Therapy

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The treatment goals for men with hypogonadism secondary to acromegaly are the normalization of serum GH, IGF-1, and PRL levels when hyperprolactinemia is present, and the preservation and restoration of gonadotropin secretion and testicular function.

Trans-sphenoidal adenomectomy is the preferred treatment for GH-secreting tumors, inducing an endocrine remission in 80% of patients with microadenomas and 50% of macroadenomas in experienced centers (22,48,49). It is likely that many cen-

Secreting Pituitary Macroadenoma
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Fig. 2. Relationship of serum growth hormone (A) and insulin-like growth factor-1 (B) levels to serum dihydrotestosterone. (From ref. 55.)

ters do not achieve these success rates, and this is a matter of concern. Surgery relieves the compression of adjacent structures, including the pituitary stalk and surrounding pituitary cells. If gonadotropin secretion is normal before surgery, gonadal function can be restored with a decrease in the serum GH concentration. Tominaga et al. (31) reported serum testosterone concentrations of less than 300 ng/dL in 14 of 20 patients (70%) with active acromegaly. Postoperatively, the serum GH level was normalized in 14 patients, whereas testosterone concentration normalized in 11 patients (79%), restoring gonadal function (31).

Table 2

Specific Clinical Features of Acromegaly

Recent acral growth Prognathism and malocclusion Frontal bossing

Widened spaces between the teeth

Increased breadth of the nose

Generalized visceromegaly

Cardiomyopathy

Hypertension

Osteoarthrosis

Kyphosis

Carpal tunnel syndrome Proximal muscle weakness Fatigue

Deep and resonant voice Hyperhidrosis Psychological disorders

Somatostatin analogs normalize IGF-1 levels in 60% to 70% of patients and achieve tumor shrinkage in approx 40% of patients. At present, long-acting analogs of somatostatin are available and improve compliance. Octreotide-LAR consists of octreotide incorporated into microspheres of a biodegradable polymer. It is injected intramuscularly at a dose of 10, 20, or 30 mg (every 4 wk). Slow-release lanreotide is a similar preparation, and is administered intramuscularly at a dose of 30 mg (every 1-2 wk) or 60 mg (every 4 wk). A new aqueous preparation of lanreotide (lanreotide autogel) was recently introduced. This preparation achieves the same results as slow-release lan-reotide, but is longer acting. It is administered by deep subcutaneous injection at a dose of 120 mg (every 6-8 wk). Important side effects of somatostatin analogs are gallstone formation, which is generally silent; abdominal cramps, and decreased glucose tolerance (50-52). It is interesting that short-term suppression of GH and IGF-1 levels after surgery or somatostatin analog therapy for 6 mo produces a significant increase in testosterone and DHT levels in most hypogonadal patients, with associated improvement in sperm number and motility (53).

Dopamine agonists are less effective than are somatostatin analogs in normalizing IGF-1 levels (10-30% of patients) and reducing the tumor mass (<20% of cases). However, dopamine agonists are effective in GH-secreting tumors that also secrete prolactin or immunostain positive for prolactin. In addition, combined treatment with somatostatin analogs and dopamine agonists induces a greater suppression of IGF-1 compared with either drug alone and improves testicular function (22,54).

Whereas somatostatin analogs and dopamine agonists bind to specific tumor receptors and inhibit GH secretion, a new drug, pegvisomant, blocks the ability of GH to stimulate IGF-1 production, the main mediator of the somatotropic actions of GH. Pegvisomant is a genetically manipulated analog of human GH that functions as a highly selective GH receptor antagonist, normalizing IGF-1 levels in approx 90% of patients with acromegaly (55-57). However, there are no studies reporting the effects of GH antagonists on hypogonadism secondary to acromegaly at this time.

Radiation therapy should be considered for patients with contraindications to pituitary surgery or whose operation and/or medical treatment has failed. Radiotherapy induces a slow response and may damage normal pituitary tissues, leading to hypopitu-itarism and worsening hypogonadism in 50% of patients 10 yr after irradiation. It must be administered during over an extended period of approx 6 wk, and in multiple fractions to minimize radiation damage to surrounding structures (49).

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