Aetiology, diagnosis, and management of hypopituitarism in adult life

Abstract

Hypopituitarism is a complex medical condition associated with increased morbidity and mortality, requires complicated treatment regimens, and necessitates lifelong follow up by the endocrinologist. The causes, clinical features, and the management of hypopituitarism including endocrine replacement therapy are considered in this review article.

Hypopituitarism is defined as either partial or complete deficiency of anterior or posterior pituitary hormone secretion, or both. Regal et al¹ reported a prevalence of 45/100 000 and an incidence of about 4/100 000/year in the normal population, with nearly 50% of patients having three to five pituitary hormone deficits. It is a complex medical condition associated with a higher mortality than that of the general population.²,³,⁴,⁵

Aetiology

Of the various causes of hypopituitarism in adults (see box), pituitary adenoma or its treatment by surgery and/or radiotherapy is by far the commonest. Macroadenomas (greater than 1 cm) are associated with one or more trophic hormone deficits in 30% of cases⁶; direct compression and destruction of the surrounding normal pituitary leads to hyposecretion. Other postulated mechanisms include primary mass effect of the tumour on the vascular portal system/pituitary stalk, raised intrasellar pressure affecting portal circulation, and focal pituitary necrosis secondary to prolonged interruption of portal blood supply.⁷,⁸ While microadenomas (less than 1 cm) rarely affect pituitary function,⁸ prolactin producing microadenomas often present with hypogonadism because of the suppressive action of a high prolactin (PRL) level on gonadotrophins' (follicle stimulating hormone FSH and luteinising hormone LH) secretion. Among the peripituitary tumours causing central endocrine dysfunction, craniopharyngioma is the commonest.

Occurrence of hypopituitarism after pituitary surgery is influenced by tumour size, extent of invasion into surrounding structures, remaining viable normal pituitary, and the skill of the neurosurgeon. Transient postoperative diabetes insipidus (DI) is seen in 5% of cases but permanent DI occurs less frequently. At least partial recovery of pituitary function in 40%–65% of patients has been reported after surgery⁷,⁹,¹⁰,¹¹ but postoperative deterioration has also been reported.¹² Patients should be made aware of the possibility of hypopituitarism before surgery. Post‐surgical endocrine assessment is mandatory.

Anterior hypopituitarism may follow cranial radiotherapy used in treating various intracranial tumours, acute lymphoblastic leukaemia (prophylactic cranial radiotherapy), and those receiving total body irradiation. The impact is dependent on the total dose, fractionation, duration of treatment, and time elapsed since radiation exposure to the hypothalamic‐pituitary axis.¹³,¹⁴ In one series after a radiotherapy dose to the hypothalamic‐pituitary axis of 37.5 to 42.5 Gy, after five years all patients were growth hormone (GH) deficient, 90% gonadotrophin deficient, 77% adrenocorticotrophic hormone (ACTH) deficient, and 42% were thyroid stimulating hormone (TSH) deficient.¹³ Gamma knife surgery for pituitary adenoma has recently been reported to affect pituitary function less than conventional radiotherapy¹⁵ although these are preliminary findings and require long term studies to determine if this is the case. Congenital isolated/multiple pituitary hormone deficiencies (MPHD) have been described. Growth hormone gene GH‐1¹⁶ and growth hormone releasing hormone receptor gene GHRH‐R¹⁷ mutations can result in isolated growth hormone deficiency where as KAL gene defect is implicated in the X‐linked form of Kallman's syndrome (isolated hypogonadotrophic hypogonadism plus hypo/anosmia). Table 1 lists the genetic forms of MPHD.

Table 1 Genetic forms of isolated and multiple pituitary hormone deficiencies.

Defective/mutant gene	Disease
GH‐1 GHRH‐R	Isolated growth hormone deficiency
TPit	Isolated ACTH deficiency
GnRH‐R	Isolated hypogonadotrophic hypogonadism
KAL	X‐linked Kallman's syndrome
PIT 1	GH, PRL, TSH deficiency
PROP 1	GH, PRL, TSH, FSH/LH ± partial ACTH deficiency
HESX1/Rpx	Septo‐optic dysplasia with isolated growth hormone deficiency/panhypopitutarism
LHX3/4	MPHD + cranial structural abnormalities
DAX‐1	X‐linked AHC (adrenal hypoplasia congenita) + hypogonadotropic hypogonadism

Lymphocytic hypophysitis first described in 1967¹⁸ is recognised as an autoimmune disorder mainly of the adenohypophysis¹⁹ wherein isolated/combined ACTH/TSH/gonadotrophin/GH deficiencies and rarely, DI²⁰ have been reported. It is an uncommon condition predominantly affecting women in late pregnancy or the early postpartum period²¹ who present with headache and visual field defects. Magnetic resonance (MR) scan is suggestive of the diagnosis but histology is the gold standard. In subclinical disease, spontaneous remission is reported but in patients with hypocortisolism or symptomatic extrasellar expansion, medical treatment and/or neurosurgical decompression is recommended.²²

Hypopituitarism after head injury tends to occur mostly within one year of injury,²³ and Aimaretti et al²⁴ reported some degree of deficiency in 35% of cases at three months after brain injury (trauma/subarachnoid haemorrhage), not specifically related to the level of consciousness (Glasgow coma scale). Growth hormone and gonadotrophin deficiencies are most common,²³,²⁵ and mandatory neuroendocrine assessment has been recommended, given the potential therapeutic implications.

Pituitary apoplexy refers to abrupt destruction of pituitary tissue after infarction/ haemorrhage within the tumourous/non‐tumourous pituitary gland, clinically characterised by acute onset headache, vomiting, visual impairment, and meningism. Partial or complete, transient or permanent hypopituitarism may result.²⁶ MR scan is diagnostic; if visual deficits are present, trans‐sphenoidal surgery may be considered and that has been reported to be safe and effective.²⁷ Postpartum pituitary necrosis is referred to as Sheehan's syndrome.

Causes of hypopituitarism

Congenital

• Isolated / multiple pituitary hormone deficits (MPHD)

Pituitary and peripituitary tumours

• Non‐functioning pituitary adenoma (NFPA)

• Functioning pituitary adenomas

  • -Prolactinoma
  • -Growth hormone secreting
  • -ACTH secreting
  • -TSH secreting
  • -Gonadotrophin secreting

• Posterior pituitary tumours

  • -Ganglioneuroma, astrocytoma

• Peripituitary lesions

  • -Craniopharyngioma
  • -Meningioma
  • -Chordoma
  • -Optic nerve glioma
  • -Germinomas

• Metastatic

  • -Breast, lungs, colon, prostate

Infiltrative conditions

• Sarcoid, histiocytosis X, lymphocytic hypophysitis, primary haemochromatosis

Infections

• TB, syphilis, mycoses

Vascular

• Pituitary apoplexy

• Carotid artery aneurysm

• Subarachnoid haemorrhage

Clinical features

The underlying pathology, severity, and the speed of onset of hypopituitarism influences the clinical picture.

Space occupying lesions causing hypopituitarism may result in symptoms such as headache, visual disturbances and rarely, personality changes, temporal lobe epilepsy, and cerebrospinal fluid (CSF) rhinorrhoea. In addition to symptoms and signs attributable to pressure effects on the pituitary gland including the stalk, actively secreting tumours can consequently produce a complex picture of combined hormonal excess and deficiencies, for example, GH secreting macroadenoma causing acromegaly and hypogonadism. Mild ACTH deficiency may be unmasked during an intercurrent illness, while severe hypopituitarism after pituitary apoplexy presents as a medical emergency. The presence of DI usually suggests a hypothalamic or stalk disorder, except when it follows intracranial surgery. Table 2 lists the clinical features of the individual hormone deficiencies.

Table 2 Symptoms and signs of pituitary insufficiency.

Hormone deficiency	Clinical features
Growth hormone	Reduced energy and vitality
	Reduced muscle mass and strength
	Increased central adiposity
	Decreased sweating and impaired thermogenesis
	Increased cardiovascular risk
	Reduced bone mineral density (BMD)
Adrenocorticotrophic hormone	Fatigue, weakness, anorexia, weight loss, nausea, vomiting, abdominal pain, hypoglycaemia, circulatory collapse if acute onset; loss of axillary and pubic hair in women
Gonadotrophins	Men: erectile dysfunction, soft testes, reduced muscle mass, erythropoiesis, reduced energy and vitality
	Women: oligomenorrhoea/amenorrhoea, dyspareunia, breast atrophy
	Both: loss of libido, flushes, infertility, regression of sexual characteristics, reduced BMD.
Thyroid stimulating hormone	Fatigue, apathy, cold intolerance, constipation, weight gain, dry skin, psychomotor retardation.
Antidiuretic hormone	Polyuria, polydipsia, nocturia.
Prolactin	Inability to breast feed

Diagnosis

The diagnosis entails clinical examination, biochemical assessment, and investigation of the cause of hypopituitarism.

A thorough physical examination including visual fields' assessment is essential. Goldmann perimetry helps in plotting the visual field defects and assists in follow up.

Simultaneous measurements of basal anterior pituitary and target organ hormone levels provide useful information to help establish the cause. TSH, thyroxine, FSH, LH, oestradiol (women)/testosterone (men), prolactin, insulin‐like growth factor 1 (IGF1) and 9 am cortisol form the baseline tests. Dynamic/provocative tests are necessary to assess GH secretory reserve²⁸ and the ACTH‐adrenal axis comprehensively.

Growth hormone deficiency (GHD)

Adult growth hormone deficiency (AGHD) should only be considered within an appropriate clinical context (patients with primary hypothalamic‐pituitary disease or those exposed to traumatic brain injury, subjects who had received cranial irradiation previously, or those with childhood onset GHD), and defined biochemically.²⁸,²⁹ In an obese patient, the diagnosis of isolated severe GHD can be difficult to substantiate because of the influence of visceral fat mass on GH status; diagnostic difficulties may also occur in certain pathophysiological disorders such as “cured” acromegaly attributable to the persistence of qualitative abnormalities in GH secretion.³⁰ Under the latter circumstances heavy reliance is placed on the presence of a abnormally low IGF1 concentration.

The consensus is that adult patients with hypothalamic‐pituitary disease and one or more additional pituitary hormone deficits require only one GH provocative test while those with suspected isolated GHD need two GH stimulatory tests.²⁹ About 40%–60% of those with a putative diagnosis of childhood onset GHD may have an impaired GH response in adult life.³¹

An insulin tolerance test (ITT) is regarded as the “gold standard” test in adults and severe deficiency is said to exist when the peak GH response is less than 3 μg/l (9 mU/l). After an overnight fast, intravenous insulin 0.05–0.15 units/kg is injected and samples are taken for blood glucose and GH levels at 0, 30, 60, 90, 120 minutes. Definition of a normal GH response to an ITT performed with an appropriate degree of hypoglycaemia (blood glucose <2.2 mmol/l) is a peak of at least 5 μg/l.³² Performed with adequate supervision in specialised units, an ITT is a safe procedure.³³ The ITT also permits concomitant assessment of ACTH status. Despite the debate about its reproducibility,³⁴ the ITT remains the best validated test. Contraindications to an ITT include ischaemic heart disease, an abnormal resting ECG, arrhythmias, epilepsy/ unexplained blackouts, etc.

Other stimulatory tests used either as a second test for the diagnosis of GHD or if the ITT is contraindicated, are necessary. The combined growth hormone releasing hormone (GHRH) + arginine test presents an excellent alternative with defined thresholds.³⁵ The use of the GH secretogoge, hexarelin³⁶ combined with GHRH in young and middle aged adults³⁷ with age specific cut offs is one of the more recently introduced tests.

Other widely used tests include glucagon stimulation (GST) and arginine stimulation. Glucagon is more potent than arginine in assessing GH reserve,³⁸ and provides a reliable alternative.³⁹ GST allows for simultaneous testing of both GH and ACTH reserve.

Circulating IGF1 can be helpful in the diagnosis of adult GHD, however, there are alternative causes of a low IGF1 level other than GHD; these include malnutrition, liver disease, diabetes mellitus, and hypothyroidism. Sufficient age adjusted normative data are crucial for interpretation of patient's IGF1 concentrations. The IGF1 estimation is most helpful in the young adult with severe GHD, and with increasing age the IGF1 concentration is less likely to be abnormally low in GHD patients⁴⁰ such that only 17% of severely growth hormone deficient adults over the age of 65 years have an IGF1 concentration below the normal range.

ACTH deficiency

A basal (9 am) cortisol less than 100 nmol/l³²,⁴¹ in untreated patients, or greater than 450–500 nmol/l³³,⁴² obviates the need for provocative tests of ACTH reserve without compromising patient care. If cortisol insufficiency is clinically suspected, particularly in an unwell patient, basal cortisol and ACTH samples are taken but cortisol replacement started awaiting results. The ITT remains the gold standard for assessing the entire hypothalamic‐pituitary‐adrenal (HPA) status and has been cross validated historically against a physical stress (major surgery), with a normal peak cortisol response of 580 nmol/l.⁴³ In response to hypoglycaemia (less than 2.2 mmol/l), a cortisol level greater than 500 nmol/l is considered to be consistent with normal ACTH status. An ITT however is not without contraindications or morbidities and hence several authors advocate the short synacthen test (SST) with appropriate cut offs as the first line test.⁴⁴,⁴⁵ While controversy exists about the cut offs and diagnostic reliability,⁴⁶,⁴⁷ the potential for missing subtle HPA defects remains a possibility; a 30 minute cortisol (after intramuscular synacthen 250 μg) of greater than 550 nmol is considered to represent a “pass”. An ITT should be performed in those who fail the screening SST.

Other tests include the GST, to which the peak cortisol response is less than that to the ITT and occurs later.⁴⁸

Patients with borderline cortisol responses to ITT (450–500 nmol/l) may only require glucocorticoid replacement during intercurrent illness/surgery.

TSH deficiency

TSH deficiency is indicated by low basal serum free/total thyroxine with an inappropriately normal or low TSH. Routine use of a thyrotrophin releasing hormone (TRH) stimulation test is not advocated⁴¹ in adults.

Gonadotrophin deficiency

This is associated with low serum testosterone in the presence of normal or low gonadotrophin levels in men and low serum oestradiol concentrations in pre‐menopausal women without appropriately increased gonadotrophins, and in post‐menopausal women the absence of the normal rise of gonadotrophin concentrations. The use of a gonadotrophin releasing hormone (GnRH) provocation test does not provide any additional information in adults.⁴¹

Antidiuretic hormone (ADH) deficiency

Under normal circumstances ADH release from the posterior pituitary is mainly influenced by changes in plasma osmolality. In cranial DI, lack of such a response results in large urinary volumes (greater than 3 l/day or 40 ml/kg/day) of low osmolality (less than 300 mOsmol/kg); ACTH deficiency can mask DI clinically, symptoms only becoming apparent on starting steroid replacement.

The standard eight hour water deprivation test entails closely supervised dehydration of a previously well hydrated patient, during which basal and hourly plasma and urine osmolalities, and urine volumes are measured as well as weight estimated two hourly (if >3% weight loss occurs, the test is terminated). After eight hours, intramuscular desmopressin 2 μg is injected, and blood and urine osmolalities and urine volumes are remeasured. Urine, dilute (less than 300 mOsmol/kg) at the end of fluid deprivation becomes concentrated (greater than 750 mOsmol/kg) after desmopressin in patients with cranial DI, but remains dilute in nephrogenic DI. In borderline cases (urine osmolality 300–750 mOsmol/kg pre‐desmopressin and less than 750 mOsmol/kg after the injection), a more definitive assessment with the hypertonic saline infusion test will aid the diagnosis.⁴⁹

Investigations

Radiological assessment

The presence of clinical and biochemical evidence of hypopituitarism necessitates imaging studies of the hypothalamic‐pituitary region, and MR imaging is currently the investigation of choice.⁶ When it is not possible, CT scan with contrast provides a suitable alternative. In cranial DI, the normal high intensity posterior‐pituitary bright spot on T1 weighted MR is generally absent.⁵⁰ It is worth noting, however, that in necropsy studies of people with no known hypothalamic‐pituitary disorder, pituitary microadenomas may be found in 10%–20%.

Other investigations

Serum and CSF angiotensin converting enzyme activities (neurosarcoid), serum ferritin (haemochromatosis), human chorionic gonadotrophin (HCG) (germ cell tumours), etc, may provide additional information to elicit the aetiology. Genetic testing is particularly helpful in isolated/syndromic MPHD.

Implications of untreated pituitary hormone deficiency

Patients with hypopituitarism have an increased mortality. Our current knowledge is based on six major retrospective studies, most of which confirmed excess mortality in hypopituitary patients.

The first large study in hypopituitary patients came from Sweden in 1990. Rosen et al² gathered mortality data in 333 hypopituitary patients, and found deaths from vascular disorders twice as common compared with the age and sex matched population; this was independent of the underlying cause for hypopituitarism or the degree of pituitary insufficiency. In their discussion, the authors proposed untreated GHD as the probable underlying cause of the excess mortality.

In 1996, Bates et al³ studied mortality data in 172 patients with hypopituitarism (mainly attributable to pituitary tumours) receiving standard endocrine replacement therapy. Of 98 patients tested for their GH status, 94 had confirmed GHD. Women had a higher standardised mortality ratio (SMR) than men (2.29 v 1.5). The only significant independent predictive factors for survival were age at diagnosis and hypogonadism, the latter being associated with a better prognosis than eugonadism. Only 27% of women were receiving HRT, and vascular deaths were (non‐significantly) more frequent in women. In the authors' follow up study⁵¹ with twice as many patients, only a slight and non‐significant increase in mortality was seen. Even more surprisingly, risk of vascular death was now significantly reduced in women with a SMR as low as 0.5 (p<0.01), whereas male mortality was no different from the normal population.

Bulow et al⁴ studied the causes of 188 deaths in 344 hypopituitary patients after surgery for pituitary tumours. Cerebrovascular deaths were more common (overall SMR 3.4, female SMR 4.9), contributing to the increased overall mortality (SMR 1.4). Younger age at diagnosis and female sex were independent risk factors of increased mortality.

Two studies in this century reviewed mortality data in larger number of hypopituitary patients. Nilsson et al⁵² reviewed 842 death certificates of patients from the Swedish Cancer Registry that included 3321 patients with pituitary tumours, and found a SMR of 2.0. Cardiovascular and cerebrovascular death rates were higher than in the normal population (SMR 1.6 and 2.4 respectively), and women had an even higher mortality compared with men (SMR 2.3 v 1.9). Limitations of the study were the unknown pituitary status of these patients and reliance on death certification.

The most recent British publication was by Tomlinson et al⁵ who analysed 181 deaths in 1014 hypopituitary patients, with excess mortality ratios seen particularly in women (2.29 v 1.57 in men). Cardiovascular, respiratory, and cerebrovascular SMRs were increased between 1.82 and 2.44. Hormone deficiencies and their treatment were not found to be independent risk factors except for untreated gonadotrophin deficiency. Growth hormone status was reported in 111 patients (11%), and GHD was present in the great majority of these patients (89%). The small total number of 37 patients with normal GH status or treated GHD (13 and 24 patients respectively) prohibits meaningful subanalysis of the role of GHD on mortality, and it was on those grounds, that the authors' dismissal of a role of GHD towards excess mortality was subsequently criticised.⁵³,⁵⁴,⁵⁵

While most of the studies above confirmed the excess mortality in hypopituitary patients, no clear answer has emerged with regards to causal relation. It has proved very difficult to be certain about the individual contribution of each risk factor in the very heterogeneous population of hypopituitary patients. GH sufficient and GH deficient patients with pituitary disease are not comparable for a number of reasons: preserved GH secretion is almost always associated with completely normal pituitary function or a less severe degree of hypopituitarism, and the insult to the hypothalamic‐pituitary axis in general would have been less noticeable in most of them. While it is comparatively straightforward to stratify patients according to other hormone deficits, underlying disorder, radiotherapy, etc, GHD largely escapes such subanalyses because of the high prevalence of GHD in hypopituitary patients. This is because of the high susceptibility of the somatotroph axis to damage from various insults, be it a pituitary mass lesion, pituitary surgery, hypothalamic irradiation, etc. With a GHD prevalence of more than 95% in hypopituitary patients, the numbers of non‐GHD patients are often simply too small to examine the possibility of GHD as an independent mortality risk factor.

It is also not clearly established how and to what extent other treatments in hypopituitary patients contribute to vascular risk, but all have been incriminated in a worsened risk profile, for example, sex steroid treatment, corticosteroid replacement, and pituitary radiotherapy.

Prolactin deficiency suppresses the ability to lactate but no other consequence is known. Prolactin deficiency however implies severe GHD,⁵⁶ as prolactin deficiency unlike GHD occurs late in the evolution of hypopituitarism.

Management of hypopituitarism

The treatment of hypopituitarism includes therapies directed at the underlying disease process, and endocrine replacement therapy. The pituitary tumours may be treated with medical therapy, surgery, radiotherapy, or a combination of these modalities. A macroprolactinoma, for instance, is amenable to treatment with dopamine agonists,⁵⁷ while there is a high surgical cure rate for GH secreting microadenoma by skilled surgeons.⁵⁸ A recurrent ACTH producing pituitary neoplasm is likely to require a combination of treatments⁵⁹ whereas debulking surgery followed by radiotherapy if there is tumour regrowth is the acceptable approach for NFPA.⁶⁰

Surgical decompression is usually required for pituitary and peripituitary tumours causing pressure effects and not responding to medical therapy. Pituitary endocrine status needs reassessing after treatment as functional improvements have been noted.⁷,⁸

Hormone replacement therapy (HRT)

The goals of HRT in hypopituitarism are to achieve normal levels of the circulating hormones, to restore normal physiology as closely as possible, and to avoid the symptoms of deficiency with minimal side effects. Target hormone rather than the deficient pituitary hormone is replaced except for GH deficiency, ADH deficiency, and when fertility is desired. Table 3 summarises the regimens of HRT.

Table 3 Pituitary hormone replacement therapy.

Hormone deficiency	Replacement	Usual dose
Growth hormone	Growth hormone	0.27–0.7 mg subcutaneously in the evening
ACTH	Hydrocortisone	10 mg on rising, 5 mg at noon, 5 mg early evening
TSH	Thyroxine	75–150 μg/day
Gonadotrophins
Men	Testosterone esters (for example, Sustanon)	250 mg intramuscularly every 2–3 weeks
	Transdermal testosterone
	Patch (for example, Andropatch)	2.5–7.5 mg/24 hours
	Gel (for example, Testogel)	5–10 g gel/24 hours
	Testosterone implant	600–800 mg every 4–6 months
	Buccal testosterone (for example, Striant SR)	1 buccal tablet (30 mg) applied to the gum every 12 hours
	Oral testosterone (for example, Restandol)	40–120 mg daily
Women	Conjugated equine oestrogens	0.625–1.25 mg daily orally
	or
	Estradiol valerate	1–2 mg daily orally
	Transdermal estradiol (patch)	25–100 μg/24 hours
	Oestrogen plus progesterone (cyclical/continuous)	Dose depends on preparation—orally or transdermal
ADH	Desmopressin	300–600 μg daily in 2–3 divided doses orally.
		10–40 μg daily in 2–3 divided doses intranasally
Prolactin	nil

Educating the patients about their disease forms an important aspect of the management, including its influence on their daily life and the need to modify/change the treatment during intercurrent illness, surgery, etc.

GH deficiency

With the production of human biosynthetic GH by DNA recombinant techniques in the late 1980s, studies followed culminating in the emergence of treatment guidelines for the AGHD syndrome.

This syndrome is characterised by abnormal body composition (increased fat mass and reduced lean body mass), reduced exercise tolerance and muscle strength, osteopenia, an adverse lipid profile, increased procoagulation factors, impaired cardiac function, and reduced psychological wellbeing.⁶¹,⁶² All patients with reported severe AGHD are eligible for GH replacement²⁹ but currently in the UK, the National Institute for Health and Clinical Excellence⁶³ recommends GH replacement for those adults with biochemically confirmed severe GHD, already taking full pituitary hormone replacement as appropriate and who have severe impairment of quality of life (QoL‐AGHDA questionnaire) assessed objectively. The administration of GH to GHD adults reverses many of the adverse changes in body composition, bone mineral density, exercise capacity and strength, and improves the lipid profile.⁶²,⁶⁴,⁶⁵ In those with severe GHD, GH replacement considerably improves QoL in the majority of cases in whom it is impaired at baseline. It should also be appreciated that therapeutic strategies differ worldwide as far as adult GH replacement is concerned. In certain countries (Scandinavia) a more holistic approach is adopted on the premise that this is simply beneficial hormone replacement for a recognised deficiency; alternatively in other countries adult GH replacement is not licensed (Australia) and therefore cannot be prescribed outside of a trial, while elsewhere there are still some endocrinologists who remain unconvinced about the solidity of the evidence base underpinning GH replacement for adults and therefore do not recommend it.

Previous weight based regimens have been replaced by individualised dosing regimens aiming at normalising age and sex matched IGF1 concentrations. The starting dose of human GH is 0.2–0.3 mg given daily as a subcutaneous injection titrating the dose every four to six weeks gradually on the basis of clinical and biochemical responses (IGF1 SD score).²⁹ Improvement in body composition and QoL often takes several months,⁶⁶ and a trial period of six months is recommended after an initial three month period of dose adjustment. Body composition and QoL is reassessed at that stage; failure to show a significant improvement in the QoL assessed objectively (AGHDA questionnaire) will lead to the withdrawal of therapy.⁶³

Side effects (seldom seen using modern day dose replacement schedules) include headache, arthralgia, myalgia, fluid retention, etc, and respond to dose reduction. Monitoring includes regular measurements of weight, BP, IGF1, fasting glucose, HbA1c, lipid profile, waist‐hip ratio, and two yearly bone densitometry in those with initial low BMD together with patient interview. Absolute contraindications are active malignancy, benign intracranial hypertension, and proliferative/preproliferative diabetic retinopathy. GH is presently not licensed for use during pregnancy and lactation.

There is no evidence of increased rate of recurrence or regrowth of pituitary/peripituitary tumours in GHD patients on GH replacement, but the standard recommendation is to perform baseline pituitary imaging in all patients with a history of pituitary disorder before starting GH replacement therapy.⁶⁷

ACTH deficiency

In ACTH deficient patients, glucocorticoid replacement is essential for life, and optimisation of replacement is important to avoid the long term consequences of over‐treatment such as osteoporosis, central obesity, etc⁶⁸ whereas under‐treatment is potentially life threatening.⁶⁹ Hydrocortisone (HC) simply replaces the missing hormone and hence is the preferred agent⁷⁰; less attractive alternatives include cortisone acetate, prednisolone, and dexamethasone.

Estimated endogenous cortisol production has been shown to be 5.7 mg/m²/day,⁷¹ and thus previous conventional HC replacement of 30 mg/day in divided doses⁷² represented over‐treatment.⁶⁸ More recent evidence suggests that a more normal cortisol profile and patient response is achieved with a dosing regimen of HC of 10 mg on rising, 5 mg at lunchtime, and 5 mg in the early evening⁷⁰ rather than twice daily therapy. A twofold to threefold increase in corticosteroid dose is needed temporarily during an intercurrent illness, surgery etc; therefore educating patients and their carers repeatedly is recommended.⁷³ A medic alert bracelet/necklace should be worn at all times by the patient.

The efficacy of the replacement is assessed both clinically and biochemically. While a 24 hour urinary free cortisol estimation is felt to be a reliable indicator of pronounced over‐replacement with HC,⁶⁸ an eight hour serum cortisol day curve, or modified three point curve can help detect subclinical over‐replacetment or under‐replacement.⁷⁰

TSH deficiency

Thyroxine is the treatment of choice taken once a day, starting with 100 μg in young patients and in the absence of cardiac disease, and 25 μg in elderly patients and those with coronary artery disease.⁷⁴ ACTH deficiency should be identified and treated if present before starting thyroxine replacement. In patients with pituitary disease, TSH monitoring is unhelpful and therefore its measurement is pointless; the goals of thyroxine replacement should be clinical improvement along with the placing of the serum free thyroxine level within the normal range.⁷⁵ Long term over‐treatment may result in an increased risk of atrial fibrillation and reduced BMD.

Gonadotrophin deficiency

In men

Androgen replacement therapy has beneficial effects on body composition, sexual function, mood, behaviour, and BMD.⁷⁶,⁷⁷ The route of delivery depends on availability and patient choice. Deep intramuscular injection of a mixture of testosterone esters every two to three weeks is commonly used but is associated with widely fluctuating testosterone levels. Transdermal patches, transdermal gel, and recently introduced buccal preparation offer alternatives with the attraction of more stable serum testosterone concentrations.

Oral testosterone replacement is of limited use given the unreliable bioavailability, varying serum testosterone level, and multiple dosaging. Subcutaneous implants every four to six months require minor surgery and may be complicated by extrusion, local infection, and scarring.

Symptoms and serum testosterone levels guide adequacy of replacement. Monitoring entails measuring haemoglobin, packed cell volume, lipid profile, and prostate specific antigen (PSA) levels. This treatment is contraindicated in patients with prostate cancer (past and current) and male breast cancer.

In women

Oestrogen replacement alleviates the symptoms of deficiency, and is bone protective⁷⁸; hence oestrogen alone in patients without a uterus or with cyclical/continuous progesterone in patients with an intact uterus is usually prescribed. Most endocrinologists treat these patients up to the age of 50 years and re‐evaluate the risks and benefits of further use as in other postmenopausal women. The long term impact of oestrogen replacement on cardiovascular morbidity or development of breast cancer in hypopituitary patients is unknown.⁷⁹

Testosterone replacement in women

Hypothalamic or pituitary abnormalities either structural or functional, are associated with a decrease in gonadotrophin secretion and possible impairment of ACTH secretion, thereby reducing both ovarian and adrenal androgen production. Symptoms such as low libido, persistent unexplained fatigue, and decreased sense of wellbeing have been noted together with negative impact on lean body mass and BMD.⁸⁰ Ensuring adequate oestrogen replacement and excluding other causes of the above symptoms, a trial of low dose testosterone replacement could be considered,⁸⁰ but a firm evidence base for this practice does not exist.

Fertility in hypogonadotrophic hypogonadism

In men

In secondary hypogonadism, spermatogenesis and fertility can be induced. In hypothalamic disorders, pulsatile GnRH given via a subcutaneous pump or subcutaneous injections of gonadotrophins can be used, while in pituitary insufficiency gonadotrophins only are capable of being effective; however the response depends on the pre‐treatment testicular volume and if there is any history of testicular maldescent.⁸¹ Androgen replacement should be stopped at least four weeks before fertility treatment. Traditionally, HCG 1000–2000 IU alone is given subcutaneously/intramuscularly two to three times a week for six months; FSH in the form of highly purified urinary human menopausal gonadotrophin, or recombinant FSH is added if adequate spermatogenesis is not achieved on HCG alone.

In women

Regimens of ovulation induction in hypopituitarism are influenced by the underlying disorder. In gonadotrophin deficiency, treatment regimens should include preparations with LH activity to ensure an adequate oestrogen response.⁸² Where a structural lesion of the pituitary is the cause, the GnRH pump is unlikely to be effective.⁸³ If the pituitary failure is secondary to hypothalamic dysfunction, pulsatile GnRH therapy may be the more attractive physiological option.

ADH deficiency

In mild cranial DI (urine output less than 4 l/day), adequate oral fluid intake should suffice whereas in more severe form, desmopressin is the treatment of choice.⁸⁴ It is given as an oral, intranasal, or parenteral preparation to control symptoms. Overdose carries the risk of hyponatraemia, and hence sodium levels should be measured after starting treatment and whenever the dose is changed.

Conclusion

Hypopituitarism is associated with increased mortality and morbidity, necessitates complicated treatment regimens, and significantly affects the economy of the healthcare system. Strategies to limit the use of conventional radiotherapy may well lead to a reduced incidence of hypopitutarism. It is probable that hormonal treatment that approaches normal physiology might have a favourable influence on the adverse outcomes; therefore optimising replacement and lifelong follow up is appropriate.

Abbreviations

NFPA - non‐functioning pituitary adenoma

PRL - prolactin

FSH - follicle stimulating hormone

LH - luteinising hormone

DI - diabetes insipidus

GH - growth hormone

ACTH - adrenocorticotrophic hormone

TSH - thyroid stimulating hormone

MPHD - multiple pituitary hormone deficiencies

MR - magnetic resonance

CSF - cerebrospinal fluid

BMD - bone mineral density

IGF1 - insulin‐like growth factor 1

GHD - growth hormone deficiency

AGHD - adult growth hormone deficiency

ITT - insulin tolerance test

GHRH - growth hormone releasing hormone

GST - glucagon stimulation test

HPA - hypothalamic‐pituitary‐adrenal

TRH - thyrotrophin releasing hormone

GnRH - gonadotrophin releasing hormone

HCG - human chorionic gonadotrophin

SMR - standardised mortality ratio

HRT - hormone replacement therapy

QoL - quality of life

HC - hydrocortisone

PSA - prostate specific antigen