J. Carl Pallais

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.).

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.

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 patients 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.

Serum chloride in heart failure: a salty prognosis.

Heart failure (HF) is a major source of morbidity, mortality, functional limitation, and cost worldwide.1 The failing myocardium, secondary maladaptive neurohormonal systems, and associated HF pharmacotherapies lead to marked perturbations of the electrolyte milieu. Serum sodium has long been considered one of the strongest markers of prognosis in both acute and chronic settings,2,3 and has sparked considerable interest in defining its role as a potential therapeutic target in HF. In contrast, serum chloride has been incompletely profiled, as it has garnered limited attention and is infrequently reported in contemporary clinical trials and registries. Serum chloride has only recently been appreciated as a key homeostatic marker in HF, which may have important prognostic and therapeutic implications. In this editorial, we discuss (i) available data clarifying the role of serum chloride in HF; (ii) mechanisms contributing to hypochloraemia; and (iii) merits of therapeutic modulation of chloride in HF.

Case 38-2015

Dr. Gregory L. Hundemer (Medicine): A 21-year-old man was admitted to this hospital because of fatigue, weight loss, and lesions in the lungs and liver on radiographic imaging. The patient had been in excellent health, running 3 to 5 miles daily and competing in sports, until approximately 3 months before this admission, when increasing fatigue occurred. During the next 6 weeks, his sleep requirement increased from 8 to 20 hours per day. Approximately 2 months before this admission, he was a passenger in a motor vehicle accident, after which he had an exacerbation of chronic back pain that he had previously attributed to sports activities. He was seen in a clinic of another hospital a few days later; a radiograph of the cervical spine was normal. He took nonsteroidal antiinflammatory drugs as needed for pain. One week later, he went to the emergency department of a second hospital because of fatigue, low back pain, and bilateral swelling of the breast tissue. Testing for Lyme disease was negative. He was advised to discontinue taking the workout supplements (which contained creatine nitrate) that he had been taking for several years. The next week, he returned to the second hospital because of worsening symptoms; test results were reportedly unchanged. A muscle relaxant was administered, without improvement. One month before this admission, anorexia, nausea, nonbilious nonbloody vomiting, weight loss, intermittent chills, and anxiety occurred, followed by dyspnea with exertion and decreased exercise tolerance (i.e., exercise was limited to walking several blocks before resting). On evaluation in the emergency department of the second hospital 3 weeks before this admission, testing for Lyme disease was negative; other test results are shown in Table 1. The stool was positive for occult blood, and urinalysis revealed trace protein, increased urobilinogen (2.0; reference range, 0.0 to 1.0), and 9 red cells per high-power field (reference range, 0 to 5). Diagnoses of anemia and hyperthyroidism were made. The patient was discharged with instructions to see a gastroenterologist and an endocrinologist. The next day, on evaluation in a gastroenterology clinic, the patient reported From the Departments of Endocrinology (J.C.P.), Radiology (M.M.), Hematology– Oncology (P.J.S.), and Pathology (R.I.W.), Massachusetts General Hospital, and the Departments of Endocrinology (J.C.P.), Radiology (M.M.), Hematology–Oncology (P.J.S.), and Pathology (R.I.W.), Harvard Medical School — both in Boston.

Case 7-2011: A 52-Year-Old Man with Upper Respiratory Symptoms and Low Oxygen Saturation Levels

Dr. Roby P. Bhattacharyya (Medicine): A 52-year-old man was seen in the urgent care outpatient medical clinic at this hospital because of upper respiratory symptoms. The patient had been in his usual state of health until 3 days earlier, when subjective fever, fatigue, headache, nasal and sinus congestion, sore throat, and a nonproductive cough developed. Three days later, he came to the outpatient clinic. He did not have chills, gastrointestinal symptoms, shortness of breath, wheezing, night sweats, or chest discomfort, and he reported that his respiratory symptoms were not as severe as those he had had during a previous episode of pneumonia. The patient had had type 1 diabetes mellitus for 17 years, for which he was followed at another hospital. Control of blood glucose levels had been poor, despite low hemoglobin A1c measurements; glycemic control was followed by measuring the levels of plasma fructosamine. Eight years before this evaluation, he had an episode of prolonged altered consciousness and somnolence, associated with a fasting blood sugar level of 49 mg per deciliter (2.7 mmol per liter); his condition improved slowly after the administration of glucagon and intravenous glucose. Eighteen months before this evaluation, he had an episode of transient expressive aphasia and was treated briefly with valproic acid. He also had hypertension, exercise-induced angina, hyperlipidemia, hyperbilirubinemia of more than 8 years’ duration, glaucoma, and dermatitis herpetiformis, for which he had taken dapsone for more than 8 years. Testing for serum endomysial antibodies had been positive, and he had briefly tried a gluten-free diet but had not adhered to it. He had migraine headaches, atypical chest pains, and peripheral neuropathy with mildly diminished vibratory sensation in his feet. Episodes of elevated aminotransferase levels had occurred 18 months, 8 months, and 2 months before this evaluation, after the initiation of valproic acid, simvastatin, and atorvastatin, respectively. A screening colonoscopy had revealed diverticulosis and a tubular adenoma (4 mm in diameter), which had been excised. Medications included the human insulin analogue lispro, insulin glargine, dapsone (200 mg daily), lisinopril, metoprolol succinate, and nitroglycerin as needed for chest pain. The patient reported omitting his antihypertensive medications for the 3 days preceding the current evaluation, and he had not taken Case 7-2011: A 52-Year-Old Man with Upper Respiratory Symptoms and Low Oxygen Saturation Levels

Fainting, Swooning, and Syncope

Have you ever been curious about how serious fainting, swooning, and syncope are or can be? Have you wondered whether, when, and how to work up these conditions? Have you ever considered how to best treat a patient with single or multiple episodes of syncope? If you have, then the following case vignette should provide a useful stimulus for discussion.

Cardiovascular Disease in Endocrine Disorders

Cardiovascular symptoms are often the first signs and symptoms of underlying endocrinopathies. This chapter reviews endocrine disorders with a focus on cardiovascular changes and presentations.

Case 33-2012

Dr. Kimberly G. Blumenthal (Medicine): A 34-year-old woman, 2.5 months post partum, was admitted to this hospital because of episodes of altered mental status. The patient had been well until approximately 3 months before admission, near the end of her pregnancy, when periodic numbness of the lower lip occurred, which resolved after approximately 30 minutes. She gave birth to a healthy baby by normal spontaneous vaginal delivery 2.5 months before admission and had been breastfeeding since then. After delivery, the patient began to have intermittent numbness in the pelvis and thighs while walking, without pain or burning. Seven weeks before admission, she began to have episodes of unusual behavior in the morning after she awakened, including pouring cereal from one container to another and making growling noises; these resolved after approximately 30 minutes, and she had minimal recollection of the episodes. She also began to have panic attacks, insomnia, episodes of crying, and increasing feelings of anxiety and hopelessness; diagnoses of anxiety and postpartum depression were made. Clonidine was administered briefly, followed by clonazepam and, 2 weeks before admission, sertraline, without improvement. Three weeks before this admission, intermittent blurring of her vision developed, associated with “wooziness” and feeling “out of it.” She had periods of numbness of the lower lip, arms, and legs and had difficulty performing routine activities, such as typing. Ten days before admission, during a 2-hour period, she had trouble conversing, folding a stroller, and fastening her seatbelt; she later had difficulty recalling the events. Similar symptoms occurred the next day, lasting approximately 1 hour. Eight days before this admission, she saw a neurologist. She was asymptomatic, and the examination was normal; additional testing and follow-up were scheduled. During the next 4 days, darkening of vision, occasionally associated with horizontal diplopia, occurred both before and after breakfast. She began to have episodes of fatigue, diminished hearing, and slowed thought processes during which she became nonverbal and unresponsive although she appeared awake; these lasted for several hours, followed by amnesia for the events. Her mother reported that during episodes, the patient lay on the couch, moving her arms slowly in front of her, occasionally tremulous and diaphoretic, without nausea, vomiting, chest pain, pal-