Hypothalamic-Pituitary-Gonadal Axis Disorders Impacting Fertility in Both Sexes and the Potential of Kisspeptin-Based Therapies to Treat Them

Overview

Journal Handb Exp Pharmacol

Specialty Pharmacology

Date 2023 Jul 13

PMID 37439848

Authors

Maricedes Acosta-Martinez

Affiliations

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Abstract

Impaired function of the hypothalamic-pituitary-gonadal (HPG) axis can lead to a vast array of reproductive disorders some of which are inherited or acquired, but many are of unknown etiology. Among the clinical consequences of HPG impairment, infertility is quite common. According to the latest report from the World Health Organization, the global prevalence of infertility during a person's lifetime is a staggering 17.5% which translate into 1 out of every 6 people experiencing it. In both sexes, infertility is associated with adverse health events, and if unresolved, infertility can cause substantial psychological stress, social stigmatization, and economic strain. Even though significant advances have been made in the management and treatment of infertility, low or variable efficacy of treatments and medication adverse effects still pose a significant problem. However, the discovery that in humans inactivating mutations in the gene encoding the kisspeptin receptor (Kiss1R) results in pubertal failure and infertility has expanded our understanding of the mechanisms underlying the neuroendocrine control of reproduction, opening up potential new therapies for the treatment of infertility disorders. In this chapter we provide an overview of common infertility disorders affecting men and women, their recommended treatments, and the potential of kisspeptin-based pharmacotherapies to treat them.

References

Abbara A, Dhillo W . Targeting Elevated GnRH Pulsatility to Treat Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2021; 106(10):e4275-e4277. PMC: 8475200. DOI: 10.1210/clinem/dgab422. View

Abbara A, Jayasena C, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Nijher G . Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy. J Clin Endocrinol Metab. 2015; 100(9):3322-31. PMC: 4570165. DOI: 10.1210/jc.2015-2332. View

Abbara A, Clarke S, Islam R, Prague J, Comninos A, Narayanaswamy S . A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial. Hum Reprod. 2017; 32(9):1915-1924. PMC: 5850304. DOI: 10.1093/humrep/dex253. View

Abbara A, Eng P, Phylactou M, Clarke S, Richardson R, Sykes C . Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders. J Clin Invest. 2020; 130(12):6739-6753. PMC: 7685751. DOI: 10.1172/JCI139681. View

Abreu A, Toro C, Song Y, Navarro V, Bosch M, Eren A . MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons. J Clin Invest. 2020; 130(8):4486-4500. PMC: 7410046. DOI: 10.1172/JCI136564. View

Acosta-Martinez M . PI3K: An Attractive Candidate for the Central Integration of Metabolism and Reproduction. Front Endocrinol (Lausanne). 2012; 2:110. PMC: 3356143. DOI: 10.3389/fendo.2011.00110. View

Agarwal A, Parekh N, Panner Selvam M, Henkel R, Shah R, Homa S . Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility. World J Mens Health. 2019; 37(3):296-312. PMC: 6704307. DOI: 10.5534/wjmh.190055. View

Agarwal A, Baskaran S, Parekh N, Cho C, Henkel R, Vij S . Male infertility. Lancet. 2020; 397(10271):319-333. DOI: 10.1016/S0140-6736(20)32667-2. View

Agarwal A, Leisegang K, Majzoub A, Henkel R, Finelli R, Panner Selvam M . Utility of Antioxidants in the Treatment of Male Infertility: Clinical Guidelines Based on a Systematic Review and Analysis of Evidence. World J Mens Health. 2021; 39(2):233-290. PMC: 7994666. DOI: 10.5534/wjmh.200196. View

10.

Bergman A, Becher G, Blumberg B, Bjerregaard P, Bornman R, Brandt I . Manufacturing doubt about endocrine disrupter science--A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012". Regul Toxicol Pharmacol. 2015; 73(3):1007-17. DOI: 10.1016/j.yrtph.2015.07.026. View

11.

Boivin J, Vassena R, Costa M, Vegni E, Dixon M, Collura B . Tailored support may reduce mental and relational impact of infertility on infertile patients and partners. Reprod Biomed Online. 2022; 44(6):1045-1054. DOI: 10.1016/j.rbmo.2022.01.015. View

12.

Brown J, Farquhar C . Clomiphene and other antioestrogens for ovulation induction in polycystic ovarian syndrome. Cochrane Database Syst Rev. 2016; 12:CD002249. PMC: 6464012. DOI: 10.1002/14651858.CD002249.pub5. View

13.

Busch A, Hagen C, Almstrup K, Juul A . Circulating MKRN3 Levels Decline During Puberty in Healthy Boys. J Clin Endocrinol Metab. 2016; 101(6):2588-93. DOI: 10.1210/jc.2016-1488. View

14.

Cai Z, Li H . Congenital Bilateral Absence of the Vas Deferens. Front Genet. 2022; 13:775123. PMC: 8873976. DOI: 10.3389/fgene.2022.775123. View

15.

Carson S, Kallen A . Diagnosis and Management of Infertility: A Review. JAMA. 2021; 326(1):65-76. PMC: 9302705. DOI: 10.1001/jama.2021.4788. View

16.

Casoni F, Malone S, Belle M, Luzzati F, Collier F, Allet C . Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains. Development. 2016; 143(21):3969-3981. DOI: 10.1242/dev.139444. View

17.

Chon S, Umair Z, Yoon M . Premature Ovarian Insufficiency: Past, Present, and Future. Front Cell Dev Biol. 2021; 9:672890. PMC: 8141617. DOI: 10.3389/fcell.2021.672890. View

18.

Choy J, Eisenberg M . Male infertility as a window to health. Fertil Steril. 2018; 110(5):810-814. DOI: 10.1016/j.fertnstert.2018.08.015. View

19.

Christian C, Moenter S . The neurobiology of preovulatory and estradiol-induced gonadotropin-releasing hormone surges. Endocr Rev. 2010; 31(4):544-77. PMC: 3365847. DOI: 10.1210/er.2009-0023. View

20.

Christou F, Pitteloud N, Gomez F . The induction of ovulation by pulsatile administration of GnRH: an appropriate method in hypothalamic amenorrhea. Gynecol Endocrinol. 2017; 33(8):598-601. DOI: 10.1080/09513590.2017.1296948. View