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Pituitary hyperplasia secondary to primary longstanding hypothyroidism has been reported in the literature in adults and rarely in children.Here we present the clinical presentation and diagnostic procedures in eight children with pituitary hyperplasia due to autoimmune thyroiditis, highlighting common findings, such as growth delay, fatigue or gaining weight, but also exceptional findings such as pericardial effusion, rhabdomyolysis, isolated hypertrichosis, and Van Wyk-Grumbach syndrome, which have rarely or never been described.Surprisingly no thyroid enlargement was detected. We discuss the unusual presenting signs of autoimmune thyroiditis that should raise the suspicion of pituitary hyperplasia. We suggest that a more elaborate clinical assessment and even modification of the diagnostic approach to autoimmune thyroiditis is needed in order to avoid its serious complications.

Objective To describe a patient who developed a thyrotropin (TSH)-Secreting adenoma in the setting of primary hypothyroidism. Methods We report the clinical, laboratory, and radiologic findings of a patient with a history of primary hypothyroidism who presented with headache, a bitemporal visual field deficit, and elevated TSH despite long-term levothyroxine therapy. We discuss the diagnostic challenges of this case and review the relevant literature. Results A 54-yearold woman with a history of primary hypothyroidism presented with a 3-year history of headache and a week of worsening vision. Imaging revealed a heterogeneous sellar mass elevating the optic chiasm. Her serum TSH was 46.5 mIU/L and free thyroxine concentration was 0.1 ng/dL. The differential diagnosis included pituitary hyperplasia and a TSH-secreting adenoma in a patient with primary hypothyroidism. The pathologic characteristics of the tumor were consistent with the latter. Conclusion In a patient with an elevated TSH concentration and a previous diagnosis of hypothyroidism, it is important to consider other entities besides medication noncompliance. TSH-secreting adenomas can also cause elevated levels of TSH. (Endocr Pract. 2011;17: e135-e139)

Long-standing hypothyroidism causing thyrotroph hyperplasia can result in enlargement of the pituitary gland and hyperprolactinemia. A 20-year-old unmarried girl presented with galactorrhea for 4 months. She was evaluated and diagnosed to have severe hypothyroidism resulting in hyperprolactinemia and reversible pituitary hyperplasia. This case helps the clinicians to be aware of an unusual presentation of severe primary hypothyroidism and reminds to consider it in the differential diagnosis of pituitary enlargement with mild hyperprolactinemia.

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Limited data are available on pituitary gigantism, as it is a rare disorder. This study was carried out to assess the clinical, hormonal, and radiologic profiles and management outcomes of patients with pituitary gigantism.We conduced a retrospective analysis of 14 patients with pituitary gigantism who presented to a single tertiary care institute from 1990 to 2014.Thirteen patients were male, and 1 was female. The mean age at diagnosis was 21.9 ± 6.1 years, with a mean lag period of 6.5 ± 5.6 years. The mean height SD score at the time of diagnosis was 3.2 ± 0.6. Symptoms of tumor mass effect were the chief presenting complaint in the majority (50%) of patients, while 2 patients were asymptomatic. Six patients had hyperprolactinemia. At presentation, the nadir PGGH (postglucose GH) and insulin-like growth factor (IGF 1)-ULN (× upper limit of normal) were 63.2 ± 94.9 ng/mL and 1.98 ± 0.5, respectively. All (except 1 with mild pituitary hyperplasia) had pituitary macroadenoma. Six patients had invasive pituitary adenoma. Transsphenoidal surgery (TSS) was the primary modality of treatment in 13/14 patients, and it achieved remission in 4/13 (30.76%) patients without recurrence over a median follow-up of 7 years. Post-TSS radiotherapy (RT) achieved remission in 3/5 (60%) patients over a median follow-up of 3.5 years. None of the patients received medical management at any point of time.Gigantism is more common in males, and remission can be achieved in the majority of the patients with the help of multimodality treatment (TSS and RT).

Objective. The follow-up of GH levels in short-stature children with pituitary hyperplasia secondary to primary hypothyroidism (PPH) is reported in a few cases. We aimed to observe changes in GH secretion in short-stature children with PPH. Methods. A total of 11 short-stature children with PPH accompanied by low GH levels were included. They received levothyroxine therapy after diagnosis. Their thyroid hormones, IGF-1, PRL, and pituitary height were measured at baseline and 3 months after therapy. GH stimulation tests were performed at baseline and after regression of thyroid hormones and pituitary. Results. At baseline, they had decreased GH peak and FT3 and FT4 levels and elevated TSH levels. Decreased IGF-1 levels were found in seven children. Elevated PRL levels and positive thyroid antibodies were found in 10 children. The mean pituitary height was 14.3±3.8 mm. After 3 months, FT3, FT4, and IGF-1 levels were significantly increased (all p<0.01), and values of TSH, PRL, and pituitary height were significantly decreased (all p<0.001). After 6 months, pituitary hyperplasia completely regressed. GH levels returned to normal in nine children and were still low in two children. Conclusion. GH secretion can be resolved in most short-stature children with PPH.

Pituitary hyperplasia with hyperprolactinemia has been described as a rare presentation of primary hypothyroidism. A 12-y-old child presented with intermittent headache, easy fatigability, coarseness of facial features, and hoarseness of voice for 6 mo duration. Brain imaging findings showed pituitary hyperplasia; hormonal assessment revealed primary hypothyroidism and hyperprolactinemia. Pituitary hyperplasia regressed with thyroid hormone replacement therapy. This report describes an unusual case of pituitary hyperplasia with hyperprolactinemia secondary to primary hypothyroidism.

Mutations in the prophet of PIT1 gene (PROP1) are the most common cause of multiple pituitary hormone deficiency in humans; however, the mechanism of PROP1 action is not well understood. We report that Prop1 is essential for dorsally restricted expression of a Groucho-related gene, transducin-like enhancer of split 3 (Tle3), which encodes a transcriptional corepressor. Deficiency of a related gene, amino terminal enhancer of split (Aes), causes pituitary anomalies and growth insufficiency. TLE3 and AES have been shown to interact with TCF/LEF (transcripiton factors of the T cell-specific and lymphoid enhancer specific group) family members in cell culture systems. In the absence of TCF4 (Tcf7L2), Prop1 levels are elevated, pituitary hyperplasia ensues and palate closure is abnormal. Thus, we demonstrate that Tcf4 and Aes influence pituitary growth and development, and place Tcf4 and Tle3 in the genetic hierarchy with Prop1.

GERIATRIC retired horses are frequently kept by their owners as a companion for their current riding horse or simply as a much loved 9lawnmower9. With age, horses experience specific clinical problems, including osteoarthritis (degenerative joint disease), weight loss, pituitary hyperplasia and related conditions. These common causes of debility in the older horse are often insidious in onset and usually progressive but, when managed appropriately, animals can maintain a reasonable quality of life. This article discusses the diagnosis and clinical management of these conditions in the older horse and pony.

Pituitary thyrotroph hyperplasia secondary to primary hypothyroidism is a rare cause of pituitary enlargement. We report a case of pituitary hyperplasia in a young woman thought to have a pituitary macroadenoma with suprasellar extension. A 21-year-old woman was admitted to our hospital, complaining of menstrual irregularity and galactorrhea. Serum thyrotropin and prolactin were high, and serum-free thyroxine was low. Magnetic resonance imaging revealed symmetrical pituitary enlargement associated with contrast enhancement simulating macroadenoma. After adequate hormone replacement therapy with levothyroxine, both symptoms and pituitary hyperplasia regressed within 4 months. It is concluded that pituitary tumor associated with elevated thyroid stimulating hormone and low levels of free T4 should always be treated with replacement thyroxine before other diagnostic tests are ordered.

The development of pituitary tumours as a consequence of primary target organ failure is rare. We report here a rare case of pituitary hyperplasia with suprasellar extension due to primary myxoedema. This case presentation suggested the importance of detailed endocrine investigation and repeated magnetic resonance imaging for the differential diagnosis of pituitary enlargement to avoid unnecessary surgery.

A 15 year-old woman with diagnosis of hypothyroidism and hyperprolactinemia had irregular treatment. She lost conscience twice and magnetic resonance (MR) was indicated. It showed image of pituitary tumor that displaced optic chiasm. She was prescribed levothyroxin 50 ug for one week and then 100 ug daily. Hormonal treatment produced normalization of hormonal values and magnetic resonance evidenced 3 mm tumor reduction without supraselar extension., Paciente mujer de 15 años referida por diagnóstico de hipotiroidismo e hiperprolactinemia, con tratamiento irregular para ambas patologías, quien presentó pérdida de conocimiento en dos oportunidades, motivo por el cual se le indicó resonancia magnética (RM) de cerebro, en la cual se evidenció imagen tumoral hipofisaria que desplazaba el quiasma óptico. Se le indicó tratamiento con levotiroxina 50 ug por 1 semana, luego 100 ug diario. Los controles hormonales posteriores mostraron normalización, la RM de control evidenció disminución de tamaño de la imagen tumoral en aproximadamente 3 mm, sin repercusión en las estructuras supraselares o paraselares, con mejoría de cuadro clínico luego del tratamiento de sustitución con hormona tiroidea.

We report an unusual case of spontaneous ovarian hyperstimulation syndrome and pituitary hyperplasia mimicking macroadenoma in an adult, non-pregnant woman. Her condition was triggered by unrecognized primary hypothyroidism, which regressed after thyroid hormone replacement therapy. This case highlights the need for clinicians and radiologists to familiarize themselves with the clinical and imaging features detected in case of these complications of primary hypothyroidism, which are not well known in the medical and radiological profession. Such improved knowledge will help avoid delays in diagnosis, progression to life-threatening complications, and unnecessary surgery.

We present the first case of iatrogenic hypothyroidism as a result of compounded thyroid hormone (T4/T3) therapy. The thyroid replacement was changed from 175 µg levothyroxine (LT4) to 57/13.5 µg compounded T4/T3 daily in order to improve the T3 level, despite normal thyroid-stimulating hormone (TSH). This resulted in clinical manifestations of hypothyroidism and high TSH level (150 µIU/mL). Six months later, the patient was referred to our clinic for abnormal pituitary magnetic resonance imaging. On reinitiating a physiologic dose of LT4, clinical and biochemical abnormalities resolved and the pituitary gland size decreased. Our case emphasizes the importance of using TSH level to gauge dose adjustments in primary hypothyroidism. Also, it underscores the current American Thyroid Association recommendation against routine use of compounded thyroid hormone therapy.

Endocrinology and Diabetology Unit (E.P., A.T., B.A., S.C.), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Policlinico San Donato, 20097 San Donato Milanese, Milan, Italy; Department of Medical-Surgical Sciences (E.P., B.A., S.C.), University of Milan, 20097 San Donato Milanese, Milan, Italy; Department of Neurosurgery (M.L.), IRCCS Fondazione Ca’ Granda Policlinico, 20122 Milano, Milan, Italy; and Endocrinology Unit (A.G.L.), Department of Medical Sciences, University of Milan, IRCCS Fondazione Ca’ Granda Policlinico, 20122 Milan, Italy

We describe a15-year-old girl presenting with compensatory pituitary enlargement due to primary hypothyroidism. The hyperplasia regressed following thyroxine administration. The clinical, laboratory and MRI features of the patients are described and the mechanisms of pituitary gland enlargement are discussed.

Pituitary hyperplasia is generally associated with end-organ failure such as primary hypothyroidism, physiological changes such as puberty and pregnancy, or neoplasms secreting releasing factors. We present a full-term infant with an enlarged pituitary height of 8 mm at age 3 days despite a normal endocrinological evaluation. Repeat imaging at 5 months of age revealed a normal-size pituitary gland. To our knowledge, pituitary hyperplasia has not been described in a neonate with normal pituitary function.

We present eight cases with short stature, pituitary hyperplasia, and hypothyroidism. Pituitary hyperplasia due to primary hypothyroidism was diagnosed on the basis of clinical manifestations, endocrine examination and MRI. After 2 to 6 months of L-thyroxine replacement therapy, the signs of hypothyroidism disappeared; free triiodothyronine, free thyroxine, thyrotropin and prolactin became normal; and pituitary enlargement regressed. In two children, the growth rate remained low when treated with L-thyroxine, but with additional recombinant human growth hormone (rhGH), the height increased by 11 cm per year. No recurrence of lesions was found on follow-up.

Pituitary hyperplasia secondary to primary hypothyroidism has been reported in the literature in both adults and children. We report a case of a young woman who was diagnosed with hypothyroidism in her teenage years. Despite frequent follow-up, her TSH levels remained greater than 100 mIU/ml. A few years later, pituitary enlargement was found on an MRI at a time when her TSH was 177 mIU/ml and her free T4 was 0.2 ng/dl. Observed administration of 600 mcg of L-thyroxine was performed to determine the effectiveness of hormone absorption. Total T4 levels of 0.2 rose to 7.1 mcg/dl at two hours with a decrease in her TSH levels from 88.6 to 66.8 mIU/ml at 24 hours. With the exception of one short period, her TSH levels have remained elevated over eight years of observation without change in the size of the pituitary mass. In our review of the literature, primary uncontrolled hypothyroidism has been described as a precursor to pituitary hyperplasia. In these patients, TSH-secreting adenomas were distinguished from pituitary hyperplasia by a blunted TRH stimulation test, elevated alpha subunit concentration values, and elevated alpha subunit concentration/TSH ratios. TSH levels ranged from 98 to 732 mIU/ml in adults, and even higher values in children. Following adequate hormone replacement with L-thyroxine doses of 25 to 300 mcg/day, both symptoms and pituitary hyperplasia regressed on average within a few months.

An eight-year, 4-month old Indian girl with low IQ and delayed milestones, presented with headache (4 years), breast development (4 months), and menstrual bleeding for 22 days. Examination revealed short stature [height: 91.5 cm; SD score: -5.59], coarse dry skin, umbilical hernia (arrow), delayed reflexes, Tanner’s stage-3 breasts, absent pubic and axillary hair

Mulher de 21 anos apresenta história de 2 anos de irregularidade menstrual, com períodos de amenorréia de até 8 meses e ganho ponderal e há 1 ano galactorréia e cefaléia holocraniana. Exames da ocasião: TSH: 1192 mUI/ml (0,27-4,2); T4T:1,0 mg/dl (4,4-11,4) ; T3T: 0,41 ng/ml (0,7-2,1); prolactina: 69,2 ng/ml (3-20). Em serviço de endocrinologia foi confirmado quadro de mixedema acompanhado de galactorréia. Ressonância magnética (RM) de hipotálamo-hipófise mostrou lesão expansiva intra e supra selar com 1,9 x 1,4 x 1,9 cm nos seus maiores diâmetros, determinando compressão e desvio do quiasma óptico. Diante da possibilidade de hiperplasia das células produtoras de TSH, optamos por iniciar o tratamento do hipotireoidismo com levotiroxina. Após 2 meses de tratamento e normalização dos níveis séricos dos hormônios tireoidianos e do TSH, nova RM mostrou hipófise de tamanho normal. A regressão do volume hipofisário após terapia com levotiroxina confirmou a hipótese diagnóstica de hiperplasia hipofisária decorrente do hipotireoidismo primário. Nossos achados reforçam a importância da avaliação dos hormônios tireoideanos e TSH na investigação de aumento de volume hipofisário prevenindo uma cirurgia desnecessária. A 21-year-old woman complaining of 8-month amenorrhea associated to weight gain, galactorrhea and frequent headaches, presented for clinical evaluation; her laboratory tests were: TSH: 1192 mUI/ml (0.27-4.2); TT4: 1.0 mg/dl (4.4-11.4l); TT3: 0.41 ng/ml (0.7-2.1); prolactin: 69.2 ng/ml (3-20) and a diagnosis of myxedema associated to galactorrhea was made. A hypothalamic-pituitary magnetic resonance imaging (MRI) showed a suprasellar and intrasellar mass lesion of 1.9 x 1.4 x 1.9 cm, determining compression and deviation of the optic chiasm. Due to the possibility of hyperplasia of the TSH-producing cells, treatment of hypothyroidism was initiated with levothyroxine. Two months later, upon normalization of thyroid hormones and TSH levels, a second MRI showed an anatomically normal pituitary gland. Regression of the pituitary mass after treatment with levothyroxine confirmed the hypothesis of pituitary hyperplasia secondary to primary hypothyroidism. Our findings support the importance of determining thyroid function tests during the investigation of pituitary masses and thus avoiding an unnecessary surgery.

Reactive enlargement of the pituitary gland in primary end organ failure may be indistinguishable from primary pituitary lesions in clinical presentation and on magnetic resonance imaging. The diagnosis of pituitary hyperplasia secondary to end organ failure must be based on endocrinologic investigations. Recognition of this condition and distinguishing it from primary pituitary tumors is important and may eliminate unnecessary surgery.

The physiological importance of and therapeutic interest in dehydroepiandrosterone (DHEA) has been predominantly in relation to its action as an inhibitor of the promotion and progression of several kinds of tumours, including those of breast, prostate, lung, colon, liver and skin tissues. The aim of the present study was to determine the role of DHEA in diethylstilboestrol (DES)-induced pituitary hyperplasia. Female Sprague-Dawley rats were divided into four treatment groups: DES (implanted s.c. with a 20 mg DES pellet), DHEA (two 50 mg DHEA pellets), DHEA/DES (both DHEA and DES pellets), and controls (not implanted). Every week, all rats were weighed and cycled, and jugular blood samples were obtained. After 7 weeks, rats were killed. Hypophyses were removed and weighed, and serum prolactin, GH, IGF-I and leptin levels were assayed by RIA. DHEA cotreatment reduced pituitary enlargement by 39% in DES-treated rats. It also reduced the hyperprolactinaemia (280.4+/-43.6 ng/ml for DHEA/DES vs 823.5+/- 127.1 ng/ml for DES) and partially reversed the loss of body weight induced by DES. DHEA treatment did not modify the effects of DES on serum GH, IGF-I and leptin levels. But DHEA per se also increased pituitary weight and induced hyperprolactinaemia, although to a lesser degree than DES. We conclude that DHEA administration has beneficial effects on oestrogen-induced pituitary hyperplasia and hyperprolactinaemia, but the fact that DHEA per se also induces diverse hormonal effects and a slight pituitary enlargement limits its use as a possible therapeutic drug. Fil: Suárez, Cecilia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Garcia Tornadu, Isabel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Khalil, W.. Lawson Research Institute; Canadá Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

This review emphasizes emerging concepts in regulation of the hypothalamicpituitary-adrenal (HPA) axis. We first discuss relevant physiologic pathways and molecular mechanisms that control the HPA axis. Imbalances at many levels can disrupt HPA axis homeostasis leading to conditions such as Cushing’s syndrome, pituitary hyperplasia, and anxiety disorders. We then describe recently developed animal models with specific alterations in corticotropin pathways. The primary elements of these pathways have been engineered for upregulation, downregulation or deficiency and thus provide a powerful collection of models for studying HPA axis regulation. These models provide new views into features critical for maintaining control of the HPA axis. They have expanded our understanding of the degree of plasticity and compensation that exists within this system. In addition, they reveal novel mechanisms whereby inappropriate or absent regulatory components lead to abnormal endocrine manifestations and behavioral states.

A 23 year old man presented with classical hypothyroidism of 9 years duration. This was associated with pituitary enlargement, documented on magnetic resonance imaging (MRI), and abnormal half-field visual evoked responses (VERs). Following the initiation of thyroxine therapy the pituitary enlargement and the VER abnormalities resolved. The final diagnosis was of primary hypothyroidism with secondary pituitary hyperplasia.

Pituitary hyperplasia consequent to untreated primary hypothyroidism undergoes impressive regression following thyroxine therapy. We describe a young man with primary hypothyroidism and pituitary hyperplasia, who showed significant but incomplete regression of pituitary enlargement despite 18 months of L-thyroxine therapy (1 year in replacement dose (150 micrograms/day) and an additional 6 months in suppressive dose (300 micrograms/day)).

Magnetic resonance imaging of pituitary hyperplasia has been rarely described in children with primary hypothyroidism. We report a case of pituitary hyperplasia in a child presented with significant growth arrest and laboratory evidence of hypothyroidism. Magnetic resonance imaging revealed symmetrical pituitary enlargement simulating macroadenoma. After thyroid hormone replacement therapy, the child's height increased and pituitary enlargement regressed to normal. Awareness of MRI appearance of pituitary hyperplasia in children with laboratory evidence of hypothyroidism might avoid misdiagnosis for pituitary tumor, which may also manifest as growth disorder, obviating unnecessary surgery.

Paciente mujer de 15 años referida por diagnóstico de hipotiroidismo e hiperprolactinemia, con tratamiento irregular para ambas patologías, quien presentó pérdida de conocimiento en dos oportunidades, motivo por el cual se le indicó resonancia magnética (RM) de cerebro, en la cual se evidenció imagen tumoral hipofisaria que desplazaba el quiasma óptico. Se le indicó tratamiento con levotiroxina 50 ug por 1 semana, luego 100 ug diario. Los controles hormonales posteriores mostraron normalización, la RM de control evidenció disminución de tamaño de la imagen tumoral en aproximadamente 3 mm, sin repercusión en las estructuras supraselares o paraselares, con mejoría de cuadro clínico luego del tratamiento de sustitución con hormona tiroidea. A 15 year-old woman with diagnosis of hypothyroidism and hyperprolactinemia had irregular treatment. She lost conscience twice and magnetic resonance (MR) was indicated. It showed image of pituitary tumor that displaced optic chiasm. She was prescribed levothyroxin 50 ug for one week and then 100 ug daily. Hormonal treatment produced normalization of hormonal values and magnetic resonance evidenced 3 mm tumor reduction without supraselar extension.

Objective “The pseudomalabsorption of thyroxine” has been used to describe patients with hypothyroidism who fail to comply with their treatment. We describe a unique case of a 32-year-old with hypothyroidism who developed pituitary hyperplasia and hyperprolactinemia secondary to the pseudomalabsorption of thyroxine. Investigations and treatment After baseline thyroid-function tests were performed, the patient was administered levothyroxine 0.5 mg under the supervision of a registered nurse. Thyroid function testing was repeated at 30, 60, 120, and 180 minutes. Arrangements were made for further daily supervised loading of levothyroxine 0.1 mg. Results With the administration of 0.5 mg levothyroxine, free thyroxine levels increased by 120 minutes, and with daily supervised dosing of 0.1 mg there was normalization of the thyroid hormone levels and a reduction of thyroid-stimulating hormone levels. Maintenance of thyroid-stimulating hormone < 15 mU/L for 2 weeks led to a reduction in prolactin levels and regression in the size of the pituitary on magnetic resonance imaging. Conclusion If left untreated, these patients face significant morbidity and are at risk of developing pituitary hyperplasia, complications from an increase in pituitary size, hyperprolactinemia, and potentially myxedema coma. Recognizing pituitary hyperplasia and hyperprolactinemia as a complication from the pseudomalabsorption of levothyroxine may prevent the potential of a misdiagnosis of a prolactinoma leading to unnecessary investigations and inappropriate treatment. Patient awareness of this serious complication and the rapid, demonstrable resolution with adequate thyroid hormone replacement may provide motivation to comply with supervised dosing of levothyroxine. It has also been suggested that supervised treatment enables the individual to maintain their patient status, which may be in part the motivation behind this disorder.

Pituitary hyperplasia secondary to primary hypothyroidism and subsequent regression following thyroid replacement has been well described. We report a 12 year-old male who was retrospectively found to have progressive pituitary hyperplasia over the course of 2 years prior to his diagnosis of primary hypothyroidism, as documented on annual brain magnetic resonance imaging (MRI) for Arnold Chiari Type 1 malformation. He presented to Endocrinology with a 2-year history of fatigue, worsening daily headaches and linear growth deceleration. The diagnosis of primary hypothyroidism as the cause for his pituitary hyperplasia was made. He was started on levothyroxine with subsequent regression of pituitary hyperplasia demonstrated on repeat brain MRI six months later. This case is the first that demonstrates progressive pituitary hyperplasia from early in the course to diagnosis of hypothyroidism. It also illustrates that pituitary hyperplasia noted on routine brain MRI can be a presenting sign of primary hypothyroidism that should prompt endocrinologic evaluation.