Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis.
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.
Jayasena
Channa N
CN
Department of Investigative Medicine, Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom.
Nijher
Gurjinder M K
GM
Chaudhri
Owais B
OB
Murphy
Kevin G
KG
Ranger
Amita
A
Lim
Adrian
A
Patel
Daksha
D
Mehta
Amrish
A
Todd
Catriona
C
Ramachandran
Radha
R
Salem
Victoria
V
Stamp
Gordon W
GW
Donaldson
Mandy
M
Ghatei
Mohammad A
MA
Bloom
Stephen R
SR
Dhillo
Waljit S
WS
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
D006062:Gonadotropins; C106628:KISS1 protein, human; D059648:Kisspeptins; D025521:Tumor Suppressor Proteins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone