Background: The brain-pituitary-gonadal tissues play a key role in the neuroendocrine regulation of reproduction in vertebrates. Brain hormones, especially gonadotropin-releasing hormone (GnRH) is considered an important stimulant of gonadotropins (luteinizing hormone and follicle-stimulating hormone) released from the anterior pituitary. The current concept proposes a single brain hormone (GnRH) stimulating the release of both gonadotropins in fish and mammals. However, two articles published in 2024 proposed a dual-hormone concept in the brain regulation of gonadotropins in female medaka and zebrafish. Summary: The emerging concept proposes GnRH as the LH releasing hormone (LH-RH), and a second hormone, cholecystokinin (Cck), as the FSH-releasing hormone (FSH-RH) in these species. The two studies discussed here found that Cck is a potent FSH-RH. The line of evidence from the first study to support this notion includes the abundance of Cck receptors in the anterior pituitary Fsh-producing gonadotrophs, and severe reproductive defects in female medaka that genetically lacks Cck receptor 2. The second study used zebrafish, and found hypothalamic expression of Cck, anterior pituitary abundance of Cck receptors, and an all-male phenotype when Cck receptor 2 was knocked out. In both studies, Cck was found to be a more potent stimulant of intracellular Ca2+, when compared to GnRH effects. Key Messages: These evidence from two independent studies indicate that Cck is a potent FSH-RH, and GnRH is the LH-RH, and supports a bihormonal model for the regulation of gonadotropin secretion from teleost pituitary. However, whether Cck elicits FSH-RH effects in other fish species remains unknown. In addition, the role of other hormones in the diverse endocrine milieu that regulate reproduction in modulating the phenotype seen in Cck receptor deficient fish warrants further consideration.

1.
Huang
T
,
Zhao
Y
,
He
J
,
Cheng
H
,
Martyniuk
CJ
.
Endocrine disruption by azole fungicides in fish: a review of the evidence
.
Sci Total Environ
.
2022
;
822
:
153412
.
2.
Prasad
P
,
Ogawa
S
,
Parhar
IS
.
Role of serotonin in fish reproduction
.
Front Neurosci
.
2015
;
9
:
195
.
3.
Kanda
S
.
Evolution of the regulatory mechanisms for the hypothalamic-pituitary-gonadal axis in vertebrates–hypothesis from a comparative view
.
Gen Comp Endocrinol
.
2019
;
284
:
113075
.
4.
Ando
H
,
Ukena
K
,
Nagata
S
, editors.
Index. Handbook of hormones
. 2nd ed.
San Diego
:
Academic Press
;
2021
. p.
1095
113
.
5.
Kho
KH
,
Sukhan
ZP
,
Yang
S-W
,
Hwang
N-Y
,
Lee
W-K
.
Gonadotropins and sex steroid hormones in captive-reared small yellow croaker (larimichthys polyactis) and their role in female reproductive dysfunction
.
Int J Mol Sci
.
2023
;
24
(
10
):
8919
.
6.
Oduwole
OO
,
Peltoketo
H
,
Huhtaniemi
IT
.
Role of follicle-stimulating hormone in spermatogenesis
.
Front Endocrinol
.
2018
;
9
:
763
.
7.
Moudgal
NR
,
Sairam
MR
.
Is there a true requirement for follicle stimulating hormone in promoting spermatogenesis and fertility in primates
.
Hum Reprod
.
1998
;
13
(
4
):
916
9
.
8.
Lei
T
,
Yang
Y
,
Yang
W-X
.
Luteinizing hormone regulates testosterone production, leydig cell proliferation, differentiation, and circadian rhythm during spermatogenesis
.
Int J Mol Sci
.
2025
;
26
(
8
):
3548
.
9.
Schally
AV
,
Arimura
A
,
Bowers
CY
,
Kastin
AJ
,
Sawano
S
,
Redding
TW
.
Hypothalamic neurohormones regulating anterior pituitary function
. In:
Proceedings of the 1967 laurentian hormone conference
.
Elsevier
;
1968
; p.
497
588
.
10.
White
WF
,
Schally
AV
,
Baba
Y
,
Arimura
A
,
Redding
TW
.
Evidence for peptide nature of LH and FSH-releasing hormones
.
Biochem Biophys Res Commun
.
1971
;
42
(
1
):
50
6
.
11.
Amoss
M
,
Burgus
R
,
Blackwell
R
,
Vale
W
,
Fellows
R
,
Guillemin
R
.
Purification, amino acid composition and N-terminus of the hypothalamic Luteinizing hormone Releasing Factor (LRF) of ovine origin
.
Biochem Biophys Res Commun
.
1971
;
44
(
1
):
205
10
.
12.
Raisman
G
.
An urge to explain the incomprehensible: geoffrey Harris and the discovery of the neural control of the pituitary gland
.
Annu Rev Neurosci
.
1997
;
20
:
533
66
.
13.
Schally
AV
,
Arimura
A
,
Kastin
AJ
,
Matsuo
H
,
Baba
Y
,
Redding
TW
, et al
.
Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones
.
Science
.
1971
;
173
(
4001
):
1036
8
.
14.
Matsuo
H
,
Baba
Y
,
Nair
RM
,
Arimura
A
,
Schally
AV
.
Structure of the porcine LH- and FSH-releasing hormone. I. The proposed amino acid sequence
.
Biochem Biophys Res Commun
.
1971
;
43
(
6
):
1334
9
.
15.
Conn
PM
,
Huckle
WR
,
Andrews
WV
,
Mcardle
CA
.
The molecular mechanism of action of Gonadotropin Releasing Hormone (GnRH) in the pituitary
. In:
Clark
JH
, editor.
Proceedings of the 1986 laurentian hormone conference
.
Boston
:
Academic Press
;
1987
. p.
29
68
.
16.
Nair
RMG
,
Schally
AV
.
Structure of a hypothalamic peptide possessing gonadotropin-releasing activity
.
Int J Pept Protein Res
.
1972
;
4
(
6
):
421
30
.
17.
Gore
AC
.
GnRH: the master molecule of reproduction
.
Boston, MA
:
Springer US
;
2002
.
18.
Gründker
C
,
Emons
G
.
Role of Gonadotropin-Releasing Hormone (GnRH) in ovarian cancer
.
Cells
.
2021
;
10
(
2
):
437
.
19.
Uehara
SK
,
Nishiike
Y
,
Maeda
K
,
Karigo
T
,
Kuraku
S
,
Okubo
K
, et al
.
Identification of the FSH-RH as the other gonadotropin-releasing hormone
.
Nat Commun
.
2024
;
15
(
1
):
5342
.
20.
Hollander-Cohen
L
,
Cohen
O
,
Shulman
M
,
Aiznkot
T
,
Fontanaud
P
,
Revah
O
, et al
.
The satiety hormone cholecystokinin gates reproduction in fish by controlling gonadotropin secretion
.
Elife
.
2024
;
13
:
RP96344
.
21.
Whitlock
KE
,
Postlethwait
J
,
Ewer
J
.
Neuroendocrinology of reproduction: is Gonadotropin-Releasing Hormone (GnRH) dispensable
.
Front Neuroendocrinol
.
2019
;
53
:
100738
.
22.
Acevedo-Rodriguez
A
,
Kauffman
AS
,
Cherrington
BD
,
Borges
CS
,
Roepke
TA
,
Laconi
M
.
Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling
.
J Neuroendocrinol
.
2018
;
30
(
10
):
e12590
.
23.
Marques
P
,
De Sousa Lages
A
,
Skorupskaite
K
,
Rozario
KS
,
Anderson
RA
,
George
JT
. In:
Feingold
KR
,
Anawalt
B
,
Blackman
MR
,
Boyce
A
,
Chrousos
G
,
Corpas
E
, et al
, editors.
Physiology of GnRH and gonadotrophin secretion
.
South Dartmouth (MA)
:
MDText.com, Inc.
;
2000
. [cited 2025 Jan 20].Available from: http://www.ncbi.nlm.nih.gov/books/NBK279070/
24.
Spicer
OS
,
Wong
T-T
,
Zmora
N
,
Zohar
Y
.
Targeted mutagenesis of the hypophysiotropic Gnrh3 in zebrafish (Danio rerio) reveals No effects on reproductive performance
.
PLoS One
.
2016
;
11
(
6
):
e0158141
.
25.
Abraham
E
,
Palevitch
O
,
Gothilf
Y
,
Zohar
Y
.
Targeted gonadotropin-releasing hormone-3 neuron ablation in zebrafish: effects on neurogenesis, neuronal migration, and reproduction
.
Endocrinology
.
2010
;
151
(
1
):
332
40
.
26.
Okubo
K
,
Aida
K
.
Gonadotropin-Releasing Hormones (GnRHs) in a primitive teleost, the arowana: phylogenetic evidence that three paralogous lineages of GnRH occurred prior to the emergence of teleosts
.
Gen Comp Endocrinol
.
2001
;
124
(
2
):
125
33
.
27.
Liu
Y
,
Tang
H
,
Xie
R
,
Li
S
,
Liu
X
,
Lin
H
, et al
.
Genetic evidence for multifactorial control of the reproductive Axis in zebrafish
.
Endocrinology
.
2017
;
158
(
3
):
604
11
.
28.
Marvel
M
,
Spicer
OS
,
Wong
T-T
,
Zmora
N
,
Zohar
Y
.
Knockout of the Gnrh genes in zebrafish: effects on reproduction and potential compensation by reproductive and feeding-related neuropeptides
.
Biol Reprod
.
2018
;
99
(
3
):
565
77
.
29.
d’Anglemont De Tassigny
X
,
Fagg
LA
,
Dixon
JPC
,
Day
K
,
Leitch
HG
,
Hendrick
AG
, et al
.
Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene
.
Proc Natl Acad Sci
.
2007
;
104
(
25
):
10714
9
.
30.
Messager
S
,
Chatzidaki
EE
,
Ma
D
,
Hendrick
AG
,
Zahn
D
,
Dixon
J
, et al
.
Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54
.
Proc Natl Acad Sci
.
2005
;
102
(
5
):
1761
6
.
31.
Takahashi
A
,
Kanda
S
,
Abe
T
,
Oka
Y
.
Evolution of the hypothalamic-pituitary-gonadal Axis regulation in vertebrates revealed by knockout medaka
.
Endocrinology
.
2016
;
157
(
10
):
3994
4002
.
32.
Nyuji
M
,
Yamamoto
I
,
Hamada
K
,
Kazeto
Y
,
Okuzawa
K
.
Effect of GnRHa on plasma levels of Fsh and Lh in the female greater amberjack Seriola dumerili
.
J Fish Biol
.
2019
;
95
(
5
):
1350
4
.
33.
Trudeau
VL
.
Facing the challenges of neuropeptide gene knockouts: why do they not inhibit reproduction in adult teleost fish
.
Front Neurosci
.
2018
;
12
:
302
.
34.
Ma
Y
,
Giardino
WJ
.
Neural circuit mechanisms of the cholecystokinin (CCK) neuropeptide system in addiction
.
Addict Neurosci
.
2022
;
3
:
100024
.
35.
Beglinger
C
,
Degen
L
.
Fat in the intestine as a regulator of appetite: role of CCK
.
Physiol Behav
.
2004
;
83
(
4
):
617
21
.
36.
Liddle
RA
.
Cholecystokinin cells
.
Annu Rev Physiol
.
1997
;
59
(
Volume 59
):
221
42
.
37.
Little
TJ
,
Horowitz
M
,
Feinle-Bisset
C
.
Role of cholecystokinin in appetite control and body weight regulation
.
Obes Rev
.
2005
;
6
(
4
):
297
306
.
38.
Russell
JA
,
Douglas
AJ
,
Brunton
PJ
.
Reduced hypothalamo-pituitary-adrenal axis stress responses in late pregnancy: central opioid inhibition and noradrenergic mechanisms
.
Ann N Y Acad Sci
.
2008
;
1148
(
1
):
428
38
.
39.
Himick
BA
,
Golosinski
AA
,
Jonsson
A-C
,
Peter
RE
.
CCK/Gastrin-like immunoreactivity in the goldfish pituitary: regulation of pituitary hormone secretion by CCK-like peptides in vitro
.
Gen Comp Endocrinol
.
1993
;
92
(
1
):
88
103
.
40.
Batten
TF
,
Cambre
ML
,
Moons
L
,
Vandesande
F
.
Comparative distribution of neuropeptide-immunoreactive systems in the brain of the green molly, Poecilia latipinna
.
J Comp Neurol
.
1990
;
302
(
4
):
893
919
.
41.
Li
H
,
Liang
H
,
Gao
X
,
Zeng
X
,
Zheng
S
,
Wang
L
, et al
.
Cholecystokinin (CCK) is a mediator between nutritional intake and gonadal development in teleosts
.
Cells
.
2025
;
14
(
2
):
78
.
42.
Himick
BA
,
Vigna
SR
,
Peter
RE
.
Characterization of cholecystokinin binding sites in goldfish brain and pituitary
.
Am J Physiol
.
1996
;
271
(
1 Pt 2
):
R137
143
.
43.
Dockray
GJ
.
Cholecystokinin
.
Curr Opin Endocrinol Diabetes Obes
.
2012
;
19
(
1
):
8
12
.
44.
Trudeau
VL
.
Neuroendocrine regulation of gonadotrophin II release and gonadal growth in the goldfish, Carassius auratus
.
Rev Reprod
.
1997
;
2
(
1
):
55
68
.
45.
Hollander-Cohen
L
,
Golan
M
,
Levavi-Sivan
B
.
Differential regulation of gonadotropins as revealed by transcriptomes of distinct LH and FSH cells of fish pituitary
.
Int J Mol Sci
.
2021
;
22
(
12
):
6478
.
46.
Guyon
R
,
Rakotomanga
M
,
Azzouzi
N
,
Coutanceau
JP
,
Bonillo
C
,
D’Cotta
H
, et al
.
A high-resolution map of the Nile tilapia genome: a resource for studying cichlids and other percomorphs
.
BMC Genomics
.
2012
;
13
(
1
):
222
.
47.
Rathore
RM
,
Angotzi
AR
,
Jordal
A-EO
,
Rønnestad
I
.
Cholecystokinin receptors in Atlantic salmon: molecular cloning, gene expression, and structural basis
.
Physiol Rep
.
2013
;
1
(
5
):
e00069
.
48.
Chu
L
,
Li
J
,
Liu
Y
,
Cheng
CHK
.
Gonadotropin signaling in zebrafish ovary and testis development: insights from gene knockout study
.
Mol Endocrinol
.
2015
;
29
(
12
):
1743
58
.
49.
Hattori
A
,
Ishii
S
,
Wada
M
,
Miyamoto
K
,
Hasegawa
Y
,
Igarashi
M
, et al
.
Effects of chicken (Gln8)- and mammalian (Arg8)-luteinizing hormone-releasing hormones on the release of gonadotrophins in vitro and in vivo from the adenohypophysis of Japanese quail
.
Gen Comp Endocrinol
.
1985
;
59
(
1
):
155
61
.
50.
Hattori
A
,
Ishii
S
,
Wada
M
.
Effects of two kinds of chicken Luteinizing Hormone-Releasing Hormone (LH-RH), mammalian LH-RH and its analogs on the release of LH and FSH in Japanese quail and chicken
.
Gen Comp Endocrinol
.
1986
;
64
(
3
):
446
55
.
51.
Hattori
A
,
Ishii
S
,
Wada
M
.
Different mechanisms controlling FSH and LH release in Japanese quail (Coturnix coturnix japonica): evidence for an inherently spontaneous release and production of FSH
.
J Endocrinol
.
1986
;
108
(
2
):
239
45
.
52.
Sower
SA
.
Landmark discoveries in elucidating the origins of the hypothalamic-pituitary system from the perspective of a basal vertebrate, sea lamprey
.
Gen Comp Endocrinol
.
2018
;
264
:
3
15
.
53.
Coss
D
.
Regulation of reproduction via tight control of gonadotropin hormone levels
.
Mol Cell Endocrinol
.
2018
;
463
:
116
30
.
54.
Vijayan
E
,
Samson
WK
,
McCann
SM
.
In vivo and in vitro effects of cholecystokinin on gonadotropin, prolactin, growth hormone and thyrotropin release in the rat
.
Brain Res
.
1979
;
172
(
2
):
295
302
.
55.
Lo
C-M
,
Samuelson
LC
,
Chambers
JB
,
King
A
,
Heiman
J
,
Jandacek
RJ
, et al
.
Characterization of mice lacking the gene for cholecystokinin
.
Am J Physiol Regul Integr Comp Physiol
.
2008
;
294
(
3
):
R803
10
.
56.
Biran
J
,
Palevitch
O
,
Ben-Dor
S
,
Levavi-Sivan
B
.
Neurokinin Bs and neurokinin B receptors in zebrafish-potential role in controlling fish reproduction
.
Proc Natl Acad Sci
.
2012
;
109
(
26
):
10269
74
.
57.
Popesku
JT
,
Martyniuk
CJ
,
Mennigen
J
,
Xiong
H
,
Zhang
D
,
Xia
X
, et al
.
The goldfish (Carassius auratus) as a model for neuroendocrine signaling
.
Mol Cell Endocrinol
.
2008
;
293
(
1–2
):
43
56
.
58.
Trudeau
VL
.
Neuroendocrine control of reproduction in teleost fish: concepts and controversies
.
Annu Rev Anim Biosci
.
2022
;
10
(
1
):
107
30
.
59.
Reinecke
M
.
Insulin-like growth factors and fish reproduction
.
Biol Reprod
.
2010
;
82
(
4
):
656
61
.
60.
Lin
S-W
,
Ge
W
.
Differential regulation of gonadotropins (FSH and LH) and Growth Hormone (GH) by neuroendocrine, endocrine, and paracrine factors in the zebrafish—an in vitro approach
.
Gen Comp Endocrinol
.
2009
;
160
(
2
):
183
93
.
61.
Uju
C
,
Karimzadeh
K
,
Unniappan
S
.
Brain-derived neurotrophic factor stimulates hypothalamic and gonadal reproductive hormones and oocyte maturation in zebrafish
.
Reprod Camb Engl
.
2025
;
169
(
1
):
e240233
.
62.
Uju
CN
,
Unniappan
S
.
Growth factors and female reproduction in vertebrates
.
Mol Cell Endocrinol
.
2024
;
579
:
112091
.
63.
Golan
M
,
Biran
J
,
Levavi-Sivan
B
.
A novel model for development, organization, and function of gonadotropes in fish pituitary
.
Front Endocrinol
.
2014
;
5
:
182
.
64.
Safian
D
,
Bogerd
J
,
Schulz
RW
.
Regulation of spermatogonial development by Fsh: the complementary roles of locally produced Igf and Wnt signaling molecules in adult zebrafish testis
.
Gen Comp Endocrinol
.
2019
;
284
:
113244
.
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