Central precocious puberty—Continuous administration of a GnRH agonist is indicated for treatment of central precocious puberty (onset of secondary sex characteristics before 7–8 years in girls or 9 years in boys). Before embarking on treatment with a GnRH agonist, one must confirm central precocious puberty by demonstrating a pubertal gonadotropin response to GnRH or a “test dose” of a GnRH analog. Treatment is typically indicated in a child whose final height would be otherwise significantly compromised (as evidenced by a significantly advanced bone age) or in whom the early development of pubertal secondary sexual characteristics or menses causes significant emotional distress. While central precocious puberty is most often idiopathic, it is important to rule out central nervous system pathology with MRI imaging of the hypothalamic-pituitary area.
Treatment is most commonly carried out with either every month or every three months intramuscular depot injection of leuprolide acetate or with a once-yearly implant of histrelin acetate. Daily subcutaneous regimens and multiple daily nasal spray regimens of GnRH agonists also are available but are not recommended due to poor adherence. Treatment with a GnRH agonist is generally continued long enough to optimize adult height and allow pubertal development that is concurrent with peers. Typically treatment is continued until age 11 in females and age 12 in males.
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Other—The gonadal suppression provided by continuous GnRH agonist treatment is used in the management of advanced breast and ovarian cancer. In addition, recently published clinical practice guidelines recommend the use of continuous GnRH agonist administration in early pubertal transgender adolescents to block endogenous puberty prior to subsequent treatment with cross-gender gonadal hormones.
Gonadorelin can cause headache, light-headedness, nausea, and flushing. Local swelling often occurs at subcutaneous injection sites. Generalized hypersensitivity dermatitis has occurred after long-term subcutaneous administration. Rare acute hypersensitivity reactions include bronchospasm and anaphylaxis. Sudden pituitary apoplexy and blindness have been reported following administration of GnRH to a patient with a gonadotropinsecreting pituitary tumor.
Continuous treatment of women with a GnRH analog (leuprolide, nafarelin, goserelin) causes the typical symptoms of menopause, which include hot flushes, sweats, and headaches. Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur. Ovarian cysts may develop within the first month of therapy due to its flare effect on gonadotropin secretion and generally resolve after an additional 6 weeks. Reduced bone mineral density and osteoporosis may occur with prolonged use, so patients should be monitored with bone densitometry before repeated treatment courses. Depending on the condition being treated with the GnRH agonist, it may be possible to ameliorate the signs and symptoms of the hypoestrogenic state without losing clinical efficacy by adding back a small dose of a progestin alone or in combination with a low dose of an estrogen. Contraindications to the use of GnRH agonists in women include pregnancy and breast-feeding.
In men treated with continuous GnRH agonist administration, adverse effects include hot flushes and sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia, and injection site reactions. GnRH analog treatment of children is generally well tolerated. However, temporary exacerbation of precocious puberty may occur during the first few weeks of therapy. Nafarelin nasal spray may cause or aggravate sinusitis.