title: GnRH and GnRH receptors in the pathophysiology of the human female reproductive system.
abstract: Human reproduction depends on an intact hypothalamic-pituitary-gonadal (HPG) axis. Hypothalamic gonadotrophin-releasing hormone (GnRH) has been recognized, since its identification in 1971, as the central regulator of the production and release of the pituitary gonadotrophins that, in turn, regulate the gonadal functions and the production of sex steroids. The characteristic peculiar development, distribution and episodic activity of GnRH-producing neurons have solicited an interdisciplinary interest on the etiopathogenesis of several reproductive diseases. The more recent identification of a GnRH/GnRH receptor (GnRHR) system in both the human endometrium and ovary has widened the spectrum of action of the peptide and of its analogues beyond its hypothalamic function.
  
  
  
  An analysis of research and review articles published in international journals until June 2015 has been carried out to comprehensively summarize both the well established and the most recent knowledge on the physiopathology of the GnRH system in the central and peripheral control of female reproductive functions and diseases.
  
  
  
  This review focuses on the role of GnRH neurons in the control of the reproductive axis. New knowledge is accumulating on the genetic programme that drives GnRH neuron development to ameliorate the diagnosis and treatment of GnRH deficiency and consequent delayed or absent puberty. Moreover, a better understanding of the mechanisms controlling the episodic release of GnRH during the onset of puberty and the ovulatory cycle has enabled the pharmacological use of GnRH itself or its synthetic analogues (agonists and antagonists) to either stimulate or to block the gonadotrophin secretion and modulate the functions of the reproductive axis in several reproductive diseases and in assisted reproduction technology. Several inputs from other neuronal populations, as well as metabolic, somatic and age-related signals, may greatly affect the functions of the GnRH pulse generator during the female lifespan; their modulation may offer new possible strategies for diagnostic and therapeutic interventions. A GnRH/GnRHR system is also expressed in female reproductive tissues (e.g. endometrium and ovary), both in normal and pathological conditions. The expression of this system in the human endometrium and ovary supports its physiological regulatory role in the processes of trophoblast invasion of the maternal endometrium and embryo implantation as well as of follicular development and corpus luteum functions. The GnRH/GnRHR system that is expressed in diseased tissues of the female reproductive tract (both benign and malignant) is at present considered an effective molecular target for the development of novel therapeutic approaches for these pathologies. GnRH agonists are also considered as a promising therapeutic approach to counteract ovarian failure in young female patients undergoing chemotherapy.
  
  
  
  Increasing knowledge about the regulation of GnRH pulsatile release, as well as the therapeutic use of its analogues, offers interesting new perspectives in the diagnosis, treatment and outcome of female reproductive disorders, including tumoral and iatrogenic diseases.
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via G. Balzaretti, 9, 20133 Milano, Italy roberto.maggi@unimi.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Maggi
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via G. Balzaretti, 9, 20133 Milano, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cariboni
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via G. Balzaretti, 9, 20133 Milano, Italy.
authors.forename: Marina Montagnani
authors.initials: MM
authors.lastname: Marelli
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via G. Balzaretti, 9, 20133 Milano, Italy.
authors.forename: Roberta Manuela
authors.initials: RM
authors.lastname: Moretti
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via G. Balzaretti, 9, 20133 Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Andrè
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via G. Balzaretti, 9, 20133 Milano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Marzagalli
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via G. Balzaretti, 9, 20133 Milano, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Limonta
mesh_terms: D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000032:analysis / Q000502:physiology*; D006066:Gonads / Q000378:metabolism; D006801:Humans; D007006:Hypogonadism; D007031:Hypothalamus; D009474:Neurons / Q000502:physiology*; D010049:Ovarian Diseases; D011966:Receptors, LHRH / Q000502:physiology*; D012098:Reproduction / Q000502:physiology*
chemical_list: C484844:GNRHR protein, human; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone
keywords: GnRH AG/ANTAG; endocrinology; female infertility; gonadotrophin; menstrual cycle