Gonadotropin-releasing hormone (GnRH) is the decapeptide hypothalamic-releasing hormone responsible for stimulating the release of gonadotropins, FSH and LH, by the anterior pituitary gonadotropes. GnRH has a very short half-life (2–4 minutes), is released intermittently (in pulses) and its release is controlled by a neural pulse generator in the hypothalamus. Such intermittent release is crucial for the proper synthesis and release of the gonadotropins, which also are released in a pulsatile fashion (Peters, 2005). Both gonadotropins and gonadal steroids regulate GnRH production in a negative feedback manner (Peters, 2005).

GnRH stimulates the synthesis and release of gonadotropins by binding to the GnRH receptor, a G protein-coupled receptor linked to the IP₃-Ca²⁺ signal transduction pathway. Pulsatile or episodic administration of GnRH stimulates the secretion of gonadotropins and forms the basis of infertility therapy and ovulation induction by increasing gonadal stimulation (see Section Clinical Uses, i). Alternatively, continuous administration of GnRH leads to desensitization and down-regulation of GnRH receptors on pituitary gonadotropes. This leads to the suppression of gonadotropin secretion and forms the basis for the clinical use of long-acting GnRH analogs (e.g., gonadorelin) to cause medical castration (see Section Clinical Use, ii) (Stout and Colenbrander, 2004).

The two principal uses of GnRH are: (i) induction of ovulation or follicular luteinization, and (ii) suppression of gonadotropin secretion (medical castration). A number of clinical GnRH analogs have been synthesized. These include synthetic GnRH (gonadorelin and buserelin) and other potent, long-acting GnRH analogs (e.g., deslorelin).

1. Ovulation induction. Gonadorelin has been used empirically to induce ovulation at the time of breeding in both cattle and horses, and is a component of the “Ovsynch” protocol. Due to physiological differences (a prolonged LH surge, lasting 24–36 hours) in horses, a single dose of gonadorelin is insufficient for reliable ovulation induction, and a long-acting formulation of deslorelin is more commonly used (Ferris et al., 2012). Gonadorelin has also been advocated for treatment of stallions with lowered libido. It is used in pulse-dosing to induce estrus in dogs and in cats with prolonged anestrus.
   
2. Cystic ovaries therapy. Gonadorelin is the drug of choice for treatment of ovarian follicular cysts (“cystic ovaries”) in cattle (and camelids). Ovarian follicular cysts in cows are defined as follicle-like structures that persist rather than ovulate. These are more than 25 mm in diameter and have been present for 10 days or more in the absence of a corpus luteum. Their occurrence is frequent in the postpartum dairy cow, but rare in beef cows (Farin and Estill, 1993). The first choice for treatment is 100 μg GnRH, which generally results in luteinization of the cystic structure, with estrus occurring in 18–23 days. The administration of PGF_2α 9 days after GnRH will often shorten the interval to estrus (see Section Prostaglandin Analogs).
   
3. Estrus synchronization in conjunction with PGF_2α: “Ovsynch” or “timed artificial insemination (AI)” protocol in cows (Lucy et al., 2004; Lamb et al., 2010; Wiltbank et al., 2011): Day 0, 100 μg GnRH; Day 7, 25 mg PGF_2α; Day 9, 100 μg GnRH; breed cattle by AI 20–24 hours after second GnRH. This allows synchronization of estrous cycles for AI without estrus detection.
   
4. Timed embryo transfer protocol, for recipient cows (Al-Katanani et al., 2002): using the “Ovsynch” treatment protocol as above, but instead of AI, transfer embryos into recipients on day 16–17. This enables preparation of recipients and embryo transfer without the need for estrus detection.
   
5. Gonadorelin is used in ferrets and induced ovulators (cats and camelids) to terminate estrus.
   
6. Gonadorelin can be used experimentally for diagnostic purposes to differentiate between pituitary and hypothalamic defects in dogs with hypogonadotropic hypogonadism.
   
7. Gonadorelin is also used to identify intact, from spayed or neutered, animals by estimating gonadorelin-stimulated release of FSH and LH.
   
8. Long-acting GnRH agonists (Ovuplant®) have been used successfully to inhibit cyclicity in domestic dogs and cats (Gobello et al., 2007).

The pituitary hormones, FSH and LH, as well as the related hormones, human chorionic gonadotropin (hCG) and equine chorionic gonadotropin (eCG or pregnant mares serum gonadotopropin, PMSG), are referred to as the “gonadotropic” hormones. Each hormone is a glycosylated heterodimer containing a common α-subunit and a distinct β-subunit that confers specificity of action. A single hypothalamic releasing factor, GnRH, controls the synthesis and release of pituitary gonadotropins, LH and FSH, in males and females. LH and FSH are synthesized and secreted by gonadotropes, which make up ∼20% of anterior pituitary cells. Gonadal steroid hormones (androgens, estrogens, and progesterone) cause feedback inhibition at the level of the pituitary and the hypothalamus to decrease pituitary gonadotropin secretion. The preovulatory surge of estrogen also can exert a stimulatory effect on the hypothalamus and thus promote pituitary gonadotropin surge release (Day, 2004). hCG is produced only in primates and is synthesized by syncytiotrophoblast cells of the placenta. eCG is produced only in equids and is secreted from the endometrial cups of pregnant mares in early pregnancy.

• In males, LH acts on testicular Leydig cells to stimulate the synthesis of androgens, primarily testosterone. FSH acts on the Sertoli cells to stimulate the production of proteins and nutrients required for the regulation of sperm production and maturation.
  
• In females, FSH and LH stimulate the growth and development of ovarian follicles, and thereby stimulate the follicle to produce estrogen, while LH induces ovulation and stimulates the developing corpus luteum (after ovulation) to secrete progesterone.

The actions of LH are mediated by the LH receptor, and those of FSH are mediated by the FSH receptor. Human chorionic gonadotropin and eCG variably stimulate one or both of the receptors, with the primary response being mediated via the LH receptor in most species. Interestingly, the chorionic gonadotropins do not reliably stimulate ovulation in the species of origin. Both of these G protein-coupled receptors are linked to adenylate cyclase and raise the intracellular levels of cAMP. There is a distinct species specificity for FSH and LH, which might lead to diminished efficacy or antibody generation in other species. hCG in particular has been shown to result in antibody production in horses (Roser et al., 1979) and has been associated with long-term or permanent infertility in some cats.

Human chorionic gonadotropin (hCG) is a gonadal stimulating hormone obtained from the urine of pregnant women. It is synthesized by syncytiotrophoblast cells of the placenta. It mainly possesses LH-like activity; therefore, it serves as a substitute for LH to promote follicle maturation, ovulation, and formation of corpus luteum. hCG is a glycoprotein and nonpituitary gonadotropin with long-lasting biological effects (>24 hours). A single injection is adequate for most reproductive uses. For example, because of its predominant LH-like activity, hCG is used to induce ovulation in the mare after an appropriate follicular size has been achieved (Wathes et al., 2003).

Equine chorionic gonadotropin (eCG; formerly known as pregnant mare serum gonadotropin, PMSG) is secreted from the endometrial cups of pregnant mares in early pregnancy in order to induce secondary and accessory corpora lutea (by developing and ovulating additional follicles) and to maintain the primary corpus luteum (and thus progesterone secretion) in the mare. Its gonadotropic activity is primarily FSH-like in the horse and increases ovarian follicular growth, but it has sufficient LH-like activity to induce ovulation or luteinization. Like hCG, eCG is a glycoprotein and nonpituitary gonadotropin with long-lasting biological effects (>24 hours). A single injection is generally sufficient for marked growth of ovarian follicles (Shelton, 1990).