Diagnosis and management of hypopituitarism

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<p>REVIEW</p><p>CURRENT</p><p>OPINION Diagnosis and management of hypopituitarism</p><p>Copyrigh</p><p>1040-8703 Copyright � 2019 Wolte</p><p>Olga Yeliosof and Mariam Gangat</p><p>Purpose of review</p><p>This review summarizes pituitary function, and the clinical presentation and treatment of hypopituitarism.</p><p>Recent findings</p><p>Updates in the field include new guidelines and meta-analyses on the diagnosis and treatment of select</p><p>hormone deficiencies, novel treatment options, and advances in next generation sequencing technology.</p><p>Summary</p><p>Hypopituitarism is defined as partial or complete loss of a single or multiple pituitary hormones. The clinical</p><p>presentation of hypopituitarism varies depending on the number and severity of hormone deficiencies.</p><p>Treatment involves the physiologic replacement of the individual end-organ hormone deficiencies and</p><p>requires close lifelong monitoring.</p><p>Keywords</p><p>growth failure, hypoglycemia, micropenis</p><p>Pediatric Endocrinology, Rutgers-Robert Wood Johnson Medical</p><p>School, New Brunswick, New Jersey, USA</p><p>Correspondence to Olga Yeliosof, MD, Fellow, Pediatric Endocrinology,</p><p>Rutgers-Robert Wood Johnson Medical School, Child Health Institute of</p><p>New Jersey, Rutgers, The State University of New Jersey, 89 French</p><p>Street, New Brunswick, NJ 08901, USA. Tel: +1 732 235 9378;</p><p>e-mail: oy15@rwjms.rutgers.edu</p><p>Curr Opin Pediatr 2019, 31:531–536</p><p>DOI:10.1097/MOP.0000000000000779</p><p>INTRODUCTION</p><p>The pituitary gland located midline in the brain</p><p>within the sella turcica is the central regulator of</p><p>the endocrine system. It consists of two lobes with</p><p>differing embryologic origin. The adenohypophysis</p><p>(anterior and intermediate lobes) develops from</p><p>Rathke’s pouch, an invagination of the oral ectoderm</p><p>whereas the neurohypophysis (posterior lobe) origi-</p><p>nates from the neural ectoderm of the ventral dien-</p><p>cephalon. The development of the pituitary gland is a</p><p>complex orchestrated process requiring sequential,</p><p>temporal, and spatial expression of numerous tran-</p><p>scription factors and signaling molecules.</p><p>The anterior lobe consists of five cell lineages</p><p>resulting in the production of six hormones: soma-</p><p>totrophs (growth hormone), thyrotrophs (thyroid</p><p>stimulating hormone, TSH), lactotrophs (prolactin,</p><p>PRL), gonadotrophs (luteinizing hormone, and fol-</p><p>licle stimulating hormone, FSH) and corticotrophs</p><p>(adrenocorticotropic hormone, ACTH). The poste-</p><p>rior lobe contains axons of neurons, the cell bodies</p><p>of which are located in the hypothalamus and are</p><p>responsible for the secretion of arginine vasopressin</p><p>(AVP) and oxytocin. The intermediate lobe contains</p><p>melanotrophs, which release pro-opiomelanocortin</p><p>(POMC).</p><p>Hypopituitarism is defined as partial or com-</p><p>plete loss of a single or multiple pituitary hormones</p><p>from the anterior or posterior pituitary [1], whereas</p><p>the term panhypopituitarism is used when all pitui-</p><p>tary hormones are affected. The reported incidence</p><p>t © 2019 Wolters Kluwe</p><p>rs Kluwer Health, Inc. All rights rese</p><p>of hypopituitarism is estimated to be 4.2 per 100 000</p><p>per year and prevalence 45.5 per 100 000 [2].</p><p>The etiology of hypopituitarism can be broadly</p><p>divided into congenital and acquired causes. Con-</p><p>genital hypopituitarism can be associated with struc-</p><p>tural pituitary abnormalities and other midline and</p><p>craniofacial defects, such as cleft lip and/or palate.</p><p>Acquired hypopituitarism can result from any insult</p><p>to the pituitary including tumor mass effect, infec-</p><p>tion, autoimmune disease, infiltrative disease, che-</p><p>motherapy and radiation exposure as well as trauma.</p><p>The clinical presentation of hypopituitarism</p><p>varies considerably depending on the number and</p><p>severity of hormone deficiencies. Individual hor-</p><p>mone deficiencies are discussed in detail in the fol-</p><p>lowing section with the exception of prolactin, as the</p><p>only specific physical finding associated with prolac-</p><p>tin deficiency is puerperal alactogenesis, and there is</p><p>no commercially available treatment for this defi-</p><p>ciency at this time. Table 1 summarizes key present-</p><p>ing features of individual hormone deficiencies.</p><p>r Health, Inc. All rights reserved.</p><p>rved. www.co-pediatrics.com</p><p>mailto:oy15@rwjms.rutgers.edu</p><p>KEY POINTS</p><p>� The pituitary gland is responsible for the production of</p><p>multiple hormones that play a crucial role in growth,</p><p>metabolism, puberty and reproduction, lactation, and</p><p>stress response.</p><p>� Hypopituitarism, the partial or complete loss of a single</p><p>or multiple pituitary hormones has a varied clinical</p><p>presentation depending on the number and severity of</p><p>hormone deficiencies.</p><p>� Treatment involves the physiologic replacement of the</p><p>individual end-organ hormone deficiencies and requires</p><p>close lifelong monitoring.</p><p>Endocrinology and metabolism</p><p>The presence of clinical features suggestive of</p><p>hypopituitarism warrants prompt further investiga-</p><p>tion including a thorough clinical history and phys-</p><p>ical examination, baseline biochemical testing</p><p>followed by appropriate stimulation testing if</p><p>needed, and MRI of the brain and pituitary with</p><p>and without contrast. Genetic testing should</p><p>be considered.</p><p>ANTERIOR PITUITARY</p><p>Growth hormone deficiency</p><p>Growth hormone is the most commonly affected</p><p>pituitary hormone in childhood [3]. Key features of</p><p>congenital growth hormone deficiency (GHD)</p><p>include hypoglycemia and microphallus. It is impor-</p><p>tant to note that GHD does not affect fetal growth,</p><p>and therefore, affected newborns are of normal</p><p>weight and length at birth, and demonstrate growth</p><p>failure postnatally [4]. GHD should be suspected in a</p><p>Copyright © 2019 Wolters Kluwer H</p><p>Table 1. Common signs and symptoms associated with hypopitu</p><p>Hormone deficiency Signs and symptoms</p><p>Growth hormone (GH) Neonate: hypoglycemia, mi</p><p>Older child: short stature, de</p><p>Thyrotropin (TSH) Neonates: coarse facial fea</p><p>hernia, hoarse cry, myxed</p><p>Older child: fatigue, dry skin</p><p>Adrenocorticotropic</p><p>hormone (ACTH)</p><p>Neonates: failure to thrive, h</p><p>Older child: fatigue, weight</p><p>Adrenal crisis: hypotension</p><p>Luteinizing hormone (LH),</p><p>follicle stimulating hormone (FSH)</p><p>Neonate: micropenis, crypto</p><p>Older child: absent puberta</p><p>boys) with lack of puberta</p><p>Arginine vasopressin (AVP) Neonate: vigorous suck, vom</p><p>crying, irritability, weight</p><p>Younger children: primary e</p><p>Older children: disturbed sle</p><p>532 www.co-pediatrics.com</p><p>child who has a reduced height velocity, low-serum</p><p>levels of insulin-like growth factor-1 (IGF-1) and</p><p>insulin-like growth factor-binding protein-3</p><p>(IGFBP-3), key surrogate markers of growth hormone,</p><p>along with delayed skeletal maturation assessed by</p><p>bone age X-ray imaging. IGF-1 levels should be cau-</p><p>tiously interpreted in certain groups of children</p><p>including age less than 6 years, those affected by</p><p>malnutrition as well as patients with suspected irra-</p><p>diation-dependent GHD [5</p><p>&</p><p>]. Direct assessment of</p><p>random growth hormone levels is not useful as</p><p>growth hormone is released in a pulsatile manner,</p><p>and therefore although controversial, the diagnosis</p><p>of GHD often includes growth hormone stimulation</p><p>testing using a variety of pharmacologic agents. One</p><p>study reported 11 different tests [6]; however, none</p><p>have been shown to accurately mimic physiologic</p><p>growth hormone secretion accurately. The most</p><p>recently devised test uses macimorelin, an orally</p><p>active growth hormone secretagogue, and is cur-</p><p>rently used in adults [7</p><p>&</p><p>]. In pediatrics, most proto-</p><p>cols include two different stimulatory agents, and</p><p>guidelines recommend sex steroid priming prior to</p><p>provocative testing in prepubertal girls older than</p><p>10 years and prepubertal boys older than 11 years to</p><p>reduce unnecessary growth hormone treatment of</p><p>children with constitutional delay of growth and</p><p>puberty (CDGP) [8]. In clinical practice, some clini-</p><p>cians advocate priming at a younger age. GHD is</p><p>defined by an arbitrary peak growth hormone level</p><p>of less than 10 ng/ml [9], a cutoff that has increased</p><p>concurrently with the production of recombinant</p><p>human GH (rhGH), and should not be used as the</p><p>sole diagnostic criterion of GHD [8].</p><p>Early recognition and treatment of GHD with</p><p>subcutaneous daily rhGH injections is important in</p><p>achieving the greatest</p><p>growth response. The initial</p><p>ealth, Inc. All rights reserved.</p><p>itarism</p><p>cropenis, prolonged jaundice</p><p>creased height velocity, reduction in lean body mass and excess fat</p><p>tures, hypotonia, hypothermia, protuberant abdomen, umbilical</p><p>ema, large anterior fontanelle</p><p>, growth failure, constipation, excessive weight gain, bradycardia</p><p>ypoglycemia, seizures, cholestatic jaundice</p><p>loss, hypotension, nausea, vomiting, hypoglycemia</p><p>and cardiac instability</p><p>rchidism</p><p>l development (breast development in girls, testicular enlargement in</p><p>l growth spurt</p><p>iting, recurrent episodes of fever without apparent cause, excessive</p><p>loss, constipation, excessively wet diapers</p><p>nuresis, difficulty in toilet training</p><p>ep, easy fatigability</p><p>Volume 31 � Number 4 � August 2019</p><p>Diagnosis and management of hypopituitarism Yeliosof and Gangat</p><p>recommended dose is 0.16–0.24 mg/kg/week,</p><p>administered in the evening to mimic physiologic</p><p>growth hormone release [8]. Subsequent dosing</p><p>should be individualized by monitoring height</p><p>velocity and IGF-1 levels, and treatment should be</p><p>discontinued when the growth velocity falls below</p><p>2–2.5 cm/year [8]. Although growth hormone treat-</p><p>ment is generally considered well tolerated, adverse</p><p>effects must be discussed prior to initiation of ther-</p><p>apy (Table 2). Patients should be monitored for</p><p>hypothyroidism and adrenal insufficiency as</p><p>growth hormone treatment increases metabolism</p><p>of thyroid hormone and cortisol, and therefore</p><p>may unmask these conditions [8].</p><p>Adherence to daily injections can be challeng-</p><p>ing, therefore, long-acting growth hormone agents</p><p>are under clinical investigation, however, not cur-</p><p>rently available in the United States [10].</p><p>Adrenocorticotropic hormone insufficiency</p><p>Central adrenal insufficiency (CAI) is characterized</p><p>by inappropriate ACTH secretion resulting in abnor-</p><p>mal adrenal cortisol production. CAI differs from</p><p>primary adrenal insufficiency (PAI) or Addison’s</p><p>disease with respect to mineralocorticoid secretion,</p><p>which is intact in CAI. However, hyponatremia can</p><p>be seen in CAI as glucocorticoids are required for</p><p>appropriate free water clearance.</p><p>Once the diurnal pattern of glucocorticoid pro-</p><p>duction with a peak value around 8.00 a.m. has been</p><p>established, at approximately 6 months of age [11],</p><p>Copyright © 2019 Wolters Kluwe</p><p>Table 2. Potential adverse effects of growth hormone treatment</p><p>Idiopathic intracranial</p><p>hypertension (IIH)</p><p>Due to physiological antidiu</p><p>Generally occurs shortly afte</p><p>discontinuation of growth</p><p>Slipped capital femoral</p><p>epiphysis (SCFE)</p><p>Should be considered in chi</p><p>Surgical treatment involves s</p><p>Insulin resistance / type</p><p>2 diabetes</p><p>Growth hormone antagoniz</p><p>glycogenolysis and lipolys</p><p>Progression of preexisting</p><p>scoliosis</p><p>More frequent in patients wi</p><p>syndrome) [8]</p><p>Risk for neoplasm For children not considered</p><p>risk</p><p>In childhood cancer survivor</p><p>2016 Guidelines: 12-month</p><p>of ongoing tumor is reaso</p><p>hormone treatment [8]</p><p>2018 meta-analysis: growth</p><p>secondary tumors, althoug</p><p>current evidence [30&&]</p><p>Other potential adverse effects Edema</p><p>Carpal tunnel syndrome</p><p>Muscular pain</p><p>Data from [28,29].</p><p>1040-8703 Copyright � 2019 Wolters Kluwer Health, Inc. All rights rese</p><p>initial testing should include early morning fasting</p><p>serum cortisol and ACTH levels. Low cortisol levels</p><p>along with low or inappropriately normal ACTH</p><p>levels are seen in CAI. A cortisol level below 3 mg/</p><p>dl is indicative of adrenal insufficiency whereas a</p><p>value greater than 13 mg/dl makes the diagnosis</p><p>unlikely [12</p><p>&&</p><p>]. Often, the early morning cortisol</p><p>level falls in an intermediate range, requiring</p><p>dynamic testing. Cosyntropin (synthetic ACTH)</p><p>stimulation testing is commonly used to directly</p><p>stimulate adrenal cortisol release at a standard dose</p><p>of 250 mg. A stimulated cortisol level at least 18 mg/dl</p><p>along with a normal baseline ACTH level makes the</p><p>diagnosis of adrenal insufficiency unlikely [13]. To</p><p>evaluate mild forms or recent onset CAI, testing</p><p>with 1 mg of cosyntropin was devised. However,</p><p>meta-analysis of 30 studies concluded both tests</p><p>had similar diagnostic accuracy [14].</p><p>In children with CAI, cortisol replacement is</p><p>typically initiated using hydrocortisone as it has less</p><p>suppressive effects on growth compared with more</p><p>potent longer acting glucocorticosteroids, such as</p><p>dexamethasone and prednisone [15</p><p>&</p><p>]. Patients with</p><p>CAI require lower physiologic replacement doses</p><p>around 7–9 mg/m2/day divided three times a day,</p><p>with the highest dose given in the morning [16].</p><p>Hydrocortisone tablets are recommended as there</p><p>have been reports of variable dose accuracy in com-</p><p>pounded preparations [17</p><p>&&</p><p>]. Treatment must be</p><p>individualized with the goal of controlling the</p><p>symptoms of adrenal insufficiency with the lowest</p><p>dose possible, and minimizing side effects [15</p><p>&</p><p>].</p><p>r Health, Inc. All rights reserved.</p><p>retic effect of rhGH</p><p>r treatment initiation or dose increase and usually resolves with</p><p>hormone therapy</p><p>ldren complaining of unilateral or bilateral pain in the hips or knees</p><p>crew fixation</p><p>es insulin effects in glucose and lipid metabolism by stimulating</p><p>is inducing insulin resistance</p><p>th a higher baseline incidence (Turner syndrome, Prader–Willi</p><p>to be at risk, current evidence does not support increased cancer</p><p>s:</p><p>waiting period after completion of tumor therapy with no evidence</p><p>nable to establish ‘successful therapy’ prior to initiating growth</p><p>hormone treatment does not appear to increase the risk of</p><p>h close monitoring remains warranted because of uncertainty in the</p><p>rved. www.co-pediatrics.com 533</p><p>Table 3. Levo thyrox ine dose and moni to r ing</p><p>recommendations</p><p>Age</p><p>Daily weight-</p><p>based dose</p><p>Frequency of</p><p>monitoring</p><p>0–12 months 10–15 mg/kg Every 1–3 months</p><p>1–5 years 4–6 mg/kg Every 3–6 months</p><p>6–12 years 3–5 mg/kg Every 6–12 months</p><p>>12 years 2–3 mg/kg Every 6–12 months</p><p>Data from [16].</p><p>Endocrinology and metabolism</p><p>There is no biochemical test available to assess the</p><p>adequacy of replacement, therefore, careful moni-</p><p>toring of symptoms and growth is required, and the</p><p>hydrocortisone dose should be decreased if exces-</p><p>sive weight gain or linear growth suppression is</p><p>seen. Medication interactions need to be monitored,</p><p>especially those affecting CYP3A4 activity [18]. Nor-</p><p>mally, cortisol secretion increases in response to</p><p>stressful conditions, such as critical illness, surgery,</p><p>or trauma, and patients must be educated on ‘stress</p><p>dosing’ ranging from 2 to 10 times the maintenance</p><p>dose based on severity, and a medic alert identifier</p><p>should be worn.</p><p>Novel treatments aimed at mimicking physio-</p><p>logic cortisol secretion include continuous subcuta-</p><p>neous hydrocortisone infusion therapy and</p><p>sustained release hydrocortisone preparations [15</p><p>&</p><p>].</p><p>These therapies are discussed by Khattab et al. in the</p><p>chapter on congenital adrenal hyperplasia.</p><p>Thyroid stimulating hormone deficiency</p><p>Central hypothyroidism characterized by a defect in</p><p>thyroid hormone production because of insufficient</p><p>TSH stimulation is uncommon, accounting for less</p><p>than 1% of all causes of hypothyroidism [5</p><p>&</p><p>]. In</p><p>central hypothyroidism, the serum free T4 level is</p><p>low; however, TSH can be low, inappropriately nor-</p><p>mal or even slightly elevated [19]. Timely and ade-</p><p>quate levothyroxine (LT4) treatment is critical for</p><p>normal neurodevelopment in the first 3 years of life.</p><p>However, adrenal insufficiency must be excluded</p><p>first as LT4 treatment increases basal metabolic rate</p><p>and enhances cortisol clearance, and therefore, may</p><p>precipitate an adrenal crisis.</p><p>LT4 tablets are the treatment of choice [20]</p><p>whereas synthetic forms of triiodothyronine (T3)</p><p>or natural desiccated thyroid should not be used.</p><p>A levothyroxine oral solution [21] was approved by</p><p>the Food and Drug Administration (FDA) in 2016,</p><p>however, only recently become available in phar-</p><p>macies, and data in pediatrics is limited. Only free</p><p>T4 levels are needed for monitoring, with the goal of</p><p>maintaining the value in the upper half of the</p><p>normal range. Infants need close monitoring with</p><p>labs at 2 and 4 weeks after treatment initiation, with</p><p>gradual spacing of monitoring</p><p>intervals. Table 3 lists</p><p>the appropriate doses of levothyroxine and moni-</p><p>toring intervals by age [16].</p><p>Gonadotropin deficiency</p><p>Congenital hypogonadotropic hypogonadism</p><p>(CHH) can be evaluated in early infancy by lack of</p><p>the postnatal rise of gonadotropin and sex steroids</p><p>during ‘mini-puberty,’ which lasts up to 6 months of</p><p>Copyright © 2019 Wolters Kluwer H</p><p>534 www.co-pediatrics.com</p><p>age in boys and 2 years in girls [22]. After this</p><p>window of opportunity, testing can be done during</p><p>the normal age of puberty and should be performed</p><p>early morning using highly sensitive assays. Low sex</p><p>steroid levels with low or inappropriately normal</p><p>gonadotropin values are seen, however, distinguish-</p><p>ing patients with CHH from those with CDGP</p><p>is challenging.</p><p>In newborn male infants, treatment is focused</p><p>on appropriate testicular descent and penile growth.</p><p>Surgical correction of cryptorchidism at 6–12</p><p>months of age is recommended [23]. Three intra-</p><p>muscular injections of a long-acting testosterone</p><p>ester at a dose of 25 mg should be given monthly,</p><p>followed by another three doses if a satisfactory</p><p>increase in penile length (>0.9 cm) has not</p><p>occurred [22].</p><p>During adolescence, the short-term goals of</p><p>treatment include induction of age-appropriate sec-</p><p>ondary sexual characteristics and height accelera-</p><p>tion, whereas at the same time avoiding premature</p><p>epiphyseal plate closure [16]. Sex steroid therapy is</p><p>initiated around the mean age of onset of pubertal</p><p>development (age 10 years in girls, 11–12 years in</p><p>boys) [16]. In males, testosterone is commonly ini-</p><p>tiated with a long-acting ester at a starting dose of</p><p>50 mg every 4 weeks with gradual dose increases</p><p>until adult dosing is achieved. Oral as well as trans-</p><p>cutaneous testosterone preparations are available,</p><p>and may be more commonly used for pubertal</p><p>induction with increased data in pediatrics.</p><p>In girls, estrogen is available in oral and trans-</p><p>cutaneous forms, with the latter being the preferred</p><p>method as it bypasses first-pass hepatic metabolism</p><p>and has a more favorable side effect profile. The</p><p>typical starting dose of 6.25 mg/day requires cutting</p><p>a matrix patch, and although this lacks manufac-</p><p>turer support, it is common practice in clinical care.</p><p>The dose is gradually increased for appropriate</p><p>breast and uterine development, linear growth,</p><p>and skeletal health maintenance. Cyclic progester-</p><p>one is added with breakthrough vaginal bleeding or</p><p>2 years after the initiation of estrogen therapy.</p><p>ealth, Inc. All rights reserved.</p><p>Volume 31 � Number 4 � August 2019</p><p>Diagnosis and management of hypopituitarism Yeliosof and Gangat</p><p>Fertility, an important yet often overlooked</p><p>topic in pediatrics, should be discussed early</p><p>[24</p><p>&&</p><p>], and information on alternative fertility-</p><p>inducing treatments, such as pulsatile gonadotro-</p><p>pin-releasing hormone or gonadotropin therapy</p><p>should be made available to patients and families.</p><p>It is also important to note that spontaneous recov-</p><p>ery of reproductive function has been reported in</p><p>10–20% of patients with CHH [23].</p><p>Posterior pituitary</p><p>Arginine vasopressin deficiency</p><p>Central diabetes insipidus is characterized by the</p><p>inability to concentrate urine secondary to AVP defi-</p><p>ciency. Polyuria, defined as urine output greater than</p><p>4 ml/kg/h in children (6 ml/kg/h in neonates), and</p><p>polydipsia as well as growth failure are the primary</p><p>clinical features, however, the presentation can vary</p><p>in different age groups depending on the ability to</p><p>replenish water (Table 1) [25]. Once polyuria has been</p><p>established with an accurate 24-h urine collection, a</p><p>first morning urine analysis and biochemistry should</p><p>be done to rule out solute diuresis and to exclude</p><p>other causes of polyuria. In patients with suspected</p><p>diabetes insipidus, early morning labs showing</p><p>dilute urine (osmolality <300 mosm/kg), elevated</p><p>serum osmolality (>300 mosm/kg), and sodium level</p><p>(>150 meq/l), makes the diagnosis of diabetes insip-</p><p>idus likely. However, a water deprivation test may be</p><p>required if the diagnosis is unclear.</p><p>Adequate free water intake is the first line treat-</p><p>ment for all patients, and this alone can lead to</p><p>appropriate regulation of plasma osmolality in those</p><p>with an intact thirst mechanism. However, excessive</p><p>fluid intake is inconvenient and may lead to compli-</p><p>cations, such as hydronephrosis and fluorosis (in</p><p>areas that provide fluorinated water), and therefore</p><p>most patients with chronic diabetes insipidus are</p><p>treated with desmopressin (dDAVP), a synthetic vaso-</p><p>pressin analog. Desmopressin is available as a liquid</p><p>that can be administered intranasally, oral tablet,</p><p>sublingual (melt), and parenteral formulations. Oral</p><p>is the preferred route in older children [26], and</p><p>because of individual differences in duration of</p><p>action, a bedtime starting dose with titration of dose</p><p>and frequency based on response is recommended.</p><p>Infants as well as patients with an impaired</p><p>thirst mechanism are particularly challenging to</p><p>manage, and require close monitoring of sodium</p><p>levels and daily intake and output. In infants, the</p><p>addition of vasopressin to the obligatory high fluid</p><p>requirement can lead to water intoxication and</p><p>hyponatremia. Therefore, fluid management with</p><p>the use of breast milk or low-solute formula is the</p><p>Copyright © 2019 Wolters Kluwe</p><p>1040-8703 Copyright � 2019 Wolters Kluwer Health, Inc. All rights rese</p><p>preferred initial treatment. Thiazide diuretics may</p><p>be needed to increase urine osmolality and further</p><p>reduce urine output [27</p><p>&&</p><p>]. Chlorothiazide is avail-</p><p>able in liquid form, and is used at a dose 5–10 mg/</p><p>kg/day, divided two to three times daily. Serum</p><p>electrolytes should be monitored as side effects</p><p>may include hypokalemia and hypercalcemia. If</p><p>desmopressin therapy is required, the subcutaneous</p><p>route is preferred in infants and young children.</p><p>Once transitioned to primarily solid food, thiazide</p><p>treatment is less efficacious with increased solute</p><p>load, and DDAVP treatment should be initiated [26].</p><p>Postoperative management of diabetes insipidus</p><p>is complicated and requires special attention and</p><p>additional management strategies.</p><p>CONCLUSION</p><p>The clinical presentation of hypopituitarism can vary</p><p>from alarming red flags, such as micropenis and</p><p>hypoglycemia at birth to more subtle growth failure</p><p>later in life. The diagnosis requires careful interpreta-</p><p>tion of laboratory results as measured pituitary hor-</p><p>mone values may be inappropriately normal in the</p><p>setting of end-organ hormone deficiencies. MRI</p><p>imaging of the brain with pituitary focus is required</p><p>to evaluate for structural abnormalities. The presence</p><p>of one pituitary hormone deficit warrants ongoing</p><p>thorough assessments of additional pituitary defi-</p><p>ciencies. Hypopituitarism is an evolving, lifelong</p><p>condition, and therefore ensuring appropriate tran-</p><p>sition of care is essential. Advances in next-genera-</p><p>tion sequencing technology is widening our</p><p>understanding of the complex molecular basis of</p><p>congenital hypopituitarism and has the potential</p><p>of transforming clinical care in the near future.</p><p>Acknowledgements</p><p>None.</p><p>Financial support and sponsorship</p><p>None.</p><p>Conflicts of interest</p><p>There are no conflicts of interest.</p><p>REFERENCES AND RECOMMENDED</p><p>READING</p><p>Papers of particular interest, published within the annual period of review, have</p><p>been highlighted as:</p><p>& of special interest</p><p>&& of outstanding interest</p><p>1. Romero CJ, Nesi-Franca S, Radovick S. The molecular basis of hypopituitar-</p><p>ism. Trends Endocrinol Metab 2009; 20:506–516.</p><p>2. Webb EA, Dattani MT. Understanding hypopituitarism. Paediatr Child Health</p><p>2011; 21:289–294.</p><p>3. Geffner ME. Hypopituitarism in childhood. Cancer Control 2002;</p><p>9:212–222.</p><p>r Health, Inc. 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