Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men

Skorupskaite, Karolina; George, Jyothis T.; Veldhuis, Johannes D.; Millar, Robert P.; Anderson, Richard A.

doi:10.1111/cen.13445

Cited by 23 publications

(18 citation statements)

References 44 publications

(65 reference statements)

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“…28 Insulin raises testosterone 29 30 providing a pathway from GnRH1 to IHD. Other potential drivers of GnRH1 include neurokinins, 31 32 nitric oxide, 33 aspartate/glutamate, 34 35 gamma-aminobutyric acid 36 and dynorphin. 37 Notably, a common feature of several successful treatments for IHD is suppression of the male reproductive axis, including spironolactone, a known anti-androgen, statins, 38 digoxin, 39 nitric oxide 40 and some hypertensives.…”

Section: Discussionmentioning

confidence: 99%

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

Schooling

2018

Preprint

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BackgroundAccording to well-established evolutionary biology theory reproduction trades-off against longevity, implying that upregulating the reproductive axis might drive major diseases. We assessed whether the central driver of reproduction gonadotropin-releasing hormone 1 (GnRH1) had a causal effect on the leading cause of global morbidity and mortality, i.e. ischemic heart disease (IHD). As a contrast we similarly examined the role of GnRH2 because it is more a driver of female sexual behavior.MethodsWe applied strong (p-value <5×10−6) and independent genetic predictors of GnRH1 and GnRH2 to an extensively genotyped IHD case (n=76,014) - control (n=264,785) study using multiplicative random effects inverse variance weighted (IVW), weighted median, MR-Egger and MR-PRESSO estimates.ResultsGnRH1, predicted by 11 genetic variants, was positively associated with IHD (IVW odds ratio (OR) 1.04 per effect size, 95% confidence interval (CI) 1.01 to 1.08), but GnRH2, predicted by 15 genetic variants, was not (IVW OR 0.98, 95% CI 0.95 to 1.02).ConclusionsGnRH1 is a potential IHD genetic target. Apart from demonstrating a central tenet of evolutionary biology in humans, our study suggests that existing treatments and environmental factors targeting GnRH1, its drivers or consequences could be re-purposed to prevent and treat IHD. Given, the importance of reproduction to the human species, many such exposures likely exist.

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Section: Discussionmentioning

confidence: 99%

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

Schooling

2018

Preprint

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“…Proof‐of‐principle studies have demonstrated that kisspeptin administration can increase LH pulse frequency and LH secretion in obese men with low testosterone . Conversely, administration of a neurokinin receptor 3 antagonist decreased gonadotrophin and testosterone secretion in healthy men …”

Section: What Are the Mechanisms Underlying The Obesity‐associated Hpmentioning

confidence: 99%

Hypogonadism and male obesity: Focus on unresolved questions

Grossmann

2018

Clinical Endocrinology

107

116

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Obesity, increasing in prevalence globally, is the clinical condition most strongly associated with lowered testosterone concentrations in men and presents as one of the strongest predictors of receiving testosterone treatment. While low circulating total testosterone concentrations in modest obesity primarily reflect reduced concentrations of sex hormone binding globulin, more marked obesity can lead to genuine hypothalamic-pituitary-testicular axis (HPT) suppression. HPT axis suppression is likely mediated via pro-inflammatory cytokine and dysregulated leptin signalling and aggravated by associated comorbidities. Whether oestradiol-mediated negative hypothalamic-pituitary feedback plays a pathogenic role requires further study. Although the obesity-hypogonadism relationship is bidirectional, the effects of obesity on testosterone concentrations are more substantial than the effects of testosterone on adiposity. In markedly obese men submitted to bariatric surgery, substantial weight loss is very effective in reactivating the HPT axis. In contrast, lifestyle measures are less effective in reducing weight and generally only associated with modest increases in circulating testosterone. In randomized controlled clinical trials (RCTs), testosterone treatment does not reduce body weight, but modestly reduces fat mass and increases muscle mass. Short-term studies have shown that testosterone treatment in carefully selected obese men may have modest benefits on symptoms of androgen deficiency and body composition even additive to diet alone. However, longer term, larger RCTs designed for patient-important outcomes and potential risks are required. Until such trials are available, testosterone treatment cannot be routinely recommended for men with obesity-associated nonclassical hypogonadism. Lifestyle measures or where indicated bariatric surgery to achieve weight loss, and optimization of comorbidities remain first line.

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“…27 Interestingly, while NKB potently stimulates LH release under physiological sex steroid levels in rodents, 26,28,[30][31][32][33][34] sheep, [35][36][37][38][39][40] goats, [41][42][43] cattle, 44 and nonhuman primates, [45][46][47] its gonadotropin-stimulating role is not observed in adult healthy men 48 or women in the follicular phase. 49 Nonetheless, NK3R antagonists decrease overall circulating LH levels and LH pulsatility in humans, [50][51][52][53] suggesting that the role of NKB to elicit kisspeptin/GnRH pulses is conserved in all species, but the optimization of the delivery method and/or concentration of the NK3R agonists is required to observe a stimulation of LH release in humans.…”

Section: New Advances On the Gonadotropin Release Activity Of Tachykimentioning

confidence: 99%

Novel Biology of Tachykinins in Gonadotropin-Releasing Hormone Secretion

León

Navarro

2019

Semin Reprod Med

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The tachykinin family of peptides, composed of the neurokinins A and B (NKA, NKB) and substance P are involved in the central control of gonadotropin-releasing hormone (GnRH) release through a variety of neuronal circuitries that mediate the activation of Kiss1 neurons and the synchronization of their activity within the arcuate nucleus. The major outcome of this role is the precise regulation of the pulsatile pattern of GnRH release. In addition, tachykinins are involved in the maturation of the reproductive axis by determining the optimal timing of puberty onset, as well as in the timing of the preovulatory luteinizing hormone surge in females. Therefore, the action of tachykinins in reproduction appears to extend to all the critical aspects required for the successful attainment and maintenance of fertility. In this review, we summarize the latest advances in our understanding of the biology of tachykinins in the control of GnRH release, addressing the existing controversies, open questions, and future perspectives.

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Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men

Abstract: 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.

Cited by 23 publications

References 44 publications

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

Hypogonadism and male obesity: Focus on unresolved questions

Novel Biology of Tachykinins in Gonadotropin-Releasing Hormone Secretion

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