Central Hypothyroidism related to Pituitary Adenomas : Resistance to Central Hypothyroidism in patients with acromegaly.

学位記番号：医博甲173

Congenital leptin deficiency and thyroid function

Thyroid function is closely related to leptin's secretion by the adipose tissue. In states of leptin-deficiency, the circadian rhythm of TSH is altered, leading to central hypothyroidism in animal models. In humans, central hypothyroidism has also been described in rare cases of congenital leptin deficiency. However, the thyroid phenotype in these cases is heterogeneous, with the occurrence of central hypothyroidism in a minority of cases. Here we describe thyroid function in four leptin-deficient humans (2 males aged 5 and 27, and 2 females aged 35 and 40), before and during leptin replacement with recombinant human methionyl leptin (r-metHuLeptin). The child was evaluated for four years, and the adults, for eight years. In addition, the adults were submitted to a brief withdrawal of leptin during six weeks in the sixth year. Our results show that, regardless of leptin replacement, our leptin-deficient patients have normal thyroid function. In spite of having an important role in regulating the hypothalamic-pituitary-thyroidal axis, leptin is not required for normal thyroid function

Hypopituitarism : a review on the diagnosis and management of central hypoadrenalism and hypothyroidism

A variety of conditions can result in hypopituitarism and this article focuses on the diagnosis, treatment and management of central hypoadrenalism and hypothyroidism. Central hypoadrenalism, if untreated, can potentially prove to be fatal and thus it is imperative that a timely diagnosis is done and life long supplementation instituted. Different glucocorticoid supplementation regimes together with possible side effects are discussed. Life long thyroxine replacement is needed for central hypothyroidism. Particular aspects regarding the diagnosis and management of central hypothyroidism are tackled. Important elements in the management of these patients, so as to ensure suitable supplementation are proper clinical and biochemical monitoring together with effective patient education.peer-reviewe

The Pathogenic TSH β-Subunit Variant C105Vfs114X Causes a Modified Signaling Profile at TSHR

1) Background: Central congenital hypothyroidism (CCH) is a rare endocrine disorder that can be caused by mutations in the β-subunit of thyrotropin (TSHB). The TSHB mutation C105Vfs114X leads to isolated thyroid-stimulating-hormone-(TSH)-deficiency and results in a severe phenotype. The aim of this study was to gain more insight into the underlying molecular mechanism and the functional effects of this mutation based on two assumptions: a) the three-dimensional (3D) structure of TSH should be modified with the C105V substitution, and/or b) whether the C-terminal modifications lead to signaling differences. 2) Methods: wild-type (WT) and different mutants of hTSH were generated in human embryonic kidney 293 cells (HEK293 cells) and TSH preparations were used to stimulate thyrotropin receptor (TSHR) stably transfected into follicular thyroid cancer cells (FTC133-TSHR cells) and transiently transfected into HEK293 cells. Functional characterization was performed by determination of Gs, mitogen activated protein kinase (MAPK) and Gq/11 activation. 3) Results: The patient mutation C105Vfs114X and further designed TSH mutants diminished cyclic adenosine monophosphate (cAMP) signaling activity. Surprisingly, MAPK signaling for all mutants was comparable to WT, while none of the mutants induced PLC activation. 4) Conclusion: We characterized the patient mutation C105Vfs114X concerning different signaling pathways. We identified a strong decrease of cAMP signaling induction and speculate that this could, in combination with diverse signaling regarding the other pathways, accounting for the patient's severe phenotype

The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways

IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of the disease remain unclear. Based on a patient with a full deletion of IGSF1 clinically followed from neonate to adulthood, we investigated a common pituitary origin for hypothyroidism and macroorchidism, and the role of IGSF1 as regulator of pituitary hormone secretion. The patient showed congenital central hypothyroidism with reduced TSH biopotency, over-secretion of FSH at neonatal minipuberty and macroorchidism from 3 years of age. His markedly elevated inhibin B was unable to inhibit FSH secretion, indicating a status of pituitary inhibin B resistance. We show here that IGSF1 is expressed both in thyrotropes and gonadotropes of the pituitary and in Leydig and germ cells in the testes, but at very low levels in Sertoli cells. Furthermore, IGSF1 stimulates transcription of the thyrotropin-releasing hormone receptor (TRHR) by negative modulation of the TGFβ1-Smad signaling pathway, and enhances the synthesis and biopotency of TSH, the hormone secreted by thyrotropes. By contrast, IGSF1 strongly down-regulates the activin-Smad pathway, leading to reduced expression of FSHB, the hormone secreted by gonadotropes. In conclusion, two relevant molecular mechanisms linked to central hypothyroidism and macroorchidism in IGSF1 deficiency are identified, revealing IGSF1 as an important regulator of TGFβ/Activin pathways in the pituitary

A smile a day keeps the lawyers away! : the importance of effective communication in preventing litigation

Effective communication is the cornerstone of the doctor/patient relationship. The British Medical Association, in its discussion paper on communication skills education for doctors , highlighted four key benefits of effective communication: • improve the doctor-patient relationship by helping the doctor seek the relevant information and recognise the problems of the patient • help the patient to understand and comply with treatment instructions, thereby improving patient satisfaction • improve patient health - better communication and dialogue between doctor and patient has a beneficial effect in terms of promoting better emotional health, resolution of symptoms and pain control • improve the overall quality of care by ensuring that patients’ views and wishes are taken into account. However, in the blame and claim world in which we live it is also essential to help prevent litigation.peer-reviewe

Current utility of first-line FT4 and TSH in screening for central hypothyroidism

Background Thyroid testing strategies vary across laboratories. First-line combined thyroid stimulating hormone (TSH) and freeT4 (FT4) have historically been preferred by many laboratories as this detects individuals with undiagnosed central hypothyroidism who can be missed with a first-line TSH-only strategy. However, an up-to-date evaluation of the utility of this approach is lacking. Objectives We investigated the clinical utility of first-line TSH and FT4 in the detection of central hypothyroidism in current day practice. Design, Patients, and Measurements The All-Wales laboratory information system was queried to identify thyroid function tests in patients aged ≥16 years with decreased FT4 and inappropriate TSH (low-FT4). The 1-year incidence of low-FT4 was determined using mid-year population data. Clinical information of patients with low-FT4 was reviewed to determine causes of low-FT4 and the incidence of central hypothyroidism. Results The incidence of low-FT4 varied according to FT4 assay method (range: 98–301 cases/100,000 population/year). Fifteen new cases of central hypothyroidism were detected in two health boards, equivalent to 2 cases/100,000 population/year. Positive predictive value of low-FT4 for central hypothyroidism was 2%–4%. In a cross-section of primary care patients, low-FT4 was detected in 0.5% of all thyroid tests with assay-related differences in detection rates. Conclusions Although low-FT4 is a common laboratory finding, the incidence of central hypothyroidism remains rare. With the currently increased rates of thyroid testing and increased use of medications that decrease FT4, low-FT4 has a much lower predictive value for central hypothyroidism than previously reported. Thyroid screening strategies will need to balance the yield from first line TSH and FT4 testing with the cost of investigating individuals with non-pathological laboratory abnormalities

Hypopituitarism following traumatic brain injury

Traumatic brain injury (TBI) is a worldwide public health problem and an important cause of hypopituitarism. The incidence of hypopituitarism following moderate to severe TBI varies in different studies and may occur as multiple or isolated hormonal deficiencies, with gonadotrophin and growth hormone insufficiencies predominating, particularly in the acute setting. Adrenocorticotropic hormone deficiency is also common during the recovery phase. Pituitary function assessment in the acute phase post TBI is subject to multiple caveats and pitfalls due to hormonal alterations which occur as normal physiological responses to critical illness and the effects of drugs that are used in the intensive care unit. Nonetheless, assessment of the hypothalamo-pituitary-adrenal axis is of paramount importance during this period. Predictors of hypopituitarism during the acute phase of TBI remain unclear - further research is warranted.peer-reviewe

An Uncommon yet Treatable Cause of Hypoglycemia

Hypoglycemia is a life-threatening condition, especially if recurrent. Most common causes include patients with diabetes due to medications, nephropathy with oral hypoglycemic drugs, faulty dietary habits and other endocrine causes. In a patient presenting with recurrent hypoglycemia with central hypothyroidism, Sheehan syndrome must be suspected as diagnosis can prevent disastrous complication