bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virilization Secondary to an Ovarian Leydig Cell Tumor
Authors: Symczyk Oksana , Turner Jennifer Sarah , Barghouthi Nadia , Perini Jessica Antoinette 
Published: May 2021

Abstract
A 60-year-old female presented with a three-year history of virilizing symptoms including facial hirsutism and deepening of voice. Her medical history was significant for renal transplantation with immunosuppressive therapy consisting of mycophenolate, cyclosporine, and low-dose prednisone. She was noted to have temporal balding and darkly pigmented terminal hair on the upper lip, cheeks, chin, shoulders, and sternum. Pelvic examination revealed clitoromegaly. Menarche occurred at age 12 with regular menstrual cycles until menopause which occurred at age 50. She had two pregnancies: a miscarriage followed by a successful pregnancy.
Labs revealed an elevated total testosterone of 530 ng/dL (&lt; 60 ng/dL), free testosterone 14.8 ng/dL (&lt;0.87 ng/dL), androstenedione 2140 ng/dL (&lt;200 ng/dL), and 17-hydroxyprogesterone 704 ng/dL (&lt;285 ng/dL). LH, FSH, and estradiol were inappropriately normal in this post-menopausal female. Prolactin, TSH, DHEA-S, IGF-1 were within normal limits. Transvaginal ultrasound found a 2 cm hypoechoic right ovarian mass which was confirmed on MRI. MRI also revealed a 5 mm right adrenal nodule. Tumor markers including CA-125, Inhibin A, Inhibin B, HCG, and AFP were within normal limits. Dexamethasone suppression testing did not lower the testosterone level. 17-hydroxyprogesterone level after cosyntropin stimulation testing was 704 ng/dL (&lt;1000 ng/dL). The patient underwent laparoscopic bilateral oophorectomy and salpingectomy, pelvic washout and omental biopsy. Pathology was consistent with a benign Leydig cell tumor. Following oophorectomy there was complete normalization of the total testosterone level (15 ng/dL, n&lt; 60 ng/dL).
A thorough history and physical exam is vital in determining the cause of hirsutism. Medications, including over-the-counter and herbal formulations should be carefully reviewed. Although cyclosporine has been associated with hirsutism, patients typically present with vellus hair formation in the affected areas rather than darkly pigmented terminal hair. In this case, hirsutism progressively worsened following menopause and physical examination was significant for virilization. Hirsutism in a combination with virilization is typically neoplastic in nature. Endogenous androgen production can originate from either the adrenal glands or ovaries. In our patient, with workup showing both ovarian and adrenal as potential sources of endogenous androgen production, an adrenal cause was excluded due to a normal DHEA-S level at baseline and a lack of suppression of testosterone after dexamethasone suppression testing. As a result, the source was localized to the ovary. While excessive androgen production resulting in virilization is seen with ovarian tumors, Leydig stromal cell tumors are extremely rare and account for less than 0.1% of all ovarian tumors.
Cardiovascular Risk Factors in Transgender Women Undergoing Long-Term Gender-Affirming Hormone Therapy: A Cross-Sectional Study
Authors: Alvares Leonardo A M , Santos Lívia M , Ramos Henrique A , Rodeghel Larissa G , Cavenaghi Nathan B , Araújo Clara M , Santana Thiago R , Mendonca Berenice Bilharinho , Costa Elaine Maria Frade , Domenice Sorahia 
Published: May 2021

Abstract
Introduction: Few data of long-term outcomes of cardiovascular (CVRF) risk factors of transgender women (TW) undergoing gender-affirming hormone therapy (GAHT) are available. Objectives: Evaluate CV risk factors after long-term GAHT in TW. Methods: A cross-sectional study was carried out with 8 TW (average age of 34.0 ±4.8 yo), 8 matched CM and 8 CW on age, body mass index (BMI) and activity level. All TW were non-gonadectomized subjects and were in estrogen [(E); transdermal estradiol (n=2), oral estradiol (n=3) and conjugated estrogen (n=3)] plus cyproterone acetate (CA) (n=8) therapy in an average time of 15.6 ±8.7 years. Results: Total Testosterone (ng/dL) level of TW, CW and CM were 83,5 (range 12,0-637,0), 20,5 (range 12,0-41,0) and 480,5 (range 264,0-843,0), respectively. It was similar between TW and CW (p=0,7284) and different in the comparison TWvsCM (p=0,0325). In TW group, the median of blood glucose was 84 mg / dL, HBA1c 5.1%, total cholesterol 146 mg / dL, HDLc 43 mg / dL, LDLc 89 mg / dL and triglycerides 81.5 mg / dL. In the comparison with other groups, there was no difference from the statistical point of view. It is necessary to emphasize the HDLc of TW (43 mg/dL) which was exactly the same of CM (p&gt;0,999) and lower than CW (60 mg/dL)(p=0,0720). Systolic Blood Pressure (SBP)(mmHg) of TW (126±13) was higher than that of CW (95±11;p&lt;0.001) and equal to that of CM (115±9;p=0.1489). Regards Diastolic Blood Pressure (DBP) (mmHg), the medians of TW, CW and CM were 80, 60 and 80, respectively, and in the comparison TWxCW p = 0.0070 and TWxCM p&gt; 0.9999. Discussion: Youth TW (16.3 ± 1.4 yo) taking an average estradiol dose of 1.5 ± 1.0 mg/day, with an average AGHT duration of 12.3 ± 9.9 months matched to controls on age and BMI did have higher HDL than CW and TW participants were more insulin resistant than CM. About SBP of that youth TW (107 ± 12), it was lower than CW 113 ± 7 (p&gt;0,05) and CM 116 ± 8 (p&lt;0,001). Other previous study showed that after 6 months of estradiol use, in doses ranging from 2 to 8 mg daily glucose enhanced 6 mg/dL (from 86 to 92) as well as TC from 170 to 178 mg/dL, HDLc from 50 to 54 mg/dL, TGL from 102 to 115 mg/dL, and LDL did not change (93), while a systematic review and meta-analysis showed increased only in TG levels. SBP and DBP increased on average of 7,2 mmHg and 5,7 mmHg, respectively. Conclusion: Metabolic findings observed after the first few months of TW GAHT appear to remain at long term, except for HDLc. SBP and DBP appear to increase in the long term, after a drop initially observed.
Case Report: Invasive Endometrial Cancer in a Trans Man and Risk of Testosterone Therapy
Authors: Jeevananthan Athavi , Iyengar Ravi M 
Published: May 2021

Abstract
Background: Only one case of uterine cancer in a trans man on testosterone is noted in literature prior to this case. No clinical evidence nor guidelines exist regarding testosterone therapy for this subset of patients.
Clinical Case: A 41-year-old trans man was seen by Gynecology for vaginal bleeding, with work-up revealing thickened endometrium and biopsy with endometrial adenocarcinoma. Testosterone therapy was held, and patient underwent total hysterectomy with BSO and bilateral pelvic/aortic lymph node dissection. Pathology demonstrated stage IIIA invasive adenocarcinoma, endometrium type with focal squamous differentiation, low grade. The tumor extended into the endocervical stroma with small metastasis to one ovary. He received adjunct pelvic radiation and sandwich chemotherapy with carboplatin and taxol. Concurrently, he was referred to Endocrinology for management of hormone replacement therapy (HRT). He originally started weekly testosterone injections and anastrozole at an outside facility in 2016 and underwent bilateral mastectomy in 2017. Testosterone was held perioperatively and during chemoradiation, for a total duration of 9 months. The patient experienced worsening gender dysphoria during this time. Discussion was held on goal to restart HRT in the setting of a theoretical risk of testosterone conversion to estradiol with increased risk of cancer recurrence; thus, patient initially chose to delay re-initiation of HRT. Following the completion of chemotherapy, he started on low-dose (30mg) weekly IM testosterone with plans for continued monitoring of testosterone and estradiol levels.
Conclusion: Research is needed in monitoring the effects of testosterone therapy on reproductive organs in patients assigned female at birth, and whether anastrozole therapy has protective effects for estrogen-driven cancers. Further, guidance is needed on monitoring of uterine lining in trans men and whether this should be standard of practice.
Partial Gender-Affirming Hormone Treatment in Non-Binary Transgender Individuals in a Referral Center Cohort
Authors: Van Dijken Josianne , Steensma Thomas , Wensing-Kruger Annelijn , Den Heijer Martin , Anton Dreijerink Koen Marie 
Published: May 2021

Abstract
Context: Hormone treatment (HT) is a cornerstone of gender-affirming therapy in transgender and gender non-conforming people. Non-binary and genderqueer (NBGQ) people, individuals identifying in between or outside the male to female binary, are increasingly recognized. Not all trans people and NBGQ binary individuals seek full HT. Current guidelines for HT of transgender and gender non-conforming people do not include specific regimens for people who seek partial treatment. Objective: To compare HT prescribed to NBGQ and binary trans people. Design: Retrospective study. Setting: Referral clinic for gender dysphoria. Participants: 602 applicants for gender care in 2013-2015. Intervention: GenderQueer Identity questionnaires at entry were used to categorize people as NBGQ or binary transgender. Medical records were assessed until the end of 2019. Main Outcome Measures: prescribed HT, serum estradiol and testosterone concentrations. Results: 113 individuals identified as non-binary and 489 as binary transgender. NBGQ persons were more likely to receive partial HT than binary transgender people (11% versus 4.7%, p=0.02). None of the NBGQ individuals who received partial HT had undergone gonadectomy, hypogonadism did not occur. NBGQ individuals assigned male at birth using only estradiol had similar estradiol and higher testosterone serum concentrations compared with individuals using conventional HT. Conclusions: NBGQ individuals are more likely to receive partial HT compared with binary transgender people. In the future, tailored endocrine counseling may further shape partial HT regimens for NBGQ individuals.
Patient Characteristics Associated With the Receipt of Hormone Therapy Among Transgender Patients in the Veterans Health Administration
Authors: Wong Denise H , Vimalananda Varsha G , Reisman Joel I , Rao Sowmya R , Shipherd Jillian C , Wolfe Hill L , Blosnich John R , Livingston Nicholas A , Jasuja Guneet K 
Published: May 2021

Abstract
Background: Many transgender patients experience gender dysphoria as a result of an incongruence between their gender identity and sex assigned at birth. Gender-affirming hormone therapy improves the quality of life for transgender patients seeking to increase alignment of their secondary sex characteristics and gender identity. However, little is known about the patient factors that are associated with receipt of this therapy which is critical to identifying areas for improvement in care for transgender patients. Objective: To evaluate patient characteristics associated with transgender patients’ receipt of hormone therapy from the Veterans Health Administration (VHA). Methods: Inpatient and outpatient data were reviewed for transgender patients, identified through ICD-9/ICD-10 diagnosis codes for gender identity disorder (GID), receiving VHA health care from January 2006 to December 2018. We evaluated receipt of hormone therapy (testosterone or estrogen +/- spironolactone) from the VHA, socio-demographics, comorbidities, social stressors, military sexual trauma, and documented suicide attempts. Adjusted Odds Ratios (aOR) and 95% Confidence Intervals (CI) were obtained from a multivariable logistic regression model used to ascertain the relationship between patient characteristics and hormone therapy. Results: Of 9,406 patients with documented GID, 5,487 (58.3%) received hormone therapy from the VHA. Compared to patients not receiving hormone therapy, a higher proportion of patients receiving hormone therapy were younger (21-29 years: 18.1% vs. 11.6%; 30-39 years: 20.0% vs. 14.6%; 40-49 years: 16.2% vs. 13.6%), had documentation of a positive military sexual trauma screening (22.2% vs. 16.2%; p&lt;0.0001), and a suicide attempt (11.4% vs. 9.9%; p=0.0067). There were significant associations between receipt of hormone therapy and: 1) younger age (aOR: 1.33; 95% CI: 1.29-1.36; p&lt;0.0001); 2) Black non-Hispanic patients (aOR: 0.58; 95% CI: 050-0.68; p&lt;0.0001); 3) increasing number of comorbidities (aOR: 0.86; 95% CI: 0.84-0.88; p&lt;0.0001); and 4) increasing number of social stressors (aOR: 0.86; 95% CI: 0.83-0.90; p&lt;0.0001). Conclusions: Age, race/ethnicity, comorbidities, and social stressors among other factors are associated with receipt of hormone therapy among transgender patients in the VHA. Subsequent efforts should focus on understanding clinician- and site-level determinants to facilitate the design of effective quality improvement measures that optimize gender affirming hormone therapy through VHA for transgender patients.
Prolactinoma in a Male to Female Transgender Woman on Gender Affirming Hormone Therapy
Authors: Harned Leighton K , Harper Rene J 
Published: May 2021

Abstract
Background: Estrogen promotes prolactin secretion and its role in prolactin secreting adenomas is still under investigation. The genesis and resolution of prolactinomas may be affected by gender affirming hormone therapy.
Case Description: A 50 year old transgender female presented with new onset tunnel vision and extremity parathesias for one day. She had been taking oral estrogen for six years. Physical exam showed bilateral gynecomastia as well as galactorrhea. Her visual fields were intact by confrontation.
Her brain MRI revealed a pituitary macroadenoma measuring 1.4cm x 1.3cm x 1.3cm. Laboratory studies showed prolactin 538 ng/mL (&lt;20 ng/mL), IGF-1 89.0 (66-303 ng/ml). TSH 1.7 (0.4-4.7 mcIU/mL), Free T4 0.997 (0.58-1.76 ng/dL) and estradiol 103 pg/ml (N/A).
She was treated with bromocriptine 5mg daily. Three months later galactorrhea had resolved, but gynecomastia was unchanged. The patient had a prolactin level of 3 ng/mL. Follow up brain MRI at one and three years showed no significant decrease in size of macroadenoma. Discussion: Despite this patient’s biochemical and symptomatic response to dopamine agonist therapy, her pituitary adenoma did not decrease in size over 3 years, which is a common occurrence with macroprolactinomas. However, her prolactin levels declined and her galactorrhea resolved with therapy. Research into the long term effects of gender transition therapy remains mainly in the realm of case reports and retrospective studies. Our review of the medical literature suggests that some transgender patients on estrogen therapy may have an increased risk of developing pituitary adenomas. However, guidelines have not yet been published and currently there are no recommendations for routine imaging or biochemical assessment during follow-up of these patients. While there are established reference ranges for prolactin levels for men, non-pregnant and pregnant women, no established reference ranges for prolactin levels are available for transgender women on gender affirming hormone therapy. Studies indicate that 76-86% of patients have a reduction in the size of their prolactinomas after dopamine agonist therapy. However, the same may not be true for transgender women on transfeminine hormone therapy with estrogen.
Conclusion: Prolactinomas may commonly occur and be masked in transgender women on gender affirming hormone therapy due to the expected symptoms of gynecomastia, erectile dysfunction, and diminished libido from reduced testosterone levels. Estrogen promotes prolactin secretion by the pituitary gland and may have a role in development and expansion of prolactinomas. More research is needed in regards to the assessment and monitoring of the pituitary gland in transgender women on gender affirming hormone therapy with estrogen.
Evaluation of Enzymatic Activity of Various HSD17B3 Mutants Using Androgen Receptor-Mediated Transactivation
Authors: Yazawa Takashi , Sato Takahiro , Ida Takanori 
Published: May 2021

Abstract
17β-Hydroxysteroid dehydrogenases (17β-HSDs, HSD17B) catalyze the reduction of 17-ketosteroids and the oxidation of 17β-hydroxysteroids to regulate the production of sex steroids. Among HSD17B family, 17β-HSD type 3 (HSD17B3) is expressed in testicular Leydig cells and contributes to development of male sexual characteristics by converting androstenedione (A4) to testosterone (T). Mutations of HSD17B3 genes cause a 46,XY disorder of sexual development (46,XY DSD) as a result of low T production. Therefore, the evaluation of HSD17B3 enzymatic activity is important for understanding and diagnosing this disorder. Although various amino acid substitutions of HSD17B3 have been reported in previous studies, the enzymatic activities of these proteins were often not defined. This is probably due to the difficulties that such enzymatic activities have been evaluated by quantifying the conversion of A4 into T using radioactive isotopes and liquid chromatography-mass spectrometry-mass spectrometry (LC-MS/MS). We adapted a method that easily evaluates enzymatic activity of HSD17B3 proteins by quantifying the conversion from A4 to T using androgen receptor (AR)-mediated transactivation. HEK293 cells were transfected to express human HSD17B3, and incubated medium containing A4. Depending on the incubation time with HSD17B3-expressing cells, the culture media progressively increased luciferase activities in CV-1 cells, transfected with the AR expression vector and androgen-responsive reporter. These luciferase activities reflected T concentrations in culture media defined by LC-MS/MS. This system is also applicable to detect the conversion of A4 to T by HSD17B1 and HSD17B5. In addition, it can evaluate the conversion of 11-ketoandrostenedione to 11-ketotestosterone by HSD17B family. Establishment of HEK293 cells expressing various missense mutations in the HSD17B3 gene with (N74T, A188V, M197K, A200V,, V225M, H271R) or without (V31I, E67K and G289S) the manifestation of 46,XY DSD revealed that this system is effective to evaluate the enzymatic activities of mutant proteins. A188V, A200V, V225M and H271R mutations completely inactivated the enzymatic function. N74T and M197K mutations showed some residual activities. In contrast, V31I, E67K and G289S substitutions showed similar activities as the wild-type protein.
Glucocorticoid Receptor Condensates Link DNA-Dependent Receptor Dimerization and Transcriptional Transactivation
Authors: Frank Filipp , Liu Xu , Ortlund Eric 
Published: May 2021

Abstract
The glucocorticoid receptor (GR) is a ligand-regulated transcription factor (TF) that controls the tissue- and gene-specific transactivation and transrepression of thousands of target genes. Distinct GR DNA binding sequences with activating or repressive activities have been identified, but how they modulate transcription in opposite ways is not known. We show that GR forms phase-separated condensates that specifically concentrate known co-regulators via their intrinsically disordered regions (IDRs) in vitro. A combination of dynamic, multivalent (between IDRs) and specific, stable interactions (between LxxLL motifs and the GR ligand binding domain) control the degree of recruitment. Importantly, GR DNA-binding directs the selective partitioning of co-regulators within GR condensates such that activating DNAs cause enhanced recruitment of co-activators. Our work shows that condensation controls GR function by modulating co-regulator recruitment and provides a mechanism for the up- and down-regulation of GR target genes controlled by distinct DNA recognition elements.
Investigating the Role Intestinal-Specific FXR and SHP in Regulating Lipid Metabolism in Mice
Authors: Nguyen James ThienToan , Anakk Sayeepriyadarshini 
Published: May 2021

Abstract
Dysregulation of lipid metabolism is a causal factor that can lead to a variety of disorders, such as obesity and metabolic syndrome. Dietary fats are digested in the small intestine by the physiological detergents known as bile acids. They emulsify the fats and break them down into smaller molecules in order for the enterocytes to absorb the nutrients through simple diffusion or through the utilization of specific lipid transporters. Interestingly, the nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) not only regulates bile acid synthesis and circulation, but also lipid metabolism. Although many studies have examined the role of FXR in hepatic and intestinal lipid metabolism, studies investigating the role of SHP in the intestine are still lacking. Although FXR and SHP cooperate to regulate many metabolic pathways, FXR or SHP knockout models exhibit different lipid phenotypes. These data indicate there are FXR-dependent and -independent pathways of SHP that controls lipid metabolism. To delineate these two interconnecting yet separate pathways, we will utilize intestine-specific Shp knockout (IShpKO) and intestine-specific Fxr knockout (IFxrKO) mice model and place them on high fat diet to investigate their intestinal intestinal absorption and transportation of lipids. We will also monitor the bile acid pool in the intestine, serum, and liver in these knockouts to evaluate the consequence of intestinal deletion of Fxr as well as Shp on bile acid homeostasis and how this may affect lipid absorption. These experiments will identify how FXR and/or SHP regulates intestinal fat digestion and absorption and if this is secondary to the alterations in bile acid concentration and lipid transporters. In addition, we will also investigate the intestinal Fxr-Shp double knockout (IDKO) mice model to determine their combined contribution in intestinal lipid metabolism. Overall, the results obtained from this research will elucidate if intestinal FXR and SHP cooperate or can independently regulate lipid metabolism and homeostasis.