Neuropsychiatric Sequelae of Thyroid Dysfunction: Evaluation and Management.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.Prim Care Companion CNS Disord 2023;25(6):23f03570. Author affiliations are listed at the end of this article.

Gonadal steroids and body composition, strength, and sexual function in men.

BACKGROUND: Current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, estradiol, or both account for clinical manifestations. METHODS: We provided 198 healthy men 20 to 50 years of age with goserelin acetate (to suppress endogenous testosterone and estradiol) and randomly assigned them to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Another 202 healthy men received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress the conversion of testosterone to estradiol). Changes in the percentage of body fat and in lean mass were the primary outcomes. Subcutaneous- and intraabdominal-fat areas, thigh-muscle area and strength, and sexual function were also assessed. RESULTS: The percentage of body fat increased in groups receiving placebo or 1.25 g or 2.5 g of testosterone daily without anastrozole (mean testosterone level, 44±13 ng per deciliter, 191±78 ng per deciliter, and 337±173 ng per deciliter, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was reduced. CONCLUSIONS: The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. Our findings support changes in the approach to evaluation and management of hypogonadism in men. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00114114.).

Autoimmune hypocalciuric hypercalcemia unresponsive to glucocorticoid therapy in a patient with blocking autoantibodies against the calcium-sensing receptor.

CONTEXT: Autoantibodies directed against the calcium-sensing receptor (CaSR) have been reported in several individuals with various autoimmune disorders and PTH-mediated hypercalcemia. Previously, glucocorticoid treatment has been shown to decrease the CaSR autoantibody titers and normalize the hypercalcemia in a patient with autoimmune hypocalciuric hypercalcemia (AHH). OBJECTIVE: The objective of the study was to evaluate a patient with AHH for the presence of blocking autoantibodies against the CaSR and to monitor her biochemical and serological responses to a trial of glucocorticoid therapy. RESULTS: Glucocorticoid treatment had no effect on serum total or ionized calcium concentration or serum PTH levels, all of which remained at higher than normal levels. In contrast, on prednisone, urinary calcium excretion increased from overtly hypocalciuric levels to normal values. Anti-CaSR autoantibodies were detected at similar levels in the patient's serum before, during, and after glucocorticoid treatment. Functional testing of these antibodies showed that they inhibited the stimulatory effect of extracellular Ca(2+) on ERK1/2 but did not suppress the calcium-induced accumulation of inositol-1-phosphate. CONCLUSIONS: We report a patient with AHH with frankly elevated PTH levels who was found to have autoantibodies against the CaSR. The hypercalcemia and CaSR autoantibody titers failed to respond to glucocorticoid therapy, unlike a previously reported patient with similar clinical and biochemical features. The anti-CaSR antibody-mediated inhibition of CaSR-stimulated ERK1/2 activity, but not of inositol-1-phosphate accumulation, suggests that ERK1/2 may mediate, at least in part, the regulation of PTH secretion and urinary calcium excretion by the CaSR.

Mapping of human autoantibody binding sites on the calcium-sensing receptor.

Previously, we have demonstrated the presence of anti-calcium-sensing receptor (CaSR) antibodies in patients with autoimmune polyglandular syndrome type 1 (APS1), a disease that is characterized in part by hypoparathyroidism involving hypocalcemia, hyperphosphatemia, and low serum levels of parathyroid hormone. The aim of this study was to define the binding domains on the CaSR of anti-CaSR antibodies found in APS1 patients and in one patient suspected of having autoimmune hypocalciuric hypercalcemia (AHH). A phage-display library of CaSR peptides was constructed and used in biopanning experiments with patient sera. Selectively enriched IgG-binding peptides were identified by DNA sequencing, and subsequently, immunoreactivity to these peptides was confirmed in ELISA. Anti-CaSR antibody binding sites were mapped to amino acid residues 41-69, 114-126, and 171-195 at the N-terminal of the extracellular domain of the receptor. The major autoepitope was localized in the 41-69 amino acid sequence of the CaSR with antibody reactivity demonstrated in 12 of 12 (100%) APS1 patients with anti-CaSR antibodies and in 1 AHH patient with anti-CaSR antibodies. Minor epitopes were located in the 114-126 and 171-195 amino acid domains, with antibody reactivity shown in 5 of 12 (42%) and 4 of 12 (33%) APS1 patients, respectively. The results indicate that epitopes for anti-CaSR antibodies in the AHH patient and in the APS1 patients who were studied are localized in the N-terminal of the extracellular domain of the receptor. The present work has demonstrated the successful use of phage-display technology in the discovery of CaSR-specific epitopes targeted by human anti-CaSR antibodies.

Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice.

The G protein-coupled receptor Gpr54 and its ligand metastin (derived from the Kiss1 gene product kisspeptin) are key gatekeepers of sexual maturation. Gpr54 knockout mice demonstrate hypogonadotropic hypogonadism, but until recently, the phenotype of Kiss1 knockout mice was unknown. This report describes the reproductive phenotypes of mice carrying targeted deletions of Kiss1 or Gpr54 on the same genetic background. Both Kiss1 and Gpr54 knockout mice are viable but infertile and have abnormal sexual maturation; the majority of males lack preputial separation, and females have delayed vaginal opening and absence of estrous cycling. Kiss1 and Gpr54 knockout males have significantly smaller testes compared with controls. Gpr54 knockout females have smaller ovaries and uteri than wild-type females. However, Kiss1 knockout females demonstrate two distinct phenotypes: half have markedly reduced gonadal weights similar to those of Gpr54 knockout mice, whereas half exhibit persistent vaginal cornification and have gonadal weights comparable with those of wild-type females. FSH levels in both Kiss1 and Gpr54 knockout males and females are significantly lower than in controls. When injected with mouse metastin 43-52, a Gpr54 agonist, Gpr54 knockout mice fail to increase gonadotropins, whereas Kiss1 knockout mice respond with increased gonadotropin levels. In summary, both Kiss1 and Gpr54 knockout mice have abnormal sexual maturation consistent with hypogonadotropic hypogonadism, although Kiss1 knockout mice appear to be less severely affected than their receptor counterparts. Kiss1 knockout females demonstrate a bimodal phenotypic variability, with some animals having higher gonadal weight, larger vaginal opening, and persistent vaginal cornification.

Neuroendocrine, gonadal, placental, and obstetric phenotypes in patients with IHH and mutations in the G-protein coupled receptor, GPR54.

The G protein coupled receptor, GPR54, is a key regulator of puberty and reproductive function. Despite its prismatic role, few patients with mutations in GPR54 and the phenotype of hypogonadotropic hypogonadism have been described. This report explores the neuroendocrine, gonadal, placental and obstetric phenotypes of patients with idiopathic hypogonadotropic hypogonadism (IHH) carrying missense (L148S), nonsense (R331X), and nonstop (X399R) mutations in GPR54. A male patient harboring the mutations R331X and X399R demonstrated (1) increased sensitivity to exogenous pulsatile GnRH compared to a cohort of IHH patients undergoing similar therapy and (2) steady increases in testicular volume, spermatogenesis, and fertility while on long-term GnRH therapy. A female patient homozygous for the L148S mutation had (1) intact responses to exogenous GnRH and gonadotropins, (2) multiple conceptions, (3) two uncomplicated pregnancies of healthy children, suggesting grossly intact placental function, (4) spontaneous initiation of uterine contractions, and (5) lactation for several months post-partum. Taken together, these observations help to tease apart the neuroendocrine and gonadal phenotypes of patients bearing mutations in GPR54.