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Gonadotropin-Releasing Hormone and Its Receptor in Normal and Malignant Cells

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Gonadotropin-Releasing Hormone and Its Receptor in Normal and Malignant Cells Endocrine-Related Cancer (2004) 11 725–748 REVIEW Gonadotropin-releasing hormone and its receptor in normal and malignant cells G S Harrison1, M E Wierman1,2, T M Nett 3 and L M Glode1 1University of Colorado Health Sciences, Department of Medicine, 4200 East Ninth Avenue, Denver, Colorado 80262, USA 2Veterans Affairs Medical Center, Denver, Colorado 80220, USA 3Colorado State University, Department of Physiology, Animal Reproduction and Biotechnology Laboratory, Fort Collins, Colorado 80523, USA (Requests for offprints should be addressed to L M Glode; Email: [email protected]) Abstract Gonadotropin-releasing hormone (GnRH) is the hypothalamic factor that mediates reproductive competence. Intermittent GnRH secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. LH and FSH then stimulate sex steroid hormone synthesis and gametogenesis in the gonads to ensure reproductive competence. The pituitary requires pulsatile stimulation by GnRH to synthesize and release the gonadotropins LH and FSH. Clinically, native GnRH is used in a pump delivery system to create an episodic delivery pattern to restore hormonal defects in patients with hypogonadotropic hypogonadism. Agonists of GnRH are delivered in a continuous mode to turn off reproductive function by inhibiting gonadotropin production, thus lowering sex steroid production, resulting in medical castration. They have been used in endocrine disorders such as precocious puberty, endometriosis and leiomyomata, but are also studied extensively in hormone-dependent malignancies. The detection of GnRH and its receptor in other tissues, including the breast, ovary, endometrium, placenta and prostate suggested that GnRH agonists and antagonists may also have direct actions at peripheral targets. This paper reviews the current data concerning differential control of GnRH and GnRH receptor expression and signaling in the hypothalamic–pituitary axis and extrapituitary tissues. Using these data as a backdrop, we then review the literature about the action of GnRH in cancer cells, the utility of GnRH analogs in various malignancies and then update the research in novel therapies targeted to the GnRH receptor in cancer cells to promote anti-proliferative effects and control of tumor burden. Endocrine-Related Cancer (2004) 11 725–748 and FSH. Continuous stimulation of pituitary GnRH receptors (GnRHR) by exogenously administered GnRH agonists, rather than pulsatile stimulation, desensitizes Introduction and down-regulates GnRHRs (Neill 2002). The ultimate Gonadotropin-releasing hormone (GnRH) is the effect of this chronic stimulation of the pituitary GnRHRs hypothalamic factor that mediates reproductive compe- is to decrease LH and FSH production, with subsequent tence (Wierman 1996, Neill 2002). Intermittent GnRH decreases in circulating sex steroid levels (Wierman 1996, secretion from the hypothalamus acts upon its receptor in Neill 2002). the anterior pituitary to regulate the production and Clinically, native GnRH is used in a pump delivery release of the gonadotropins luteinizing hormone (LH) system to create an episodic delivery pattern to restore and follicle-stimulating hormone (FSH) (see Fig. 1). LH hormonal defects in patients with hypogonadotropic and FSH then stimulate sex steroid hormone synthesis hypogonadism (Pitteloud et al. 2002). On the other and gametogenesis in the gonads to ensure reproductive hand, agonists of GnRH are delivered in a continuous competence. The pituitary requires pulsatile stimulation mode to turn off reproductive function by inhibiting by GnRH to synthesize and release the gonadotropins LH gonadotropin production (Labrie et al. 1981), thus Endocrine-Related Cancer (2004) 11 725–748 DOI:10.1677/erc.1.00777 1351-0088/04/011–725 # 2004 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/25/2021 05:45:52AM via free access Harrison et al.: GnRH and its receptor Hypothalamus GnRH (-) GnRHR Pituitary (-) FSH LH Gonadal peptides Gonad Sex Steroids Gametogenesis E, P, T Secondary Sex Characteristics Figure 1 The hypothalamic–pituitary–gonadal axis. Secretion of GnRH from the hypothalamus occurs in a pulsatile fashion and is partially responsible for controlling the number of GnRHRs in the pituitary gland and controls synthesis and secretion of FSH and LH. These gonadotropins in turn regulate function of the testes and ovaries. E, estrogen; P, progesterone; T, testosterone. lowering sex steroid production, resulting in medical promote anti-proliferative effects and control of tumor castration (Labrie 1991, Labrie et al. 1993, Huirne & burden. Lambalk 2001). They have been used in endocrine disorders such as precocious puberty, endometriosis and GnRH expression and control leiomyomata, but are also studied extensively in hormone- dependent malignancies (Labrie et al. 1980, 1996, Huirne GnRH expression profile & Lambalk 2001). More recently, pure GnRH antagonists At least two isoforms of GnRH have been identified in the have been devised to directly block GnRHRs on the mammalian central nervous system (CNS), GnRH-I and pituitary and inhibit LH and FSH production (Huirne & GnRH-II. GnRH-I is the hypothalamic decapeptide Lambalk 2001). Currently, they are indicated for the responsible for LH and FSH secretion from the anterior treatment of female infertility as adjunct therapy during pituitary originally isolated by Guillemin and Schally ovarian hyperstimulation for in vitro fertilization and are (Guillemin 1967). GnRH-II was initially discovered as under active investigation in various malignancies (Labrie chicken GnRH-II and displays a diffuse pattern of et al. 1996, Huirne & Lambalk 2001). localization in most tissues (Densmore & Urbanski The detection of GnRH and its receptor in other 2003, Pawson et al. 2003). In the CNS, GnRH-II has tissues including the breast, ovary, endometrium, placenta been hypothesized to play a role in the behavioral and prostate suggested that GnRH agonists and antago- components of reproduction (Pawson et al. 2003). The nists may also have direct actions at peripheral targets. genes for human GnRH-I and GnRH-II are on chromo- This paper will review the current data concerning somes 8 and 20 respectively (Wierman 1996, Limonta et differential control of GnRH and GnRHR expression al. 2003). Both isoforms of GnRH are decapeptides that and signaling in the hypothalamic–pituitary axis and are characterized by post-translational modifications, extrapituitary tissues. Using these data as a backdrop, we including the pyro-glutamic acid at the amino termini will then review the literature about GnRH action in and amidated glycine at the carboxy termini. GnRH-I is cancer cells, the utility of GnRH analogs in various conserved throughout evolution and has been identified in malignancies and then update the research in novel both vertebrates and invertebrates (Wierman 1996, therapies targeted to the GnRHR in cancer cells to Limonta et al. 2003). GnRH-I shares a 60% identity 726 www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/25/2021 05:45:52AM via free access Endocrine-Related Cancer (2004) 11 725–748 between mammals and tunicates, whereas GnRH-II is couple with Gqa and function in the inositol phosphate even more highly conserved with 100% identity between signaling pathway (see Fig. 2). In functional studies that birds and mammals (Wierman 1996, Limonta et al. 2003). measured inositol phosphate production, primate GnRH- GnRH-I is synthesized as a prohormone, human prepro- I receptors demonstrated an approximate 48-fold selec- GnRH that contains 92 amino acids. A signal peptide is tivity for GnRH-I versus GnRH-II (Gault et al. 2003, contained in the first 23 amino acids, followed by the Pawson et al. 2003, Terasawa 2003). Conversely, GnRH- GnRH decapeptide, a 3 amino acid cleavage site and a 56 II receptors demonstrated a 421-fold preference for amino acid product known as GnRH-associated peptide GnRH-II versus GnRH-I (Gault et al. 2003, Pawson et (GAP). Post-translational processing of GnRH involves al. 2003, Terasawa 2003). Unlike the unique GnRH-II cleaving by a prohormone convertase, removal of basic receptor and most other GPCRs, the GnRH-I receptor amino acids by a carboxypeptidase, amino-terminus contains no large cytoplasmic C-terminal tail (Clayton & modification through the action of glutaminyl cyclase Catt 1981, Grundker et al. 2002a, McArdle et al. 2002, and carboxy-terminus modification by peptidylglycine a- Kang et al. 2003, Ruf et al. 2003). The C-terminus of both amidating mono-oxygenase (Wierman 1996, Limonta et types of receptors are phosphorylated in response to al. 2003). This enzymatic processing produces mature GnRH, leading to receptor desensitization. The GnRHR- GnRH and GAP. A physiologic role for GAP has not I is on chromosome 4 and the GnRHR-II is on 1q been determined, although it has been postulated to act as (Pawson et al. 2003). Although the mRNA for GnRHR-II a prolactin-inhibitory factor. has been cloned from monkey as well as rodent and fish species, these investigators have suggested that it is not Control of GnRH expression expressed into a functional protein in the mouse or human, making the physiologic relevance of GnRHR-II There are approximately 1500–2000 GnRH neurons in the in human biology a question for further study (Pawson et human (in contrast to the 800 neurons in the rodent) that al. 2003).
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