J Chin Med Assoc
Editorial
Kisspeptin in male reproduction
Wen-Ling Leea,b,c, Fa-Kung Leed, Peng-Hui Wangc,e,f,g,*
a
Department of Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; bDepartment of Nursing, Oriental Institute of
Technology, New Taipei City, Taiwan, ROC; cInstitute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,
ROC; dDepartment of Obstetrics and Gynecology, Cathy General Hospital, Taipei, Taiwan, ROC; eDepartment of Obstetrics and
Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; fDepartment of Medical Research, China Medical University
Hospital, Taichung, Taiwan, ROC; gFemale Cancer Foundation, Taipei, Taiwan, ROC
In 1996, and its following 20 years, kisspeptin1 (KiSS1, fulllength human KiSS1, a 145 amino acid protein) and KiSS1derived peptides (KiSS 54,14, 13, 10) and their receptor calling
G protein coupled receptor 54 (GPR54, called KiSS1R) system
are initially found to possess a strong antimetastatic ability
(called a metastasis suppressor).1 The largely antimetastatic role
is found in various kinds of cancers, such as melanoma, ovarian, bladder, endometrial cancers, and others.1 However, reports
have shown that KiSS/KiSS1R system involved in cancers is not
only limited on antimetastatic process but also plays a promotion of cancer metastases or dissemination, of which depending
on the type of cancers. The diverse actions of either anti- or prometastatic effects of cancers remain unclear, although there are
several pathways, including autocrine, paracrine, and endocrine
pathway as well as epigenetic control of the KiSS/KiSS1R system
reported to be involved in the reciprocal results.2 Furthermore, a
reciprocal communication between KiSS/KiSS1R of the tumorsurrounding cells in the tumor microenvironment (TEM) is
also a reason.3,4 Moreover, it is also possible that an existence
of other unknown mediators modifies KiSS/KiSS1R system in
cancers.1 All are too complex, with resultant research for KiSS/
KiSS1R system hampering the progress in gaining mechanistic
insights on the KiSS/KiSS1R axis in cancers.
Unlike to the uncertain role of KiSS/KiSS1R on cancers, the
progress on the role of KiSS/KiSS1R system in reproduction
has been rapidly developed since 2003, after an identification
of KiSS/KiSS1R inactivating/hyperactivating mutations causing hypogonadotropic hypogonadism/precocious puberty,5,6 in
turn drawing a bright picture in the endocrine and local control
of reproduction, which includes an initiation of puberty, timing control of puberty, and regulation of fertility in adulthood.7
Within the central neurological system (brain), KiSS/KiSS1R system is a positive modulator of gonadotropin-releasing hormone
(GnRH) secreting neurons located in the arcuate nucleus (ARC)
*Address correspondence. Dr. Peng-Hui Wang, Department of Obstetrics and
Gynecology, Taipei Veterans General Hospital, 201, Section 2, Shi-Pai Road,
Taipei 112, Taiwan, ROC. E-mail address: phwang@vghtpe.gov.tw (P.-H. Wang).
Conflicts of interest: The authors declare that they have no conflicts of interest
related to the subject matter or materials discussed in this article.
Journal of Chinese Medical Association. (2021) 84: 667-668.
Received April 13, 2021; accepted April 13, 2021.
doi: 10.1097/JCMA.0000000000000545.
Copyright © 2021, the Chinese Medical Association. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/)
thus affecting gonadotropin (follicular stimulating hormone
[FSH] and luteinizing hormone [LH]) secretion, sex maturation,
and sex hormone biosynthesis (called as hypothalamic-pituitary-gonadal [HPG] axis), and mediating sex hormone positive and negative feedback mechanisms by gonadal steroids.5–7
Furthermore, the KiSS/KiSS1R system also represents a fundamental “sensor” for environmental cues like energy availability
and thus linking reproductive ability to metabolism with epigenetic mechanism.6
Besides in brain, KiSS/KiSS1R system is widely distributed in
peripheral tissues, including gonads, adipose tissue, liver, placenta, pancreas and small bowel, contributing to a wider spectrum of action related to reproduction, fertility, body weight,
and energy homeostasis, and cardiovascular system.7–11 Based
on above-mentioned observation, we are happy to introduce
the recent article entitled “Role of the kisspeptin/KISS1 receptor system in the testicular development of mice” published
in this February issue of the Journal of the Chinese Medical
Association.12
In the current article, Dr. Chiang et al’s12 group carried out
an in vivo observation of cellular pattern of KiSS/KiSS1R in
testis tissue of mice model and found that KiSS was identified
clearly in the cytoplasm of Leydig cells located adjacent to the
seminiferous tubules and KiSS1R was observed in the seminiferous tubules by immunohistochemical staining. Furthermore,
gene expression of KiSS was detected in the fourth postnatal
week (initiation of maturation of mice), but gene expression of
KiSS1R has been already existed immediately when these mice
were born with at least 4 weeks of lag.12 A further in vitro study,
the expression of KiSS in the testis was related to the maturation process, which was responsible to LH stimulation.12 Further
dissection of this observation, the authors found that KiSS secretion in Leydig cells was mediated through LH-associated cyclic
adenosine monophosphate/protein kinase A (cAMP/PKA) pathway.12 Taken together, the authors suggested that KiSS- and
development-related factors have synergistic effects on spermatogenesis.12 This finding further draws the important role of
KiSS/KiSS1R system in male reproduction and some are worthy
of discussion.
Classically, spermatogenesis is tightly orchestrated step by step
leading to the production of male gametes within the testis by
coordination of mitotic, meiotic, and maturation events, mediated by endocrine, paracrine, autocrine, and epigenetic effect.7
Based on the facts showing (1) peripheral KiSS administration
accelerates spermatogenesis; (2) over-activating mutations in
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Lee et al
KiSS/KiSS1R signaling result in precocious puberty; (3) silencing mutations in KiSS/KiSS1R system lead to hypogonadotropic
hypogonadism; (4) in-activating mutations in KiSS/KiSS1R
system decrease the testosterone biosynthesis, which cannot be
reversed by gonadotropin stimulation; (5) the conditional KiSS/
KiSS1R system reactivation in the GnRH secreting neuron in
total knockout of KiSS1R−/− (KiSS1R KO) mice cannot restore
the normal spermatogenesis; and (6) subcutaneous testosterone
supplementation for 6 weeks restores plasma and intratesticular
testosterone levels, elicits testicular descent, and induces complete spermatogenesis from spermatocytes to elongated spermatids in the testis, resulting in an increase in epididymal sperm
number in testosterone-supplemented KiSS−/− (KiSS KO) male
mice but those KiSS KO male mice do not ejaculate or form copulatory plugs, all indicate that normal function of KiSS/KiSS1R
system within the testis is critical for steroid genesis and spermatogenesis.7,13,14 As shown by authors,12 the persistent expression of KiSS1R in the interstitial cells (Leydig cells) was found
when male mice were born (0 postnatal week) and the expression of KiSS occurred when sexual maturation of male mice was
induced by LH stimulation (the fourth postnatal week), indicating that the sexual maturation of male mice indeed requests
the cooperation of central and peripheral function. However,
the LH secretion is controlled by GnRH, which needs the KiSS/
KiSS1R system in brain, suggesting that it is uncertain the role
of KiSS on the impact of the next upward rung in the pubertal cascade and how that impacts initiation and maintenance of
spermatogenesis and male fertility.
There is no doubt that the intratesticular role of KiSS/KiSS1R
system is far away to be elucidated, although KiSS/KiSS1R system can locally modulate different aspect of male reproduction,
from spermatogenesis progression to the acquisition of sperm
maturation and normal sperm functions, with effects being
dependent on species, dose or spice form of KiSS, and extra
administration of KiSS by different routes and durations.7 All
factors are involved in the balance of ARC-HPG axis, leading to impairment or enhancement of steroid production and
spermatogenesis.
Additionally, the fundamental limitation of the current Dr.
Chiang et al’s study12 is the underestimation of role secondary
to paracrine, and endocrine effect in the testis development.
The authors did not evaluate the connection, relation, or communication between targeted cells (Leydig cells or germ cells)
and their surrounding cells within the testis structure. In fact,
extra KiSS administration resulting in hyperstimulation and
subsequent downregulation of HPG axis in mammals contributes to end points of testis degeneration.7 Therefore, most studies used the in vitro cell treatment model to investigate the role
of KiSS/KiSS1R system in reproduction function, a situation in
which the precise effects of paracrine and endocrine interaction
between somatic (Leydig cells) and germ cells (spermatogenesis)
are totally lost.7
In conclusion, issue about the fertility and enhanced fecundability ability becomes more and more urgent because of aged
population and dramatical change of the environment, such as a
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lots of toxins or pollutions in modern society.15,16 The mysteries
of KiSS/KiSS1R system either in reproduction or in oncology
may need more efforts to dissect and we believe that the KiSS/
KiSS1R system may become one of the most promising targeted
sites in dealing with various kinds of global health problems in
the near future.
ACKNOWLEDGMENTS
This article was supported by grants from the Ministry of
Science and Technology, Executive Yuan, Taiwan (MOST
109-2314-B-075B-014-MY2 and MOST 109-2314-B-075056), and Taipei Veterans General Hospital (V110C-082, and
VGH109E-005-5).
The authors appreciate the support from Female Cancer
Foundation, Taipei, Taiwan.
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