocytosis Associated With Oral Testosterone Replacement
Authors: Engel Ashley A , Sarvaideo Jenna Lynne 
Published: October 2023

Abstract
Disclosure: A.A. Engel: None. J.L. Sarvaideo: None.
Background: A growing prevalence in male hypogonadism has led to increased interest in the most common adverse event, erythrocytosis. Defined by hematocrit (HCT) &gt; 49-51%, the incidence varies depending on the testosterone formulation.3 The formulations with the lowest risk of erythrocytosis are intranasal testosterone (0-2%) and oral testosterone (0.03%).3 A phase 3 clinical trial of testosterone undecanoate (Jatenzo) reported 4.8% patients experienced an increase in hematocrit, although not severe enough to warrant therapy discontinuation.2 We present a case of erythrocytosis with oral testosterone undecanoate that prompted a change in therapy. Clinical Case: Our patient is a 55-year-old male with secondary hypogonadism potentially related to obesity (BMI 37 kg/m²). AM total testosterone (TT) 151 (348-1197 ng/dL), free testosterone 4.6 pg/mL (6.8-21.5 pg/mL) and LH 3.8 mIU/mL. Labs confirmed. Secondary work-up negative. HCT 43.6% prior to any therapy. Patient treated with injectable testosterone. Despite decreasing to testosterone cypionate 80 mg weekly his HCT increased to 52.7% with a TT of 544 ng/dL. He was switched to oral testosterone undecanoate 237 mg twice daily given presumably lower risk of erythrocytosis. However, HCT increased to 55.1% and TT to 1542 ng/dL. Patient donated blood and oral testosterone dose decreased to 158 mg twice daily with starting HCT 48.9%, but this increased to 53.7%. TT 522 ng/dL. Therapy stopped with improvement of HCT to 45.8%-48.9%, TT 192 ng/dL, and SHBG 20 g/dL. Erythropoietin remained normal. Patient does not smoke cigarettes nor has OSA. Conclusion: We present a case of oral testosterone undecanoate complicated by persistent erythrocytosis despite dose reduction. Testing for contributing etiology was unrevealing. Oral testosterone replacement is considered the formulation least likely to cause erythrocytosis. Certain patient characteristics like OSA, advanced age, obesity, type II diabetes mellitus and an elevated HCT &gt; 50% can predict the likelihood of erythrocytosis although its specific etiology is unclear.3 Proposed mechanisms include elevation in dihydrotestosterone, erythropoietin stimulation, suppression of hepcidin and relation to androgen receptor CAG repeat length.1 Providers should be aware of the possibility of erythrocytosis on oral testosterone. Further research is needed to determine predictive characteristics for erythrocytosis and etiology.
Reference: 1. Aghazadeh, M, et al. Elevated dihydrotestosterone is associated with testosterone induced erythrocytosis. J Urol. 2015; 194(1): 160-165. 2. Swerdloff, S, et al. A new oral testosterone undecanoate formulation restores testosterone to normal concentrations in hypogonadal men. J Clin Endocrinol Metab. 2020; 105)8): 1-17. 3. White, J, et al. Testosterone therapy and secondary erythrocytosis. IJIR: Your Sexual Medicine Journal. 2022; 34: 693-697.
Presentation: Friday, June 16, 2023
FRI442 Ongoing Clomiphene Treatment For Men With Hypogonadotropic Hypogonadism
Authors: Smith Stephen Ross 
Published: October 2023

Abstract
Disclosure: S.R. Smith: None.
Context: Male hypogonadism is becoming recognized with increasing frequency. Testosterone products remain the only approved medical therapy, although highly problematic in men with hypogonadotropic hypogonadism because of inconvenient routes of administration, high cost, and unavoidable suppression of the hypothalamic-pituitary-gonadal axis. There is a need for effective and safe alternative medication.
Objective: The purpose of this study was to evaluate the use of clomiphene long term in men with hypogonadotropic hypogonadism.
Methods: Thirty-one men with non-congenital hypogonadotropic hypogonadism were treated with clomiphene citrate on an ongoing basis for up to 20 years. Seven patients were treated for &gt; 12 years; 20 patients were treated for &gt; 4 years. Initial age range was from 23 to 74 years, with a mean of 52. Serum testosterone and LH levels were monitored periodically. Clomiphene dose was adjusted at each office visit as required to achieve and maintain normal testosterone levels and improvement in hypogonadal symptoms in each individual patient. Patients were monitored for adverse effects. Data generated were analyzed retrospectively with Microsoft Excel statistical programs.
Results: Improvement in hypogonadal symptoms occurred in nearly all patients. All 31 men experienced increases in serum testosterone and LH levels into the normal range, and statistical analysis showed these increases to be highly significant. Testosterone levels increased from 226 +/- 12 to 542 +/- 35 (mean +/- SEM) ng/dl through the period of treatment (P &lt; .0001). LH levels increased from 3.6 +/- 0.4 to 10.0 +/- 1.6 mIU/ml (P &lt; .0002). Clomiphene dose required to achieve and maintain appropriate responses was highly variable within the group of patients, ranging from 3.57 to 200 mg daily, with a mean dose of 54.4 mg daily. There was evidence of diminishing returns with dosage increases to &gt; 100 mg daily. However, response to adjusted clomiphene dose, once established, was generally quite stable for each patient over extended periods of time, up to 20 years. No major adverse effects were encountered. Conclusions: Clomiphene is an effective and safe long-term treatment for men with non-congenital hypogonadotropic hypogonadism. It should be made available as an alternative to testosterone products for this group of men.
Presentation: Friday, June 16, 2023
FRI445 A Late Diagnosis Of Complete Androgen Insensitivity Syndrome
Authors: Muuse Janelle , Shah Rutu Jatin , Belany Paul A 
Published: October 2023

Abstract
Disclosure: J. Muuse: None. R.J. Shah: None. P.A. Belany: None.
Introduction: Complete Androgen Insensitivity Syndrome (CAIS) is a rare disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype. Individuals with CAIS are born unambiguously female without any apparent abnormalities. They develop a short blind ending vaginal canal, with absence of Wolffian duct derived structures (vas deferens, seminal vesicles). Breast development advances regularly at puberty, while there is absent pubic and axillary hair, both due to peripheral conversion of testosterone to estrogen. Testes remain undescended in the abdominal cavity.
Case: A 28 year old female with a past medical history of bipolar disorder presented to her primary care physician’s office with a chief complaint of fatigue. Blood work revealed an elevated testosterone level of 686, at which time she was referred to endocrinology for further work up. On further history gathering, she endorsed a life long history of amenorrhea. She saw an OB-GYN at 19 years old and was told she had a short vaginal canal. A pelvic ultrasound revealed no uterus and one left ovary. She was not given a diagnosis other than congenital absence of a uterus. She was lost to follow up until 28 years of age when she sought medical help for her fatigue. Physical exam was pertinent for a tall female with no signs of hirsuitism. Additional blood work revealed normal LH, FSH, and DHEA-S. A chromosomal analysis revealed XY. She was referred to gynecology for further management and assessment for orchiectomy.
Discussion: This was an unusual case of CAIS, as this was diagnosed far past menarche. Most cases are diagnosed during puberty- which aids in an early approach towards the psychological and social well being of the individual as well as close follow up for evaluation of orchiectomy. Orchiectomy is recommended due to the increased risk of gonadal malignancy following puberty. The risk of developing malignancy increases with age, and has been reported to be between 15-22%. Thus it is important to identify this syndrome early in life to ensure this is addressed. It is followed by long term hormonal therapy with estrogen to maintain normal breast and bone development. This case highlights the importance of maintaining a high clinical suspicion of CAIS in females presenting with short vaginal canal and absence of a uterus in order to prevent malignancy and provide optimal psychological support to the individual.
Presentation: Friday, June 16, 2023