Approach
Where possible, the underlying cause must be addressed.
Some causes, such as prior surgery or radiation therapy, 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 adrenocorticotropic hormone (ACTH).
Patient education about hypopituitarism and the need to modify treatment during intercurrent illness is vital.
Adrenocorticotropic 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 hemorrhage 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.[73] The efficacy of glucocorticoid replacement is assessed clinically. Long-term glucocorticoid over-replacement is associated with the development of iatrogenic Cushing syndrome.[74]
There is no universal consensus on the appropriate dosing or timing of glucocorticoid replacement.
Stress dosing with intravenous or intramuscular hydrocortisone is mandatory during major surgery, trauma, or severe illnesses. All patients should carry a corticosteroid 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.[47]
Occasionally, glucocorticoid replacement may unmask an underlying central diabetes insipidus, leading to marked polyuria and nocturia.[75]
For patients with hypophysitis associated with anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) immunotherapy (e.g., ipilimumab, tremelimumab), 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 with physiologic replacement doses of corticosteroids.[76] These patients are at risk for adrenal insufficiency long-term.[77] 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 (using levothyroxine, a synthetic form of thyroxine). The goal of treatment is a normal serum free thyroxine value.
Prior to initiating levothyroxine, it is vital that ACTH deficiency is diagnosed and treated to avoid adrenal crisis (due to increased cortisol clearance).
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 ischemia.
Long-term over-replacement of thyroid hormone has been associated with an increased risk of atrial fibrillation and low bone mineral density.[3]
Prolactin deficiency
There is currently no available therapy.
Gonadotropin deficiency
Treatment of follicle-stimulating hormone and luteinizing hormone deficiency depends upon the sex of the patient and whether or not fertility is desired.
Women: hormone therapy
Estrogen therapy alleviates symptoms - namely, hot flashes - and prevents osteoporosis in women.[78] The majority of endocrinologists treat women with hypopituitarism up to age 50 years.[56] In postmenopausal women, the risks and benefits of therapy need to be assessed and discussed with the patient.
Progesterone must be given with estrogen in women with a uterus to prevent unopposed estrogenic stimulation of the endometrium. The long-term effects of estrogen therapy on cardiovascular morbidity or the development of breast malignancies in women with hypopituitarism is unknown.[79]
Estrogen therapy is usually administered via the oral or transdermal routes. Transdermal estrogen is the optimal route in patients with hypopituitarism, as it avoids the effects of oral estrogens on other hormone-binding proteins and less GH therapy needs to be administered, compared with the oral route.
In women with secondary hypogonadism who desire fertility, treatment with gonadotropins 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.[80]
Men: androgen replacement therapy
Androgen replacement is recommended in hypogonadal men; it has beneficial effects on mood, body composition, sexual function, and bone mineral density, if there are no contraindications.[47][65] Testosterone replacement therapy is not recommended in patients planning fertility or in those with elevated prostate-specific antigen (PSA) levels, elevated hematocrit, severe untreated obstructive sleep apnea, severe lower urinary tract symptoms, thrombophilia, uncontrolled heart failure, or myocardial infarction or stroke within the past 6 months.[65]
Testosterone replacement therapy 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.[81] Testosterone replacement therapy has been associated with beneficial effects in hypogonadal males with metabolic syndrome.[82]
Caution should be exercised in the administration of exogenous testosterone to hypogonadal men; it has been shown to increase the rate of adverse cardiovascular events compared with placebo.[83] In a subsequent large randomized double-blind, placebo-controlled trial of testosterone replacement therapy in men with hypogonadism and preexisting or a high risk of cardiovascular disease, there was no increase in overall risk for major adverse cardiac events in the testosterone group.[84] However, incidence of pulmonary embolism and atrial fibrillation was greater in the testosterone therapy group in this trial.[84]
The Food and Drug Administration (FDA) recommends that men on testosterone treatment be advised of the potential cardiovascular risks.[85] The European Medicines Agency (EMA) has previously reported that there is no consistent evidence of increased cardiovascular risk with testosterone therapy.[86]
Short-acting intramuscular formulations of testosterone (e.g., testosterone cypionate, testosterone enanthate) are associated with fluctuations in serum testosterone levels and need to be given every 1-4 weeks. A long-acting intramuscular formulation (testosterone undecanoate) can be given every 8-12 weeks to maintain testosterone levels within the normal physiologic range.
Transdermal testosterone gels and solutions (as well as patches in some countries), subcutaneous injections and implants, intranasal formulations, and oral formulations are available. These preparations offer stable serum testosterone levels. The adequacy of treatment is assessed by the patient's clinical response and serum testosterone levels, targeted to the mid-normal range.[65]
PSA, hematocrit, liver function tests, and lipid levels need to be monitored periodically. Androgen replacement therapy is contraindicated in patients with prostate cancer and breast cancer.[65]
Men with secondary hypogonadism who desire fertility can be treated with gonadotropins. These drugs should only be utilized by experienced practitioners, and advice should be sought from a specialist.
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, unfavorable lipid profile, low muscle mass or strength, and low bone mineral density. GH therapy in adults with GH deficiency improves quality of life and body composition.[87] Long-term GH replacement has favorable effects on bone density and cholesterol parameters.[88]
In adults, recombinant human GH is administered by subcutaneous injection once a day, usually in the evening.[89] The dose is gradually increased to minimize 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 estrogen orally need higher doses than women taking transdermal estrogen, and higher doses than men.
Children with acquired or inherited growth hormone deficiency benefit greatly from growth hormone therapy.[90]
Adverse effects include peripheral edema, hypertension, rash, gynecomastia, arthralgias, carpal tunnel syndrome, paresthesias, hyperlipidemia, and worsening of glucose tolerance, all of which respond to a dose reduction. One systematic review and meta-analysis found that GH treatment in adults with hypopituitarism appears to be relatively safe with respect to risk for pituitary tumor recurrence, malignancy, or stroke.[91]
Patients on maintenance GH therapy should have serum IGF-1, fasting blood glucose, lipid profile, hemoglobin A1c, serum free thyroxine, waist circumference, waist-to-hip ratio, and body mass index performed at 6- to 12-month intervals.[92]
Antidiuretic hormone deficiency
Desmopressin, a synthetic analog of antidiuretic hormone, 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 hyponatremia 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.
In post-pituitary surgery diabetes insipidus, clinicians should attempt to discontinue desmopressin at least once during the weeks/months after surgery to determine if the posterior pituitary function has recovered.[47]
Patients with diabetes insipidus should wear an emergency bracelet or necklace documenting their diagnosis.[47]
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