Congenital

Formation of the normal pituitary during embryonic development depends on the juxtaposition of cells of neuroectodermal origin, which form the posterior pituitary, and endodermal cells derived from the primitive stomodeum, which form the anterior pituitary. Congenital forms of hypopituitarism are best considered as being derived either from hypothalamic or pituitary origin. Defects of RPX/HESX1, PROP1, and PIT1 are associated with varying degrees of inherited hypopituitarism in humans (1). Autosomal dominant mutations of the arginine vasopressin-neurophysin II gene give rise to familial antidiuretic hormone (ADH) deficiency (central diabetes insipidus, CDI). Congenital combined pituitary hormone deficiency (CPHD) (or multiple pituitary hormone deficiency (MPHD)) may be associated with hypoplasia of the anterior pituitary and ectopic siting of the posterior pituitary in a superior position. The underlying mechanism for this condition, once thought to be a consequence of birth trauma, remains undetermined but a congenital molecular defect is likely. Furthermore, since some genetic mutations affect early development, they may include extra-pituitary features or midline anomalies as a part of a syndrome. For instance, the transcription factors, including HESX1, SOX2, SOX3, and OTX2, are the most common genes involved in the etiology of septo-optic dysplasia. Hypogonadotropic hypogonadism is a recognized feature of both Prader-Willi and Bardet-Biedl syndromes. The salient features of the currently described transcription factor defects are indicated below.

Tumors

Pituitary adenomas are the most common cause of adult-onset hypopituitarism (18,19). Craniopharyngiomas are numerically the next most prevalent and may present as sellar and/or suprasellar masses.

Vascular Causes

The term pituitary apoplexy denotes the clinical consequences of hemorrhage or infarction in a pre-existing adenoma. The expansion of pituitary mass to neighboring cranial nerves, cavernous sinus, optic pathways, or diencephalon results in localizing signs or altered conscious state. It frequently manifests as a sudden onset of severe headache, a visual disturbance, or ophthalmoplegia as a result of cranial nerve III IV or VI palsies (29). The clinical syndrome of pituitary apoplexy usually evolves fully within only hours to two days. The incidence of surgically treated pituitary adenomas ranges from 0.6 to 9.1%, (30) with a broad age range of occurrence from the first to the ninth decade. Although apoplexy usually occurs spontaneously, systolic and/or diastolic hypertension was seen in 26% of patient in a retrospective analysis, making it an important predisposing factor. (31). Other reported predisposing factors include diabetes mellitus, radiation therapy, anticoagulant therapy, bleeding disorders, head trauma, sudden changes in arterial or intracranial pressure, such as during carotid angiography, the use of bromocriptine, and postpartum hemorrhage (Sheehan's syndrome). Sheehan's syndrome, which denotes pituitary necrosis after postpartum hemorrhage and hypovolemia, may result in hypopituitarism, that is either immediate or delayed over several years depending on the extent of tissue destruction. However, this condition is rare with modern obstetric care (32).

Suprasellar or intrasellar aneurysms of the carotid arteries, as well as suprasellar aneurysms of the anterior or posterior communicating arteries can manifest as an expanding mass inside the fossa. Hypopituitarism may result directly from intrasellar aneurysms. Histologically, typical degenerative sclerotic changes of the arterial wall are found along with chronic inflammatory changes. An arteriovenous fistula may occasionally develop in the cavernous sinus as a result of an aneurysm.

Immunological/Inflammatory Disease

Inflammatory lesions of the pituitary gland can clinically and radiologically mimic pituitary tumors, with varying degrees of hypopituitarism and mass effects like headaches and visual field impairment.

Lymphocytic hypophysitis classically presents as partial hypopituitarism associated with a pituitary mass lesion, particularly in relation to pregnancy (33). It has been speculated that many cases of postpartum pituitary failure, previously attributed to Sheehan's syndrome, may in fact have been caused by lymphocytic hypophysitis (34,35). In this condition, the interstitial tissue of the adenohypophysis is more or less densely infiltrated by lymphocytes and plasma cells. As a result, the anterior pituitary exhibits necrosis and subsequent fibrosis of hormone-producing cells. Since the histological findings are similar to those of other organ-specific autoimmune diseases, the primary etiology is considered to be autoimmune (36,37). Partial hypopituitarism, commonly with isolated ACTH deficiency, or with TSH deficiency, is seen in approximately 80% of patients, with LH and FSH generally remaining unaffected.

Sarcoidosis is a multisystem disorder, which is characterized by the presence of non-caseating granulomas. It most often affects lungs and reticuloendothelial system but can involve any organ. Central nervous system sarcoidosis occurs with an incidence of 5-15% (38,39) and less than 1% of patients have symptoms of a hypothalamic-pituitary disease (40). Neurosarcoidosis affects primarily the leptomeninges of the brain base and posterior fossa; the hypothalamus and/or pituitary subsequently experience local granulomatous infiltration. Coexisting optic nerve infiltration occurs in many patients causing central and peripheral visual defects. In terms of anterior pituitary function, LH, FSH and GH deficiency are frequent, but TSH and ACTH are relatively preserved.

Langerhans cell histiocytosis is a rare disease characterized by aberrant proliferation of a specific dendritic (Langerhans) cell belonging to the monocyte-macrophage system (41). Deposits occur at multiple sites within the body, and frequently involve the hypothalamo-pituitary axis (42). Diabetes insipidus is a well-recognized and common feature of this condition but anterior pituitary dysfunction also occurs frequently.

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor, a IgG1 monoclonal antibody against CTLA-4 is used for metastatic melanoma and other neoplasms. As a consequence of immune activation, secondary hypophysitis has been reported in 10-15% of ipilimumab treated patients (36). In severe hypophysitis, immune reactions induced extensive necrosis of the adenohypophyseal architecture. Pituitary autoantibodies against thyrotrophs, corticotrophs, and gonadotrophs were identified in patients with ipilimumab induced hypophysitis (37). Patients usually present with headache and fatigue, the diagnosis of hypopituitarism with multiple deficiencies is made 2-3 months or later after initiation of ipilimumab. Central hypothyroidism is the most frequent deficit, followed by central hypocortisolism, and hypogonadism.

Infections

Bacterial pituitary sepsis is a rare phenomenon which may arise as a consequence of hematogenous spread or by extension from sinus or meningeal sepsis with subsequent pituitary abscess formation. Small pituitary abscesses have been described at postmortem in patients dying from septicemia. Chronic infection predisposes to necrosis of pituitary tissue with subsequent hypopituitarism. Pituitary tuberculomas may present as space occupying lesions (43) but this appears to be a very rare phenomenon; isolated manifestation of the disease is rare and it is more likely to occur in the context of generalized tuberculous infection with meningitis. Gumma formation, as a manifestation of tertiary syphilis, may occur in the sella region but is extremely rare.

Fungal pituitary infection may occur as a complication of AIDS (44) and pituitary necrosis with hypopituitarism has been described in toxoplasmosis (45).

Radiation Therapy

Hypopituitarism is a common complication of irradiation administered for pituitary adenomas, head and neck tumors, intracranial malignancy, or as adjunctive cranial irradiation for acute lymphoblastic leukemia. Although fractionated radiotherapy with daily doses of <200cGy is well tolerated and safe in terms of neurological sequelae, the majority of patients who have undergone external irradiation will manifest some degree of pituitary failure during long term follow up. In general, this is a relatively late complication and is rarely evident in less than 3 years in patients with completely normal baseline pituitary function. Growth hormone reserve is particularly susceptible and is progressively more likely with time so that periodic assessment of residual pituitary function is mandatory; a five year follow up study after external pituitary irradiation therapy reported, 100% GH deficiency, 91% LH-FSH deficiency, 77% ACTH deficiency and 42% TSH deficiency (46).

Traumatic Brain Injury

Traumatic brain injury (TBI) is common, the prevalence of endocrine dysfunction in these patients ranges from 15-68% (47), with estimated annual incidence 30 patients per 100,000 population per year. Abnormal axes during the acute phase of injury may recover over time, but other pituitary hormone deficits may evolve later even at 6 months after the initial insult. A prospective longitudinal study looking at patients with severe TBI, found that 6% of their patients had proven severe GHD when evaluated after 12 months (48). Multiple pituitary deficiencies or isolated pituitary deficiencies (TSH or ACTH) were very rare.

Empty Sella Syndrome

An enlarged empty sella may be primary (due to a congenital diaphragmatic defect) or secondary to surgery, radiation, or pituitary infarction. The majority of patients with congenital empty sella have normal pituitary function. Hypopituitarism (and/or hyperprolactinemia) may be found in instances due to previous pituitary disease. Occasionally, a cystic pituitary mass may simulate an empty sella on CT or MRI, necessitating a cisternogram for precise delineation.

Growth Hormone Deficiency

GH deficiency (GHD) in adults is characterized by decreased exercise tolerance, decreased mood and general well-being, decreased quality of life, central adiposity, hyperlipidemia, increased predisposition to atherogenesis, and reduced bone remodeling activity. Fine facial wrinkles may result from a deficiency of growth hormone in addition to hypogonadism. The patient will usually have dry thin skin which contrasts with the thickened skin and increased sweating found in acromegaly. Adults with long-standing GHD are often overweight, have reduced lean body mass, increased fat mass, especially visceral fat, relative insulin resistance, and reduced total bone mass. There is a reduction in cardiac and physical performance. GHD is associated with increases in total cholesterol, LDL-cholesterol and apolipoprotein B (49-51). Studies in Sweden and the UK in patients with hypopituitarism receiving controlled thyroid and steroid hormone replacement but without growth hormone replacement, have demonstrated an approximately two fold increase in cardiovascular mortality compared to the general population. (51) and the increase in standardized mortality ratio is more striking in females (52).

The accumulating evidence suggests that the cardiovascular morbidity cannot be explained solely by suboptimal glucocorticoid, gonadal steroid, or thyroid hormone replacement and unsubstituted growth hormone deficiency is probably an important contributing factor. The decreased bone mineral density found in GHD is associated with increased fracture risk (53).

Adrenocorticotrophic Hormone Deficiency

Cortisol and adrenal androgen secretion are ACTH-dependent and are variably decreased in hypopituitarism. Patients with combined ACTH and LH deficiency are completely androgen deficient, a phenomenon that may be particularly important when considering optimum regimens for gonadal steroid replacement in females. Since aldosterone secretion is largely determined by activation of the renin-angiotensin-aldosterone system, it is relatively preserved in the hypopituitary patients. Major symptoms of ACTH deficiency are non-specific, including fatigue, weakness, headache, anorexia, weight loss, nausea, vomiting, abdominal pain, myalgia, and decreased concentration. Hypoglycemia may be present at diagnosis. Hyponatremia is common and is attributable to reduced renal free water clearance as a result of cortisol deficiency with an additional contribution from TSH deficiency if present. Hyperkalemia, which is a frequent finding in primary adrenal failure, does not occur in patients with hypopituitarism due to the relative preservation of aldosterone secretion. Over and above the effects of secondary hypogonadism, reduced adrenal androgen production further exacerbates loss of body hair, particularly in women.

Gonadotrophin Deficiency

Gonadotrophins are responsible for gonadal sex-steroid production, secondary sexual development, maintenance of secondary sexual characteristics, and fertility.

Gonadotrophin deficiency in males’ results in secondary hypogonadism with consequent testosterone deficiency. Clinical features include loss of libido, erectile impotence, oligospermia, reduced erythropoiesis, and decreased lean body mass. Testosterone, via estradiol derived by aromatization, plays an important role in the regulation of bone mineralization, therefore, hypogonadism results in decreased bone mineral density.

Clinical features of secondary hypogonadism in females include oligo/amenorrhea, breast atrophy, diminished secondary sexual hair especially when combined with ACTH deficiency, and a predisposition to osteoporosis.

Thyroid Stimulating Hormone Deficiency

The clinical features of secondary thyroid failure are similar to those of primary thyroid failure with the exception that weight gain is less likely to be a feature if ACTH deficiency is also present. Classical features include cold intolerance, fatigue, and myalgia. Physical examination may demonstrate periorbital edema and delayed reflex relaxation. Additionally, hyponatremia and normochromic normocytic anemia are observed, with the former being exacerbated by cortisol deficit while the latter is aggravated by secondary hypogonadism and GH deficiency.

Prolactin Deficiency

Prolactin deficiency in females result in puerperal alactogenesis, However, isolated prolactin deficiency is uncommon because the great majority of prolactin deficiency states develop as a result of general anterior pituitary problems or as a result of treatment intervention. On the other hand, hyperprolactinemia, which is caused by stalk disruption and results in a lack of dopaminergic regulation from the hypothalamus, is more frequent and can manifest as galactorrhea, abnormal menstruation, loss of libido, and decreased bone density.

Antidiuretic Hormone Deficiency

Antidiuretic Hormone Deficiency (AHD) previously called central diabetes insipidus (CDI) is characterized by polyuria and polydipsia due to decreased secretion of antidiuretic hormone by the neurosecretory cells terminating in the posterior pituitary. If excessive water excretion exceeds intake, patients will progressively become water-depleted and eventually have a reduction in circulating volume. It occurs more frequently in associated with tumors of the hypothalamus, pituitary metastases, lymphocytic hypophysitis, sarcoidosis, Langerhans cell histiocytosis, craniopharyngiomas, and Rathke's cleft cysts. (54). Additionally, it is commonly observed following neurosurgery and head injury. As cortisol is an essential prerequisite for normal glomerular filtration and free water clearance, it should be highlighted that AHD is masked by co-existing ACTH deficiency and only becomes clinically evident after commencement of glucocorticoid replacement. However, it is extremely unusual for AHD to be a primary manifestation of pituitary adenoma.

Baseline Investigations

Basal concentrations of the anterior pituitary hormones and hormones produced by their respective target glands should be measured. Serum samples should be taken unstressed, with no physiological or pharmacological manipulation, between 7 and 9 AM when serum cortisol and testosterone levels are highest. This is important given that the decision to proceed to dynamic testing is based on these levels. The pituitary hormones may remain within the normal range despite low levels of the target hormones indicating that target gland failure is a consequence of inadequate pituitary stimulation. Baseline investigations (Table 3) are sufficient for the diagnosis of secondary hypothyroidism and hypogonadism and will also confirm virtually complete ACTH deficiency (55).

It should be mentioned that the serum total testosterone measurement should be performed in the morning by a reliable assay and the test should be repeated before verifying the diagnosis of testosterone deficiency. Measuring the level of free or bioavailable testosterone level should be performed in those whose total testosterone levels are close to the lower limit of the normal range or whose SHBG is suspected to have altered (56).

Dynamic Testing

Stimulation tests are used when hypofunction is suspected and are designed to assess the reserve capacity to form and secrete hormone. In contrast, suppression tests are used when endocrine hyperfunction is suspected and are designed to determine whether negative-feedback control is intact, as in the administration of glucocorticoids to inhibit corticotrophin secretion in patients with suspected Cushing’s syndrome or in the administration of glucose in patients with suspected acromegaly. Dynamic pituitary function tests may assess the hypothalamic-pituitary unit (e.g., insulin tolerance test, glucagon, and arginine tests) or directly stimulate the anterior pituitary with pharmacological doses of synthetic hypothalamic peptides and the pituitary hormone response measured (e.g., TRH, GnRH, GHRH tests).

Imaging the Pituitary

Magnetic resonance imaging (MRI) is the optimum method of imaging, with computerized tomography (CT) as an acceptable alternative. The only disadvantage to MRI is its insensitivity in defining pathological calcification and lack of signal from corticated bone. CT may be required to demonstrate calcification in craniopharyngiomas and hyperostosis; it is also used by many surgeons to define skeletal anatomy prior to surgery.

Hypocortisolism

Hydrocortisone is now the most widely used form of glucocorticoid replacement in patients with primary and secondary adrenal insufficiency. There is no universal agreement regarding the appropriate dose, timing, and monitoring of hydrocortisone replacement. Normal individuals demonstrate undetectable serum cortisol and ACTH when asleep at midnight, with a rise during the early hours of the morning to reach a peak at 0800-0900h, followed by a steady decline throughout the rest of the waking day. There are variable peaks of cortisol secretion due to other factors such as stress, meals, and exercise. Since cortisone acetate requires conversion into hydrocortisone under the influence of 11ß-hydroxysteroid dehydrogenase type 1 (11β-HSD1), and the fact that the enzyme activity is altered in patients with GHD; therefore, cortisone renders intuitively less satisfactory than hydrocortisone for replacement purposes in this condition. Prednisolone has been advocated by some on account of its longer duration of action than hydrocortisone. However, because it cannot be routinely measured, it is impossible to fine tune the replacement dose. Dexamethasone, the alternative synthetic glucocorticoid replacement, is even less satisfactory because of wide interindividual variations in metabolic clearance rates.

Traditional hydrocortisone replacement utilized twice daily dosing but many patients report fatigue or headache in the afternoon on this regimen. There is evidence that many patients 'feel better' on thrice daily regimes (71). Recent cross-sectional studies did not demonstrate any superiority between three times a day versus twice daily replacement in terms of quality of life (72). The average daily requirement is approximately 20mg of hydrocortisone. This should be given as 10mg on waking, 5mg at lunchtime and 5mg in the early evening. Enzyme-inducing drugs, especially, phenytoin, carbamazepine, and rifampicin can increase the metabolism of corticosteroids and should prompt an increment in replacement doses. Doses are therefore fine-tuned according to patient’s well-being and multiple serum cortisol levels (hydrocortisone day curve, HCDC) taken during the day in many centers. (55,73). Some centers have attempted to utilize urine free cortisol measurements to adjust the hydrocortisone dose; however, this is unreliable because saturation of cortisol binding globulin (CBG) following oral hydrocortisone results in supraphysiological urine free cortisol excretion (74). The HCDC should demonstrate adequate levels of cortisol throughout the day, without excess peak (cortisol e.g., >1000 nmol/L (36.25 µg/dL)) or trough (e.g., <100 nmol/L (3.625 µg/dL)) levels before or after doses.

In clinical practice, there is no reliable measure to be certain if patients are receiving optimal glucocorticoid replacement therapy. As a result, patients may be over- or under- treated with resultant morbidity (65). There is a significant increase in 11β-HSD1 activity resulting in abnormalities in corticosteroid metabolism in patients with ACTH deficiency treated with conventional doses of hydrocortisone (66). In ACTH-deficient patients daily hydrocortisone dose exceeding 20mg/day is associated with increase waist to hip ratio. The induction of 11β-HSD1 is associated with central adiposity and has an important role in the development of the metabolically adverse hypopituitary phenotype.

Conventional hydrocortisone cannot mimic the circadian rhythms of cortisol release; in particular the early morning rise in cortisol which slowly declines throughout the day. This has led to the development of a modified release formulation of hydrocortisone (MR-HC, Chronocort®) which can be taken late at night thus allowing a delayed and sustained release (75). A study in healthy men demonstrated that MR-HC 20mg and 10mg, given at 2300 and 0700 hours respectively, could achieve a near normal cortisol circadian rhythm (76). A subsequent phase II study demonstrated that the MR-HC mimics the normal circadian pattern closer to physiological baseline (77); however, the studied preparation is no longer available. An alternative modified formulation (Plenadren®) incorporates an immediate release and delayed release components, which displays diurnal plasma cortisol levels similar to physiological profile. Once daily Plenadren® has been shown to reduce weight, blood pressure and improve glucose metabolism when compared with thrice daily dosing (78).

Another newer oral immediate-release granule formulation of HC (Alkindi®) was approved in EU in 2018. This is an immediate-release hydrocortisone preparation specifically designed for pediatric dosing, which is available in four doses: 0.5mg, 1mg, 2mg and 5mg (79).

Table 4 summarizes the glucocorticoid compounds currently available for adrenal insufficiency.

The effects of continuous subcutaneous hydrocortisone infusion (CSHI) have been compared with conventional oral hydrocortisone in patients with Addison’s disease (80). CSHI produced a more physiological circadian rhythm, normalization of morning ACTH and restoration of nocturnal serum cortisol levels. These infusions are cumbersome and impractical outside of expert centers. Despite a more circadian pattern of cortisol exposure, subcutaneous hydrocortisone infusion was not associated with improved quality of life scores, casting doubt on the potential quality of life effects of circadian cortisol delivery (81).

There is a push to design orally active delayed or sustained release formulations of hydrocortisone to aid the physiological replacement of hydrocortisone and ultimately improve quality of life and side effect profiles in patients requiring lifelong glucocorticoid replacement.

Patients with ACTH deficiency receiving hydrocortisone therapy are unable to respond to surgery, trauma, infections, and severe illnesses by increasing their cortisol concentrations. They therefore require supplemental hydrocortisone therapy with increased oral doses during minor illness, or administration of intramuscular hydrocortisone 100mg four times per day with more severe disease or if oral intake is compromised. When intramuscular injections are contraindicated, a continuous intravenous infusion of hydrocortisone at a rate of 1-3mg per hour provides satisfactory replacement for the severely ill patient. Maintenance mineralocorticoid is not required since aldosterone secretion is usually preserved.

Patients should carry a 'steroid card' and wear a 'medic-alert' bracelet to indicate their requirement for supplemental hydrocortisone in the event of severe illness or trauma. They and their families should understand the importance of life-long compliance, be taught to double the hydrocortisone dose in the event of pyrexial illness, and understand the need for parenteral glucocorticoid replacement if vomiting or diarrhea occurs. An 'emergency' ampoule of hydrocortisone should be provided for domiciliary emergency intramuscular injection and the patient instructed on its use.

Dehydroepiandrosterone (DHEA) is an androgen produced by the adrenal cortex and is also under the regulation of corticotrophin, and is thus deficient in hypopituitarism. In hypopituitarism, DHEA supplementation (25-50mg per day) has shown benefit with respect to well-being and sexual function (82,83). Furthermore, in patients who are replaced with GH, DHEA can augment the IGF-1 response hence leading to a reduction of GH dose in females (84). Currently, there is no licensed preparation of DHEA available, and it is considered to be a food supplement rather than a bioactive drug. However, not all patients respond. Moreover, the androgenic side effects such as greasy skin, acne, and increased body hair may be a limiting factor although generally responsive to dose reduction.

Secondary Hypothyroidism

Synthetic levothyroxine sodium (for example, Synthroid) is the preferred form of replacement. It has a long half-life, allowing a once daily dose. Liothyronine (T3) displays superior gastrointestinal absorption, but its short half-life requires two to three daily doses. Use of T3 is largely restricted to thyroid cancer patients undergoing frequent isotopic imaging or treatment, and occasionally the initiation of thyroid hormone replacement when a gradual increase is desired. Although some experts consider using a T4/T3 combination as an experimental treatment for patients with persistent hypothyroid symptoms on LT4 since patients with normal thyrotropin levels may have lower T3 levels, the evidence is primarily limited to athyreotic patients.(85,86)

Commencing thyroid hormone replacement in patients with severe, untreated ACTH deficiency may result in hypoadrenal crisis. In the situation of combined deficiency, hydrocortisone should always be commenced before thyroxine. The duration of hypopituitarism and presence of co-morbidities, especially ischemic heart disease, should be considered. Young patients with a short history of hypopituitarism and TSH deficiency may commence an initial thyroxine dose of 100µg daily. On the other hand, in patients with a long history of hypopituitarism or elderly patients, a low dose of 25-50µg daily should be commenced, in order to minimize the risk of precipitation of cardiac events.

Alteration of the hypothalamic-pituitary-thyroid axis following growth hormone replacement is well documented (87-89). GHD will mask central hypothyroidism in a significant proportion of hypopituitary patients both in children and adults. It has been observed that apparently euthyroid hypopituitary patients will require commencement or an increase in thyroxine replacement following initiation of GH replacement. A higher target serum free T4 in the upper half of reference range is appropriate in the GH deficient patient who is not on GH replacement.

Unlike primary hypothyroidism, in which serum TSH is a sensitive marker of under-or over-replacement, there is no biochemical marker to indicate the optimum level of replacement in TSH deficiency. The serum free T4 is the best marker for assessing replacement adequacy in hypopituitarism. By analogy with serum T4 levels in adequately replaced primary hypothyroidism, a conventional recommendation is to maintain serum free T4 in the upper part of the reference range for normal individuals (90). Serum total T4 levels are elevated artefactually by conditions which increase serum thyronine binding globulin, especially estrogen administration.

Gonadotrophin Deficiency

Choice of replacement ranges from oral, transdermal, intramuscular, or subcutaneous administration of gonadal steroids to gonadotropin or gonadotropin-releasing hormone therapy if and when fertility is desired.

Growth Hormone Deficiency

The rationale and protocol for growth hormone replacement in adults is discussed in detail in the "Adult Growth Hormone Deficiency" chapter.

Diabetes Insipidus

1-desamino-8-D-arginine-vasopressin (DDAVP) is a synthetic analogue of arginine vasopressin which produces prolonged antidiuresis after intravenous, intranasal or oral administration in patients with AHD. A therapeutic trial of DDAVP, 10-20 mcg intranasally should control polyuria for up to 16 hours. Patients with AHD must have instant improvement in symptoms. In the acute clinical setting, for example where diabetes insipidus follows pituitary surgery, DDAVP is best administrated via the subcutaneous route at a dose of 0.5-1μg. Doses of DDAVP that are too high can lead to hyponatremia if patients continue to drink inappropriately despite antidiuresis. Patient education is required to achieve optimum symptom control particularly at night and to maintain a normal serum osmolality and sodium concentration (102). Slight undertreatment, with normal water homeostasis being maintained by thirst mechanisms, is the preferred approach. Many patients demonstrate adequate control of the condition with a single bedtime dose of intranasal DDAVP but an additional morning dose may be required. Mild degrees of AHD may be treated with oral DDAVP up to 600µg daily in divided doses. If ADH deficiency is accompanied by a reduced thirst threshold, it is most important to monitor body weight and urine output on a fixed dose of DDAVP and adjust fluid intake accordingly.

A recent guideline has been developed for inpatient treatment of diabetes insipidus highlighting that this can develop into a life-threatening situation if inappropriately managed (103). This again highlights that there is an increased risk of mortality and adverse outcomes in patient with hypopituitarism admitted for acute medical conditions especially ones with diabetes insipidus (104).