Gonadotropin-Releasing Hormone Agonists- Uses and Side Effects

Introduction

Gonadotropins are protein hormones that regulate ovarian (female reproductive organ) and testicular (male reproductive organ) functions. Hence, they are crucial for growth, sexual development, and reproduction. The human gonadotropins include follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (produced in the pituitary gland), and human chorionic gonadotropin (hCG) (made by the placenta).

The gonadotropin-releasing hormone (GnRH) agonists (GnRH-a; drugs that work similarly to GnRH) are short protein analogs of GnRH that cause potent inhibition of estrogen (female reproductive hormone) and androgen (male reproductive hormone). GnRH-a are more potent and have a sustained action than GnRH. They are extensively used in regulating reproductive hormone synthesis.

What Is the Mechanism of Action of Gonadotropin-Releasing Hormone Agonists?

GnRH agonists are derived from the native GnRH by substitution of amino acids at various positions. As a result, this substitution increases the half-life (time required for a particular drug to decrease to half of its starting dose) of GnRH. It also makes the agonist resistant to degradation. The mechanism of action of GnRH-a is:

• FSH and LH production requires a pulsatile secretion of GnRH from the hypothalamus. It allows receptors to be replenished between pulses.
• A constant GnRH-a administration causes an initial agonistic action (flare response), followed by decreased receptor concentrations. The “flare” response is due to the release of the gonadotropins already stored in the pituitary gland.
• Subsequently, it desensitizes the pituitary gland to continuous stimulation.
• After about four weeks, it induces a hypogonadotropic-hypogonadal (HH) state (decreased hormones produced by the hypothalamus and pituitary gland). HH response is due to the loss of receptors and their uncoupling from the respective hormones.

Women under GnRH-a treatment do not produce estrogen because their ovaries do not receive stimulation, and their gonadotropin levels are less. About 75 percent of women become hypogonadal within a month of treatment. #GnRH-a are given oral, intravenous (IV; through the vein), intramuscular (IM; through the muscle), nasal spray, sustained-release implants, and biodegradable microsphere injections. Higher subcutaneous doses achieve an equal effect as with IV and IM treatment.

What Are the Different Gonadotropin-Releasing Hormone Agonists and Their Uses?

1. Goserelin: It is administered parenterally (IV, IM, or subcutaneously). Goserelin is used alone or with other antiandrogens in advanced prostate cancer. Goserelin is also approved for advanced breast cancer and benign conditions such as endometriosis. Goserelin is also used for precocious puberty (early onset of puberty) and infertility.

2. Histrelin: Histrelin is a GnRH-a with potent inhibition of testosterone (in men) and estrogen (in women). It is used predominantly for advanced prostate cancer. Histrelin is associated with transient liver enzyme elevations during administration. However, it has not been linked to clinically apparent acute liver injury (ALI) cases. Its main uses are advanced prostate cancer and precocious puberty.

3. Leuprolide: It is a parenterally administered GnRH-a that causes inhibition of estrogen and androgen production and is used to treat advanced prostate cancer. Leuprolide is associated with a moderate rate of liver enzyme elevations during therapy. Leuprolide was approved in the United States (US) in 1989. It is the first-line therapy in the management of prostate cancer. Leuprolide is also used for endometriosis, uterine fibroids (growths made of muscle and fibrous tissue in the uterus), precocious puberty, and infertility.

4. Triptorelin: Triptorelin can also be used to manage advanced prostate cancer. It causes low liver enzyme elevations during treatment. But, it is not associated with ALI. Triptorelin is palliative in advanced prostate cancer and as effective as surgical castration. Triptorelin got approval in the US for prostate cancer in 2000. It is widely used as the first-line treatment of hormone-dependent cancer (cancer dependent on a hormone for growth and survival). Examples are breast cancer (dependent on estrogens) and prostate cancer (dependent on androgens such as testosterone).

Some other uses are the management of heavy menstrual bleeding and severe premenstrual syndrome (PMS). Evidence suggests that GnRH-a can also preserve ovarian function in women undergoing breast cancer chemotherapy. GnRH-a is also used for endometrial cancer (EC; cancer of the uterine lining) and atypical endometrial hyperplasia (AEH, a condition in which the uterine lining increases in size). GnRH-a has also replaced surgical castration in prostate cancer management. Various studies have shown the direct antitumor and cytotoxic (cell-killing) effects of GnRH-analogs in EC. It is because of the high affinity for GnRH-a in EC. GnRH-a also carries anti-proliferative effects for EC.

What Are the Adverse Events Related To Gonadotropin-Releasing Hormone Agonists?

1. Goserelin: It causes hypogonadism (medical castration, a condition in which drugs are used to stop reproductive hormone production). The common side effects of hypogonadism are hot flashes, loss of libido (sex drive), erectile dysfunction, depression, anxiety, nausea, diarrhea, weight gain, and fluid retention. The severe short-term adverse events include immediate hypersensitivity reactions and pituitary apoplexy (bleeding within the pituitary gland). Long-term use can cause weight gain, metabolic alterations, diabetes mellitus, and osteoporosis.

2. Histrelin: The side effects are the same as those of Goserelin. But, a potentially severe adverse event is transient tumor flare with the first dose. Transient tumor flare reaction (TFR) is associated with painful and swollen lymph nodes, fever, bone pain, and skin rash during treatment with GnRH-a.

3. Leuprolide: It has similar side effects as other GnRH-a. Leuprolide is associated with mild serum enzyme elevations in three to five percent of patients. However, values above the upper limit are rare (less than one percent of recipients). The serum enzyme elevations during leuprolide therapy are transient and asymptomatic (without any symptoms).

4. Triptorelin: It has similar side effects as other GnRH-a.

Other side effects of GnRH-a are vaginal dryness, headache, mood changes, and gynecomastia (an increase in the breast gland tissue in men). Long-term therapy can result in metabolic abnormalities, worsening of diabetes mellitus, and osteoporosis. A serious side effect is the temporary worsening of prostate cancer due to testosterone spike with the initial GnRH-a dose. Single instances of ALI have been reported with some GnRH-a (Histrelin and Goserelin). Another notable adverse event is decreased bone mineral density (BMD). To prevent bone loss, the doctor prescribes a progestin or estrogen and progestin combination (add-back therapy) that can prevent bone loss associated with prolonged GnRH-a use. Furthermore, it can also reduce the severity of hot flashes.

Conclusion

GnRH-a is a powerful therapeutic approach to treating many reproductive disorders. Ongoing research and clinical studies can further identify their indications. Awareness regarding these drugs is pertinent among clinicians. Also, the synthesis of GnRH-a with better tolerance might open new research prospects and clinical applications. As a result, the GnRH-a can be used to its full potential.