Effect of kisspeptin on reproductive function in women with hypothalamic amenorrhea

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Amennorhea is the term used describe women who have no periods and this results in infertility. In many women the cause of the problem is due to a problem in a part of the brain called the hypothalamus and this is termed hypothalamic amenorrhea. The cause of hypothalamic amenorrhea is not known and treatments are associated with significant side effects. Recent evidence in rodents suggests that a new hormone called kisspeptin may be the missing factor in women with hypothalamic amenorrhea. Administration of kisspeptin to rodents with hypothalamic amenorrhea resulted in an increase in restoration of normal periods and fertility. Women with hypothalamic amenorrhea are infertile and have increased risk of osteoporosis and fractures, which is associated with increased illness and earlier death. The inability to have children is often devastating, and can result in severe depression which can lead to marital breakdown.
Investigators in the Department of Metabolic Medicine at Imperial College London will be carrying out the research in this application. They have considerable experience of human infusion studies in order to investigate the physiology of novel hormones and peptides and have developed protocols that ensure reliable, safe delivery of a dose of peptide into humans. The investigators have recently completed the first human infusion studies of kisspeptin in males and females and shown that it stimulates reproductive hormone secretion.
The investigators now intend to conduct a study to chronically administer subcutaneous kisspeptin to women with hypothalamic amenorrhea and investigate whether this can restore circulating reproductive hormones and restore their periods and fertility.

Technical Summary

Hypothalamic amenorrhea is defined as the cessation of menstruation due to abnormal signalling between the hypothalamus and the pituitary gland. Women with hypothalamic amenorrhea are infertile and have increased risk of osteoporosis and fractures, which is associated with increased morbidity and mortality. The inability to have children can be devastating, and has important implications for mental, social, and reproductive health. The currently treatments for women with hypothalamic amenorrhea are associated with significant side effects. In healthy women, the reproductive cycle is controlled by the hypothalamic-pituitary gonadal (HPG) axis. Gonadotrophin-releasing hormone (GnRH) released from the hypothalamus stimulates the release of the gonadotrophins, luteinising hormone (LH) and follicle-stimulating hormone (FSH), from the anterior pituitary gland. These gonadotrophins in turn regulate ovarian function. Women with hypothalamic amenorrhea typically have reduced GnRH and gonadotrophin release, without obvious hypothalamic or pituitary structural abnormalities. Kisspeptin is a novel hypothalamic neuropeptide vital to the regulation of GnRH release which may represent a common signalling pathway disturbed in all forms of hypothalamic amenorrhea. We propose to investigate whether the peripheral administration of kisspeptin to women with hypothalamic amenorrhea can restore circulating reproductive hormones and ovarian follicular development.
Kisspeptin is the endogenous neuropeptide agonist of the G protein-coupled receptor, GPR54. Kisspeptin and GPR54 play a critical role in the central regulation of the HPG axis. GPR54 mutations in humans have been shown to cause hypogonadotrophic hypogonadism and pubertal delay, and GPR54 deficient mice have abnormal sexual development, low circulating gonadotrophin concentrations, and are incapable of reproducing. These findings demonstrate that GPR54 is necessary for normal pubertal development and reproductive function. Interestingly, kisspeptin can stimulate precocious activation of the reproductive axis even in rodent models of hypothalamic amenorrhoea. We have recently demonstrated for the first time that kisspeptin administration stimulates the HPG axis in human males and females, without side effects, demonstrating that kisspeptin represents a novel tool for HPG axis manipulation in disorders of the reproductive system in humans.
We now intend to chronically administer subcutaneous kisspeptin to women with hypothalamic amenorrhea and investigate whether this can restore circulating reproductive hormones and ovarian follicular development. These experiments will provide proof of concept that kisspeptin can stimulate the reproductive axis in females with hypothalamic amenorrhea.

Publications

10 25 50
 
Description NIHR Career Development Award
Amount £105,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2008 
End 03/2017
 
Description 'Kisspeptin - hormonal regulator of puberty, reproduction and sexual emotion', Talk at Barts Endocrine Club, London November 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 'Kisspeptin - hormonal regulator of puberty, reproduction and sexual emotion'
Talk at Barts Endocrine Club, London November 2016
Year(s) Of Engagement Activity 2016
 
Description 'We all remember our first kiss' - using hormones to treat infertility, Pint of Science Festival - my talk on infertility, May 2016 London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 'We all remember our first kiss' - using hormones to treat infertility
Pint of Science Festival - my talk on infertility, May 2016 London
Year(s) Of Engagement Activity 2016
URL http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/eventssummary/event_20-5-2016-16-45-16
 
Description BBC filming, July 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact BBC filming
Year(s) Of Engagement Activity 2018
 
Description Kisspeptin - a vital trigger for puberty, Great Ormond Street Hospital Paediatric Endocrine Seminar, Jan 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Great Ormond Street Hospital Paediatric Endocrine Seminar, Jan 2016
Year(s) Of Engagement Activity 2016
 
Description Kisspeptin and fertility, Erasmus Lectures on Endocrinology, Erasmus University, Rotterdam, The Netherlands, December 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Kisspeptin and fertility
Erasmus Lectures on Endocrinology
Erasmus University, Rotterdam, The Netherlands, December 2016
Year(s) Of Engagement Activity 2016
 
Description Kisspeptin and fertility, FOCUS meeting 2016 - International Annual Scientific Meeting of the Association for Clinical Biochemistry and Laboratory Medicine, Warwick, 21st April 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Kisspeptin and fertility
FOCUS meeting 2016 - International Annual Scientific Meeting of the Association for Clinical Biochemistry and Laboratory Medicine, Warwick, 21st April 2016
Year(s) Of Engagement Activity 2016
 
Description Kisspeptin and hypothalamic amenorrhea, COST meeting Budapest, 6-9th March 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact COST meeting Budapest, 6-9th March 2016
Year(s) Of Engagement Activity 2016
 
Description Knighthood honour for 'outstanding' obesity expert 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact http://www.bbc.co.uk/news/health-16363464

Publicity regarding laboratory's work.
Year(s) Of Engagement Activity 2012
 
Description Management of Menopausal Hot Flashes: Hormonal and Nonhormonal Therapy, Oct 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Management of Menopausal Hot Flashes: Hormonal and Nonhormonal Therapy
Year(s) Of Engagement Activity 2018
 
Description Metabolic effects of kisspeptin 1st European Congress of Reproductive Endocrinology (EUCRE) Conference, Prato Italy, March 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Talk-Metabolic effects of kisspeptin
1st European Congress of Reproductive Endocrinology (EUCRE) Conference, Prato Italy, March 2018
Year(s) Of Engagement Activity 2018
 
Description Opportunities for clinical academic training, Clinical Update Meeting, Society for Endocrinology, 21st March 2016, Birmingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Clinical Update Meeting, Society for Endocrinology, 21st March 2016, Birmingham
Year(s) Of Engagement Activity 2016
 
Description Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Our work was widely disseminated in the media: http://news.bbc.co.uk/1/hi/health/7945600.stm Interview: Dr. Waljit Dhillo on BBC Radio 4 Woman's Hour (via Real Player): http://www.bbc.co.uk/radio4/womanshour/04/2009_11_tue.shtml http://www.wellcome.ac.uk/News/2009/News/WTX053781.htm http://www.channel4.com/news/articles/society/health/kiss+therapy+infertility+hope/3034102 http://latimesblogs.latimes.com/booster_shots/2009/03/new-hope-for-in.html http://www.figo.org/content/hormone-raises-fertility-stimulation-hopes http://health.msn.com/pregnancy/articlepage.aspx?cp-documentid=100234803 http://www.mickl.com/?p=3059 http://europa-gopa.info/2009/03/17/hormone-kisspeptin-shows-promise-as-fertility-treatment/ http://insciences.org/article.php?article_id=3363 http://www.irishhealth.com/article.html?level=4&id=15223 http://latestnews.virginmedia.com/news/health/2009/03/17/kiss_therapy_infertility_hope http://netdoctor.co.uk/interactive/news/theme_news_detail.php?id=19077665&tab_id=122 http://www.news-medical.net/?id=46953 http://www.thaindian.com/newsportal/sci-tech/kisspeptin-stimulates-sex-hormone-in-infertile-women_100167497.html http://www.medicalnewsbase.com/medical-research-news/hormone-kisspeptin-shows-promise-as-fertility-treatment/ http://www.bio-medicine.org/medicine-news-1/Hormone-Might-Help-Restore-Female-Fertility--39813-1/ http://esciencenews.com/articles/2009/03/16/hormone.offers.promise.fertility.treatment http://insidekerala.com/n/index.php?mod=article&cat=Health&article=42467 http://www.zeenews.com/sci-tech/health-medicine/2009-03-17/515567news.html http://www.prokerala.com/news/articles/a39900.html http://timesofindia.indiatimes.com/Health--Science/KISS-therapy-Hope-for-infertile-women/articleshow/4277155.cms http://bihartimes.com/NewsAll/2009/March/newsAll17March11.html http://www.repubblica.it/2009/03/sezioni/scienze/proteina-fertilita/proteina-fertilita/proteina-fertilita.html?ref=hpspr1 http://www.laopinion.es/secciones/noticia.jsp?pRef=2009031700_18_206878__Ciencia-y-Tecnologia-Descubren-nueva-hormona-para-ayudar-tratamientos-fertilidad http://www.focus.de/gesundheit/baby/news/hormontherapie-neustart-fuer-die-fruchtbarkeit_aid_381165.html http://www.focus.de/gesundheit/baby/news/hormontherapie-neustart-fuer-die-fruchtbarkeit_aid_381165.html http://www.sciencedaily.com/releases/2009/03/090316191139.htm http://www.ivf.net/ivf/kiss_hormone_to_give_new_hope_to_infertile_women-o4061.html http://www.newstin.com/related.a?edition=us&group_id=en-010-012049364~ilarFilter=ALL http://www.businessweek.com/lifestyle/content/healthday/625105.html

Widespread dissemination of our work to the public
Year(s) Of Engagement Activity 2009
 
Description Talk Radio with Eammon Holmes- Chocolate, Kisspeptin Oct, 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk show radio discussion on Chocolate, Kisspeptin and effects of hormones.
Year(s) Of Engagement Activity 2018
 
Description Talk at Annual Academic Meeting/ Blair Bell Research Society, Royal College of Obstetricians and Gynaecologists, London Jan 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Royal College of Obstetricians and Gynaecologists, London
Year(s) Of Engagement Activity 2018
 
Description The importance of academic medicine and supporting academic clinical careers Pathway to Independence - developing future clinical academic leaders in cancer research, Moller Centre Cambridge, Nov 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The importance of academic medicine and supporting academic clinical careers Pathway to Independence - developing future clinical academic leaders in cancer research
Moller Centre Cambridge, Nov 2016
Year(s) Of Engagement Activity 2016
 
Description Translating Novel Hormones into New Therapies for Reproductive Disorders 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Talk/Seminar Translating Novel Hormones into New Therapies for Reproductive Disorders
Year(s) Of Engagement Activity 2019
 
Description Update on clinical kisspeptin studies Kisspeptin 2017, Orlando USA, March 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Update on clinical kisspeptin studies
Kisspeptin 2017, Orlando USA, March 2016
Year(s) Of Engagement Activity 2016