Mitchell E. Geffner, MD

Disclosures

Cancer Control. 2002;9(3) 

In This Article

Treatment of Hypopituitarism

If an underlying cause is discovered on the MRI of the head, such as a tumor and/or hydrocephalus, appropriate neurosurgical intervention is required. For example, removal or debulking of a tumor and shunting for hydrocephalus, respectively, would be undertaken. Additionally, radiation therapy may be required to treat certain types of tumors. Chemotherapy is used less often to treat brain tumors. In most cases, these treatments, while potentially life-saving, do not reverse the hypopituitarism. The diagnosis of specific hormonal deficiencies present prior to any neurosurgical procedure has limited importance as all deficiencies will persist and all intact axes will likely be sacrificed during the surgical procedure. Since these patients uniformly receive high-dose glucocorticoid (dexamethasone) treatment to reduce any swelling around the tumor before and during the surgery, this serves to prevent possible adrenal insufficiency that, if present and not managed aggressively, could lead to great morbidity and even death. If DI is present preoperatively, it should be readily apparent on clinical and biochemical grounds and easily managed by a capable anesthesiologist. If GH, thyroid hormone, and/or gonadotropin deficiencies are present preoperatively and not recognized and treated, there would be no significant effect on the immediate postoperative recovery.

To treat GH deficiency in a child with remaining growth potential, replacement with GH is usually undertaken. GHRH, the hypothalamic stimulator of GH, is also approved by the US Food and Drug Administration (FDA) for this purpose, but it is effective only if the pituitary gland is fully functional. Unfortunately, optimal dosing and frequency of administration of GHRH remain unknown. Thus, GH itself is preferentially administered. It is typically given subcutaneously either with a 31-gauge needle and syringe, pen system with a 31-gauge needle, or "needleless" injector system. The usual dose range is between 0.18 and 0.3 mg per kilogram of body weight per week divided into 6 or 7 daily doses administered generally in the evening to simulate the fact that most of the GH manufactured by the body is at night during sleep (nyctohemeral rhythm).[30] A long-acting, once-or twice-monthly formulation of GH administered subcutaneously with a special 22-gauge needle has recently been approved by the FDA. If the hypopituitarism is caused by a brain tumor or its treatment, commencement of GH treatment is usually delayed for 1 year until the clinical status of the tumor is clearly defined. This practice is based on logic because there are no scientific data showing that GH causes tumor growth or recurrence. Other GH formulations delivered intranasally or by inhalation are under development. When the growth potential of a child with hypopituitarism has been fully or nearly fully attained, a transition to adult GH dosing should be considered (approximately one sixth to one third the pediatric dose). While the need for GH retesting is recommended for children with isolated GH deficiency before commencing adult dosing (as approximately 50% will have normal GH responses on retesting[31]), this should not be required when there are multiple hormone deficiencies.

One unusual circumstance, which usually arises following surgery for a craniopharyngioma, occurs when the child begins to gain excess weight and grow normally to excessively in height with documented GH deficiency and without institution of GH treatment. The cause of this paradox, dubbed "the growth without GH syndrome,"[32] is unknown, but the condition can be debilitating secondary to large weight accumulation. There is no proven treatment for this situation, although research trials with appetite depressants, anti-neurosis/anti-anxiety drugs, and analogs of somatostatin that inhibit GH, insulin, and other hormones are in progress.[33]

Oral levothyroxine (brand name or generic) is the specific treatment for central hypothyroidism, as TRH and thyrotropin (TSH), while available as drugs for dynamic testing of thyroid function, are not FDA-approved for treatment purposes. The dose of levothyroxine for treatment of central hypothyroidism in children is approximately 50 µg/m2 per day (or approximately half that used to treat primary hypothyroidism). The adequacy of the dose can be readily determined by measuring the serum level of free T4. TSH levels should not be monitored as the patients are TSH-deficient.

For documented deficiencies of LH and FSH, a more practical approach than replacing the gonadotropins is replacing the corresponding sex steroid(s), ie, estrogen (orally or by patch) and progesterone (orally) in girls and testosterone in boys (by long-acting monthly injection in the early adolescent period or by injection, daily skin patch, or daily skin gel in the late adolescent period). Some pediatric endocrinologists will also prescribe a low dose of testosterone to adolescent girls without which they may not have any pubic or axillary hair development, although this is not currently the general standard of care. These approaches will provide appropriate adolescent physical development and protect against osteoporosis but, as such, will not restore fertility. When affected subjects reach the age when they are imminently ready to have children, their hormone replacement regimens need to be altered based on the location of the damage. More specifically, if the hypothalamus is damaged and the pituitary gland is proven to be intact, treatment with the hypothalamic hormone GnRH by pump will stimulate the subject's pituitary gland to produce LH and FSH and, thus, induce egg or sperm development. If pituitary function is damaged, coordinated treatment with synthetic LH (as human chorionogonadotropin [hCG]) and FSH (either as human menopausal gonadotropin [hMG] or recombinant FSH) needs to be initiated. In either case, the treatment program is complex and requires the supervision of an experienced endocrinologist with expertise in reproductive disorders.

The most practical approach to restoration of normal adrenal function is replacement of cortisol (also known as hydrocortisone), since CRH and ACTH are approved only for testing of the adrenal axis. In children, oral hydrocortisone is usually given 2 or 3 times daily at a dose of 10 to 15 mg/m2 per day. This dose is equal to approximately 1.5 to 2 times the body's normal daily production rate of cortisol but provides appropriate replacement as only 50% to 90% of an oral dose is absorbed. Many of the commonly used replacement regimens use a higher dose in the morning than at other times of the day in an attempt to simulate the normal diurnal variation in cortisol production, in which the adrenal glands make more cortisol earlier than later in the day. Recently, liquid suspensions of cortisol were removed from the market so that only tablet formulations remain, with the lowest pill dose containing 5 mg. To provide a liquid glucocorticoid formulation as required by infants and toddlers, prednisone suspension (5 mg/5 mL) can be used, remembering that prednisone is 4 times the milligram-for-milligram potency of cortisol. Thus, a 10-mg dose of cortisol is equal to a 2.5-mg dose of prednisone. Another glucocorticoid formulation that can be used (and is available in both tablets and liquid) is dexamethasone that is 25 to 100 times more potent than cortisol. Because of the wide range of potency equivalence between dexamethasone and hydrocortisone, use of this formulation is sometimes problematic as it is easy to unintentionally overdose. As stated previously, there is no need to prescribe replacement of mineralocorticoid as, with central adrenal insufficiency, the kidney still responds normally in terms of sodium and potassium balance that is regulated by the reninangiotensin system. With significant illness, stress, and/or injury, the glucocorticoid dose must be doubled or tripled for 1 or more days depending on the length and severity of the illness, stress, and/or injury. If there is significant vomiting, a child with adrenal insufficiency should be taken to the physician or to the emergency room. As a precaution, all children should have injectable hydrocortisone at home (in the form of 100-or 250-mg Solu-Cortef Act-o-Vials). Lastly, older children (who are not with their parents all the time) and adolescents must wear Medic-Alert identification indicating the presence of hypopituitarism and adrenal insufficiency.

For the treatment of central DI, replacement of ADH may be accomplished with a number of formulations. During surgery and other critical situations, ADH should be administered as a continuous intravenous infusion. In most day-to day situations, desmopressin acetate is the preferred replacement therapy. This formulation has been structurally modified to prolong its duration of action and to eliminate any tendency of the drug to cause hypertension. Desmopressin acetate was originally developed for intranasal administration using a "rhinal tube"(allowing provision of doses as low as 2.5 µg that might be required in a young child). In infants, desmopressin acetate use requires even more attention to fluid intake and formulation. Subcutaneous administration may be the optimal method of delivery in this age group. More recently, the nasal preparation became available as a fixed-dose, metered pulse spray (similar to asthma medication), with each pulse providing a 10-µg dose. Most recently, an oral formulation of desmopressin acetate has become available as 0.1- or 0.2-mg tablets. In prescribing oral desmopressin acetate, it is important to remember that, since most of the drug is inactivated in the stomach, a 20-fold higher oral dose (compared to the nasal dose) must be prescribed.[34]

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