Approach
Where possible, the underlying cause must be addressed. Some causes, such as prior surgery or radiotherapy, are not correctable and treatment thus focuses on replacing the target hormones.
Endocrine replacement therapy should aim to mimic the normal hormonal milieu as far as possible, thus improving symptoms while avoiding over-treatment. With the exception of growth hormone (GH) and antidiuretic hormone (ADH) replacement, target hormones (those hormones stimulated by the pituitary-produced hormone) rather than the deficient pituitary hormone are replaced: for example, replacing with corticosteroids instead of adrenocorticotrophic hormone (ACTH). Patient education about hypopituitarism and the need to modify treatment during intercurrent illness is vital.
Adrenocorticotrophic hormone deficiency
Cortisol is essential for life, and therefore replacement is of critical importance.
Acute severe hypopituitarism may occur following pituitary apoplexy (sudden spontaneous development of a haemorrhage into or infarction of a pre-existing adenoma). This may present with nausea, vomiting, fatigue, weakness, dizziness, and circulatory collapse secondary to acute loss of ACTH. These patients should be treated presumptively for suspected acute cortisol deficiency with hydrocortisone.
Lifelong glucocorticoid replacement is a balance between avoiding long-term complications of over-treatment and avoiding under-replacement, which can be life-threatening.[54] The efficacy of glucocorticoid replacement is assessed clinically. Long-term over-replacement has been associated with the development of iatrogenic Cushing syndrome.
There is no universal consensus on the appropriate dosing or timing of glucocorticoid replacement. The normal daily cortisol production rate is equivalent to the oral administration of hydrocortisone 15-20 mg/day, given as 2 or 3 divided doses (for adults). The optimal dosing regimen of hydrocortisone is 10 mg on rising, 5 mg at lunchtime, and 5 mg in the early evening.[55] The Endocrine Society supports doses of 15-20 mg/day.[32] A specialist should be consulted for guidance on dosing for children.
Stress dosing with intravenous or intramuscular hydrocortisone is mandatory during major surgery, trauma, or severe illnesses. All patients should carry a steroid emergency card or bracelet with instructions about stress-related dose adjustments. A 2- to 3-fold increase in corticosteroid replacement is required, during 'sick day' dosing. If adrenal crisis (also known as acute cortisol insufficiency or Addisonian crisis) is suspected, patients should be given an immediate parenteral injection of hydrocortisone.[32]
Occasionally, glucocorticoid replacement may unmask an underlying central diabetes insipidus, leading to marked polyuria and nocturia.[56]
For patients with hypophysitis associated with anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) immunotherapy (e.g., ipilimumab), high doses of corticosteroids to reduce inflammation and to preserve and reverse pituitary damage do not appear to improve hormonal recovery or improve survival, compared to physiological replacement doses of corticosteroids.[57] These patients are at risk for adrenal insufficiency long-term.[58] CTLA-4 inhibitor therapy may need to be interrupted or discontinued depending on the severity of hypophysitis.
Thyroid deficiency
Secondary hypothyroidism is treated with replacement of thyroid hormone. It is vital that ACTH deficiency is diagnosed and treated appropriately prior to initiating thyroid hormone in order not to provoke an adrenal crisis due to increased cortisol clearance.
The goal of treatment is a normal serum free thyroxine value. Measurement of serum thyroid-stimulating hormone cannot be used as a guide to the adequacy of levothyroxine replacement therapy.
Cautious titration in older adults is important to avoid precipitating myocardial ischaemia.
Long-term over-replacement has been associated with an increased risk of atrial fibrillation and low bone mineral density.[59]
Prolactin deficiency
There is currently no available therapy.
Gonadotrophin deficiency
Treatment of follicle-stimulating hormone and luteinising hormone deficiency depends upon the sex of the patient and whether or not fertility is desired.
Women
Oestrogen therapy alleviates symptoms - namely, hot flushes - and prevents osteoporosis in women.[60] The majority of endocrinologists treat patients up to age 50.[7] In post-menopausal women, the risks and benefits of therapy need to be assessed and discussed with the patient.
Progesterone must be given with oestrogen in women with a uterus to prevent unopposed oestrogenic stimulation of the endometrium. The long-term effects of oestrogen therapy on cardiovascular morbidity or the development of breast malignancies in women with hypopituitarism is unknown.[61] Oestrogen therapy is usually administered via the oral or transdermal routes. Transdermal oestrogen is the optimal route in patients with hypopituitarism, as it avoids the effects of oral oestrogens on other hormone-binding proteins and less GH therapy needs to be administered compared with the oral route. This is due to the fact that oestrogen stimulates the production of binding proteins by the liver. If there are high levels of binding proteins, less free hormone is available. Therefore, when GH is replaced in the setting of oestrogen therapy, more GH is required and it is very costly.
In women with secondary hypogonadism who desire fertility, treatment with gonadotrophins is recommended.
Serum androgen levels in women with hypopituitarism are significantly lower than those in normal control women; however, testosterone replacement therapy is not routine.[62]
Men
Androgen replacement therapy is recommended in hypogonadal men as it has beneficial effects on mood, body composition, sexual function, and bone mineral density, if there are no contraindications.[32][45]
Testosterone replacement is not recommended in patients planning fertility or in those with elevated prostate-specific antigen (PSA) levels, elevated haematocrit, severe untreated obstructive sleep apnoea, severe lower urinary tract symptoms, thrombophilia, uncontrolled heart failure, or myocardial infarction or stroke within the last 6 months.[45]
Testosterone replacement therapy has been associated with beneficial effects in hypogonadal males with metabolic syndrome.[63] It is especially beneficial in males who have not initiated puberty by the age of 14 and in males with low testosterone levels due to hypothalamic-pituitary disease.[64] Caution should be exercised in the administration of exogenous testosterone to hypogonadal men >65 years with multiple cardiovascular risk factors, as it has been shown to increase the rate of adverse cardiovascular events compared with placebo.[65]
Androgen replacement therapy for men is available as intramuscular injections of testosterone. However, the intramuscular formulation is associated with wide fluctuations in testosterone levels. Transdermal patches and gels, subcutaneous injections, and oral preparations are also available. These preparations offer more stable testosterone levels compared with the intramuscular route. The adequacy of treatment is assessed by the patient's clinical response and serum testosterone levels, targeted to the mid-normal range.[45]
PSA, haematocrit, liver function tests, and lipid levels need to be monitored periodically. Androgen replacement therapy is contraindicated in patients with prostate cancer and breast cancer.[45]
Men with secondary hypogonadism who wish to become fertile can be treated with gonadotrophins.
Growth hormone deficiency
GH treatment should be encouraged in patients with severe clinical manifestations of GH deficiency such as fatigue, poor quality of life, increased truncal obesity, unfavourable lipid profile, low muscle mass or strength, and low bone mineral density. GH therapy in adults with GH deficiency has been shown to improve quality of life and body composition.[66] Long-term GH replacement has favourable effects on bone density and cholesterol parameters.[67]
In adults, recombinant human GH is administered by subcutaneous injection once a day, usually in the evening.[68] The dose is gradually increased to minimise adverse effects, to a goal dose that maintains insulin-like growth factor-1 (IGF-1) levels within the middle of the age- and sex-adjusted normal range. If serum IGF-1 does not reach target within 2 months, the dose should be titrated in stepwise increments at 2-month intervals. The dose should be decreased if adverse effects occur or IGF-1 levels increase to above normal. Women taking oestrogen orally need higher doses than women taking transdermal oestrogen and higher doses than men.
Children with acquired or inherited growth hormone deficiency also benefit greatly from growth hormone therapy.[69][70]
Adverse effects include peripheral oedema, hypertension, rash, gynaecomastia, arthralgias, carpal tunnel syndrome, paraesthesias, hyperlipidaemia, and worsening of glucose tolerance, all of which respond to a dose reduction.
Patients on maintenance GH therapy should have serum IGF-1, fasting blood glucose and lipid profiles, haemoglobin A1c, serum free thyroxine, and body mass index performed at 6- to 12-month intervals.[70]
Antidiuretic hormone deficiency
Desmopressin is a synthetic analogue of antidiuretic hormone and is the drug of choice for antidiuretic hormone replacement. It is available in oral, intranasal, and intravenous/subcutaneous preparations. Dosages vary widely with no relationship to age, sex, or weight. Over-replacement leads to hyponatraemia and water intoxication; therefore, serum sodium levels should be checked after commencing therapy and on changing the dose. Patients should be educated about the risks of over-replacement.
It is recommended in post-pituitary surgery diabetes insipidus that clinicians attempt to discontinue desmopressin at least once during the weeks/months after surgery to determine if the posterior pituitary function has recovered.[32]
It is recommended that patients with diabetes insipidus wear an emergency bracelet or necklace documenting their diagnosis.[32]
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