Key Points

• Hydrocortisone is given to ACTH-deficient adults at 20 to 30 mg/ day and increased twofold to threefold during times of illness and other stresses.

• The goal of thyroid replacement is to achieve a normal serum free thyroxine concentration and clinical euthyroidism.

• Thyroid replacement will increase the clearance of cortisol, so ACTH status is assessed; if deficient or uncertain, glucocorticoid replacement is indicated before replacing thyroid hormone.

• Treatment of secondary hypogonadism depends on gender and whether fertility is desired.

• Serum IGF-1 concentration and growth rate in children are used for monitoring the effectiveness of GH replacement.

The treatment of hypopituitarism depends on the etiology and the particular hormonal deficiency. Surgical and medical interventions may be necessary for treatment of pituitary masses, infiltrative diseases, and carotid aneurysms.

Growth hormone deficiency is treated with recombinant human GH (somatotropin) preparations (Gharib et al., 2003). The recommended GH dose in children with GH deficiency is 0.04 mg/kg/day. In adults, recombinant human GH is administered subcutaneously (SC) at 0.001 to 0.008 mg/kg/day. The usual starting dose is 0.1 to 0.3 mg/day for a 70-kg man, with a typical maintenance dose of 0.3 to 0.6 mg/day. In general, women require higher doses than men because estrogen increases GH resistance. Serum IGF-1 concentration should be monitored to maintain it at the mid-normal range. Side effects that should be monitored include edema, carpal tunnel syndrome, arrhythmias, paresthesias, and glucose intolerance.

Levothyroxine (L-thyroxine) is the hormone of choice for the treatment of patients with TSH-deficient hypothyroidism (Oiknine and Mooradian, 2006). A typical replacement dose in adults is approximately 1.6 ^/kg/day. The daily requirements should be individually determined based on clinical and biochemical evaluations. The free T4 level should be in the middle to upper third of the normal range. Since thyroid replacement will increase the clearance of cortisol and uncover a subclinical adrenal insufficiency, the ACTH status should be assessed, and if deficient or uncertain, glucocor-ticoid replacement is indicated before thyroid hormone is replaced.

Treatment of secondary hypogonadism depends on the patient's gender and whether or not fertility is desired. Estradiol and progesterone replacement is the treatment of choice for secondary hypogonadism in premenopausal women who have an intact uterus and do not desire fertility. These hormones can be given cyclically or daily in fixed-dose combinations. In women with hysterectomy, estrogen replacement is sufficient, to maintain vulvar and vaginal lubrication, relieve symptoms of vasomotor instability, and reduce bone loss. Women wanting to restore fertility should be referred to specialized centers for pharmacologic induction of ovulation with exogenous pulsatile GnRH and exogenous FSH and LH treatment. GnRH can be used to restore fertility when hypothalamic disease and tertiary hypogonadism are present. Women over age 50 with secondary hypogonadism should be treated as menopausal, taking into consideration the risk/benefit ratio of estrogen replacement therapy in this age group.

Secondary hypogonadism in men is treated with testosterone replacement. Fertility can be restored in men with pituitary disease using gonadotropin replacement or human chorionic gonadotropin (hCG) therapy. GnRH can be used when hypothalamic disease is the cause of hypogonadism.

Many preparations are available for testosterone replacement. Traditional oral androgens, including 17a-methyltestosterone, fluoxymesterone, and other 17a-alkylated steroids, may cause hepatic toxicity and should be avoided. The current injectable testosterone esters, such as testosterone enanthate or testosterone cypionate, act similarly. The usual replacement dose is 200 mg IM every 2 weeks. In older men, it may be prudent to start at 50 to 75 mg weekly. Testosterone undecanoate is available as an oral preparation that does not have hepatotoxicity; because of its short half-life, however, it must be taken three times daily. Transdermal preparations can be given as patches or gels. Some androgen skin patches are associated with a high incidence of skin reactions. The commercially available transdermal gel preparations (Andro-gel 1% , Testim 1%) are applied over the trunk daily. Sublingual and buccal preparations of testosterone (e.g., Striant) are also available for replacement therapy (Mooradian and Korenman, 2006).

Side effects of testosterone replacement should be monitored carefully. Digital rectal examination (DRE), hematocrit (Hct), and prostate-specific antigen (PSA) should be measured at 3, 6, and 12 months follow-up, then annually or semiannually. Bone density measurements should be obtained at baseline and if low, at 2-year intervals to monitor improvement. In addition to monitoring clinical response, serum testosterone levels should be measured with the goal of achieving a midnormal range at 7 days after injection of testosterone enanthate or cypionate, at 3 to 10 hours after application of a testosterone patch, or at any time after application of a testosterone gel.

Absolute contraindications to testosterone therapy are prostate or breast cancer, Hct of 55% or more, or sensitivity to ingredients of the testosterone preparation (Mooradian and Korenman, 2006). Relative contraindications include obstructive sleep apnea, congestive heart failure, obstructive symptoms of prostatic hyperplasia, and Hct of 52% or greater. However, there are no data to suggest that testosterone replacement aggravates subclinical prostate cancer.

Patients with ACTH deficiency should be treated with glu-cocorticoids, preferably hydrocortisone, which the adrenals produce. Hydrocortisone replacement should be given orally as 20 to 30 mg/day divided into two doses, with two thirds of the daily dose given in the morning and one third given in the early afternoon or evening (Coursin and Wood, 2002; Toogood and Stewart, 2008). Alternatively, prednisone is given at a total daily dosage of 5 to 7.5 mg/m2/day in one to two doses. Clinical evaluation is the primary modality to assess the adequacy of cortisol replacement. It is important to increase the dose of hydrocortisone twofold to threefold during illness and other stresses. All patients should carry medical alert tags or cards to identify the need for high-dose glucocor-ticoids in an emergency. Those with secondary adrenal insufficiency usually do not require mineralocorticoid replacement because ACTH is not essential for aldosterone secretion.

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