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A previously fit and well male in his early 40s, presented to the emergency department, hypotensive, bradycardic and hypothermic with reduced levels of consciousness after being found diaphoretic and unwell at his home. Despite fluid resuscitation with warmed saline, he remained hypotensive and required vasopressor support leading to intensive care admission. Initially, the patient was managed for suspected meningoencephalitis but was later found to have hypopituitarism leading to secondary hypothyroidism and adrenal insufficiency. Subsequent investigations revealed it is due to empty sella syndrome., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder that is characterized by a segmental dermatomal facial port-wine stain birthmark and is frequently accompanied by ipsilateral brain and eye abnormalities. We present a case of a patient with SWS who exhibited hypogonadotropic hypogonadism, growth hormone (GH) deficiency, and central hypothyroidism at the age of 20 despite the absence of radiographic findings in the pituitary and hypothalamus., Case Presentation: A 20-year-old male with SWS with epilepsy and Klippel-Trenaunay syndrome presents with delayed pubertal development, short stature, and obesity. Upon further examination, he was found to have biochemical and clinical evidence of hypogonadism, hypothyroidism, and GH deficiency. A pituitary MRI displayed no abnormalities of the pituitary or hypothalamus. Treatment with testosterone cypionate and levothyroxine was initiated. Despite successful pubertal induction, IGF-1 levels have remained low and treatment with recombinant human growth hormone (rhGH) is now being considered for metabolic benefits., Conclusions: This case emphasizes the importance of endocrine evaluation and treatment of hormonal deficiencies in patients with SWS despite the absence of radiographic findings., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: The aim of this study was to investigate the association between intraoperative intrasellar pressure (ISP) and pre- and postoperative endocrine disturbances with focus on hyperprolactinemia and hypopituitarism in patients with pituitary tumors., Methods: The study is a consecutive, retrospective study with ISP collected prospectively. One hundred patients operated with transsphenoidal surgery due to a pituitary tumor, who had their ISP measured intraoperatively, were included. Data on patient endocrine status preoperatively and from 3-month postoperative follow-up were collected from medical records., Results: The risk of preoperative hyperprolactinemia in patients with nonprolactinoma pituitary tumors increased with ISP (unit odds ratio 1.067, n = 70) (P = 0.041). Preoperative hyperprolactinemia was normalized at 3 months after surgery. Mean ISP was higher in patients with preoperative thyroid-stimulating hormone (TSH) deficiency (25.3 ± 9.2 mmHg, n = 37) than in patients with intact thyroid axis (21.6 ± 7.2 mmHg, n = 50) (P = 0.041). No significant difference in ISP was found between patients with and without adrenocorticotropic hormone(ACTH) deficiency. No association was found between ISP and postoperative hypopituitarism at 3 months after surgery., Conclusions: In patients with pituitary tumors, preoperative hypothyroidism and hyperprolactinemia may be associated with higher ISP. This is in line with the theory of pituitary stalk compression, suggested to be mediated by an elevated ISP. ISP does not predict the risk of postoperative hypopituitarism 3 months after surgical treatment., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pituitary insufficiency is a common toxicity of cranial radiotherapy received in childhood for central nervous system, head and neck, and hematological malignancies. There is a recognized deficiency pattern and correlation with prescribed radiotherapy dose; however, correlation with measured pituitary dose (which can be minimized with modern radiotherapy techniques) has not previously been assessed., Procedure: Retrospective analysis was carried out of measured pituitary dose and endocrine outcomes of patients receiving cranial, total body, or head and neck photon beam radiotherapy at a tertiary center from July 2008 to October 2019., Results: Complete data for 102 patients were available. Median (IQR) age at radiotherapy was 9.0 (6.0-12.0) and follow-up 5.7 years (3.5-9.1). Most patients received focal brain radiotherapy (36.3%) or total body irradiation (32.4%); most frequent diagnoses were acute lymphoblastic leukemia (25.5%) and medulloblastoma (17.6%). The majority developed pituitary insufficiency (64; 62.7%); 41% had one and 38% had two hormone deficiencies. Growth hormone deficiency (GHD) (58; 56.9%) and thyroid-stimulating hormone deficiency (TSHD) (32; 31.4%) were most common. Patients who developed pituitary insufficiency received higher maximum pituitary dose-median (IQR) Gy, 44.0 (20.4-54.0) vs 18.2 (14.4-52.6); P = 0.008. Doses of 40-49 Gy or >50 Gy led to a higher cumulative incident rate than <20 Gy (HR 4.07, P < 0.001 and HR 3.04, P < 0.001, respectively). However, even at lower dose bands, levels of pituitary insufficiency were significant with a five-year cumulative incidence of GHD for <20 Gy and TSHD for 20-29 Gy reaching >30%., Conclusions: Our findings confirm a correlation between measured pituitary dose and risk of insufficiency even at lower doses, despite modern radiotherapy techniques. These data highlight the importance of minimizing pituitary dose and early specialist endocrine follow-up., (© 2022 Wiley Periodicals LLC.)

Myxoedema can have a variety of presentations, from mild cognitive impairment to psychosis, to overt coma. While majority of cases have primary hypothyroidism as the underlying aetiology, very few cases have central hypothyroidism. We report two patients who presented with myxoedema and were diagnosed with central hypothyroidism. A man in his 50s with a history of panhypopituitarism presented with hypotension, slurring of speech and psychosis that worsened to coma. He was initially treated as adrenal crisis, and on failing to improve he was later treated correctly as myxoedema coma. A woman in her 30s presented with bradykinesia and shock and was diagnosed with Sheehan's syndrome based on hormonal and imaging features. Both patients improved with a loading dose of oral thyroxine and intravenous steroids. Central hypothyroidism presenting with myxoedema is often complicated by coexisting pituitary hormone deficiencies. A high index of suspicion is required for better treatment outcomes., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

A late preterm female neonate presented with initial respiratory distress and heart murmur attributed to a haemodynamically significant patent ductus arteriosus (hsPDA) not responding to two courses of ibuprofen. Thyroid function performed for prolonged neonatal jaundice at 3 weeks of life suggested central hypothyroidism. Subsequent adrenocorticotropic hormone stimulation test showing hypocortisolism and MRI revealing adenohypophysis hypoplasia confirmed the diagnosis of congenital hypopituitarism (CH). Commencement of hydrocortisone followed by thyroxine replacement coincided with clinical closure of the hsPDA within 72 hours of treatment. Hypothyroidism and hypocortisolism may have contributed to persistent hsPDA. Thyroid hormone increases cytochrome P450 activity, endothelin-1 and fibronectin expression. Hydrocortisone decreases sensitivity of ductus arteriosus to PGE 2 These mechanisms have been postulated to cause ductal constriction and closure. Our case supports this association. hsPDA in a term and near-term neonate with a protracted disease course or associated midline defects should prompt the clinician to suspect CH (hypothyroidism and/or hypocortisolism)., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Slipped capital femoral epiphysis (SCFE) is a common disease in pediatric orthopedics. Most research on SCFE has focused on high-risk groups or the whole population, and studies focusing on adult SCFE patients are rare. In the present study, we report the case of an adult patient with SCFE., Patient Concern: A 37-year-old man presented to our clinic with persistent pain that was poorly localized to both hips, groin regions, and thighs for more than 1 year., Diagnoses: A bilateral hip X-ray examination was performed, and the femoral epiphyses were found to be unfused on both sides. Low levels of growth hormone (GH), insulin-like growth factor-1 (IGF-1), triiodothyronine (T3), thyroxine (T4), follicle-stimulating hormone, luteinizing hormone, estradiol, and testosterone, and high levels of thyroid-stimulating hormone, prolactin, and cortisol., Interventions: Hormone-substitution therapies (levothyroxine sodium to treat hypothyroidism and testosterone enanthate to treat hypogonadism) were prescribed. Total hip arthroplasty was performed to treat femoral epiphysis slippage., Outcomes: After 6 months of postoperative follow-up, the patient's gait improved significantly, and bilateral hip pain was relieved., Lessons: When treating adults with SCFE, clinicians must be alert to endocrine disorders. Comprehensive imaging evaluation is crucial for the accurate diagnosis and selection of an appropriate treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The rarity of congenital hypopituitarism (CHP) makes it essential for clinicians to be aware of its varying clinical manifestations. We report a neonate with one such unique presentation. A preterm girl baby was managed for respiratory distress. Diffuse cutis marmorata was present since birth; septic screens were positive with placental histopathology showing chorioamnionitis. Newborn screening showed low free thyroxine and normal TSH. Transient hypothyroxinaemia of prematurity was considered. Her respiratory status worsened on day 9, followed by refractory shock. She was treated for sepsis. Further evaluation for absent heart rate variability in response to vasopressor resistant shock led to the detection of hypocortisolism. Low cortisol along with hypothyroxinaemia made hypopituitarism the working diagnosis. Owing to the variable clinical spectrum of CHP, diagnosis is challenging. We highlight a few clinical and laboratory features, which would help in earlier diagnosis of CHP., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Mutations in the HESX1 gene can give rise to complex phenotypes that involve variable pituitary hormone deficiencies and other developmental defects., Case Description: A 14-year-old boy presented with short stature and delayed puberty and received a diagnosis of GH deficiency, central hypothyroidism, hypogonadotropic hypogonadism, and secondary adrenal insufficiency. He had anterior pituitary hypoplasia, ectopic posterior pituitary, and an interrupted pituitary stalk. Genetic studies uncovered a heterozygous variant in exon 2 of the HESX1 gene (c.219C>T; p.Ser73Ser). This single base change was predicted to be synonymous at the translational level but was shown to cause skipping of exon 2 in the RNA transcript., Conclusions: This study of a patient with combined pituitary hormone deficiency revealed an unusual synonymous mutation of the HESX1 gene leading to abnormal RNA processing and indicates the importance of investigating silent variants that at first glance appear to be benign., (Copyright © 2019 Endocrine Society.)

Hypothyroidism is characterized by hypometabolism, and may be seen as a part of secondary failure due to pituitary insufficiency or tertiary due to hypothalamic disease. Secondary and tertiary failures are also referred to as central hypothyroidism. Whereas overt primary hypothyroidism has a well-known affection on the heart and cardiovascular system, and may result in cardiac failure, cardiovascular affection is less well recognized in central hypothyroidism. Studies on central hypothyroidism and cardiovascular outcome are few and given the rarity of the diseases often small. Further, there are several limitations given vast difficulties in diagnosing the condition correctly biochemically, and difficulties monitoring the treatment because normal thyroid-pituitary feedback interrelationships are disrupted. The present review summarizes available studies of central adult hypothyroidism and its possible influence on the cardiovascular system, describe differences from primary thyroid failure and seek evidence for performing guidelines for clinical management of this particular thyroid and hypothalamo-pituitary disorder.

Context: Thyroid dysfunction may have detrimental effects on patient outcomes. Few studies have assessed this issue in patients with secondary hypothyroidism., Objective: Our objective was to test the hypothesis that thyroid hormone status has an impact on cardiovascular risk factors in adult patients with hypopituitarism., Design and Setting: This was a retrospective observational study (1993-2012) at a tertiary referral university hospital., Patients: All GH-deficient patients starting GH replacement (1993-2009) with measured free T4 (fT4) (n = 208). Baseline fT4 defined patients as TSH-sufficient and TSH-deficient (further divided into tertiles according to baseline fT4; first tertile had lowest fT4)., Main Outcome Measures: Anthropometric (body mass index [BMI], waist circumference, total fat (fat mass) and lean body mass [LBM]) and biochemical (lipids and fasting plasma glucose) data were collected at baseline and a median 4.1 years after commencement of GH., Results: At baseline, fT4 was negatively associated with BMI and waist circumference, but positively with high-density lipoprotein, independent of age, gender, and IGF-I (SD score). Only first-tertile TSH-deficient patients had higher BMI (P = .02), fat mass (P = .03), total cholesterol (P = .05), triglycerides (P < .01), and waist circumference (P = .01), and lower high-density lipoprotein cholesterol (P = .03) as compared with TSH-sufficient patients. At follow-up, IGF-I, LBM, and plasma glucose had increased in all subgroups (P < .01). The change in fT4 (ΔfT4) (follow-up - baseline) was negatively correlated to ΔBMI, ΔLBM, Δtotal cholesterol, and Δlow-density lipoprotein cholesterol (all P < .05, adjusted for ΔIGF-I and ΔGH and hydrocortisone dose). The negative correlation to Δtotal cholesterol and Δlow-density lipoprotein cholesterol persisted only in first-tertile TSH-deficient patients., Conclusion: This single-center study over a 20-year period has strengthened the importance of improved awareness of thyroid status and optimal thyroid replacement of hypopituitary patients to reduce cardiovascular risks in hypopituitary patients.

Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient's quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents.

Unlabelled: The standard treatment of hypothyroidism (central and primary) consists of thyroxine (T4) administration alone. However, the normal thyroid gland produces a small proportion of triiodothyronine (T3) directly into the circulation., Aim: We aimed to study the free T3 to free T4 ratio in treated central hypothyroidism compared with euthyroidism and treated primary hypothyroidism., Methods: Eighty-three subjects were included in this cross-sectional study: 36 with central hypothyroidism, 20 with primary hypothyroidism and 27 healthy controls. A clinical history and a physical examination, including height and weight measurement, were performed and body mass index (BMI) was calculated. Fasting blood was drawn to measure T3, T4, free T3, free T4 and TSH., Results: The free T3 to free T4 ratio was lower in treated central hypothyroidism than in euthyroidism but was similar to treated primary hypothyroidism. Free T4 was higher in treated central and primary hypothyroidism than in euthyroidism. Age, sex and BMI did not affect the free T3 to free T4 ratio., Conclusions: Treated patients with central hypothyroidism had a lower free T3 to free T4 ratio, similar free T3 levels and higher free T4 concentrations than euthyroid controls, whereas all these parameters were similar in central and primary hypothyroid patients treated with T4. The question of whether these findings translate into adequate tissue concentrations of free thyroid hormones in all tissues remains to be answered. Further studies should aim to determine whether clinical outcomes could be improved by a treatment achieving more physiological plasma concentrations., (Copyright © 2010 SEEN. Published by Elsevier Espana. All rights reserved.)

A case of hypothyroid cardiomyopathy secondary to hypopituitarism posed a diagnostic challenge. This lesson describes the patient's presentation with simultaneous acute heart failure and neurological signs; the investigations and imaging findings which initially suggested myocardial infarction (MI) and/or infiltration; and the response to treatment, with biochemical, sonographic and clinical resolution of the cardiomyopathy following thyroxine replacement therapy. This lesson illustrates the cardiovascular sequelae of severe hypothyroidism, and physicians are reminded of the difficulties involved in investigating putative coronary events in hypothyroid patients, since hypothyroidism itself may mimic MI.

Objective: To evaluate the diagnostic value of the thyrotropin-releasing hormone (TRH) stimulation test in the diagnosis of central hypothyroidism in patients with Sheehan's syndrome., Design: TRH stimulation test was performed in 72 patients with Sheehan's syndrome. Basal free triiodothyronine (fT(3)) and free thyroxine (fT(4)) levels were measured. Serum thyrotropin (TSH) concentration was determined before and 30, 60, 90, and 120 minutes after 200 mug TRH IV bolus injection. The peak TSH values <5.5 microIU/ml were defined as inadequate response. A peak TSH at 60 minutes or later was considered as delayed response. If TSH (60 minutes after peak), was more than 40% of the peak value it was considered as prolonged response. The diagnosis of central hypothyroidism (CH) was made if either serum fT(4) concentration was subnormal with an inappropriately low serum TSH concentration or inadequate response to TRH stimulation test and/or a delayed or prolonged response to TRH stimulation test., Main Outcome: Fifty-six (77.7%) of the patients had low serum fT(4) and fT(3) levels with an inappropriately low serum TSH levels were defined as CH (CH0 group). Ten (13.8%) patients with normal and low-normal fT(4) levels had no response and/or delayed or prolonged response to TRH stimulation test (CH1group). Six (8.3%) patients had fT(3), fT(4), and TSH levels within normal limits and peak TSH responses >/=5.5 microIU/ml consistent with euthyroidism (euthyroid group). Thus, 66 (91.6%) of 72 patients with Sheehan's syndrome had CH. Although fT(4) levels were within normal reference range, TRH stimulation test revealed that 10 (13.8%) of these had CH., Conclusion: TRH stimulation test is useful in the diagnosis of central hypothyroidism, especially in whom fT(4) and/or TSH is low-normal and known to have hypothalamo-pituitary pathology.

Background: The effect of GH replacement on thyroid function in hypopituitary patients has hitherto been studied in small groups of children and adults with conflicting results., Objective: We aimed to define the effect and clinical significance of adult GH replacement on thyroid status in a large cohort of GH-deficient patients., Patients and Method: We studied 243 patients with severe GH deficiency due to various hypothalamo-pituitary disorders. Before GH treatment, 159 patients had treated central hypothyroidism (treated group) while 84 patients were considered euthyroid (untreated group). GH dose was titrated over 3 months to achieve serum IGF-1 concentration in the upper half of the age-adjusted normal range. Serial measurements of serum T4, T3, TSH and quality of life were made at baseline and at 3 and 6 months after commencing GH replacement., Results: In the untreated group, we observed a significant reduction in serum T4 concentration without a significant increase in serum T3 or TSH concentration; 30/84 patients (36%) became hypothyroid and needed initiation of T4 therapy. Similar but lesser changes were seen in the treated group, 25 of whom (16%) required an increase in T4 dose. Patients who became hypothyroid after GH replacement had lower baseline serum T4 concentration, were more likely to have multiple pituitary hormone deficiencies and showed less improvement in quality of life compared with patients who remained euthyroid., Conclusion: GH deficiency masks central hypothyroidism in a significant proportion of hypopituitary patients and this is exposed after GH replacement. We recommend that hypopituitary patients with GH deficiency and low normal serum T4 concentration should be considered for T4 replacement prior to commencement of GH in order to provide a robust baseline from which to judge the clinical effects of GH replacement.

Objective: To describe the effect of T4 replacement in patients with primary and central hypothyroidism on components of the IGF binding protein complex: IGF-I, the acid-labile subunit (ALS) and IGFBP-3., Patients and Methods: We determined IGF-I, ALS and IGFBP-3 (by 125I-IGF-II ligand blots and immunoblots) in serum of 19 patients with primary and 11 patients with central hypothyroidism., Results: Mean (+/- SD) free T4 (fT4) increased from 4.4 +/- 2.4 pmol/l at baseline to 18.6 +/- 5.2 pmol/l following T4 therapy. In patients with primary hypothyroidism, IGF-I concentrations increased from 101 +/- 57 to 158 +/- 60 microg/l (P < 0.001) and ALS from 12.6 +/- 4.7 to 15.6 +/- 5.2 mg/l (P = 0.001). IGFBP-3 levels (in arbitrary units, AU), assessed by 125I-IGF-II ligand blot and by Western blot (the intensity of the 45/42-kDa doublet following T4 replacement defined as 1 AU) increased from 0.74 +/- 0.47 to 1 (P = 0.029) and from 0.76 +/- 0.42 to 1 (P = 0.018), respectively. In patients with hypopituitarism, IGF-I and ALS concentrations increased on T4 therapy from 49 +/- 23 to 97 +/- 36 microg/l (P < 0.001) and from 7.8 +/- 4.1 to 11.0 +/- 2.7 mg/l (P = 0.010), respectively. IGFBP-3 remained unchanged during T4 replacement., Conclusions: T4 replacement increases the serum levels of IGF-I and ALS in patients with primary as well as central hypothyroidism. IGFBP-3 levels increase in response to T4 replacement in patients with primary hypothyroidism but not in those with central hypothyroidism, suggesting that thyroid hormones increase IGF-I and ALS but not IGFBP-3 in patients with GH deficiency.

In this study, which aims to investigate for the first time auditoty sensitivity in congenital central hypothyroidism (CH), we concluded that: (1) permanent sensorineural hearing loss may be observed not only in congenital primary disorders of thyroid function, as reported hitherto; (2) it may also be found in patients with congenital CH, at least when substitutive treatment is started many years after thyroid failure presentation; (3) the concept of a 'critical therapeutic window' in preventing hearing impairment also holds true for children with congenital CH; (4) the therapeutic window in CH is wider than in primary hypothyroidism; (5) this is probably due to the less severe thyroid impairment in the cases with a central origin of hypothyroidism. These conclusions were suggested by the following data obtained in a cohort of 10 patients with congenital CH who were euthyroid at the time of audiological evaluation thanks to long-standing substitutive therapy: (a) four out of 10 patients exhibited a bilateral sensorineural hearing loss; (b) hearing impaired patients were the oldest of the entire series at diagnosis of hypothyroidism and none of them was aged less than 7 years at the time of the start of replacement therapy; (c) a strong positive relationship was found between age at therapy start and hearing loss.

Background: An elevation of serum creatine kinase (CK) level is diagnosed in about every third patient with hypothyroidism. This is a well-known laboratory finding which is described in all standard books of internal medicine. Nevertheless it is difficult to diagnose an indistinct elevation of serum CK if a cardiac event is excluded and especially diseases of skeletal muscle system are considered in differential diagnoses. Despite better knowledge a hypothyroidism is rejected in cases of normal basic TSH level although typical clinical signs in addition to myopathic pain are available. Describing three patients with secondary hypothyroidism we want to demonstrate the danger of overestimating laboratory parameters by ignoring clinical symptoms., Case Report: Three patients came under medical observation due to unclear elevation of serum CK. Additional therapy with CSE inhibitors in two of the three patients led to the wrong conclusion as drug-specific side effect. The basic TSH level was normal in all patients, the main reason for late diagnosis of secondary hypothyroidism., Conclusion: Paying attention to clinical signs of hypothyroidism is elementary in cases of elevation of serum CK level. The secondary cause of hypothyroidism on basis of anterior pituitary gland insufficiency has to be included in differential diagnoses.

To evaluate the frequency of clinical manifestations and to study the etiological aspects of hypothyroidism in hypothyroid patients in Cotonou, we carried out a retrospective analysis of the medical reports on hypothyroid patients followed in our clinical practice. A total of 33 patients was thus studied, comprising 8 men (24%) and 25 women (76%) with mean age of 45,8 years for men and 40,4 years for women. The more frequent clinical manifestations observed were: face edema (45%), weight gain (45%), paresthesia (42%), fatigue (39%), lethargy (30%) and bradycardia (24%). Constipation (12%), sensation of cold (9%), depilation (6%) and dry skin (6%) were less frequently observed. Myalgia, hoarseness and menstrual irregularities were present in 15% of the cases respectively. Regarding the etiology, 82% of the cases were primary hypothyroidism and only 18% were of central origin. Thyroidectomy was the leading cause in our hypothyroid patients, representing 70% of all cases and 85% of primary hypothyroidism. Radioiodine treatment and autoimmune thyroiditis were equally found in 6% of the cases. Central hypothyroidism was related to a pituitary adenoma in four cases (12%) and to Sheehan syndrome in two cases (6%). As it can be expected, hypercholesterolemia was present in 82% of the patients but creatine phosphokinase elevation was more frequent (94% of the patients). Compared to the data reported in the literature, the frequency of the symptoms and signs of hypothyroidism seems to be underevaluated in our study and the frequency of autoimmune thyroiditis as a cause of hypothyroidism is low.

Serum TSH levels are often paradoxically elevated in patients with hypothyroidism due to Sheehan's syndrome. To investigate this apparent discrepancy, the biological activity and glycosylation of serum TSH were studied in 9 untreated patients with Sheehan's syndrome and 11 normal controls. TSH bioassay was based on cAMP generation, measured by RIA, in a culture system of CHO cells transfected with recombinant human TSH receptor. The oligosaccharide branching of TSH was studied by Con A lectin affinity chromatography, which discriminates TSH isoforms according to their mannose content, and the sialic acid content of TSH was studied by Ricinus communis affinity chromatography in combination with enzymatic removal of sialic acid with neuraminidase treatment. TSH bioactivity was expressed as the ratio between biological and immunofluorometric assays (B/I). Bioactive TSH concentrations were calculated by multiplying serum TSH intrinsic bioactivity by serum immunoreactive TSH concentration (B/I x I). Serum free T(4) (FT(4)) levels were lower in patients than in controls (3.7 +/- 0.4 vs. 14.0 +/- 0.9 pmol/L, respectively; P < 0.0001). Circulating immunoreactive TSH was higher in patients with Sheehan's syndrome than in controls (3.8 +/- 0.8 vs. 1.8 +/- 0.2 mU/L, respectively; P = 0.01). In contrast, TSH B/I was significantly decreased in Sheehan's patients compared with controls (0.6 +/- 0.4 vs. 1.7 +/- 0.8, respectively; P = 0.003). However, the resultant bioactive TSH concentrations in serum of Sheehan's patients were not significantly different from control values (2.1 +/- 0.6 vs. 3.0 +/- 0.4; P = 0.25). A significant correlation was found between the bioactive TSH concentrations and serum FT(4) levels in patients with Sheehan's syndrome (r = 0.66; P = 0.05), but not between serum immunoreactive TSH and FT(4) levels (r = 0.21; P = 0.59) or between intrinsic TSH bioactivity and FT(4) levels (r = 0.56; P = 0.12). The Con A chromatography of serum TSH showed a similar distribution (0.3 < P < 0.5) of unbound, weakly bound, and firmly bound TSH in Sheehan's patients (16%, 38%, and 47%, respectively) and controls (15%, 34%, and 52%, respectively). The ricin chromatography of serum TSH showed a higher proportion of sialylated TSH molecules in Sheehan's patients than in controls (55% vs. 29%; P = 0.02). These results show that circulating TSH in Sheehan's syndrome, albeit increased, has decreased biological activity. The relevance of this finding is supported by the direct correlation between bioactive serum TSH concentrations and circulating FT(4). The reduced intrinsic TSH bioactivity in pituitary hypothyroidism of Sheehan's syndrome results from increased sialylation of TSH.

A 49-year-old man with herpes simplex encephalitis at age 22 was admitted with hypotension (90/60 mm Hg) and hypothermia (33.7 degrees C). His blood pressure was 80-90/50-60 mm Hg, with temperatures averaging 35 degrees C, for at least 3 years before admission. Evaluation of his hypothermia and hypotension revealed a low free triiodothyronine, low normal thyrotropin, luteinizing hormone < 2 mIU/L, follicle stimulating hormone <3 mIU/L, and low testosterone of 1.39 ng/dL. A baseline cortisol of 13.9 microg/dL was stimulated to 41.8 microg/dL with corticotropin, indicating he had partial anterior hypopituitarism with an intact pituitary-adrenal axis. Posterior pituitary function was normal. MRI revealed a "bright" posterior pituitary on a T1-weighted image, further indicating a normal posterior pituitary. Extensive decreased T1-weighting on MRI in the right and left temporal lobes was consistent with encephalomalacia. With thyroid hormone replacement, his blood pressure increased to 110/70 mm Hg with a temperature of 37 degrees C.

Concern arises when a sick infant is found to have a low serum T4, normal thyroid hormone binding, and a nonelevated thyroid-stimulating hormone. Hypothyroxinemia in this situation can result from either euthyroid sick syndrome or central hypothyroidism. To help distinguish between these diagnostic possibilities, we have measured reverse T3 and other thyroid function chemistries in six neonates who have central hypothyroidism in association with hypopituitarism. We found that these infants all had reverse T3 levels that were much lower than reported normal levels for premature and term neonates. This finding suggests that low reverse T3 levels can help to distinguish infants with central hypothyroidism from sick and well infants who tend to have relatively elevated reverse T3 levels.

6 years after surgery for epidermoid lung cancer, a 58-year-old man presented with atopic dermatitis and a high level of IgE, primary hypothyroidism of autoimmune origin, slight hyperprolactinemia and adrenal insufficiency of pituitary origin. ACTH levels were low and unresponsive to CRH. There was no deficiency of the other pituitary hormones and the MRI of the pituitary was normal. The other instances of autoimmune thyroiditis associated with ACTH deficiency are reviewed. The etiology of the deficiency is discussed in the context of a possible hypophysitis.

We have described a patient with panhypopituitarism who developed thyrotoxicosis. There is a widespread belief that pituitary thyrotropin (TSH) is not a pathogenetic factor in most patients with thyrotoxicosis. Due to technical reasons, however, it has been difficult to entirely exclude the role(s) of TSH in the development of thyrotoxicosis. In this report hyperthyroidism appeared in a patient with TSH deficiency proved by the lack of response to TRH administration. This is the first known case in which TRH stimulation demonstrated total abscence of TSH before the onset of thyrotoxicosis. We cannot exclude the possibility that factors of adenohypophyseal origin play some role in the pathogenesis of thyrotoxicosis, but TSH per se does not play a role in the development of Graves' thyrotoxicosis.

We describe a patient with panhypopituitarism whose only clinical symptoms were related to Raynaud's phenomenon. Previously described patients with Raynaud's phenomenon due to hypothyroidism had Hashimoto's thyroiditis, an autoimmune disease associated with multisystem autoimmune disorders. The occurrence of Raynaud's phenomenon in hypothyroidism without thyroiditis and its prompt disappearance with thyroid replacement therapy demonstrate that decreased thyroid function per se is a cause of this vasospastic syndrome. Raynaud's phenomenon may be an early clue to the diagnosis of hypothyroidism.

A 40-year-old man with primary hypothyroidism and sellar enlargement is described. There was deficiency of all pituitary tropic hormones except TSH which was elevated. TRH stimulation revealed responsiveness of pituitary thyrotropic cells, and thyroxine administration suppressed the elevated TSH. These findings are compatible with either a TSH-producing chromophobe adenoma resulting from primary hypothyroidism or, because of the suppressibility of the TSH secretion, thyrotropic hyperplasia secondary to hypothyroidism maintaining TSH secretion in the face of a non-TSH-secreting pituitary tumor.

Intelligence quotient (IQ), school and professional performance were reviewed in 33 patients with idiopathic hypothalamo-pituitary hypothyroidism. Diagnosis was based on low T4 values and clinical signs. All were treated with growth hormone (HGH). In some, hypothyroidism became manifest only after HGH therapy. Birth history revealed breech delivery in 24 and perinatal asphyxia in 15 of them. Thyroid treatment was started at a mean age of 9.8 (range 4-18 years). The mean IQ was 103.4 +/- 16.7 (SD). 9 patients had IQs below 90, 8 of them were born by breech delivery, 3 had severe perinatal asphyxia, one recurrent symptomatic hypoglycemia, and one a micropenis. Of those patients who have reached the respective age, 7 attended college, 3 university, and 9 had skilled professions. Only 7 required special education. For comparison, 52 patients with primary hypothyroidism were studied. Their mean IQ was with 89.3 +/- 18.1 (SD) significantly lower (p < 0.001) than the mean IQ of patients with hypothalamo-pituitary hypothyroidism. The best IQ (96.8 +/- 16.9) was attained when thyroid treatment was started before the age of 4 months, the lowest IQ (78.2 +/- 19.2) was found in the group of patients in whom thyroid substitution was initiated between 5 and 12 months. Patients who were treated after one year of age, had a mean IQ of 90.0 +/- 15.7. This group includes patients with ectopic thyroid glands or acquired hypothyroidism such as Hashimoto's thyroiditis.

Two cases of primary hypothyroidism with hypopituitarism in elderly patients are reported. The elevated levels of thyroid stimulating hormone led to delay in the recognition of accompanying pituitary failure. Elderly patients should not be commenced on thyroxine replacement therapy until the possibility of hypopituitarism and cortisol deficiency has been excluded.

Basal TSH levels were found to be elevated in 6 patients with documented growth hormone deficiency and hypothyroidism. TRH (200 mug/m2 administered intravenously) led to an exaggerated TSH response. This is in contrast to the results in other GH-deficient children, with either a delayed rise of TSH (hypothalamic hypothyroidism due to TRH deficiency, n = 22), an absent TSH response (pituitary hypothyroidism due to TSH deficiency, n = 7), or a normal increase of TSH (isolated GH deficiency, n = 20). Elevated plasma TSH in the presence of hypothyroidism as seen in 6 of our patients with idiopathic hypopituitarism or craniopharyngioma, indicates an intact feedback action between the pituitary and the thyroid gland. TSH, however, seems to be inadequate for the maintenance of normal thyroid function. It is suggested that in certain patients with hypothalamic disorders, TSH is secreted in a biologically less active form.

Deficiencies of corticotrophin (ACTH), growth hormone, and prolactin were documented in a woman with diabetes mellitus and Sheehan's syndrome. The patient's ACTH deficit appeared to be secondary to a hypothalamic abnormality since on two occasions the patient had a marked plasma ACTH response to vasopressin but not to insulin induced hypoglycaemia. It is postulated that the deficits of these three adenohypophysial hormones were instrumental in causing a severely impaired aldosterone secretory capacity in response to sodium restriction and an angiotensin infusion. In addition, the patient had an unusual form of thyroid dysfunction that was in part reversed with hydrocortisone replacement. The patient's unfortunate death during a hypoglycaemic crisis allowed correlation between her extensive antemortum endocrine testing and her pathologic anatomy.

A patient with hypopituitarism which is believed to have developed immediately after birth had been treated with thyroid hormones alone for a prolonged year of seven years until the time of the initial examination by the author. The subject has severe emaciation and lack of secondary sexual characteristics, but no past history of adrenocortical crisis was present, and, in fact, she manifested hyperthyroidism. It is questionable whether the preceding administration of thyroid hormones on the case with hypopituitarism should have been contraindicated. The two major complaints were improved through proper supplementary hormone treatment.

We investigated the thyroid and pituitary functions of six of the seven patients with nasopharyngeal carcinoma who had been previously treated with external radiation, and who were seen at the San Francisco Veterans Administration Hospital within a recent 18 month period. Two patients had primary hypothyroidism, and four had secondary hypothyroidism. These findings suggest that thyroid and pituitary abnormalities are frequent complications of both nasopharyngeal carcinoma and its treatment.

A patient with clinical signs of hypothyroidism, low basal serum thyrotropin (TSH) and lack of response to releasing-factor (TRH) is described. The normal secretion of other anterior pituitary hormones both basal and after stimulation tests and the absence of hypophysial sella alterations found with computed axial tomography suggest the presence of a selective idiopathic TSH deficiency. The pituitary origin of this defect has been reported in literature only in five further patients, tested with TRH. The exact pathogenetic mechanism of these cases is still unknown: in the patient observed by the authors unresponsiveness both to TRH and to metoclopramide suggest an absence of TSH-producing pituitary cells or an alteration of the mechanism beyond the receptor and within the cell. However the possibility that such a secretion defect may represent a first sign of a pituitary tumor should not be excluded.

Congenital hypopituitarism was found in two female infants who had profound hypoglycemia and hypothyroidism. In both infants, death occurred despite recognition of the disorder and institution of appropriate therapy. Autopsy findings showed an absent pituitary gland and sella turcica, with hypoplastic adrenal and thyroid glands, and ovaries in one case, and pituitary gland aplasia with absent thyroid and right adrenal glands plus a hypoplastic left adrenal gland in the other case.