Cause Of Central Hypothyroidism Research Articles

Особливості діагностики та лікування вторинного гіпотиреозу

Огляд літератури присвячений вторинному гіпотиреозу — рідкісній патології, при діагностиці та лікуванні якої виникає низка питань і труднощів. Основними причинами вторинного гіпотиреозу у дорослих є пухлини гіпоталамо-гіпофізарної ділянки, а також стан після оперативного і променевого впливу на цю ділянку. Гормонально активні та неактивні макроаденоми гіпофіза є причиною розвитку набутого вторинного гіпотиреозу в більше ніж 50 % випадків. При променевій терапії пухлин головного мозку розвиток вторинного гіпотиреозу можливий через декілька років після проведеного лікування. Як і при первинному гіпотиреозі, клінічні прояви вторинного гіпотиреозу неспецифічні. Діагностика та лікування цього захворювання найчастіше ускладнюються його поєднанням з недостатністю інших тропних гормонів. Основу діагностики вторинного гіпотиреозу становлять анамнестичні дані і лабораторні показники — одночасне визначення концентрації тиреотропного гормона і вільного тироксину. Вміст вільного тироксину також використовують як основний маркер адекватності дози левотироксину при лікуванні вторинного гіпотиреозу. Результати нещодавно опублікованих праць дозволяють оптимізувати замісну терапію при вторинному гіпотиреозі, однак дотепер залишається невивченим питання використання додаткових біохімічних маркерів для оцінки адекватності замісної терапії.

SUN-LB130 Identification of IGSF1 Ligands

Immunoglobulin superfamily, member 1 (IGSF1), is an X-linked, type 1 transmembrane glycoprotein that is highly expressed in the anterior pituitary gland and testes. Mutations in the IGSF1 gene cause congenital central hypothyroidism, variable hypoprolactinemia, growth hormone dysregulation, and macroorchidism. Igsf1 knockout mice exhibit reduced pituitary TRH receptor (Trhr1) expression with an associated impairment in TRH-stimulated TSH secretion. The mechanism through which IGSF1 loss leads to reductions in Trhr1 levels is unresolved, at least in part because IGSF1’s cellular functions are unknown. The mature form of the IGSF1 protein consists of seven extracellular Ig loops, a single transmembrane domain containing a positively charged arginine, and a short intracellular carboxy-tail devoid of known functional motifs. Recently, IGSF1 was argued to be a member of the leukocyte receptor cluster (LRC) family. LRC proteins act as cell surface receptors for soluble or membrane-bound proteins. We therefore hypothesized that IGSF1 is a cell surface receptor for a presently undescribed ligand that regulates Trhr1 expression in pituitary thyrotrope cells. To identify candidate IGSF1 ligands, we implemented a new ligand trapping method, Ecto-Fc MS. We fused the extracellular (Ecto) domain of IGSF1 to the fragment crystallizable (Fc) region of human IgG, creating an Ecto-Fc fusion protein. Secreted IGSF1-Fc was purified and used as a ligand trap for bait proteins extracted from rat testes. The protein complexes were affinity purified with protein A beads, trypsin digested into peptides, subjected to orthogonal high-pH fractionation, and identified by tandem LC-MS/MS. More than 700 proteins were enriched in IGSF1-Fc preparations compared to an Fc-only negative control. Several secreted ligands and plasma-membrane proteins were identified, many of which are also expressed in pituitary thyrotrope cells. Identifying the ligand or ligands will enable us to determine IGSF1 function, and may lead to the discovery of novel causes of central hypothyroidism and macroorchidism.

Central Hypothyroidism Related to Pituitary Adenomas: Low Incidence of Central Hypothyroidism in Patients With Acromegaly.

The most frequent cause of central hypothyroidism (CeH) is pituitary adenomas, but the mechanisms remain unclear. We investigated serum thyroid levels and GH/IGF-1 in central hypothyroidism in untreated patients with pituitary nonfunctioning and GH-secreting adenomas. This was a retrospective cross-sectional study of cases collected from Gunma University and Toranomon Hospitals between 2007 and 2016. One-hundred thirty-nine cases of nonfunctioning pituitary adenoma (NFPA) and 150 cases of GH-secreting pituitary adenoma (GHPA) were analyzed. The correlations between thyroid levels, several clinicopathological parameters, and GH/IGF-1 were examined. Twenty-four percent of NFPA patients had CeH. The severity did not correlate with tumor size, age, or sex, and all cases had normal TSH levels. In contrast, only 8.7% of GHPA patients had CeH; approximately half had normal TSH levels and approximately half had low TSH levels. Serum TSH levels in GHPA patients were significantly lower and free T4 (FT4) and free T3 levels were higher than those in patients with NFPA. Furthermore, approximately one-fourth of GHPA patients had normal FT4 and low TSH levels. In addition, serum FT4 levels and serum TSH levels were positively and negatively correlated, respectively, with serum IGF-1 levels. Furthermore, IGF-1 levels in patients with GHPA decreased with age. (i) NFPA patients with CeH had TSH levels within a normal range. (ii) GHPA patients had a low incidence of CeH, which may be a result of stimulated thyroid function by GH/IGF-1. (iii) We found an age-dependent decrease in serum IGF-1 levels in patients with GHPA.

Central Hypothyroidism Related to Pituitary Adenomas: Resistance to Central Hypothyroidism in Patients with GH Secreting Pituitary Adenomas

Background: most frequent cause of central hypothyroidism (CeH) is pituitary adenomas, but the mechanisms remain unclear. We investigated thyroid status and GH/IGF-1 in CeH in untreated patients with pituitary non-functioning and GH-secreting adenomas. Methods: This was a retrospective cross-sectional study of cases collected from two Hospitals between 2007 and 2016. One hundred-thirty-nine cases of non-functioning (NFPA) and 150 cases of GH-secreting pituitary adenoma (GHPA) were analyzed. correlations between the thyroid status, several clinicopathological parameters, and GH/IGF-1 were examined. Findings: Twenty-four percent of NFPA patients had CeH. severity did not correlate with tumor size and age, and all cases had normal TSH levels. In contrast, only 8.7% of GHPA patients had CeH; about half had normal TSH levels and about half had low TSH levels. Serum TSH levels in GHPA patients were significantly lower and free T4 (FT4) and free T3 levels were higher than those in NFPA patients. One-fourth of GHPA patients had normal FT4 levels and low TSH levels. In addition, serum FT4 levels and serum TSH levels were positively and negatively correlated, respectively, with serum IGF-1 levels. Furthermore, IGF-1 levels in patients with GHPA decreased with age. Interpretation: 1) NFPA patients with CeH had TSH levels within a normal range. 2) GHPA patients were resistant to CeH, which may be a result of stimulated thyroid function by GH/IGF-1. 3) We found an age-dependent decrease in serum IGF-1 levels in a large cohort of GHPAs. Funding Statement: This work was supported by JSPS KAKENHI Grants 16K15493, 23591345, and 20591087 (to M.Y.) and 16K19551 (to K.H.). This work was partially supported by the Advancing Care of Hypothalamic-Pituitary Dysfunction in Japan Study (to M.Y.) from the Japan Agency for Medical Research and Development, and the Research on Rare and Intractable Disease, Health and Labour Sciences Research Grants (to M.Y.). Declaration of Interests: authors state: The authors have nothing to disclose. Ethics Approval Statement: studies were conducted in accordance with the principles of the Declaration of Helsinki and were approved by the Ethics Committee on human research of Gunma University (Approval number 535: Gunma University Human Genome Ethics Committee).

Thyrotrophic status in patients with pituitary stalk interruption syndrome.

Pituitary stalk interruption syndrome (PSIS) is associated with simultaneous or subsequent pituitary hormone deficiencies (PHDs). Although the clinical features of multiple PHDs are well known, the status of the thyrotrophic axis in PSIS has not been thoroughly investigated.The clinical data of 89 PSIS patients and 34 Sheehan syndrome (SS) patients were retrospectively analyzed.The prevalence of central hypothyroidism in the PSIS patients and the SS patients was 79.8% and 70.6%, respectively. The thyroid-stimulating hormone (TSH) levels in the PSIS patients were significantly higher in comparison with the SS patients (5.13 ± 3.40 vs 1.67 ± 1.20 mU/L, P < .05). TSH elevation (8.79 ± 3.17 mU/L) was noticed in 29 of 71 (40.85%) hypothyroid PSIS patients but not in the 24 hypothyroid SS patients. The TSH levels in the hypothyroid PSIS patients were significantly higher in comparison with the euthyroid PSIS patients (5.42 ± 3.67 vs 3.66 ± 1.50 mU/L). Thyroid hormone replacement significantly reduced the TSH levels in the PSIS patients with elevated TSH levels from 7.24 ± 0.98 to 1.67 ± 1.51 mU/L (P < .05). The logistic regression analysis suggested that TSH level was not significantly associated with pituitary stalk status and height of the anterior pituitary gland.PSIS is a newly recognized cause of central hypothyroidism. The proportion and amplitude of TSH elevations are higher in PSIS than in other causes of central hypothyroidism.

Central hypothyroidism - a neglected thyroid disorder.

Central hypothyroidism is a rare and heterogeneous disorder that is characterized by a defect in thyroid hormone secretion in an otherwise normal thyroid gland due to insufficient stimulation by TSH. The disease results from the abnormal function of the pituitary gland, the hypothalamus, or both. Moreover, central hypothyroidism can be isolated or combined with other pituitary hormone deficiencies, which are mostly acquired and are rarely congenital. The clinical manifestations of central hypothyroidism are usually milder than those observed in primary hypothyroidism. Obtaining a positive diagnosis for central hypothyroidism can be difficult from both a clinical and a biochemical perspective. The diagnosis of central hypothyroidism is based on low circulating levels of free T4 in the presence of low to normal TSH concentrations. The correct diagnosis of both acquired (also termed sporadic) and congenital (also termed genetic) central hypothyroidism can be hindered by methodological interference in free T4 or TSH measurements; routine utilization of total T4 or T3 measurements; concurrent systemic illness that is characterized by low levels of free T4 and normal TSH concentrations; the use of the sole TSH-reflex strategy, which is the measurement of the sole level of TSH, without free T4, if levels of TSH are in the normal range; and the diagnosis of congenital hypothyroidism based on TSH analysis without the concomitant measurement of serum levels of T4. In this Review, we discuss current knowledge of the causes of central hypothyroidism, emphasizing possible pitfalls in the diagnosis and treatment of this disorder.

IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.

Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.

The IGSF1 Deficiency Syndrome: Characteristics of Male and Female Patients

Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes. All patients (n = 42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

TSH Regulation Dynamics in Central and Extreme Primary Hypothyroidism

Thyrotropin (TSH) changes in extreme primary hypothyroidism include increased secretion, slowed degradation, and diminished or absent TSH circadian rhythms. Diminished rhythms are also observed in central hypothyroid patients and have been speculated to be a cause of central hypothyroidism. We examined whether TSH secretion saturation, previously suggested in extreme primary hypothyroidism, might explain diminished circadian rhythms in both disorders. We augmented and extended the range of our published feedback control system model to reflect nonlinear changes in extreme primary hypothyroidism, including putative TSH secretion saturation, and quantified and validated it using multiple clinical datasets ranging from euthyroid to extreme hypothyroid (postthyroidectomy). We simulated central hypothyroidism by reducing overall TSH secretion and also simulated normal TSH secretion without circadian oscillation, maintaining plasma TSH at constant normal levels. We also utilized the validated model to explore thyroid hormone withdrawal protocols used to prepare remnant ablation in thyroid cancer patients postthyroidectomy. Both central and extreme primary hypothyroidism simulations yielded low thyroid hormone levels and reduced circadian rhythms, with simulated daytime TSH levels low-to-normal for central hypothyroidism and increased in primary hypothyroidism. Simulated plasma TSH showed a rapid rise immediately following triiodothyronine (T(3)) withdrawal postthyroidectomy, compared with a slower rise after thyroxine withdrawal or postthyroidectomy without replacement. Diminished circadian rhythms in central and extreme primary hypothyroidism can both be explained by pituitary TSH secretion reaching maximum capacity. In simulated remnant ablation protocols using the extended model, TSH shows a more rapid rise after T(3) withdrawal than after thyroxine withdrawal postthyroidectomy, supporting the use of replacement with T(3) prior to (131)I treatment.

A Rare Form of Hypothyroidism

Secondary hypothyroidism is extremely rare. In the majority of cases, there is a genetic (gene mutations) or structural (mass effect or infiltration) basis for central hypothyroidism, and there is simultaneous deficiency of other adenohypophysial hormones. Isolated deficiency of thyrotropin is even rarer. This report features the case of a woman who had isolated thyrotropin deficiency, with the remainder of the anterior pituitary hormones being normal. The various causes of central hypothyroidism and the role of the thyrotropin-releasing hormone test are briefly described.

Disorders of thyrotropin synthesis, secretion, and function.

Advances related to thyrotropin during 1999 included better understanding of the genetic basis of pituitary development and genetic advances in identifying clinical entities and their mechanisms and enabling new therapies. Initial clinical use of recombinant thyrotropin in evaluation of thyroid cancer recurrence was described. The importance of glycosylation pattern was clarified including the role of thyrotropin-releasing hormone in synthesis of thyrotropin molecules with mature glycosylation, and the impact of abnormal glycosylation in loss-of-function and gain-of-function mutations of the thyrotropin receptor. Causes of excessive thyrotropin secretion were evaluated, including pituitary thyrotropin-secreting adenomas. The fairly common causes of central hypothyroidism including ischemic injury, cranial irradiation, psychiatric conditions, or medical illness were assessed. The action of thyrotropin at the thyroid cell was assessed as a growth factor and as an influence on tyrosine sulfate content of thyroglobulin. Such basic and clinical science advances are rapidly affecting clinical care.