Effect of gonadotropin inhibitory hormone (GnIH) secretion on post-ejaculatory refractory period: A hypothesis

Abstract

The exact underlying mechanism regulating the human post-ejacu-latory refractory period is not yet known. The main finding of previous research has been an occurrence of surge-like increases in plasma prolactin and oxytocin levels immediately after orgasm. However, recent advances in neuroendocrinology have resulted in the identification of a new pep-tide, the gonadotropin inhibitory hormone (GnIH), which is considered to inhibit the hypothalamic-pituitary-gonadal axis and sexual functions. This paper hypothesizes that GnIH causes refractoriness of the post-ejaculatory refractory period, and on the basis of studies on hormonal fluctuations at the time of orgasm, we hypothesize that in addition to its pulsatile pattern of secretion, GnIH might also exhibit a surge-like pattern of secretion.

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Vol.11, No.1 | 2013 | hypothesisjournal.com
HYPOTHESIS
HYPOTHESIS
ABSTRACT The exact underlying mecha-
nism regulating the human post-ejacu-
latory refractory period is not yet known.
The main nding of previous research has
been an occurrence of surge-like increas-
es in plasma prolactin and oxytocin levels
immediately after orgasm. However, recent
advances in neuroendocrinology have re-
sulted in the identication of a new pep-
tide, the gonadotropin inhibitory hormone
(GnIH), which is considered to inhibit the
hypothalamic-pituitary-gonadal axis and
sexual functions. This paper hypothesizes
that GnIH causes refractoriness of the
post-ejaculatory refractory period, and on
the basis of studies on hormonal uctua-
tions at the time of orgasm, we hypothe-
size that in addition to its pulsatile pattern
of secretion, GnIH might also exhibit a
surge-like pattern of secretion.
INTRODUCTION The neuroendocrino-
logical effects on sexual arousal and or-
gasm in humans are poorly understood.
As a recent review states, our knowl-
edge of the post-ejaculatory refractory
period mechanism is limited1. Krüger et
al.2 analyzed plasma concentrations of
adrenaline, noradrenaline, cortisol, lu-
teinizing hormone (LH), follicle stimulat-
ing hormone (FSH), prolactin, growth
hormone (GH), ß-endorphin, and testos-
terone before, during, and after mastur-
bation-induced orgasm and showed that
only plasma concentration of prolactin
increased significantly in both men and
women. Thereafter, Exton et al.3 showed
that this increase in plasma prolactin
during sexual stimulation is orgasm-
dependent and does not increase with-
out orgasm. Prolactin concentration has
been shown to increase during orgasm
and remain elevated for 60 minutes2,4,5 .
However, in those men who exhibit mul-
tiple orgasms and a short refractory pe-
riod, the orgasm-induced prolactin surge
appears to be absent6. Therefore, it has
been proposed that the orgasm-induced
surge of prolactin controls sexual drive
and refractoriness through the central
nervous system (CNS)7. Nevertheless,
the mechanism of prolactin regulation fol-
lowing orgasm remains unknown.
Interestingly, it seems that the high post-
ejaculatory levels of plasma prolactin are
identical to levels of this hormone de-
tected in lactating females8,9. There are
similar patterns of hormonal release ex-
hibited by lactating females and those
experiencing the post-ejaculatory re-
fractory period. In a series of studies,
McIntash and Barfield10-12 investigated
the role of brain serotonin, dopamine and
norepinephrine in the control of copula-
tion and the post-ejaculatory refractory
period in rats. They showed that nor-
adrenaline and dopamine pathways de-
crease the duration of the post-ejaculato-
ry refractory period, whereas the duration
is lengthened by the serotonergic path-
ways. Additionally, in lactating female
rats, suckling has been found to increase
the activity of serotonin-containing neu-
rons13 that facilitate prolactin release dur-
ing lactation14 , whereas norepinephrine15
and dopamine16,17 are inhibited by suck-
ling. Therefore, we hypothesize that the
underlying mechanisms for inhibition of
reproductive functions during lactation
and during the post-ejaculatory refrac-
tory period are similar.
Recently, a new RFamide-related pep-
tide (RFRP) has been discovered18 which
is considered to have inhibitory effects on
reproductive functions. This peptide is a
homolog of gonadotropin inhibitory hor-
mone (GnIH)19, an RFamide duodeca-
peptide in the hypothalamus of quails
(Coturnix japonica), which inhibits LH re-
lease from the anterior pituitary18. The in-
hibitory effects of GnIH on gonadotropin
release have also been identified in mam-
mals, such as hamsters (Mesocricetus
auratus), rats (Rattus norvegicus), and
mice (Mus musculus)20, and have also
been confirmed in male and female
rats21,22, sheep23,24, and humans2 5. Studies
of the inhibitory effects of this RFRP on
the hypothalamus, pituitar y, and gonads
of mammals are reviewed elsewhere26.
© 2013 Farid Pazhoohi and Mohammad Saied Salehi.
This is an Open Access article distributed by Hypothesis
under the terms of the Creative Commons Attribution
License (http://creativecommons.org/licenses/by/3.0/),
which permits unrestricted use, distribution, and repro-
duction in any medium, provided the original work is
properly cited.
1,2Department of Animal Science,
College of Agriculture, Shiraz University, Shiraz, Iran
*Correspondence:
pazhoohi@gmail.com
Received: 2012/11/24; Accepted: 2013/02/20;
Posted online: 2013/06/03
Please cite this article as:
Farid Pazhoohi and Mohammad Saied Salehi, Effect of gonadotropin
inhibitory hormone (GnIH) secretion on post-ejaculatory refractory period:
A hypothesis. Hypothesis 2013, 11(1): e2, doi:10.5779/hypothesis.v11i1.286
HYPOTHESIS
Effect of gonadotropin inhibitory hormone (GnIH)
secretion on post-ejaculatory refractory period:
A hypothesis
Farid Pazhoohi*1 and Mohammad Saied Salehi2

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Vol.11, No.1 | 2013 | hypothesisjournal.com
HYPOTHESIS
HYPOTHESIS
Pazhoohi and Salehi
Effect of gonadotropin inhibitory hormone (GnIH) secretion on post-ejaculatory refractory period: A hypothesis
HYPOTHESIS This paper hypothesizes
that after orgasm, a GnIH surge occurs
which increases plasma prolactin levels
and inhibits the hypothalamic-pituitary-
gonadal axis, which leads to the occur-
rence of a refractory period after ejacula-
tion in males.
Supporting Argument Krüger et al.27 ana-
lyzed the effects of acute pharmacologi-
cal manipulations of plasma prolactin lev-
els on sexual arousal, orgasm, and the
refractory period. They observed that
increasing prolactin concentrations by
protirelin administration could not alter
sexual parameters such as the refracto-
ry period. Therefore, they concluded that
post-orgasmic increases of prolactin do
not provide direct negative feedback to
the CNS. Hinuma et al.28 examined the
effects of hRFRP-1 on pituitary-hormone
secretions in rats and showed that plas-
ma prolactin levels begin to increase 10
minutes after administration and then de-
cline, reaching baseline levels at 60 min-
utes. RFRPs did not alter plasma levels
of other pituitary hormones (GH, FSH,
LH, thyroid-stimulating hormone, and
adrenocorticotropic hormone). Also, this
study showed that the effect of RFRPs on
plasma prolactin levels is dose-depen-
dent, which suggests a surge-like pattern.
The relationship between RFRP release
and plasma levels of prolactin has been
confirmed, as it has been shown that
during lactation, while prolactin levels
are higher, GnIH expression increases in
lactating rats29. These results are consis-
tent with the reported increasing patterns
of prolactin after orgasm2,4,5.
In many mammals such as sheep30, rhe-
sus macaques31, and humans25 , GnIH
neuron terminals have been identified
in proximity to gonadotropin-releasing
hormone (GnRH) neuron bodies, and
more than 85 percent of GnRH neurons
in hamsters also have GnIH receptors
(GPR147)32. Because GnIH hyperpolar-
ized33 and decreased electrical activity
of GnRH neurons in mice34, it is possible
that GnIH surge through the inactivation
of GnRH neurons, inhibits the hypotha-
lamic-pituitary-gonadal axis.
In addition, GnIH axons project to the
median eminence in humans25, rhe-
sus macaques25, and hamsters32, which
might directly regulate pituitary function
through the hypophysial portal system.
GnIH has also been identified in the hy-
pophyseal portal system and GPR147 is
found to be expressed in the pituitary
gonadotropes of sheep36. Therefore, it is
plausible that after orgasm, GnIH releas-
es into hypothalamic-hypophyseal portal
veins with a direct effect on the pituitary
and induced refractoriness.
Another probable neuronal pathway in
which GnIH surge can cause the post-
ejaculatory refractory period is through
the inhibition of dopaminergic neurons.
Dopamine expressing neurons that are
located in the arcuate and paraventric-
ular nuclei of the hypothalamus inhibit
prolactin secretion from the pituitary37.
Because of the expression of GPR147
mRNA in dopaminergic neurons35 and
increased prolactin secretion after RFRP
administration in rats28, along with the ex-
istence of a strong connection between
GnIH neuron fibers and dopaminergic
neurons in the arcuate of rhesus ma-
caque35, it is plausible that a GnIH surge
increases prolactin secretion after or-
gasm via the inhibition of dopaminergic
neurons.
An oxytocin surge occurs at the time of
and immediately after orgasm in men 5,38 ;
for a revi ew, see39. A recent study showed that in-
tracerebroventricular injection of RFRPs
increased the expression of Fos-protein
in oxytocin neurons in the hypothalamus
of rats and increased oxytocin plasma
concentrations40. Also, it showed that the
hypothalamic paraventricular and su-
praoptic nuclei expressed GPR147
mRNA, and applying RFRPs to the iso-
lated supraoptic nuclei facilitated oxy to-
cin release. Therefore, they concluded
that RFRPs activate oxytocin neurons
directly40. The pattern of oxytocin surge
at the time of and after orgasm supports
the surge secretion of GnIH in the current
hypothesis.
Testing the Hypothesis GnIH expression
is investigated in different species using
different methods and techniques. For
example, using immunohistochemistry in
rodents20, sheep30, rhesus macaques35,
and humans25; using in situ hybridiza-
tion in rhesus macaques31, mice41, and
rats42; and using RT-PCR in rats43,44. It
should also be noted that GnIH concen-
tration has been investigated in hypotha-
lamic portal blood vessels as an in-vivo
method recently3 6. To test the current hy-
pothesis, GnIH expression and its con-
centration in the portal system should
be investigated before, during, and after
orgasm. Another possible condition that
may be useful for testing this hypothesis
is the comparison of GnIH expression in
animals with high and low libidos.
CONCLUSION This paper hypothesizes
that, first, gonadotropin inhibitory hor-
mone (GnIH) secretion, in addition to
exhibiting a pulsatile pattern, shows a
surge-like pattern of release at the time
of orgasm, and second, the post-ejac-
ulatory refractory period is due to high
levels of secretion of this hormone after
orgasm, which inhibits sexual functions.
If this hypothesis stands, it can explain
the reason behind sexual exhaustion and
post-ejaculatory refractory period after
orgasm. Therefore, using GnIH antago-
nists, low libido and sexual exhaustion
in men could potentially be remedied. It
should be noted that the refractory peri-
od ranges from 15 minutes for 18-year-
old men to 20 hours for seniors4 5. In ad-
dition to decreasing erectile disfunction,
sildenafil (Viagra™) reduces the post-
ejaculatory refractory period, but its ef-
fect does not seem to involve an interac-
tion with central monoaminergic control
pathways46. On the contrary, a GnIH an-
tagonist might affect the hypothalamic-
pituitary-gonadal axis at the brain level
and probably would result in the fewest
side effects. Also, from a psychological
point of view, this hypothesis can explain
why men need to separate from post-
coital connection. Although there exist
some evolutionary hypotheses47, there is
no definite and objective explanation for
this behavior yet.
Finally, it should be noted that in addi-
tion to the role of GnIH in the post-ejac-
ulatory refractory period, it is also possi-
ble that alternative mechanisms through
other neuronal and hormonal pathways,
which are not mentioned here, may be in
action.H
AUTHO R’S CONTRIBUTIONS FP contrib-
uted to the conception of the study; FP

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HYPOTHESIS
Pazhoohi and Salehi
Effect of gonadotropin inhibitory hormone (GnIH) secretion on post-ejaculatory refractory period: A hypothesis HYPOTHESIS
and MSS wrote and revised the manu-
script. Both authors read and approved
the final draft of the manuscript.
ACKNOWLEDGEMENT The authors would
like to thank James R. Liddle at Florida
Atlantic University for language editing
and two anonymous reviewers whose
comments improved the manuscript.
CONFLI CTS OF INTERES T Authors de-
clare no conflicts of interest.
ABOUT THE AUTHORS Farid Pazhoohi and
Mohammad Saied Salehi are post-gradu-
ate students in animal physiology investi-
gating neuroendocrinology of reproduction
in animal models. Beside physiology, Farid
Pazhoohi has conducted experiments in
the fields of human perception, evolutionary
psychology and physical anthropology.
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