title: Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis.
abstract: BACKGROUND
  Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown.
  
  
  OBJECTIVE
  The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA.
  
  
  METHODS
  We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed.
  
  
  RESULTS
  On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 +/- 3.5 IU/liter; FSH, 9.1 +/- 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 +/- 2.2 IU/liter, P < 0.05; FSH, 0.5 +/- 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed.
  
  
  CONCLUSIONS
  Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.
authors.affiliation: Department of Investigative Medicine, Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom.
authors.forename: Channa N
authors.initials: CN
authors.lastname: Jayasena
authors.forename: Gurjinder M K
authors.initials: GM
authors.lastname: Nijher
authors.forename: Owais B
authors.initials: OB
authors.lastname: Chaudhri
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Murphy
authors.forename: Amita
authors.initials: A
authors.lastname: Ranger
authors.forename: Adrian
authors.initials: A
authors.lastname: Lim
authors.forename: Daksha
authors.initials: D
authors.lastname: Patel
authors.forename: Amrish
authors.initials: A
authors.lastname: Mehta
authors.forename: Catriona
authors.initials: C
authors.lastname: Todd
authors.forename: Radha
authors.initials: R
authors.lastname: Ramachandran
authors.forename: Victoria
authors.initials: V
authors.lastname: Salem
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Stamp
authors.forename: Mandy
authors.initials: M
authors.lastname: Donaldson
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
authors.forename: Waljit S
authors.initials: WS
authors.lastname: Dhillo
mesh_terms: D000328:Adult; D000568:Amenorrhea / Q000188:drug therapy*; D015992:Body Mass Index; D001835:Body Weight; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006062:Gonadotropins / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007031:Hypothalamus / Q000503:physiopathology; D059648:Kisspeptins; D007986:Luteinizing Hormone / Q000097:blood; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013618:Tachyphylaxis / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D015430:Weight Gain; D055815:Young Adult
chemical_list: D006062:Gonadotropins; C106628:KISS1 protein, human; D059648:Kisspeptins; D025521:Tumor Suppressor Proteins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone