Kisspeptin and other neuropeptides. New opportunities for reproductive endocrinology Nobel Laureates. Richard A Anderson

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Kisspeptin and other neuropeptides Higher centres

reproductive endocrinology E2 +ve E2 -ve Richard A

Edinburgh gonadotrope LH/FSH gonad sex steroids 1977

Stress obesity Leptin Adiponectin E2 +ve E2 -ve

Yallow LH/FSH for their discoveries concerning the

1 Kisspeptin and other neuropeptides Higher centres Timing of puberty Stress New opportunities for reproductive endocrinology E2 +ve E2 -ve Richard A Anderson Obstetrics and Gynaecology University of Edinburgh gonadotrope LH/FSH gonad sex steroids 1977 Nobel Laureates Higher centres Timing of puberty Stress obesity Leptin Adiponectin E2 +ve E2 -ve gonadotrope Andrew Schally Roger Guilleman Rosalyn Yallow LH/FSH for their discoveries concerning the peptide hormone production of the brain [LHRH: 1971] gonad sex steroids

De Roux index case Seminara et al, N Engl J Med. 23; 349(17):1614-27 LH 1.5 FSH.5 IU/L, T 5-26ng/dl (26-69) 69) test peak LH 3.6 FSH 1.7 de Roux et al.

2 De Roux index case Seminara et al, N Engl J Med. 23; 349(17): LH 1.5 FSH.5 IU/L, T 5-26ng/dl (26-69) 69) test peak LH 3.6 FSH 1.7 de Roux et al. Proc Natl Acad Sci USA 23; 1: Exon 5 GPR54 Teles et al N Engl J Med.28; 358(7): de Roux N et al. PNAS 23;1: Kisspeptin (icv) stimulates and LH in sheep Biologically active forms of kisspeptin Kisspeptin 5nmol/4 hours hours 5 1 Kp administration ineffective in gpr54-/- mice Messager S et al. PNAS 25;12: Roseweir, A.K. et al. Hum Reprod Update 29 15:23-212

29;29:392-3929 KP antagonist-234 inhibits KPinduced excitation of neurons KP antagonist-234 inhibits LH pulses

3 Kisspeptin-54 stimulates LH in normal men Development of a KP antagonist Dhillo WS et al.25 Antonia Roseweir and Bob Millar, MRC HRSU Roseweir AK et al. J Neurosci. 29;29: KP antagonist-234 inhibits KPinduced excitation of neurons KP antagonist-234 inhibits LH pulses in OVX ewes Mouse brain slices: Sue Monter, Virginia Roseweir, A. K. et al. J. Neurosci. 29;29: Ian Clarke, Monash Roseweir, A. K. et al. J. Neurosci. 29;29:

Kp antagonist 234 suppresses release in vivo KP antagonist-234 i.c.

monkeys Teresawa: Wisconsin Roseweir, A. K. et al. J. Neurosci.

opening) Roseweir, A. K. et al. J. Neurosci.

Administration of KP234 slows LH pulses in Arc but not mpoa Arcuate

4 Kp antagonist 234 suppresses release in vivo KP antagonist-234 i.c.v. delays vaginal opening in pubertal rats Pubertal female Rhesus monkeys Teresawa: Wisconsin Roseweir, A. K. et al. J. Neurosci. 29;29: Manuel Tene-Sempere, Cordoba (Kp1 advances vaginal opening) Roseweir, A. K. et al. J. Neurosci. 29;29: KP antagonist-234 inhibits the LH surge in rats Administration of KP234 slows LH pulses in Arc but not mpoa Arcuate mpoa Roseweir, A. K. et al. J. Neurosci. 29;29: Kevin O Byrne, UCL Li et al PLoS One 29 4 e8334

5 Kiss1 signaling in mouse forebrain Kisspeptin fibres innervate neurones in the human hypothalamus Brown: Black: kisspeptin Oakley, A. E. et al. Endocr Rev 29;3: E Hrabovszky et al 21 Eur J Neurosci 31, Higher centres Timing of puberty Stress GH IGF-1 KISSPEPTIN obesity Leptin Adiponectin E2 +ve E2 -ve gonadotrope LH/FSH gonad sex steroids

Kisspeptin neurones of the human hypothalamus also express neurokinin B Confocal

(green fluorescence) and dynorphin (Dyn) (red fluorescence) at low (top) and high (bottom)

Endocrinology 27;148:5752-576 E Hrabovszky et al 21 Eur J Neurosci 31, 1984-1998 27 by

6 Kisspeptin neurones of the human hypothalamus also express neurokinin B Confocal microscopic images of a section through the caudal ARC stained for both kisspeptin (Kiss) (green fluorescence) and dynorphin (Dyn) (red fluorescence) at low (top) and high (bottom) magnifications. Goodman R L et al. Endocrinology 27;148: E Hrabovszky et al 21 Eur J Neurosci 31, by Endocrine Society KNDy peptide interactions determine output Kisspeptin-54 stimulates LH in normal men Navarro VM Front Endocrinol 212, 3, 48 Dhillo WS et al.25

LH response to Kp1 in men Change in Area-under-curve of LH LH IU/l 15 13 11 9 7 5 3 1-1 -9-6 -3 3 6 9 Time (minutes)..3 mcg/kg 3. mcg/kg Vehicle LH (mu/ml) hour 1 8 6 4 2-2 Vehicle.1.3.1 * *.

7 LH response to Kp1 in men Change in Area-under-curve of LH LH IU/l Time (minutes)..3 mcg/kg 3. mcg/kg Vehicle LH (mu/ml) hour Vehicle * *.3 * ns 1 * * 3 Doses of kisspeptin (Kp1) - mcg/kg * George et al. 211 JCEM 96, E1228 George et al. 211 JCEM 96, E1228 Limited FSH response to kisspeptin Kp1 infusion increases LH pulsatility George et al. 211 JCEM 96, E1228 Hours George et al. 211 JCEM 96, E1228

Kp1 induces an LH pulse and resets the pulse generator Does ongoing stimulation cause desensitisation? B2=A B indicates resetting Chan Y et al. JCEM 211;96:E98-E915 Lower dose (1.

8 Kp1 induces an LH pulse and resets the pulse generator Does ongoing stimulation cause desensitisation? B2=A B indicates resetting Chan Y et al. JCEM 211;96:E98-E915 Lower dose (1.5 mcg/kg/hr) infusions George et al. 211 JCEM 96, E1228 Higher dose (4 mcg/kg/hr) Kp1 infusion Kp1 infusion stimulates LH and testosterone in hypogonadal men with diabetes LH(IU/L) FSH (IU/L) T (nmol/l) A: LH B: FSH C: Testosterone Baseline Kisspeptin-1 infusion George et al. 211 JCEM 96, E1228 * *** LH 25 (IU/L) LH 3 (IU/L) Hours Testosterone increased from 8 1 to nmol/l (p= 2) Hours George J et al 212, Clin Endo 15 epub

Kisspeptin-IR after sc injection of kisspeptin-54 in women LH, FSH and FEI after kisspeptin-54 sc in women (follicular phase) HA study Phases study Dhillo, W. S. et al.

9 Kisspeptin-IR after sc injection of kisspeptin-54 in women LH, FSH and FEI after kisspeptin-54 sc in women (follicular phase) HA study Phases study Dhillo, W. S. et al. J Clin Endocrinol Metab 27;92: Dhillo WS et al. J Clin Endocrinol Metab 27;92: LH after.4 nmol/kg kisspeptin-54 in women across the menstrual cycle LH response to Kp-1 is dependent on steroid environment Pre-ovulatory AUC LH Luteal Follicular Follicular Progestogen implant COCP Postmenopausal Dhillo WS et al. J Clin Endocrinol Metab 27;92: George et al 212 Hum Reprod 27:3552-9

sc bolus injection of kisspeptin-1 in the follicular phase does not stimulate LH secretion Kp1 increases LH in women

Jayasena C N et al. JCEM 211;96:E1963-E1972 Jayasena C N et al.

LH FSH E2 Kisspeptin and the LH surge 35 3 25 1st 2 LH (IU/L) 15 1 5 Last 6.

10 sc bolus injection of kisspeptin-1 in the follicular phase does not stimulate LH secretion Kp1 increases LH in women only in the preovulatory phase Explanation: little baseline sampling reduces ability to detect small increases Jayasena C N et al. JCEM 211;96:E1963-E1972 Jayasena C N et al. JCEM 211;96:E1963-E1972 Repeated administration in women with HA: desensitisation? LH FSH E2 Kisspeptin and the LH surge st 2 LH (IU/L) Last 6.4 nmol/kg KP54 sc bd x 7 days Minutes Potential application in IVF? Advantage: reduce risk of OHSS Preliminary data: nmol/kg Kp54 bolus ESHRE 213, Jayasena et al Jayasena CN et al J Clin Endocrinol Metab 29;94:

Kp54 in IVF Is Kp tone highest in the follicular phase?

AMH >1 pmol/l 1/11 women had oocyte maturation No of

determine output Kp1 increases LH pulsatility in the

homozygous mutation Pt 3: female, TACR3 homozygous

11 Kp54 in IVF Is Kp tone highest in the follicular phase? 11 women, antagonist/icsi Good responders age<35 yr, AMH >1 pmol/l 1/11 women had oocyte maturation No of oocytes = 6.2 9/11 had embryos 1 pregnancy (so far?) Chan Y et al. JCEM 212;97:E1458-E1467 KNDy peptide interactions determine output Kp1 increases LH pulsatility in the absence of NKB signalling Pts 1 and 2: males, TAC3 homozygous mutation Pt 3: female, TACR3 homozygous mutation Pt 4: male, TACR3 homozygous mutation Navarro VM Front Endocrinol 212, 3, 48 Young, J 213 Neuroendocrinol 97, 193

12 Hierarchical relationship between NKB and Kp LH KNDY neuron Normal NKB Kp NKB neuron Kp NKB and NK3R mutations LH KNDY neuron NKB Kp NKB neuron Kp Therapeutic implications Ability to manipulate a dimmer switch rather than on/off Stimulate secretion Hypothal amenorrhoea, delayed puberty, ovulation Kisspeptin (or NKB?) antagonist would slow LH pulses PCOS, endometriosis, fibroids, BPH Contraception? Complete suppression of? Prostate cancer FSH FSH Young, J 213 Neuroendocrinol 97, 193 Chronic sc administration of KISS1-35, TAK-448 or leuprolide in male rats Matsui H et al. Endocrinology 212;153:

Higher centres obesity Leptin Adiponectin Estrogen positively and negatively

Experimental Medicine grant G71682 Navarro VM Front Endocrinol 212, 3, 48 KP

colocalization of kisspeptin (Kiss) and dynorphin (Dyn) in POA.

section stained for both kisspeptin (green fluorescence) and dynorphin (red

13 Higher centres obesity Leptin Adiponectin Estrogen positively and negatively regulates Kiss1 mrna E2 +ve E2 -ve gonadotrope LH/FSH gonad sex steroids MRC Experimental Medicine grant G71682 Navarro VM Front Endocrinol 212, 3, 48 KP antagonist-234 prevents castrationinduced rise in LH in mice Lack of colocalization of kisspeptin (Kiss) and dynorphin (Dyn) in POA. Top and bottom panels are medium and high-magnification images, respectively, of a section stained for both kisspeptin (green fluorescence) and dynorphin (red fluorescence). Goodman R L et al. Endocrinology 27;148: Roseweir, A. K. et al. J. Neurosci. 29;29: by Endocrine Society

14 Kisspeptin-1 also stimulates LH secretion in men Kisspeptin-1 increases pulse frequency AUC of LH Pulses/hr LH (IU/L) George et al. 211 JCEM 96, E1228 George et al. 211 JCEM 96, E1228 Development of KP neuronal circuitry in human hypothalamus Fasting suppresses Kiss mrna but enhances response to KP Red: KP Green: NK-B Javier Tello Females: males similar Castellano, J. M. et al. Endocrinology 25;146:

Figure 1 Schematic representation of the potential mechanisms for transmitting the actions of leptin, produced by the white adipose tissue (WAT) in

hence puberty onset. Plasma kisspeptin IR and serum reproductive hormone levels after iv bolus injection of kisspeptin-1 to healthy male volunteers.

15 Figure 1 Schematic representation of the potential mechanisms for transmitting the actions of leptin, produced by the white adipose tissue (WAT) in proportion to body energy stores, to neurons in the basal forebrain, as a major output pathway for the downstream control of the gonadotropic axis and hence puberty onset. Plasma kisspeptin IR and serum reproductive hormone levels after iv bolus injection of kisspeptin-1 to healthy male volunteers. Tena-Sempere M Eur J Endocrinol 212;167: Jayasena C N et al. JCEM 211;96:E1963-E European Society of Endocrinology 211 by Endocrine Society

Edinburgh Research Explorer

Edinburgh Research Explorer Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men Citation for published version: Skorupskaite, K, Jyothis, GT, Veldhuis, JD,