Hormones Affecting Reproduction

Hormones Affecting Reproduction

Wolfgang Bäumer, C. Scott Bailey, and John Gadsby


The brain (hypothalamus) regulates overall reproduction in animals via the synthesis and release of several peptide hormones. It is affected by the physiological status of the animal, and (depending on species) by environmental cues. The best-described and most potent environmental factor is day length, which affects gonadotropin secretion by inhibiting melatonin secretion. Hypothalamic hormones are released from hypothalamic neurons in the region of the median eminence, and they reach the anterior pituitary through the hypothalamic–adenohypophyseal portal system. The two main hypothalamic hormones relevant to reproduction are gonadotropin releasing hormone (GnRH) and the prolactin-inhibitory hormone known as dopamine. The primary function of these hormones is to stimulate or inhibit the release of specific anterior pituitary hormones.

The pituitary gland is essential for the regulation of reproduction, as well as growth, stress, and intermediary metabolism. The pituitary gland consists of three separate lobes in vertebrates: the anterior (adenohypophysis), posterior (neurohypophysis), and intermediate lobes. The anterior pituitary lobe releases two distinct types of reproductive “trophic” hormones: the gonadotropins (follicle stimulating hormone, FSH, and luteinizing hormone, LH) and prolactin. Based on evolutionary and structural considerations, FSH and LH are grouped together and are glycoprotein hormones, while prolactin is related to growth hormone and is known as a somatomammotropin. A large number of reproductive states as well as a diverse group of drugs also affect their secretion and function (Wright and Malmo, 1992; Driancourt, 2001; Wiltbank et al., 2011).

Steroid hormones play vital roles in reproduction. The ovary (females) and testis (males) are the primary sources of reproductive steroid hormones in animals. The gonadotropins, FSH and LH, which are secreted in response to hypothalamic GnRH, stimulate the secretion of gonadal steroids (primarily estrogens and progesterone in the female, and testosterone and estrogen in the male). A list of hormones and drugs affecting reproduction is summarized in Table 27.1.

Table 27.1 Reproductive hormones and related agents

Hormone Indications
Gonadotropin releasing hormone (GnRH) and gonadotropins
GnRH Ovulation induction, infertility therapy
Gonadorelin (synthetic GnRH) Ovulation induction, infertility therapy

Follicle stimulating hormone (FSH)

Human chorionic gonadotropin (hCG)

Follicle development for embryo transfer

Ovulation induction, infertility therapy

Equine chorionic gonadotropin (eCG) Ovulation induction, infertility therapy
Oxytocics (ecbolics = uterotonics)
Oxytocin Labor induction, milk letdown
Altrenogest Synchronization of estrus in mare and pig
Melengestrol acetate (MGA) Synchronization of estrus in cattle
Progesterone (injectable or intravaginal delivery – CIDR) Synchronization of estrus in cattle, sheep, goats, and mare
Nandrolone Catabolic disease states in horses and dogs
Stanazolol Catabolic disease states in horses and dogs
Finasteride Benign prostatic hypertrophy in dogs
Lutalyse® Regulation of the estrous cycle in ruminants (e.g., cows)
            Induction of abortion (various species)
Estrumate® (cloprostenol) Induction of parturition in sows
            Induction of abortion (various species)

Estrous Cycle

In females, GnRH from the hypothalamus and the gonadotropins, FSH and LH, from the pituitary, regulate the estrous cycle (Figure 27.1). GnRH secreted from the hypothalamus is transported by the hypophyseal portal blood vessels to the pituitary gland, where it increases secretion of the gonadotropins, FSH and LH. Gonadotropins stimulate the secretion of gonadal steroids (estrogens and progesterone). Estrogens and progesterone have prominent stimulatory effects upon the female reproductive tract and the mammary gland, while increased circulating levels of these steroids decrease gonadotropin secretion (via negative feedback). Each estrous cycle consists of the following phases:

  1. Follicular phase (= proestrus and estrus): during the follicular phase ovarian follicles (one or more depending on the species) develop and mature, secreting increasing amounts of estrogen. These increased amounts of estrogen trigger a surge in release of LH from the pituitary gland, causing ovulation of follicles and the release of ova into the oviduct (see ** in Figure 27.1 ; except in the queen and in camelids, which are induced ovulators).
  2. Luteal phase (= metestrus and diestrus): following ovulation the remnants of each follicle develop into a corpus luteum, whose primary function is secretion of progesterone, which is required to act on the uterus to create an environment compatible with attachment/ implantation of the embryo. If the ova are not fertilized, or if embryos fail to develop or attach/ implant, the corpus luteum regresses (degenerates) in most species, leading to the cessation of progesterone secretion. However, during pregnancy, the life-span of the corpus luteum is lengthened (except in the bitch), resulting in continued progesterone secretion, which is necessary for pregnancy maintenance.
Flow chart shows hypothalamus leading to anterior pituitary leading to ovary to estrogen and progesterone.

Figure 27.1 Regulation of estrous cycle and gonadal hormone secretion. Gonadotropin-releasing hormone (GnRH) stimulates gonadotropin (follicle stimulating hormone, FSH; luteinizing hormone, LH) release, which subsequently increases ovarian steroid hormone production during the estrous cycle. Like natural estrogen and progesterone, synthetic agents such as altrenogest and melengestrol acetate (MGA) control the estrous cycle by negative feedback mechanisms.

Note: ** indicates that estrogen at high levels during the follicular phase of the natural estrous cycle, induce a positive feedback effect on the hypothalamus to generate GnRH and LH-surges, resulting in ovulation. CIDR, controlled internal drug release.

In nonpregnant polyestrous animals, during the late stages of the luteal phase of the estrous cycle, the uterus (endometrium) releases a hormone called prostaglandin F (PGF). This hormone causes corpus luteum regression and a decline in progesterone secretion. The withdrawal of progesterone removes negative feedback control on the hypothalamus/ pituitary, allowing increased gonadotropin secretion and the initiation of another estrous cycle (follicular phase followed by luteal phase). It is not secreted in detectable amounts in nonpregnant domestic carnivores (dogs and cats), resulting in a much longer return to estrus in these species. During the breeding season, estrus (female reproductive behavior induced by follicular estrogen) follows corpus luteum regression within a few days.

The onset and maintenance of cyclicity are coordinated by a complex set of negative and positive feedback mechanisms. Consequently, therapeutic administration of natural or synthetic hormones have been used extensively in the control and synchronization of estrous cycles for breeding purposes (discussed in the sections on each drug in this chapter). Progesterone-like hormones (progestins; e.g., MGA or altrenogest) are the frequently used hormones in theriogenology (Wright and Malmo, 1992).

Gonadotropin-Releasing Hormone, Gonadorelin, and Gonadotropins

The neurohormones such as GnRH (and analogs), gonadotropins (FSH and LH), prolactin and oxytocin, that are important in veterinary medicine are discussed here.

Gonadotropin-Releasing Hormone

Structure and Function

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).

Clinical Uses

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).


Gonadorelin (Cystorelin® or Factrel®) is a synthetic preparation of GnRH used to treat animals that fail to ovulate or develop follicular cysts. Deslorelin is available for horses and dogs as a SQ implant (Ovuplant®) or injectable formulation (Sucromate®). Both stimulate the synthesis and secretion of FSH and LH by interacting with GnRH receptors on the pituitary gonadotropes. However, the continuous exposure to gonadorelin or deslorelin leads to desensitization and down-regulation of GnRH receptors on pituitary gonadotropes, which may be the basis for its clinical use to limit estrus in some animals. Thus, the response to these GnRH analogs depends on the dose and time course (first stimulatory, then long-term inhibitory) (Thatcher et al., 2001; Johnson et al., 2002).


  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 9 days after GnRH will often shorten the interval to estrus (see Section Prostaglandin Analogs).
  3. Estrus synchronization in conjunction with PGF: “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 PGF2α; 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).


Veterinary products are listed in Table 27.2.

Table 27.2 Drugs affecting reproduction in animals

Class Preparation             Dosage
Follicle stimulating hormone Follitropin®-V                        
Equine chorionic gonadotropin (eCG) PG600® Combination of 400 IU eCG, 200 IU hCG Pig: 1 ml PG600 IM
Human chorionic gonadotropin (hCG) Follutein® Injection 5,000 U and 10,000 U Dog: 50–100 μg, SC, IV
            Chrorulon®             Cat: 25 μg, IM
                                    Horse:1,000 U, IV
                                    Cattle: 1,000–2,500 U, IV
                                    Sheep: 400–800 U, IV, IM
                                    Goat: 3,000 U, IV
Gonadorelin (synthetic GnRH) Cystorelin® Injection 50, 100 μg/ml Dog: 50–100 μg, SC, IV
            Factrel®             Cat: 25 μg, IM
                                    Horse: 50 mg, SC
                                    Cattle: 100 mg, IM (100 μg)
Oxytocin Pitocin® Synthetic oxytocin injection 20 U/ml Dog: 5–20 U, IM or IV once
            Syntocinon®             Cat: 2.5–5 U, IM once
                                    Pig: 10–20 U, IM
                                    Horse: 50–100 U, IV, IM, SC
                                    Cattle: 50–100 U, IV, IM, SC
                                    Sheep: 30–50 U, IV, IM, SC
Altrenogest Regumate® Solution: 2.2 mg/ml Horse: 0.044 mg/kg/day for 15 days
Progesterone Eazi-Breed CIDRTM Vaginal drug delivery devices Cattle: 1.38 g for 7 days
Stanazolol Vinstrol-V® Tablets: 2 mg Horse: 0.55 mg/kg, IM up to 4 doses once weekly
                        Injection: 50 mg/ml            
Finasteride Proscar® Tablets Dog: 0.1–0.5 mg/kg, once daily for up to 16 weeks
Prostaglandins (PGF agents)                                    
Dinoprost Lutalyse® Vials: 5 mg/ml Cattle: 25 mg, IM injection
                                    Pig: 10 mg, IM injection
                                    Horse: 1 mg/100 lb body weight, IM injection
                                    Dog: 0.1–0.2 mg/kg daily for 5 days SQ (pyometra)
                                    0.025–0.05 mg/kg q 12 h IM (termination of pregnancy)
                                    Cats: 0.1–0.25 mg/kg daily for 5 days SQ (pyometra)
                                    0.5–1 mg/kg IM for 2 injection (termination of pregnancy)
Cloprostenol Estrumate® Vials: 0.25 mg/ml Cattle, horse: 0.5 mg, IM injection


Secretion and Function

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.

Therapeutic Uses

Apart from diagnostic application in pregnancy detection kits (i.e., hCG in early pregnancy tests for humans), gonadotropins are used in (i) promoting female and male fertility and (ii) treating cryptorchidism (Table 27.2).

The gonadotropin preparations that are available and commonly used clinically in animals are: human chorionic gonadotropin (hCG), equine chorionic gonadotropin (eCG), and follicle stimulating hormone (Follitropin-V) (Table 27.2).

Human chorionic gonadotropin

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).


  1. hCG is widely used for infertility therapy. It is used in female horses for hypogonadism due to pituitary hypofunction, and to hasten or induce ovulation (Samper, 2001).
  2. hCG is used for the treatment of cystic ovaries in cows, by luteinizing the cystic structures to form a corpus luteum. The corpus luteum either regresses naturally or can be induced to regress with PGF analogs (see Section Prostaglandin Analogs). Treatment recommendations are either hCG 5000 IU IV or 10,000 IU IM. Most cows respond with the establishment of an estrous cycle within 3–4 weeks.
  3. eCG (400 IU) and hCG (200 IU) together make up PG600®, which is used in pigs to promote follicle development and induce estrous cycles in prepubertal gilts.
  4. hCG is useful for treating male infertility due to impotence, particularly in the stallion. In the male, hCG stimulates the interstitial cells to produce testosterone.
  5. hCG has been used for the correction of cryptorchidism in dogs. This practice has a low success rate in boys with congenital cryptorchidism and is considered controversial in all species (Henna et al., 2004; Thorsson et al., 2007). For details see Section Specific Uses of Reproductive Hormonal Drugs.
  6. hCG may be used in sequence with eCG for the induction of pseudopregnancy in cats and fertile estrus in dogs (Stornelli et al., 2012).

Adverse reactions and side effects

Immunological reactions such as hives and anaphylaxis due to antihormone antibody production have been reported. Prolonged usage may produce loss of efficacy, which is not reliably correlated with circulating antibody titers in horses (Roser et al., 1979). Use has been associated with prolonged and permanent infertility in cats.


Veterinary preparations and dosage are listed in Table 27.2.

Equine chorionic gonadotropin (eCG)

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).


  1. eCG is frequently used to stimulate ovarian follicular growth in the anestrous sheep or goat. It is used in combination with hCG for induction of ovulation and corpus luteum formation.
  2. eCG (400 IU) and hCG (200 IU) together make up PG600®, which is used in pigs for inducing follicular growth and estrous cycles in prepubertal gilts (see Section Human Chorionic Gonadotropin).
  3. eCG followed by hCG have been used successfully to induce fertile estrus in dogs (Stornelli et al., 2012).

Follicle stimulating hormone (FSH)

Two preparations are available: (i) Folltropin V® (porcine FSH), Vetrepharm, Canada; and (ii) Ovagen® (ovine FSH), ICP Bio, New Zealand. FSH is used to develop multiple follicles in donor cattle for ovulation (superovulation) and oocyte collection, and for production of multiple embryos which may be used in embryo transfer procedures (Hasler, 2002).


Structure and function

Feb 8, 2018 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Hormones Affecting Reproduction

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