Joshua D. Safer

DEFECTIVE RELEASE OF COREPRESSOR BY HINGE MUTANTS OF THE THYROID HORMONE RECEPTOR FOUND IN PATIENTS WITH RESISTANCE TO THYROID HORMONE

On positive thyroid hormone response elements (pTREs), thyroid hormone receptor (TR) binding to DNA in the absence of ligand (thyroid hormone, T3) decreases transcription (silencing). Silencing is due to a family of recently described nuclear corepressor proteins (NCoR and SMRT) which bind to the CoR box in the hinge region of TR. Ligand-dependent activation of TR is associated with displacement of corepressors and recruitment of coactivating proteins. Resistance to thyroid hormone (RTH) is due to mutations in the β isoform of the thyroid hormone receptor (TR-β). To date, three RTH mutations reportedly with near-normal T3binding (A234T, R243Q, and R243W) have been described in or near the CoR box. To determine the mechanism of RTH caused by these mutants, the interaction of wild type (wt) and mutant TRs with the corepressor, NCoR, and the coactivator, SRC-1, was tested in gel-shift assays. As expected, NCoR bound wt TR in the absence of T3 and dissociated from TR with increasing T3 concentration. SRC-1 failed to bind wt TR in the absence of T3, but bound to TR with increasing avidity as T3 concentrations rose. At no T3 concentration did both NCoR and SRC-1 bind to wt TR, indicating that their binding to TR was mutually exclusive. Hinge mutants bound NCoR normally in the absence of T3; however, dissociation of NCoR and recruitment of SRC-1 was markedly impaired except at very high T3 concentrations. Importantly, hinge mutant TRs when complexed to DNA bound T3 poorly despite their near-normal T3 binding in solution. These binding studies correlated with functional assays showing defective transactivation of pTREs by hinge mutants except at high T3concentrations. Thus, we describe a novel mechanism of RTH whereby TR hinge mutants selectively affect T3 binding when complexed to DNA, and prevent NCoR dissociation from TR. Our data also suggest that solution T3 binding by RTH mutants may not accurately reflect physiologically relevant T3 binding by TR when bound to DNA.

A Unique Role of the β-2 Thyroid Hormone Receptor Isoform in Negative Regulation by Thyroid Hormone MAPPING OF A NOVEL AMINO-TERMINAL DOMAIN IMPORTANT FOR LIGAND-INDEPENDENT ACTIVATION

Negative regulation by thyroid hormone is mediated by nuclear thyroid hormone receptors (TRs) acting on thyroid hormone response elements (TREs). We examine here the role of human TR-β2, a TR isoform with central nervous system-restricted expression, in the regulation of target genes whose expression are decreased by triiodothyronine (T3). Using transient transfection studies, we found that TR-β2 achieved significantly greater ligand-independent activation on the thyrotropin-releasing hormone (TRH) and common glycoprotein α-subunit genes than either TR-β1 or TR-α1. A chimeric TR-β isoform containing the TR-β2 amino terminus linked to the TR-α1 DNA- and ligand-binding domains functioned like the TR-β2 isoform on these promoters, confirming that the amino terminus of TR-β2 was both necessary and sufficient to mediate this effect. By constructing deletion mutants of the TR-β2 amino terminus, we demonstrate that amino acids 89–116 mediate this function. This domain, important in ligand-independent activation on negative TREs, is discrete from a previously described activation domain in the amino-terminal portion of TR-β2. We conclude that the central nervous system-restricted TR-β2 isoform has a unique effect on negative regulation by T3 that can be mapped to amino acids 89–116 of the amino terminus of the human TR-β2.

A Pituitary Tumor in a Patient with Thyroid Hormone Resistance: A Diagnostic Dilemma

Resistance to thyroid hormone (RTH) is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin (TSH) from the anterior pituitary, despite elevated levels of thyroid hormone thyroxine (T4) and triiodothyronine (T3). Thyrotropin-secreting tumors are presumed to represent clonal expansion of abnormal cells. Because the diagnosis of TSH-secreting tumors tends to be delayed and curative surgical resection remains under 50%, early diagnosis is paramount. Current diagnostic strategies suggest that RTH patients are distinguishable from patients with TSH-secreting pituitary tumors by the use of standard laboratory tests and imaging. Here, we present a woman in whom the standard evaluation for inappropriate TSH secretion was insufficient to distinguish these entities. The patient had a low-normal TRH stimulation test and an unmeasurable alpha-glycoprotein subunit level; however, a pituitary magnetic resonance imaging (MRI) revealed an adenoma. More testing using a T3 suppression test supported a RTH diagnosis and a R438H mutation was found in the TR-beta gene. To our knowledge, this represents the first report of an apparently incidental pituitary adenoma in the setting of documented resistance to thyroid hormone. As such, it raises the question of whether RTH predisposes to pituitary hyperplasia and adenoma development.

Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline

Objective: To update the “Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline,” published by the Endocrine Society in 2009. Participants: The participants include an Endocrine Society‐appointed task force of nine experts, a methodologist, and a medical writer. Evidence: This evidence‐based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: Group meetings, conference calls, and e‐mail communications enabled consensus. Endocrine Society committees, members and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. Conclusion: Gender affirmation is multidisciplinary treatment in which endocrinologists play an important role. Gender‐dysphoric/gender‐incongruent persons seek and/or are referred to endocrinologists to develop the physical characteristics of the affirmed gender. They require a safe and effective hormone regimen that will (1) suppress endogenous sex hormone secretion determined by the persons genetic/gonadal sex and (2) maintain sex hormone levels within the normal range for the persons affirmed gender. Hormone treatment is not recommended for prepubertal gender‐dysphoric/gender‐incongruent persons. Those clinicians who recommend gender‐affirming endocrine treatments—appropriately trained diagnosing clinicians (required), a mental health provider for adolescents (required) and mental health professional for adults (recommended)—should be knowledgeable about the diagnostic criteria and criteria for gender‐affirming treatment, have sufficient training and experience in assessing psychopathology, and be willing to participate in the ongoing care throughout the endocrine transition. We recommend treating gender‐dysphoric/gender‐incongruent adolescents who have entered puberty at Tanner Stage G2/B2 by suppression with gonadotropin‐releasing hormone agonists. Clinicians may add gender‐affirming hormones after a multidisciplinary team has confirmed the persistence of gender dysphoria/gender incongruence and sufficient mental capacity to give informed consent to this partially irreversible treatment. Most adolescents have this capacity by age 16 years old. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to age 16 years, although there is minimal published experience treating prior to 13.5 to 14 years of age. For the care of peripubertal youths and older adolescents, we recommend that an expert multidisciplinary team comprised of medical professionals and mental health professionals manage this treatment. The treating physician must confirm the criteria for treatment used by the referring mental health practitioner and collaborate with them in decisions about gender‐affirming surgery in older adolescents. For adult gender‐dysphoric/gender‐incongruent persons, the treating clinicians (collectively) should have expertise in transgender‐specific diagnostic criteria, mental health, primary care, hormone treatment, and surgery, as needed by the patient. We suggest maintaining physiologic levels of gender‐appropriate hormones and monitoring for known risks and complications. When high doses of sex steroids are required to suppress endogenous sex steroids and/or in advanced age, clinicians may consider surgically removing natal gonads along with reducing sex steroid treatment. Clinicians should monitor both transgender males (female to male) and transgender females (male to female) for reproductive organ cancer risk when surgical removal is incomplete. Additionally, clinicians should persistently monitor adverse effects of sex steroids. For gender‐affirming surgeries in adults, the treating physician must collaborate with and confirm the criteria for treatment used by the referring physician. Clinicians should avoid harming individuals (via hormone treatment) who have conditions other than gender dysphoria/gender incongruence and who may not benefit from the physical changes associated with this treatment.

Thyroid Hormone Action on Skin: Diverging Effects of Topical versus Intraperitoneal Administration

Previously, we demonstrated stimulation of epidermal proliferation and hair growth in triiodothyronine (T(3)) treated mice. To distinguish skin effects of directly applied T(3) from those of systemic hyperthyroidism, we treated CD-1 mice with either intraperitoneally (IP) or topically administered T(3). Relative to controls, mice receiving T(3) IP had 10% thinner epidermis (p < 0.01) and 48% fewer hairs (p < 0.001). By contrast, mice receiving T(3) topically had 78% thicker epidermis (p < 0.01) and 160% more hairs (p < 0.01). To gain insight into factors responsible for the diverging effects, we contrasted T(3) effect on proliferation of isolated keratinocyte cultures versus keratinocytes cocultured with dermal fibroblasts. For keratinocytes grown in the absence of fibroblasts, T(3) stimulated proliferation in a dose-dependent, biphasic pattern with the peak at 0.5 nM T(3) (84 +/- 30%, p < 0.05). Paradoxically, T(3) inhibited proliferation of keratinocytes cocultured with fibroblasts, the nadir at 0.1 nM T(3) (34% +/- 4%, p < 0.001). These studies are the first describing divergent effects of IP and topically administered thyroid hormone. The data suggest that while T(3) stimulated keratinocyte proliferation, T(3) also stimulated proliferation inhibitory factor(s) from skin fibroblasts. Insight into the interplay among the competing factors will be important in understanding thyroid hormone regulation of skin physiology.

Barriers to healthcare for transgender individuals.

Purpose of reviewTransgender persons suffer significant health disparities and may require medical intervention as part of their care. The purpose of this manuscript is to briefly review the literature characterizing barriers to healthcare for transgender individuals and to propose research priorities to understand mechanisms of those barriers and interventions to overcome them. Recent findingsCurrent research emphasizes sexual minorities’ self-report of barriers, rather than using direct methods. The biggest barrier to healthcare reported by transgender individuals is lack of access because of lack of providers who are sufficiently knowledgeable on the topic. Other barriers include: financial barriers, discrimination, lack of cultural competence by providers, health systems barriers, and socioeconomic barriers. SummaryNational research priorities should include rigorous determination of the capacity of the US healthcare system to provide adequate care for transgender individuals. Studies should determine knowledge and biases of the medical workforce across the spectrum of medical training with regard to transgender medical care; adequacy of sufficient providers for the care required, larger social structural barriers, and status of a framework to pay for appropriate care. As well, studies should propose and validate potential solutions to address identified gaps.

Twenty-One- Gauge Needles Provide More Cellular Samples than Twenty-Five- Gauge Needles in Fine-Needle Aspiration Biopsy of the Thyroid but may not Provide Increased Diagnostic Accuracy

The technique of fine-needle aspiration (FNA) biopsy of the thyroid is important to evaluate malignancy in thyroid nodules. Eighty-five percent of thyroid FNA procedures lead to sufficient cellular material for diagnosis. With more cells aspirated, the chance of sufficiency for diagnosis increases. Large-bore needles lead to more cellular material being aspirated but bloodier specimens that may interfere with cytologic interpretation. Small-bore needles may result in too few cells for diagnosis. We conducted a randomized prospective study contrasting 21-gauge and 25-gauge needles in the evaluation of 50 consecutively enrolled nodules at our institution. In our investigation, 21-gauge needles more frequently provided superior biopsy specimens (50%) than did 25-gauge needles (18%). In the remaining specimens (32%), the 21-gauge and 25-gauge needles provided similar cellular material. The rate of sufficient samples was the same. We conclude that use of 21-gauge needles results in more cellular specimens but may not result in increased diagnostic accuracy.

Hormone therapy in transgender adults is safe with provider supervision; A review of hormone therapy sequelae for transgender individuals

Introduction Some providers report concern for the safety of transgender hormone therapy (HT). Methods This is a systematic literature review of HT safety for transgender adults. Results Current literature suggests HT is safe when followed carefully for certain risks. The greatest health concern for HT in transgender women is venous thromboembolism. HT among transgender men appears to cause polycythemia. Both groups experienced elevated fasting glucose. There is no increase in cancer prevalence or mortality due to transgender HT. Conclusion Although current data support the safety of transgender HT with physician supervision, larger, long-term studies are needed in transgender medicine.

Advancing methods for US transgender health research

Purpose of reviewThis article describes methodological challenges, gaps, and opportunities in US transgender health research. Recent findingsLack of large prospective observational studies and intervention trials, limited data on risks and benefits of sex affirmation (e.g., hormones and surgical interventions), and inconsistent use of definitions across studies hinder evidence-based care for transgender people. Systematic high-quality observational and intervention-testing studies may be carried out using several approaches, including general population-based, health systems-based, clinic-based, venue-based, and hybrid designs. Each of these approaches has its strength and limitations; however, harmonization of research efforts is needed. Ongoing development of evidence-based clinical recommendations will benefit from a series of observational and intervention studies aimed at identification, recruitment, and follow-up of transgender people of different ages, from different racial, ethnic, and socioeconomic backgrounds and with diverse gender identities. SummaryTransgender health research faces challenges that include standardization of lexicon, agreed upon population definitions, study design, sampling, measurement, outcome ascertainment, and sample size. Application of existing and new methods is needed to fill existing gaps, increase the scientific rigor and reach of transgender health research, and inform evidence-based prevention and care for this underserved population.

Progress on the road to better medical care for transgender patients.

Purpose of reviewIn order to improve transgender individuals’ access to healthcare, primary care physicians and specialists alike should be knowledgeable about transgender medicine. This review is intended to provide concise transgender hormone treatment guidelines. Recent findingsTransgender individuals report that the lack of knowledgeable providers represents the greatest barrier to transgender medical care. Hormone treatments are generally well tolerated and greatly benefit transgender patients. After physicians recognize that gender identity is stable, hormone treatments for transgender patients are often straightforward.A practical target for hormone therapy for transgender men (female to male) is to increase testosterone levels to the normal male physiological range (300–1000 ng/dl) by administering testosterone. A practical target for hormone therapy for transgender women (male to female) is to decrease testosterone levels to the normal female range (30–100 ng/dl) without supra-physiological levels of estradiol (<200 pg/ml) by administering an antiandrogen and estrogen. Patients should be monitored every 3 months for the first year and then every 6–12 months for hormonal effects. SummaryAlthough more studies are required, recently published transgender medical treatment guidelines provide a good start toward making care of transgender patients more generalized and accessible to healthcare providers.