GnRH/kisspeptin/nkb/GNIH

[kpavel]

Hey guys, I recently researched why we have usually have low side FSH. So apart from known GnRH/LHRH/Inhibin B or kisspeptin there is formed research on gonadotropin‐inhibitory hormone (same as RFRP-3). First of all it appears that GNIH can be upregulated by strong stress and interestingly with antidepressants, specifically SSRI citalopram.

Citalopram (antidepressant) administration causes sexual dysfunction in male mice through RF-amide related peptide in the dorsomedial hypothalamus.
Citalopram is the most potent selective serotonin reuptake inhibitor (SSRI) which is used as an antidepressant but causes sexual dysfunction. Whether citalopram induced sexual dysfunction is a result of gonadotropin-releasing hormone (GnRH), kisspeptin or RF-amide related peptide (RFRP) alteration is unknown. In this study, we tested mice for sexual behavior after vehicle (0.9% NaCl) and citalopram treatment (5 mg/kg) daily for 1 day (acute) and 21 or 28 days (chronic). Effects of acute and chronic treatments on neuronal numbers and mRNA expression of GnRH, kisspeptin and RFRP were measured. In addition, RFRP fiber projections to preoptic (POA)-GnRH neurons were analyzed using double-label immunohistochemistry. The expression of 14 different serotonin receptor types mRNA was examined in immunostained laser dissected single RFRP neurons in the dorsomedial hypothalamus (DMH), however only 11 receptors types were identified. Acute citalopram treatment did not affect sexual behavior, whereas, the total duration of intromission was reduced with chronic treatment. There was no effect in the expression of kisspeptin (neuronal numbers and mRNA) in the anteroventral periventricular nucleus and the arcuate nucleus and expression of GnRH (neuronal numbers and mRNA) in the POA after citalopram treatment. However, RFRP neuronal numbers in the DMH and fiber projections to the POA were significantly increased after chronic citalopram treatment, which suggests citalopram induced inhibition of sexual behavior involves the modulation of RFRP through serotonin receptors in the DMH.
Note that it resides in DMH and has neuron fibers in MPOA

[kpavel]

So I think the best and shortest review is the newest one by Kazuyoshi Tsutsui who worked with GNIH for 20 years.
SEE
Reproductive neuroendocrinology of mammalian gonadotropin‐inhibitory hormone
This article alone gives next interesting facts I will be citing:
1) mouse RFRP1 and RFRP3 suppressed cAMP production induced by gonadotropin‐releasing hormone (GnRH), suggesting that GnIH (RFRP) inhibits adenylate cyclase (AC) activity.
2) In mouse and hamster brains, GnIH precursor mRNA is expressed in neuronal cell bodies located in the dorsomedial hypothalamic area (DMH).
3) Distribution of GnIH neuronal fibers and interaction with neurons in the brain were investigated in detail in the macaque brain.10 GnIH neuronal fibers were abundant in the stria terminalis in the telencephalon, habenular nucleus, paraventricular nucleus of the thalamus, preoptic area (POA), PVN, IPe, arcuate nucleus (Arc), median eminence, and dorsal hypothalamic area in the diencephalon, medial region of the superior colliculus, central gray substance, and dorsal raphe nucleus in the midbrain. GnIH neuronal fibers are in close proximity to GnRH1, dopamine, pro‐opiomelanocortin (POMC), and GnRH2 neurons in the POA, IPe, Arc, and central gray substance of the midbrain, respectively.10 In sheep, GnIH neurons project to neuropeptide Y (NPY) and POMC neurons in the Arc, orexin, and melanin‐concentrating hormone neurons in the lateral hypothalamic area, orexin cells in the DMN, corticotrophin‐releasing hormone and oxytocin cells in the PVN, and GnRH neurons in the POA.29 Kisspeptin is a hypothalamic neuropeptide that stimulates GnRH release.30 Kisspeptin neurons form two populations in the anteroventral periventricular nucleus (AVPV) and Arc. Approximately 35% of Arc kisspeptin cells are contacted by GnIH neuronal fibers and 25% express GPR147 or GPR74 in mice.31 Therefore, GnIH may also suppress gonadotropin release by suppressing kisspeptin neurons in the Arc.32
4) Central administration of RFRP3 and RF9, an antagonist of RFRP, to female mice decreases and increases GnRH mRNA expression, respectively
(NPFF and kisspeptin are involved in nociception by the way)
5) Peripheral administration of GnIH (RFRP3) also suppresses gonadotropin release in sheep,26 rats,41 cattle,40 and humans.42
6) Hypothyroidism shows delayed pubertal onset with increased GnIH expression. However, GnIH knockout prevents delayed pubertal onset in hypothyroidism, indicating that increased GnIH expression induced by hypothyroidism may delay puberty. Administration of thyroid hormone suppresses GnIH expression in hypothalamic explants, and GnIH neurons express thyroid hormone receptors to convey thyroid status.
7) high estradiol concentration in the afternoon of the proestrus phase increases the frequency and amplitude of GnRH/LH pulse resulting in GnRH/LH surge that induces ovulation.50, 51, 52
Estradiol induces kisspeptin precursor mRNA expression in the AVPV possibly via ERα
(progesterone and estradiol however may decrease GnRH pulse, specifically by frequency and amplitue as I read )
Estradiol administration for 4 days suppresses GnIH precursor mRNA expression in ovariectomized mice.59 The cellular activity of GnIH neurons and GnIH precursor mRNA expression is low at the time of LH surge in female hamsters or proestrus in female rats and mice, suggesting that reduction in GnIH neuronal activity may contribute to GnRH/LH surge.60, 61, 62
It may be possible that GnIH acts more as a translator of environmental and social information in the regulation of menstrual cycle, such as translating environmental or psychological stress to inhibit ovulation, rather than a member of the rigid periodic machinery that propels the reproductive cycle in primates.
8) Kirby et al (2009) showed that both acute and chronic immobilization stress up‐regulates GnIH expression in the DMH of adult male rats. Adrenal glucocorticoids (GC) may increase GnIH expression because adrenalectomy blocks stress‐induced increase in GnIH expression and 53% of GnIH cells express receptors for GC.77 Administration of a high dose of lipopolysaccharide, an endotoxin, increases GnIH and GPR147 mRNA levels in both OVX and gonadal intact female rats, while kisspeptin and GnRH mRNA levels are decreased.78 Food restriction also up‐regulates GnIH mRNA expression and suppresses ovarian development and follicular growth in prepubertal ewes.79 Metabolic challenges, such as short‐term fasting and high‐fat diet, are less effective in decreasing LH secretion in GPR147‐deficient male mice, suggesting that the GnIH‐GPR147 inhibitory pathway mediates gonadotropin suppression by metabolic stress.80 Stressful stimuli also activate GnIH‐ir neurons or increase GnIH expression in rats and mice.81, 82, 83 It was further shown that GnIH administration activates hypothalamic‐pituitary‐adrenal (HPA) axis in rats,81 mice,84 and rhesus monkeys.85 Administration of GnIH (RFRPs) induces anxiety‐related behavior in rats 81 and mice,84 suggesting that GnIH also mediates behavioral stress responses, although its mechanism of action should be investigated in future studies.3, 86
9) GnIH (RFRP3) administration also suppresses testosterone synthesis in the testis both in vivo and in vitro.90
GnIH and GPR147 are also expressed in the epididymis of male rat. Intratesticular administration of RFRP3 decreases spermatozoa and increases degenerated and vacuolated epididymal epithelial cells.92
A significant increase in GnIH (RFRP3) immunoreactivity during LATE DIESTRUS (in human late luteal phase of the menstrual cycle) 2 coincided with the decline in corpus luteum activity and initiation of follicular growth and selection.95
Treatment of human granulosa‐lutein cells with GnIH (RFRP3) reduces FSH‐, LH‐, and forskolin‐stimulated progesterone production and steroidogenic acute regulatory protein (StAR) expression. GnIH (RFRP3) also suppresses gonadotropin‐ and forskolin‐induced intracellular cAMP accumulation.
10) Note also that one scientist made a hypothesis that GNIH can be increased on ejaculaton and thus amplify refractory period (wiki). So here
I wanna ask, what the point of this neighborhood 'orexin, and melanin‐concentrating hormone neurons in the lateral hypothalamic area, orexin cells in the DMN', 'oxytocin cells in the PVN', 'pro‐opiomelanocortin (POMC), and GnRH2 neurons in the POA'. Melanotan and oxytocin are very important.
But orexin may be one of ways to combat anhedonia and as one of Elaine Hull's pupils Muschamp had shown dopamine burst is strongly positively modulated via ERalpha->()->orexin.
see
A Role for Hypocretin (Orexin) in Male Sexual Behavior
And again refractory (see Sex, drugs and gluttony: how the brain controls motivated behaviors) period
So some orexin may be needed to restore? I think it directly relates to pssd symptoms. Attention, addiction and anhedonia disturbance are pointed quite often.
One kind guy on longecity made a cool post on orexin modulaion.

Interestingly, noticed in this winter erections were quicker fading while experimenting wih Butcher's Broom during agiotage with Betanechol. Well alpha2 agonism seems to modulate GNIH - see study
A new pathway mediating social effects on the endocrine system: female presence acting via norepinephrine release stimulates gonadotropin-inhibitory hormone in the paraventricular nucleus and suppresses luteinizing hormone in quail.

That's my thoughts for now. What do you think guys?
Sorry if made some mistypings or such. It's late evening here, Friday on my mind and almost a hard day's night.)

[mrstaircase]

Interesting read. I wonder if Melanotan II is worth trying because of this. It's been known to increase libido

[GIXXER]

Interesting read. I wonder if Melanotan II is worth trying because of this. It's been known to increase libido

Ive tried Melanotan II and PT 141. They gave me crazy hard eretions but no libido

[supertucker1]

Fascinating article on the connection between GABA and Kisspeptin and their impact on reproduction.

https://rep.bioscientifica.com/view/jou ... 8-0527.xml

[kpavel]

Fascinating article on the connection between GABA and Kisspeptin and their impact on reproduction.

https://rep.bioscientifica.com/view/jou ... 8-0527.xml

Kisspeptin is a positive emotion anti-anxiety thing, so likely gaba plays role.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518874/

[kpavel]

Interesting read. I wonder if Melanotan II is worth trying because of this. It's been known to increase libido

Ive tried Melanotan II and PT 141. They gave me crazy hard eretions but no libido

I never tried, on the one hand I also didn't see any study about strong MC4receptor downregulation or related.
However the topic study shows that citalopram changes GNIH neuronal fibers thickness in POA where alpha-msh may have a large role.

Also if it gave you easy noncontact erections it's a big sign.

[kpavel]

Interestingly children with narcolepsy may have early puberty onset and obesity.
https://www.ncbi.nlm.nih.gov/pubmed/30556659

[finities infinities]

I also I would like try melanotan 2, but I don't know how it work in longterm.
I'm very unatractive men.

[kpavel]

I'm very unatractive men.

you're just not in your type