12 research outputs found
Kisspeptin and neurokinin B in the regulation of the human hypothalamic-pituitary-gonadal axis
Background: Hypothalamic kisspeptin and neurokinin B (NKB) are central
regulators of GnRH and thus gonadotropin (LH and FSH) secretion. Men and
women with loss-of-function mutations in NKB-kisspeptin pathway show
hypogonadotropic pubertal delay with reduced GnRH/LH pulsatility. Studies in
patients with defects in NKB signalling suggest that kisspeptin is functionally
downstream of NKB, although there are very limited data on the relevance of the
NKB pathway in normal men or women, and no hierarchical data on this. The studies
described in this thesis have investigated the interaction between these neuropeptides
in the control of human reproduction in conditions of varying sex-steroid
environment, and in states of fast and slow LH secretion (men, menopause, various
stages across the menstrual cycle).
Overall hypothesis: Pharmacological blockade of NKB signalling will decrease LH
secretion by modulating GnRH/LH pulsatility, indicating the involvement of the
NKB pathway in normal human reproductive function. It is also hypothesised that
this will not abrogate the stimulatory kisspeptin response, revealing a functional
hierarchy whereby NKB signalling is upstream of kisspeptin.
Research strategy: A specific neurokinin-3 receptor antagonist (NK3R antagonist,
AZD4901) was administered 40 mg twice daily orally for 7 days with and without
kisspeptin-10 (KP-10) challenge. Response of reproductive hormones (serum and
urinary where applicable) was measured. LH was sampled every 10 minutes for 8
hours to assess LH pulsatility by blinded deconvolution.
Results:
Role of neurokinin B and kisspeptin in healthy men
Six healthy men underwent LH pulsatility study pre-treatment and on day 7 of NK3R
antagonist administration with iv KP-10 bolus (0.3 μg/kg) at 6 hours. NK3R
antagonist reduced LH and testosterone secretion, whilst stimulatory LH response to
KP-10 was unaffected. LH pulse frequency was unchanged by the NK3R antagonist
but basal (nonpulsatile) and pulsatile LH secretion was markedly reduced.
Role of neurokinin B and kisspeptin in postmenopausal women
Eleven postmenopausal women underwent LH pulsatility study pre-treatment and on
day 7 of NK3R antagonist administration with iv KP-10 bolus (0.3 μg/kg) at 6 hours.
NK3R antagonist decreased LH secretion. Basal (nonpulsatile) LH secretion also fell
and while LH pulse frequency did not change in a group as a whole, it did fall in the
8 of 11 postmenopausal womenwith hot flushes. These women reported a reduction
in hot flush frequency (3.4±1.2 vs 1.0± 0.6 flushes/day with NK3Ra, p=0.008) and
severity whilst on NK3R antagonist. LH response to KP-10 was minimal and
unaffected by the NK3R antagonist.
Role of neurokinin B across different phases of menstrual cycle
The effect of NK3R antagonist on ovarian function was compared in early follicular
(n=13), late follicular (n=6) and luteal phase (n=6) to no treatment control cycle.
Early follicular: NK3R antagonist was commenced from cycle day 5-6. The diameter
of the leading follicle was smaller than in controls at the end of treatment (9.3±0.4 vs
15.1±0.9 mm, p<0.0001). Serum estradiol was also reduced and the endometrium
was thinner. Although NK3R antagonist had no effect on LH pulse frequency, basal
(nonpulsatile) LH secretion was decreased, suggesting that NKB modulates GnRH
secretion. After stopping treatment, follicle development resumed and estradiol
secretion increased thereby delaying the LH surge in 11/13 women (LH surge cycle
day 22±1 vs 15±1, p=0.0006). The delayed LH surge and ovulation were confirmed
by a similarly delayed rise in urinary progesterone and prolonged cycle length.
NK3R antagonist did not affect luteal function.
Late follicular: NK3R antagonist was administered from the emergence of a
dominant follicle (≥12mm). Whilst there was an LH surge in all treated cycles,
estrogen feedback was perturbed by the NK3R antagonist, as there was increased
variation in the timing of LH surge compared to control cycle. NK3R antagonist had
no effect on the growth of a dominant follicle and luteal function was unaffected.
Luteal: NK3R antagonist was administered from day +2-3 of the disappearance of
the dominant follicle. NK3R antagonist reduced the variation in the timing of peak
estradiol secretion. Estradiol and progesterone concentrations remained unchanged,
suggesting that luteal function was overall unaffected by this treatment. No
difference in mean LH was observed, although LH pulsatility was not assessed.
Role of neurokinin B and kisspeptin in the mid-cycle LH surge
A model of follicular phase (cycle day 9-11) administration of estradiol (200μg/day)
to induce LH secretion at 48 hours was used in twenty women, mimicking LH
surge. In this model, KP-10 infusion (4μg/kg/hr for 7 hours) enhanced LH secretion,
the response of which was directly correlated with estrogen concentration, indicating
a role of kisspeptin in estrogen feedback. Pre-treatment with NK3R antagonist
decreased LH pulse frequency and whilst the immediate LH response to KP-10 was
unaffected, it blunted the duration of this response and abolished the relationship
between estradiol and kisspeptin-induced LH secretion.
Conclusions: These data indicate the role of NKB-KP pathway in regulating human
reproductive function and that this is via the modulation of pulsatile GnRH secretion.
Whilst NKB is predominantly proximal to kisspeptin, the hierarchy is more complex
than simply linear in the control of human HPG axis. Manipulation of NKB-KP
signalling has therapeutic potential in regulating GnRH/LH secretion in wide range
of clinical settings, including contraception, sex-steroid dependent disorders and in
the treatment of hot flushes
Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men
OBJECTIVE : Patients with mutations of neurokinin B (NKB) and its receptor show hypogonadotrophic
hypogonadism, but there is little evidence for the importance of this pathway
in reproductive function in normal men, or its functional hierarchy with kisspeptin.
DESIGN : An open label study wherein men (n = 6) were administered the NK3R antagonist
MLE4901 40 mg orally twice a day for 7 days. Kisspeptin-10
(0.3 μg/kg iv bolus)
was given before and on day 7 of NK3R antagonist treatment.
PATIENTS : Subjects were healthy men.
MEASUREMENTS : Reproductive hormones were measured before and during the NK3R
antagonist administration, including frequent sampling on two occasions for analysis
of pulsatile LH secretion.
RESULTS : LH, FSH and testosterone secretion were decreased during NK3R antagonist
administration. LH showed a biphasic response, being reduced after 24 hours of treatment
(4.5 ± 0.6 IU/L pretreatment to 1.7 ± 0.2 IU/L, P < .05), with partial recovery thereafter,
but it was again decreased on day 7 (2.5 ± 0.6 IU/L, P < .05 vs pretreatment). FSH
secretion was also suppressed, with a similar temporal pattern to that of LH. Testosterone
secretion was decreased from 24 hours (18.4 ± 1.6 pretreatment vs 5.6 ± 1.5 nmol/L,
P < .01) and remained suppressed throughout the treatment period. Analysis of LH pulsatility
showed that both basal and pulsatile LH secretion were markedly suppressed but
there was no detected change in LH pulse frequency. Kisspeptin-10
stimulated LH secretion,
with similar responses before and during NK3R antagonist administration.
CONCLUSIONS : These data demonstrate a central role for NKB/NK3R in the physiological
regulation of reproductive function in men, and that this is functionally upstream of kisspeptin-mediated
GnRH secretion.The Wellcome
Trust Scottish Translational Medicine and
Therapeutics Initiative STMTI and MRC grant
G0701682 to RAA and RPMhttp://wileyonlinelibrary.com/journal/cenam2017Mammal Research Institut
Neurokinin B Receptor Antagonism in Women with Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial
Context:
Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high secretion levels of LH and T. Currently, there is no treatment licensed specifically for PCOS.
Objective:
The objective of this study was to investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and T concentrations and thereby presenting a novel therapeutic approach to the management of PCOS.
Design:
This study is a double-blind, double-dummy, placebo-controlled, phase 2 trial.
Settings:
University hospitals and private clinical research centers were included.
Participants:
Women with PCOS aged 18–45 years participated.
Intervention:
Intervention included AZD4901 (a specific neurokinin-3 [NK3] receptor antagonist) at a dose of 20, 40, or 80 mg/day or matching placebo for 28 days.
Main Outcome Measure:
Change from baseline in the area under the LH serum concentration–time curve over 8 hours (area under the curve) on day 7 relative to placebo was measured.
Results:
Of a total 67 randomized patients, 65 were evaluable. On day 7, the following baseline-adjusted changes relative to placebo were observed in patients receiving AZD4901 80 mg/day: 1) a reduction of 52.0% (95% confidence interval [CI], 29.6–67.3%) in LH area under the curve; 2) a reduction of 28.7% (95% CI, 13.9–40.9%) in total T concentration; and 3) a reduction of 3.55 LH pulses/8 hours (95% CI, 2.0–5.1) (all nominal P &lt; .05).
Conclusions:
The NK3 receptor antagonist AZD4901 specifically reduced LH pulse frequency and subsequently serum LH and T concentrations, thus presenting NK3 receptor antagonism as a potential approach to treating the central neuroendocrine pathophysiology of PCOS.
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Interactions between neurokinin B and kisspeptin in mediating estrogen feedback in healthy women
CONTEXT: Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women. OBJECTIVE: To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion. DESIGN: Women were treated with neurokinin-3 receptor (NK3R) antagonist followed by transdermal estradiol to induce LH secretion 48 hours later, with kisspeptin-10 or vehicle infusion during estrogen administration in a 2-way crossover study. SETTING: Clinical research facility. PATIENTS OR OTHER PARTICIPANTS: Healthy females with regular menses. INTERVENTION(S): NK3R antagonist AZD4901 40 mg twice daily orally was taken from cycle day 4–6 for 6 days (n = 10, with 10 no treatment controls). Transdermal estradiol patches (200 μg/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 μg/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle. MAIN OUTCOME MEASURE(S): Plasma gonadotropin and estradiol secretion. RESULTS: After an initial suppression, LH secretion was increased 48 hours after estradiol treatment. Kisspeptin-10 increased LH secretion during the inhibitory phase, and LH remained elevated beyond the discontinuation of kisspeptin-10 infusion. NK3R antagonist decreased LH pulse frequency (0.5 ± 0.2 vs 0.7 ± 0.2 pulses/h, P < .05) and stimulated FSH response to kisspeptin-10 infusion (10.7 ± 11.0 vs 5.0 ± 3.6 IU/L, P < .05) with a nonsignificant rise in LH. The duration of LH response was blunted, with LH being lower at 48 hours (7.5 ± 4.8 vs 15.0 ± 11.4 IU/L, P < .05). CONCLUSIONS: These data demonstrate that NKB signaling regulates GnRH/LH secretion in normal women, and is predominantly proximal to kisspeptin in mediating estrogenic positive and negative feedback on LH secretion
The kisspeptin-GnRH pathway in human reproductive health and disease
BACKGROUND: The discovery of kisspeptin as key central regulator of GnRH secretion has led to a new level of understanding of the neuroendocrine regulation of human reproduction. The related discovery of the kisspeptin-neurokinin B-dynorphin (KNDy) pathway in the last decade has further strengthened our understanding of the modulation of GnRH secretion by endocrine, metabolic and environmental inputs. In this review, we summarize current understanding of the physiological roles of these novel neuropeptides, and discuss the clinical relevance of these discoveries and their potential translational applications. METHODS: A systematic literature search was performed using PUBMED for all English language articles up to January 2014. In addition, the reference lists of all relevant original research articles and reviews were examined. This review focuses mainly on published human studies but also draws on relevant animal data. RESULTS: Kisspeptin is a principal regulator of the secretion of gonadotrophins, and through this key role it is critical for the onset of puberty, the regulation of sex steroid-mediated feedback and the control of adult fertility. Although there is some sexual dimorphism, both neuroanatomically and functionally, these functions are apparent in both men and women. Kisspeptin acts upstream of GnRH and, following paracrine stimulatory and inhibitory inputs from neurokinin B and dynorphin (KNDy neuropeptides), signals directly to GnRH neurones to control pulsatile GnRH release. When administered to humans in different isoforms, routes and doses, kisspeptin robustly stimulates LH secretion and LH pulse frequency. Manipulation of the KNDy system is currently the focus of translational research with the possibility of future clinical application to regulate LH pulsatility, increasing gonadal sex steroid secretion in reproductive disorders characterized by decreased LH pulsatility, including hypothalamic amenorrhoea and hypogonadotropic hypogonadism. Conversely there may be scope to reduce the activity of the KNDy system to reduce LH secretion where hypersecretion of LH adds to the phenotype, such as in polycystic ovary syndrome. CONCLUSIONS: Kisspeptin is a recently discovered neuromodulator that controls GnRH secretion mediating endocrine and metabolic inputs to the regulation of human reproduction. Manipulation of kisspeptin signalling has the potential for novel therapies in patients with pathologically low or high LH pulsatility
Neurokinin 3 Receptor Antagonism Reveals Roles for Neurokinin B in the Regulation of Gonadotropin Secretion and Hot Flashes in Postmenopausal Women
OBJECTIVES : Neurokinin B (NKB) and kisspeptin are obligate
for normal gonadotropin secretion, and links between gonadotropin-
releasing hormone (GnRH) pulsatility and vasomotor
symptoms have been proposed. Using a selective NKB
receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic
state in menopausal women was explored.
METHODS : Eleven postmenopausal women were administered
the NK3R antagonist MLE4901 at 40 mg twice daily
orally for 7 days. Ten-minute blood sampling for 8 h was performed
before and on the last day of NK3R antagonist treatment
for luteinising hormone (LH) pulsatility analysis with
kisspeptin-10 (0.3 μg/kg i.v. bolus) administered at 6 h on
both days. Hot flash frequency and severity were self-reported
for 7 days before and during NK3R antagonist administration.
RESULTS : LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L
(p < 0.05) after 7 days of NK3R antagonist treatment, with
no change in follicle-stimulating hormone (FSH). Basal (non-The Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative (STMTI; 102419/Z/13/A), MRC grant G0701682 and AstraZeneca [AZD4901/MLE4901.http://www.karger.com/Journal/Home/223855am2018Mammal Research Institut