Chorionic gonadotropin is approved for the treatment of prepubertal cryptorchidism. Prepubertal boys were treated with intramuscular injections of hCG for 2–6 weeks. However, this clinical use is no longer supported because the long-term efficacy of hormonal treatment of cryptorchidism (~20%) is much lower than the long-term efficacy of surgical treatment (>95%), and because of concerns that early childhood treatment with hCG treatment has a negative impact on germ cells in addition to increasing the risk of precocious puberty.
In the United States, chorionic gonadotropin has a black-box warning against its use for weight loss. The use of hCG plus severe calorie restriction for weight loss was popularized by a publication in the 1950s claiming that the hCG selectively mobilizes body fat stores. This practice continues today, despite a preponderance of subsequent scientific evidence from placebo-controlled trials that hCG does not provide any weight loss benefit beyond the weight loss associated with severe calorie restriction alone.
In women treated with gonadotropins and hCG, the two most serious complications are OHSS and multiple pregnancies. Stimulation of the ovary during ovulation induction often leads to uncomplicated ovarian enlargement that usually resolves spontaneously. However, OHSS may occur and can be associated with ovarian enlargement, intravascular depletion, ascites, liver dysfunction, pulmonary edema, electrolyte imbalance, and thromboembolic events. Although OHSS is often self-limited, with spontaneous resolution within a few days, severe disease may require hospitalization and intensive care. Triggering the final oocyte maturation with hCG carries the risk of inducing OHSS. GnRH agonists also induce this final oocyte maturation by promoting the release of endogenous gonadotropin stores from the hypophysis and can be used as an alternative to hCG. Use of the GnRH agonist trigger dramatically reduces the risk of OHSS, owing to the short half-life of the GnRH agonist–induced endogenous LH surge.
The probability of multiple pregnancies is greatly increased when ovulation induction and assisted reproductive technologies are used. In ovulation induction, the risk of a multiple pregnancy is estimated to be 5–10%, whereas the percentage of multiple pregnancies in the general population is closer to 1%. Multiple pregnancies carry an increased risk of complications, such as gestational diabetes, preeclampsia, and preterm labor. For in vitro fertilization procedures, the risk of a multiple pregnancy is determined primarily by the number of embryos transferred to the recipient. A strong trend in recent years has been to transfer single embryos.
Other reported adverse effects of gonadotropin treatment are headache, depression, edema, precocious puberty, and (rarely) production of antibodies to hCG. In men treated with gonadotropins, the risk of gynecomastia is directly correlated with the level of testosterone produced in response to treatment.
Gonadotropin-releasing hormone is secreted by neurons in the hypothalamus. It travels through the hypothalamic-pituitary venous portal plexus to the anterior pituitary, where it binds to G protein-coupled receptors on the plasma membranes of gonadotrophs. Pulsatile GnRH secretion is required to stimulate the gonadotrophs to produce and release LH and FSH.
Sustained nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both women and men, resulting in hypogonadotropic hypogonadism. GnRH agonists are used to induce gonadal suppression in men with prostate cancer or children with central precocious puberty. They are also used in women who are undergoing assisted reproductive technology procedures or who have a gynecologic problem that is benefited by ovarian suppression.
A. Structure