Gonadotropin Releasing Hormone

Gonadotropin Releasing Hormone

Abstract

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1. Introduction:

Gonadotropin-releasing hormone (GnRH) is a decapeptide as shown in Figure 1 produced in the hypothalamus.  It is also known as Luteinizing Hormone-Releasing Hormone (LHRH), gonadoliberin, luliberin, gonadorelin and GnRH I. Despite various functions reported for GnRH in mammals, biochemical, molecular, neuroanatomical, pharmacological and physiological studies have mainly focused on its role as a gonadotrophin-releasing factor (Sealfon, 1997). In human, the reproductive system is regulated by a process that requires the action of hormones in the hypothalamic-pituitary-gonadal (HPG) axis loop. In adult males and females, the hypothalamic pulsatile secretion of the GnRH stimulates the expression and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. FSH and LH (gonadotropins) regulate the function of the testes and ovaries (gonads). In both sexes, FSH stimulates gamete production, and LH stimulates the expression of steroid hormones by the gonads. An increased level of steroid hormones inhibits GnRH production through a negative feedback loop (Schally AV, 2000). Over twenty isoforms of GnRH has been identified among vertebrate and protochordate species. Some of these isoforms are shown in Table 1. These structures have been conserved for more than 500 million years of evolution (Karten, 1986b). In most vertebrates at least two, and usually, three, forms of GnRH is present including GnRH-I (GnRH), GnRH-II (also known as chicken GnRH) and GnRH-III (also called lamprey GnRH-III). Studies on different forms of GnRH and its receptor among vertebrates implicated GnRH as a development element in the early evolutionary sequence. In these isoforms of GnRH, the N-terminal (pGlu-His-Trp-Ser) and C-terminal (Pro-Gly-NH₂) amino acid sequences of decapeptide are conserved as it is shown in Table 1 (Millar, 2005, Okubo K, 2008). The first identified structure was mammalian GnRH or GnRH-I (Miyamoto K, 1984). The second discovered structure in vertebrate was GnRH-II and isolated from the chicken brain (White SA, 1994). The third isoform has been called GnRH-III and was isolated from fish. As In mammalian, physiological functions and activities are restricted to GnRH I, hence, in the human GnRH-I is referred to as GnRH (Gault PM, 2003), while GnRH-II is also expressed in human(Chen A, 1998). GnRH-II and its structure are uniquely conserved from bony fish to mammals (Millar RP, 2003).

GnRH should specifically bind to the GnRH receptor (GnRH-R), on the surface of gonadotropins cells in the pituitary. This binding results in the stimulation of pituitary gonadotropin release that regulate sperm and ovum maturation and steroidogenesis in the gonads (Harrison et al., 2004). The C and N-termini of the GnRH decapeptide have a role to bind and activate its receptor (Figure 1) (Sealfon, 1997).

GnRH-R is expressed in the pituitary to control the release of gonadotropin hormones LH and FSH (Kakar SS. et al., 1992). GnRH-R is a member of a G-protein coupled receptor (GPCR) family that activates mitogen-activated protein kinase (MAPK) cascades and shows the role of GnRH-R in the regulating of cell growth and proliferation (Zvi Naor, 2000). Hence, expression of GnRH-R has been observed in pituitary adenomas (Alexander JM. and A., 1994) ovary, breast, testis, prostate (Kakar SS. et al., 1992), and granulosa-luteal cells (Derman SG. et al.). GnRH-R is also overexpressed in cancers of gonadal steroid-dependent organs. For instance, in 86% of prostate cancers, 80% of endometrial and ovarian adenocarcinomas, and 50% of breast cancer cases an overexpression of medium to high-affinity binding sites was observed for GnRH and its analogs [Halmos, 2000 #1113;Grundker, 2001 #1119].

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GnRH derivatives have been used as therapeutic agents for pharmacological interventions in reproductive dysfunctions including infertility and subfertility, fertility preservation, precious puberty, delayed puberty and endometriosis (Blumenfeld, 2017). The ligands of GnRH-R are extensively used for the treatment of different sex organ-related cancers of women and men, including hormone-sensitive tumors of prostate, breast, ovary, and endometrium. In addition to the primary action of the GnRH receptor ligands in hormone-dependent cancers, a direct growth inhibition has been reported in several hormone-independent cancers of prostate, ovary, and pancreas. It has been shown that this effect of the GnRH analogs was linked to the GnRH receptors overexpression in these tumors (Conn).

This comprehensive overview describes the pivotal roles and mechanisms of GnRH in normal reproduction and GnRH ligands in different complications

2. GnRH and GnRH-R gene expression in the hypothalamus-pituitary unit

2-1- GnRH gene expression in hypothalamus

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In human, reproductive competence is controlled centrally and linked to the expression of the gene for GnRH (Millar, 2005). A gene on a short arm of chromosome 8 (Region 8p11.2, p21) encodes a 10-kD protein that upon processing yields two biologically peptides of 10 and 56 amino acid residues called GnRH and GnRH-associated peptide (GAP) respectively (Yang-Feng Teresa L. et al., 1985). These peptides are released pulsatile into the portal vascular system that connects the hypothalamus with the pituitary; it has assumed that GAP selectively suppresses releasing of prolactin in the rat, but the physiologic role of GAP has not been well defined. GnRH starts a cascade of neuroendocrine events to change the hormone secretion in pituitary and gonadal steroid output and gametogenesis (RISSMAN et al., 1997).

The gene sequence of the coding region and signal peptide sequence is highly conserved across a wide range of species, differing only in a few amino acids (Clarke and Pompolo, 2005). The 5’ side region of GnRH gene is highly homologous between species (Nelson et al., 1998) and includes two main regions for transcription(Clarke and Pompolo, 2005).

As shown in Figure 2, the primary RNA transcript of GnRH consists of four exons and three introns. The first exon is the 5’ untranslated region (5’-UTR). The second exon encodes the signal peptide, the GnRH decapeptide, the enzymatic amidation and precursor processing site, and the first 11 amino acids of the GnRH-associated peptide (GAP). The third exon encodes the amino acids 12 to 43 of GAP; the fourth exon encodes the remaining amino acids of GAP and the 3’-untranslated region (3’-UTR). After RNA splicing, the most stable and efficient outcome is pro GnRH mRNA which is transferred to the cytoplasm for translation to the peptide (Figure 2). The yield of mature GnRH peptide can be affected by transcription rate, mRNA stability, and post-translational processing (Gore  and Roberts, 1997).

A gene on chromosome 20 encodes GnRH-II which at the amino acid level, shows 70% similarity to  GnRH differing from its structure by three amino acids. This isoform of GnRH is widely identified in the central nervous system, where it seems to act as a neuromodulator of sexual behavior (Chen A, 1998, Millar, 2005, Conn, 1984). GnRH-II is also expressed in different peripheral tissues of the female reproductive system,  like the endometrium, ovary, and placenta as well as in tumors derived from these tissues (Cheon KW, 2001, Millar RP, 2003, Hong IS, 2008).

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2-2- GnRH-R gene expression in pituitary

In humans, GnRH receptor (GnRH-R) gene is located on chromosome 4 (4q13.2,3) and includes three exons and two introns which encode for a 328 amino acid protein (Kottler ML, 1995). The type II GnRH-R coding gene consists of a missing nucleotide in the 5’ sequence which possibly caused a frameshift mutation which led to the substitution of a single base change in an Arg codon in exon 2 to a stop codon. So, the type II receptor in humans remains dysfunctional, and its function is now served by GnRH-R for GnRH-II. GnRH-II has shown high affinity to GnRH-R with a different signaling than GnRH (Millar RP, 2003).

Studying of GnRH and its receptor cDNA has been provided that GnRH and GnRH-R are expressed not only in the human reproductive organs but also in liver, heart, skeletal muscle, kidney. This evidence infers that as the main function GnRH and GnRH-R; within the regulation of FSH and LH secretion from the anterior pituitary gonadotropic cells, these may regulate the cellular growth and proliferation while any changes in receptor structure or its expression may lead to uncontrolled growth and proliferation of the cells(Sham S. Kakar and Jennes, 1995).

3. GnRH endocrine mechanism of action and regulation:

3-1- Endocrine mechanism of action of GnRH and GnRH-R ligands:

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GnRH should specifically bind to its receptor, GnRH-R, to stimulate pituitary gonadotropic cells in the anterior pituitary to release LH and FSH that regulate sperm and ovum maturation and steroidogenesis in the gonads (Conn PM. et al., 1986).

GnRH-R binding and activation are properties of the amino and carboxy-terminal domains of the peptide hormone. The amino-terminal domain is responsible for receptor activation. Other residues outside of the amino-terminal domain can affect receptor activation by altering the peptide conformation (Padula, 2005, Sealfon, 1997).

The GnRH-R is a membrane protein from the family of G-protein-coupled receptors (GPCRs) with seven hydrophobic transmembrane domains (TMD). The amino acid sequence pattern of the GnRH receptor is highly conserved among GPCRs. It contains a single amino acid chain with an extracellular amino-terminal domain and a cytosolic carboxy-terminal domain with no separate terminal signal sequence, and seven hydrophobic parts that are attached to extra and intracellular loops with their α-helical bundle form of membrane spanning (Figure 3). C- terminal of GPCRs family shows the main role to rapid desensitization of receptor, but the lack of a carboxy-terminal tail and an unusual long cytoplasmic loop (Figure 3) in GnRH-R show some unique features in its structure for slow desensitization and internalization (Tsutsumi M, 1992).

Similar to other GPCRs, disulfide bonds between cysteine (Cys) residues are substantial for GnRH-R function. Disruption of the disulfide bonds significantly decreases the affinity of the receptor to GnRH (Figure3) (Fernald and White, 1999). GnRH interacts with the extracellular face of the receptor, inducing a conformational change in the receptor to convert it into its active state. The active conformation spreads signal transduction via associated G-proteins .

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Activation of GnRH-R by GnRH causes indirect stimulation of phospholipase C (PLC), which hydrolyzes membrane phosphoinositides to inositol1,4,5-trisphosphate (IP3). IP3 mobilizes intracellular Ca²⁺ (Colonna, 2008). GnRH increases Ca²⁺ entry via voltage-operated channels into gonadotropic cells. This intensification in the concentration of cytosolic Ca²⁺ is primarily responsible for the LH release (Hislop JN et al., 2000).

The results of binding GnRH to its receptor is followed by two cellular responses. First, the rapid influx of Ca²⁺ into cells the and activation of calmodulin (an intermediate calcium-binding messenger protein). Second, stimulation of the cell production of specific membrane-associated lipid-like diacylglycerols as a second messenger to activate the enzyme protein kinase C (PKC). PKC activates the MAPK cascades which increase LH and FSH transcription in pituitary cells(Harrison et al., 2004). Consequently, activated calmodulin and activated PKC enhance the release of gonadotropins. Simultaneous, diacylglycerols amplify the action of calmodulin to increase the release of gonadotropins(Conn, 1986).

In pituitary gonadotropic cells, GnRH-R activates some other pathways like cytoskeletal remodeling and cyclic AMP-dependent protein kinase A (cAMP/PKA) pathways signaling (Perrett and McArdle, 2013, Bhave and Hoffman, 2003). cAMP/PKA pathway possibly activate gonadotropin subunit transcription that has cAMP response elements (CREs) as a promoter subunits (25). Cytoskeletal remodeling amplifies the tyrosine phosphorylation status of a series of cytoskeleton-associated proteins that have an anti-apoptotic effect on neurons and prevent neurodegeneration (Perrett and McArdle, 2013, Hsueh and Jones, 1983).

2.          Regulation of gonadotropins and GnRH:

It is a poorly understood how GnRH secretion in the hypothalamus and GnRH-R expression in the pituitary neurons are regulated. GnRH secretion can be influenced by a range of factors, such as stress, nutrition and gonadal feedback (Clarke and Pompolo, 2005).

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1.      Regulation of gonadotropins secretion at the pituitary level

GnRH is released in a pulsatile manner from the hypothalamus and binds to the GnRH-R on the cell surface of the gonadotropic cells. The secretion patterns of FSH and LH is dependent on the differential GnRH pulse frequencies and amplitudes (Savoy-Moore RT, 1987). It is not clearly known how the gonadotropic cells decode the pulsatile GnRH signal. However, it is known that multiple distinct signaling pathways are activated by varying frequencies of pulsatile GnRH. Both stimulatory and repressive transcription factors are activated by pulsatile GnRH. Increasing frequencies results in preferential secretion of LH while decreasing frequencies leads to FSH release. Apart from the fundamental role of slow and fast GnRH frequencies in activating signaling pathways for FSH and LH synthesis, other pathways such as inhibins and activins, sex steroid feedback, or epigenetic regulation are involved in the process (Thompson and Kaiser, 2014).

Intermediate-to-high GnRH pulse frequencies favor the transcription of the ß-subunit of LH, while the lower GnRH pulse frequencies result in the greater production of FSH ß-subunit. In children, GnRH secretion occurs at a low amplitude and frequency and both amplitude and frequency increase during pubertal maturation. In men, secretion of GnRH is varied with pulses occurring approximately every two hours keeping a relatively consistent pattern throughout adult life. In women, the pattern of GnRH pulses changes during the menstrual cycle to maintain cyclic ovulation. The pulse frequencies increase during the follicular phase and before ovulation, which contributes to the generation of the preovulatory gonadotropin surge (Ferris H.A., 2006). Pulse frequencies are reduced post-ovulation phase due to feedback by estradiol and progesterone from the corpus luteum (Marshall JC, 1993).

GnRH-R regulation is also depended on GnRH pulse frequency secretion. At high GnRH pulse frequencies, a Regulator of G-protein signaling (RGS)-2 inhibits signaling of the GnRH-R via a negative transcription-dependent feedback on upstream inputs (Perrett and McArdle, 2013). While GnRH interacts with GnRH-R to induce gonadotropin release, it regulates the expression of GnRH-R. The pituitary cells response to GnRH pulses to change numbers receptor due to different states of the ovulation cycle (Clarke and Pompolo, 2005). The regulation of the number of GnRH-R is also affected by gonadal steroids, inhibin, gonadotropins, and GnRH (Kovacs and Schally, 2001).  Dysfunctional GnRH pulsatility has seen in polycystic ovary syndrome, obesity, hypothalamic amenorrhea and pubertal disorders (Marques P, 2000).

The energy stress due to periods of starvation/energy-deprivation suppresses GnRH pulsatility (De Souza MJ, 2007). This suppression reduces pituitary secretion of the gonadotropins and leading to hypothalamic hypogonadism (Compagnucci C and Cebral E, 2002, Huang W, 2008 ). GnRH neurons can directly sense nutritional signals like insulin and ghrelin level (Farkas I, 2013, Evans MC, 2014, Evans and Anderson, 2017).

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2.   Regulation of GnRH by Gonadal Feedback

Estrogen and progesterone level in females and testosterone in males have been shown to play a major role in the GnRH regulation. In males, testosterone has been shown to have a strong and direct negative feedback on the GnRH secretion from the hypothalamus. Under certain circumstances, the steroids directly affect the GnRH release at the pituitary gland. Furthermore, FSH production is inhibited by the hormone inhibin, which is released by the testes (Figure 4) (Tilbrook AJ1, 1995).

In females, at the beginning of the menstrual cycle known as follicular phase, GnRH is secreted pulsatile from the mediobasal of the hypothalamus and internalized to gonadotropic cells in the anterior pituitary via its receptors. Then GnRH stimulates pulsatile releasing of FSH and LH which are leading to the follicular growth and the ovarian secretion of estrogen. The high levels of estrogen and the LH surge induce ovulation (Alyasin A. et al., 2016). After releasing of the ovum, at the beginning of the luteal phase, the secretion of progesterone increases while estrogen level drops down. At the middle of luteal phase increase at estrogen level and progesterone surges down regulates GnRH. At the end of the luteal phase, a decrease in the plasma progesterone levels leads to an increase in GnRH pulse frequencies and subsequent LH release (Clarke, 1995, Moenter, 1991, Clarke, 1987).

In males, GnRH stimulatory actions on the pituitary induce releasing of FSH and LH; FSH stimulates the production of sperm cells by signaling to undergo meiosis while LH stimulates the Leydig cells and the testes to synthesize and secrete testosterone to encourage sperm production and secondary sexual characteristics (Tilbrook and Clarke, 1995).

The effects of sex steroids on the GnRH regulation change the patterns of LH secretion in males and females during the gametogenesis cycles. It had been hypothesized that regulation of GnRH, LH, and sex steroid hormones are a direct cycle, i.e. GnRH pulses regulate LH pattern, LH pattern regulates sex steroid hormones release, and sex steroid hormones regulate GnRH (Clarke and Pompolo, 2005). However, studies showed that GnRH neurons neither express progesterone or androgen receptor (Skinner, 2001) nor do they express estrogen receptor (ER) (Herbison, 2001). Hence, the effects of steroid hormones on GnRH synthesis supposed to involve neuronal intermediaries as represented in Figure 4 (Tilbrook, 2002. ).

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Estradiol (E2) regulates GnRH secretion through positive feedback on GnRH neurons via direct and indirect pathways. E2 exerts feedback directly on GnRH neurons through rapid membrane-associated responses that involve G-proteins STX-R and GPR30 shown in Figure2. It has been demonstrated that membrane-associated receptors including GPR30 and a diphenyl acrylamide compound (STX)-sensitive receptors have an intermediary role for the prompt direct action of estradiol in the GnRH-secreting hypothalamic neurons (Figure 2)(Kenealy and Terasawa, 2011). E2 signal to GnRH neurons indirectly through various neural afferent networks and neuromodulators shown in Figure3.

3.   Regulation of GnRH secretion by neuronal intermediaries

Neurotransmitter systems and ionotropic GABA-ergic neurons have been shown to moderate the effects of estrogen (Nunemaker, 2002). This indicates while gonadal steroids such as estrogen and progesterone are the regulators of GnRH secretion, they might not have direct effects on GnRH-secreting neurons. Hence, the effects of steroid hormones on the GnRH synthesis is believed to involve neuronal intermediaries. Kisspeptin plays a key role as GnRH regulator. It is released in the infundibular nucleus and acts as an intermediate to induce negative feedback in estrogen release in humans (Tilbrook, 2002. ). Kisspeptin is a strong stimulator of the HPG axis in both animal models and humans. Kisspeptin is known as a hypothalamic peptide encoded by the KISS1 gene, and acts as a neuromodulator upstream of GnRH and sensitizes to sex steroid feedback and metabolic strings. Expression of the KISS1 gene is under the control of both estrogens and androgens (Rometo AM, 2007). Kisspeptin is now well known to be essential for the control of fertility and regulation of the sexual maturity via sex hormone-mediated secretion of gonadotropins (Pinilla L, 2012).

Kisspeptin directly sends signals to GnRH neurons, which express KISS1R. The location of kisspeptin neurons within the hypothalamus is species-specific. Kisspeptin neurons in humans are within the preoptic area (POA) and the infundibular nucleus. Kisspeptin neurons in the infundibular nucleus co-express neurokinin B and dynorphin (KNDy neurons), which auto-synoptically regulate kisspeptin secretion (through the neurokinin B receptor and kappa opioid peptide receptor). In humans, infundibular KNDy neurons transmit negative and positive feedbacks. The role of POA kisspeptin neurons in sex steroid feedback is not clear yet (Skorupskaite et al., 2014).

Regarding Kisspeptin and KNDy neurons key role in the control of GnRH release, a therapeutic approach to modify the activity of the GnRH pulse frequency based on the utilization of kisspeptin, Neurokinin B or dynorphin analogs has emerged. This approach could lead to an inefficient GnRH pulse modulation which is more efficient than a complete activation/ suppression by analogs, thus reducing the possible GnRH analogue-related side effects (Skorupskaite et al., 2014).

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4.   Other regulating factors

The role of other hormones in the GnRH regulation has also been studied. Serotoninergic system is shown to have a negative feedback on the GnRH biosynthesis, but still, the effect of serotonin on GnRH mRNA expression in females is unknown (Li, 1992). Additionally, noradrenaline represents dual effects on GnRH, and LH secretion according to steroid level status (Kalra, 1993).

The neuroactive substances that are well studied in the regulation of GnRH gene expression are glutamate, catecholamine norepinephrine, and γ-aminobutyric acid (GABA). Early studies showed that the inhibitory neurotransmitter GABA is an inhibitor of GnRH secretion (Herbison, 1998), but later studies demonstrated a stimulatory role for the GABA in  GnRH secretion through activating Ca²⁺ channels and increasing level of Ca²⁺ (Figure 2).  The effect of GABA on GnRH mRNA levels is not clear (Clarke and Pompolo, 2005). The excitatory neurotransmitter glutamate involves in the regulation of GnRH secretion. Glutamate stimulates GnRH release from hypothalamic neurons by activating the release of nitric oxide (NO).  NO increases the level of cGMP by activating guanylate cyclase which leads to stimulating GnRH secretion (Figure 2) (Dhandapani, 2000).

It has been reported that PKA activators (Wetsel WC, 1993), protein kinase C (PKC)(Eraly SA, 1995), Ca²⁺ (Krsmanovic LZ, 1992), or PLC bypass the binding of the ligand to its receptor and directly activate the intracellular second messenger cascades. These intermediates are found to have stimulatory effects on the GnRH secretion (Gore  and Roberts, 1997).

 

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4. Clinical application of GnRH and its analogs

GnRH analogs have been used as therapeutic agents for pharmacological interventions in reproductive dysfunctions including infertility and subfertility, fertility preservation, precious puberty, delayed puberty and endometriosis. GnRH analogs are also widely prescribed for reduction of gonadotoxicity side effects of chemotherapy in young women, assisted reproduction (ART)/in vitro fertilization (IVF), benign prostate hyperplasia, uterine leiomyomata, polycystic ovary syndrome (PCOS), and precocious puberty (Blumenfeld, 2017). The ligands of GnRH-R are extensively used for the treatment of different sex organ-related cancers of women and men, including hormone-sensitive tumors of prostate, breast, ovary, and endometrium (Conn).

Clinical use of GnRH is summarized in Table 2.

    5-1- GnRH analogs – Endocrine activity

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The desired aim of the treatment with GnRH analogs is to suppress the gonadotropin surge and sex steroid secretion by GnRH-R desensitization (Kovacs and Schally, 2001). Overstimulation of GnRH-R by GnRH agonists and blocking the receptor to inhibit gonadotropin release by GnRH antagonists down-regulate GnRH-R, which results in a significant reduction in endogenous sex hormones.

The molecular structure of GnRH is simple enough to synthesize thousands of active chemical analogs (agonistic and antagonistic) (Conn PM. et al., 1986, Karten, 1986a). Advanced technology in solid-phase peptide synthesis provides the automated production of short peptides (Merrifield, 1966). It has been estimated that over thousand different analogs of GnRH have subsequently been synthesized (Karten, 1986b).

The C-terminal of the GnRH decapeptide is essential for the binding to the receptor while its N-terminal is critical for both receptor binding and activation. Substitution of the primary amino acids of GnRH initially targeted the C-terminus because the N-terminal domain residues are mostly responsible for receptor activation (His and Trp) as shown in Figure 1 and Table 3. Modification of residues outside of the N-terminal domain can affect receptor activation (Padula, 2005, Sealfon, 1997). Studies demonstrated that amino acids in positions 1 and 4–10 are also essential to provide the proper conformation (Schally, 1999).

Rapid cleavage of the Gly-Leu bonds in GnRH has been shown to result in a short half-life of 2–4 min. Thus, to increase the stability of the GnRH analogs, the Gly at the 6^th  position of decapeptide has been substituted. This leads to a higher plasma half-life compared to the native peptide (Maggi et al., 2016).

5-1- 1- GnRH agonist

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Agonists of GnRH are pharmacologically more active than GnRH, and they are usually modified at the 6^th and 10^th position of the GnRH peptide chain to achieve an extended half life and receptor binding affinity (Vickery, 1986). Substitution of Gly at the 6^th position by D-amino acid increases receptor binding affinity by stabilizing the ß-turn conformation that has been shown to be essential for ligand interaction (Laimou, 2010). To increase the agonist binding affinity to GnRH-R, Gly at the 10^th position has been replaced by ethylamide residue that binds to Pro⁹. This substitution enhances the potency of the peptide for inducing receptor because Pro-alkylamine moiety induces a prolonged duration of action (Karten, 1986b). GnRH agonists such as triptorelin, leuprolide (Wilson AC, 2007), buserelin, and goserelin, have been used worldwide for nearly two decades (Laimou et al., 2012). The sequences of these GnRH agonists are shown in Table 4.

Like GnRH, GnRH agonists stimulate gonadotropins biosynthesis and secretion which causes an increase in the number of GnRH-R, gonadotropin and sex steroids secretion (Perrett and McArdle, 2013). This initial sex steroid surge is known as “flare-up reaction” and results in the down regulation of GnRH release (as shown in Figure) and followed by desensitization of the receptor in gonadotrophs (J. Waxman, 1985). While an acute injection of the GnRH agonists increases the number of GnRH-R and induces the release of LH and FSH, chronic administration results in inhibitory effects. Chronic administration of GnRH agonists continuously stimulates the receptors in the pituitary gonadotropes which then downregulates and desensitizes receptors in gonadotrophs followed by LH surge and sex steroid levels inhibition (Kovacs and Schally, 2001, Wilson AC, 2007).

In prostate cancer, the stimulatory actions of the agonists on the pituitary induces an initial release of LH and FSH, which acts to increase plasma testosterone levels until downregulation has occurred and eventual castrate levels of testosterone is reached. The flare-up response temporary worsens the existing signs with increased bone pain in up to 20% of patients. Pretreatment with an anti-androgens can reduce the flare-up side effect of GnRH agonist (Padula, 2005).

As GnRH agonist showed well controlled ovarian stimulation (COS), triptorelin is administrated for the treatment of infertility related to PCOs(Chang RJ, 1984).

In breast cancer therapy the lowest level of estrogen by ovarian steroidogenesis suppression within chemotherapy is desired. In premenopausal women, a combination therapy of GnRH agonists goserelin (Zoladex) and chemotherapy drugs like tamoxifen have shown significant therapeutic effects via causing estrogen deprivation (A.V. Schally, 1976). In advanced breast cancer, GnRH agonist within temporary convert the premenopausal women to postmenopausal can increase the chemotherapy drug choices and survival (Robertson and Blamey, 2003).

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The primary route of administration of GnRH agonist is intravenous (IV), intramuscular (IM), and subcutaneous (SC). While the oral route is the preferred route of administration by patients, poor membrane permeability and susceptible to gastrointestinal peptidase degradation, making the oral administration of GnRH agonists unsuitable with less than 0.1% bioavailability (Iqbal et al., 2012). Developing oral administration route of GnRH agonist is under further investigation (Moradi et al., 2015). The intranasal route is well tolerated in humans. However, intranasal administration is inefficient and variable with necessitating frequent large doses (Padula, 2005).

5-1-2- GnRH antagonist

GnRH antagonists produce a competitive and permanent blockade of GnRH-R and immediately stop the gonadotropins and sex steroids release. Hence, compared with the agonists their onset of action is significantly faster(Kovacs and Schally, 2001, Karten, 1986b, Hahn, 1981). GnRH antagonists have a long half life and high affinity to bind to the GnRH receptors but without activating them (Karten, 1986b). Studies showed that any changes at positions 1 and 10 notably increase the receptor binding efficiency of the peptide and substitutions at positions 2 and 3 inhibit gonadotropin release activity (A.V. Schally, 1976). It was also considered that the insertion of D-Arg or other related basic amino acid residues at 6^th  position of GnRH antagonists intensify its potential (J.E. Rivier, 1986). However, this modification induced histamine liberation resulting in transient edema and other anaphylactoid reactions. Substitution of the neutral residues like D-Cit at 6^th  position in cetrorelix has not shown any anaphylactoid reactions and more confidence for clinical use. Cetrorelix also shows the higher suppression effect rate than other GnRH antagonists (Schally, 1999).

GnRH antagonists such as Ganirelix, Cetrorelix, and Abarelix has been introduced into the clinical practice (Laimou et al., 2012). The amino acid sequence of some GnRH antagonists is shown in Table 5.

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However, studies demonstrated that chronic administration of cetrorelix also induces desensitization of gonadotropes, down-regulation of GnRH-R in the pituitary, and reduce the levels of mRNA for GnRH-R. Thus, the down-regulation of GnRH-R in pituitary by antagonists of  GnRH seems to be similar to those resulting from the agonists without flare-up reaction. Due to the absence of flare-up response within rapid down-regulation, there is no need for any combinatorial treatment with anti-sex steroids in GnRH antagonist treatments. GnRH antagonist is suggested to be more suitable for clinical practice than agonists (Al-Inany et al., 2011).

In prostate cancer, antagonists induce a down-regulation of GnRH-R in pituitary during long term administration of cetrorelix in men (Pinski J, 1996, Behre HM, 1997). In patients with advanced prostate cancer treatment with cetrorelix decreased their testosterone and prostate specific antigen (PSA) level and prostate size as measured by ultrasonography (Gonzalez–Barcena D, 1994).

Administration of GnRH antagonist can rapidly suppress LH and testosterone levels and inhibit ovarian hyperstimulation in women with polycystic ovarian disease (Hayes FJ, 1998).

5. Significant in preclinical investigation of GnRH analogs

The overexpression of GnRH-R has been well reported in many cancer tumors especially breast, ovary, endometrial and prostate cancer. Many studies have targeted GnRH or conjugation of the GnRH analog for anti-cancer therapy due to the high expression levels of GnRH receptors in some various malignant human tumor cell lines. Direct anticancer activity of GnRH analogs has been reported (Montagnani Marelli, 2007). Activation of GnRH-R in these cell lines has shown strong antiproliferative, antimetastatic, and antiangiogenic activity (Parborell F, 2008). GnRH or its analogs can be conjugated as targeting ligands to drugs and nanocarriers containing cytotoxic drugs agents. The combination can directly target cancer cells with overexpressed GnRH-R, by increasing toxic effects in tumor and spare benign cells from undesired damage (Schally AV, 2004). The uptake of the cytotoxic drug or nanocarrier occurs via an interaction between GnRH and its receptor and then endocytosis by the cell membrane. As normal cells with no overexpression of GnRH-R could not uptake the drug or nanocarrier, the side effects of the cytotoxic drug are significantly reduced (Arangoa MA, 2001).

AEZS-108 (formerly known as AN-152) is a GnRH agonist conjugation with doxorubicin that has shown anti-cancer activity in phase II clinical trial of gynecological cancers and a promising result for prostate cancer (Engel J, 2012).

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EP-100 is another successful GnRH agonist conjugated compound for a solid tumor in phase II clinical trial. In this formulation GnRH linked to a cationic membrane-disrupting peptide that interacts with the negatively charged membrane of cancer cells and inducing apoptosis through the plasma and mitochondrial membrane lysis (Curtis et al., 2014).

TB1 is a triptorelin (T) as GnRH agonist conjugated to antimicrobial peptides (B1) with anti cancer activity and has been investigated in vitro. TB1 showed anti cancer effects on breast, prostate, cervical, hepatic, leukemia, gastric epithelial and kidney cancer cell lines which had been proven to overexpress GnRH-H on their membrane (Deng et al., 2015).

GnRH has been conjugated for targeted delivery of encapsulated cisplatin in dextran nanoparticle to breast cancer to suppress cancer growth and metastasis in mice model. GnRH-nanoparticles has shown great potential for the targeted chemotherapy of metastatic breast cancer. (Li M, 2015).

The conjugation of the GnRH analog to lipophilic and glycosyl moieties has demonstrated to increase the stability and membrane permeability of the peptide, which induced variable antiproliferative effects in hormone dependent prostate and ovarian cancer cell proliferation (Varamini et al., 2017, Goodwin et al., 2015).

Due to the poor stability and low oral bioavailability of GnRH, no oral analog for clinical use exist. Lactose conjugated of GnRH not only has resulted in increased stability of peptide but also enhanced the oral bioavailability in rats significantly (Moradi et al., 2015).

A novel approach of therapeutical application of GnRH is to use vaccination against GnRH in which anti-GnRH antibodies neutralize GnRH and suppress LH and FSH secretion and decrease sex steroids levels. Vaccination with anti-GnRH has suggested the treatment for hormone-dependent cancer and as a potential alternative to surgical castration (Chang et al., 2015). Some fusion proteins as a toxoid carrier have been developed for the conjugation to anti-GnRH antibodies (Miller et al., 2008). A recombinant fusion protein consisting of GnRH and diphtheria toxoid was successful in phase I/II clinical trials of prostate cancer (Parkinson et al., 2004). A novel design of an anti-GnRH vaccine with assembling of aCD4 T-cell epitope (an influenzaHA2 light chain), the self-peptide GnRH (the B-cell epitope), and lipid moiety to improve the immunogenicity of the anti-GnRH vaccine constructs, has shown significant results for gynecological cancer in vivo and prostate cancer in vitro (Chang et al., 2015).

The further preclinical investigation is summarized in table 5.

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6. Conclusion:

Hypothalamic pulsatile secretion of the GnRH is a key control of the reproductive system by stimulating the expression and release of FSH and LH from the anterior pituitary gland to regulate the function of the gonads for gametogenesis and steroidogenesis. As a key control, GnRH has a major therapeutic role in any reproductive dysfunctions and sex-hormone dependent disease. The main therapeutic aim of GnRH is to suppress the gonadotropin surge and sex steroid secretion. Since the native GnRH is not stable, synthesize the analog of GnRH well studied for clinical use. Temporary Overstimulation of GnRH-R by GnRH agonists and permanently blocking the receptor to inhibit gonadotropin release by GnRH antagonists down-regulate GnRH-R, which results in a significant reduction in endogenous sex hormones. Targeted drug delivery investigations based on GnRH and its receptor for hormone dependent these cancers have emerged since overexpression of GnRH-R well reported in these cancer tumors. Vaccination against GnRH is a novel approach of therapeutical application of GnRH under further investigations.

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