Gender-affirming hormone therapy effect on cortisol levels in trans males and trans females.

PURPOSE: Previous studies have shown differences in baseline and stimulated cortisol levels between men and women. Whether this difference is secondary to sex hormones or to other factors, such as genetic or epigenetic changes, is unknown. We investigated the effect of gender-affirming hormone treatment (GAHT) on the hypothalamo-pituitary-adrenal axis of transgender subjects in an effort to throw light on this question. METHODS: Ten transgender males (TM) and eight transgender females (TF) underwent a low-dose (1 µg) adrenocorticotropic hormone (ACTH) stimulation test before and 6 months after GAHT initiation. Serum total, free and salivary cortisol (SC) levels were measured at baseline and at 20, 30 and 40 min. RESULTS: For the TM, all three levels were significantly lower at several time points after ACTH injection compared to pretreatment levels following 6 months of treatment (p < .05). Likewise, the overall SC response as calculated by the area under the curve was significantly lower (p = .0053). For the TF, the basal total cortisol (TC) level increased after 6 months of treatment (p < .01) while ACTH-stimulated SC levels decreased significantly. The basal ACTH levels were significantly lower following hormonal therapy (p < .001). CONCLUSION: Stimulated salivary cortisol levels decreased significantly after 6 months of GAHT in both male and female transgender subjects, possibly reflecting a decreased state of anxiety associated with treatment initiation. Additionally, basal and stimulated serum TC levels increased after hormonal treatment in the TF, probably secondary to the effect of oestrogen on cortisol-binding globulin.

Generation of isogenic and homozygous MEN1 mutant cell lines from patient-derived iPSCs using CRISPR/Cas9.

MEN1, an autosomal dominant disorder caused by mutations in the tumor suppressor gene MEN1, manifests with co-occurrence of multiple endocrine/neuroendocrine neoplasms. An iPSC line derived from an index patient carrying the mutation c.1273C>T (p.Arg465*) was edited using a single multiplex CRISPR/Cas approach to create an isogenic control non-mutated line and a homozygous double mutant line. These cell lines will be useful for elucidating subcellular MEN1 pathophysiology and for screening to identify potential MEN1 therapeutic targets.

Current medical treatment and perspective in gonadotroph tumors.

Gonadotroph cell adenoma is the most common clinically nonfunctioning pituitary adenoma; and is pathologically defined by immunopositivity for SF-1, GATA2 and ER-α. Most tumors also stain for follicle stimulating hormone and luteinizing hormone ß-subunits, but are usually hormonally silent and discovered incidentally or due to local mass effects. Complete transsphenoidal resection should be attempted when surgery is indicated. Post-surgical treatment can include radiation of the tumor remnant and medical treatment. Among medical treatments, dopamine agonists show the best evidence for preventing the need for recurrent surgery or radiation, and should be considered in patients with relatively bulky remnants or who have high risk features associated with tumor progression. Temozolomide is indicated for aggressive adenomas and carcinomas. Less well-established treatments include somatostatin receptor ligands, peptide receptor radionucleotide therapy and immunomodulatory agents.

Low-Dose Cyproterone Acetate Treatment for Transgender Women.

BACKGROUND: Transgender women with intact gonads receive lifelong hormonal treatment to suppress physiologic androgen production, the optimal efficacious and safe cyproterone acetate (CPA) dose has not been established. AIM: To assess the effectiveness and safety of low-dose (10-20 mg/day) compared with high-dose (50-100 mg/day) CPA treatment. METHODS: We conducted a historical cohort study of transgender women treated at a tertiary center for transgender health. OUTCOME MEASURES: Serum levels of testosterone, estradiol, prolactin, gonadotrophins, liver enzymes, and lipids. RESULTS: There were 38 transgender women in the low-dose group and 26 in the high-dose group. Age (median 24.9 years, interquartile range [IQR] 21-30 vs 25 years, IQR 19-35) and follow-up time (median 12 months, IQR 6-23 vs 15 months, IQR 12-36) were similar in the low- and high-dose groups, respectively. Serum gonadotropins and testosterone were suppressed to a similar level at all time points in both groups. Prolactin levels increased significantly in both groups, however, with a more substantial increase in the high- vs the low-dose group (804 ± 121 vs 398 ± 69 mIU/ml at 12 months, respectively, P = .004). Total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were not significantly affected by the dose. CLINICAL IMPLICATIONS: We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women. STRENGTHS & LIMITATIONS: This is the first demonstration that low-dose CPA treatment of transgender women is effective. Limitations include a relatively small sample and retrospective study design. CONCLUSION: Low-dose CPA treatment of transgender women is as effective as high-dose treatment and possibly safer. Zohar NE, Sofer Y, Yaish I, et al. Low-Dose Cyproterone Acetate Treatment for Transgender Women. J Sex Med 2021;18:1292-1298.

Pituitary stem cells.

The anterior pituitary is derived from Rathke's pouch precursors, which differentiate into specific hormone-secreting cell lineages. Sustained low postnatal and adult pituitary cell turnover is governed by stem/progenitor cells that undergo slow mitotic activity and give rise to hormone-secreting cells in response to physiological demands and feedback loops. Pituitary cell populations exhibit stem cell properties, which include stem cell marker expression, non-hormone expression, and the ability to self-renew and to potentially differentiate into any of five hormone-secreting cell lineages. Specific signaling pathways underlie differentiated pituitary cell development and regulation. Several validated pituitary stem cell models have been reported and have the potential for functional regeneration of pituitary hormone-secreting cell functions.

Management of NFAs: medical treatment.

INTRODUCTION: Non-functioning pituitary adenomas (NFPAs) are in general large tumors that present with symptoms secondary to local pressure on adjacent structures. Transsphenoidal surgery is the first line of treatment but residual tumor mass is often detected post-operatively. Medical therapy, in any stage of tumor management, is not well established. METHODS: A literature search was performed to review the available data on medical treatment of NFPAs. RESULTS: Medications investigated for the treatment of NFPAs include dopamine receptor agonists (DA) and somatostatin receptor ligands. Randomized controlled trials are lacking, but available data suggest that DA have a positive effect on tumor remnant stabilization after surgery and could be considered in this setting. Temozolomide is reserved for aggressive tumors, although future studies are required. CONCLUSIONS: NFPA are often not amenable to complete surgical resection. Conservative follow-up after surgery is associated with a high prevalence of tumor remnant progression. DA therapy may prevent residual tumor enlargement in over 85% of these patients, with a substantial consequent reduction in the need for repeat surgery or radiation therapy. It is our view that DA treatment should be routinely considered for the management of NFPA patients with incompletely resected tumors.

MicroRNAs in the growth plate are responsive to nutritional cues: association between miR-140 and SIRT1.

MicroRNAs (miRNAs) have been reported to be involved in a variety of functions, including skeletal development and longitudinal growth. The aim of this study was to investigate the role of miRNAs in food-restriction-induced growth attenuation and nutrition-induced catch-up growth in the epiphyseal growth plate (EGP). Prepubertal rats were fed ad libitum or were subjected to 40% food restriction for 10 days followed by a renewal of the regular food supply. At sacrifice, tibial EGPs were excised, and the total RNA was extracted and loaded on miRNA microarrays. The miRNA microarray yielded more than 400 miRNAs that are expressed in the EGP of mature animals. Results were confirmed by quantitative polymerase chain reaction. Chondrocyte-specific miR-140-3p showed the highest expression in the mature EGP, and it was one of the few miRNAs that were significantly reduced following nutrition restriction. Changes in predicted miRNA targets were then followed with Western immunoblotting. Direct binding was demonstrated using exogenous miRNA, the 3'UTR of the target mRNA and a luciferase reporter assay. Nutrition restriction induced an increase in the level of the miR-140-3p target, NAD+-dependent SIRT1. This study is the first to show that SIRT1 and miRNAs expressed in the mature EGP are responsive to nutritional cues. Nutrition-induced epigenetic regulation of growth activates two parts of the epigenetic world - miRNAs and histone deacetylases - that are interconnected. Deciphering the role of epigenetic regulation in growth may open a new era of research and pave the way for the development of new treatments for children with growth disorders.

The role of p27Kip1 in the regulation of growth plate chondrocyte proliferation in mice.

p27/Kip1, a cyclin-dependent kinase inhibitor, negatively regulates proliferation of multiple cell types. The goal of this study was to assess the role of p27 in the spatial, temporal, and conditional regulation of growth plate chondrocyte proliferation. p27 mRNA expression was detected by real-time RT-PCR in all zones of the mouse growth plate at levels approximately 2-fold lower than in the surrounding bone. To determine whether this expression is physiologically important, we studied skeletal growth in 7-wk-old mice lacking a functional p27 gene. In these mice, body length was modestly increased and proliferation of proximal tibial growth plate chondrocytes was increased, but tibia length was not significantly greater than in controls. p27 ablation had no measurable effect on growth plate morphology. Treatment with dexamethasone inhibited longitudinal bone growth similarly in p27-deficient mice and controls, indicating that p27 is not required for the inhibitory effects of glucocorticoids on longitudinal growth. p27-deficient mice had increased width of the femoral diaphysis, suggesting that p27 acts normally to inhibit periosteal bone growth. In conclusion, our findings suggest that p27 has modest inhibitory effects on growth plate chondrocyte proliferation but is not required for the spatial or temporal regulation of proliferation or the conditional regulation by glucocorticoid.