1. Editorial
Why does human chorionic gonadotropin have
such a broad regulatory roles in the body and are
they totally unexpected?
Hormones are chemical messengers that nature has evolved
them primarily for internal communication in living organ-
isms. Both hydrophilic protein hormones and hydrophobic
steroid hormones are present in animal and plant kingdoms
throughout the evolutionary history and these molecules
probably evolved around 4000 million years ago. Reproductive
and endocrine systems have likely been evolved with hor-
mones from the early living organisms. Hormones require
cognate receptors, which in turn require signaling molecules
to complete their actions. This would mean a co-evolution of
all three molecular entities more or less simultaneously. Thus,
hormones, receptors and signaling molecules have also been
identified in primitive unicellular organisms, primitive fish,
and nematodes such as Caenorhabditis elegans (C. elegans) and
round worms.1e5
For example, the simple genome of C. elegans
contains six times more nuclear hormone receptor encoding
genes than vertebrates.2
It is not known, however, why its
genome has such a large number of nuclear hormone receptor
encoding genes?
This preface leads to human chorionic gonadotropin (hCG).
It is commonly known as a pregnancy hormone and widely
used for pregnancy testing. Chorionic gonadotropin is also
found in subhuman primates.6
Human placenta secretes large
quantities and a number of normal and cancer tissues can
secrete small quantities of hCG.7,8
The difference is non-
placental source of hCG has a shorter circulatory half-life
than placental hCG, which has a half-life of about 12 h.
Placental hCG is quite heterogeneous and in fact, it is a
collection of molecules differing in protein and carbohydrate
structures, function and circulatory half-lives.
hCG is a protein that contains large amounts of carbohy-
drate, especially when it is derived from placenta. Hence, it is
called a glycoprotein hormone. It contains two non-covalently
bound a- and b-subunits. The a-subunit is encoded by a single
gene and highly conserved among luteinizing hormone (LH),
follicle stimulating hormone (FSH) and thyroid stimulating
hormone (TSH). In fact, the same gene encodes the a-subunit
of all four hormones. Gonadotropes in anterior pituitary gland
secretes LH and FSH, and thyrotropes secrete TSH. The
b-subunit is hormone specific, which bears a significant
homology between hCG and LH. Single genes encode b-
subunits of LH, FSH and TSH. A six gene cluster, containing
pseudogenes, encodes the hCG-b subunit. Not all of them are
equally expressed and, moreover, contribution of each of the
six to mature hCG, may vary with the pregnancy states.
Nevertheless, the cluster is likely to have been evolved from a
single LH-b-subunit gene, through a process of duplication
and mutations, which probably shifted the transcription start
site and c-terminus extension. Because there is only one re-
ceptor for hCG and LH, they mimic each other's functions.
However, these functions differ quantitatively, which is pri-
marily due to the differences in their circulatory half-lives.
Due to a lower abundance of carbohydrate residues, LH has
a shorter circulatory half-life than hCG.9
In addition, LH has a
lower binding affinity than hCG for the receptor.7,8
It is theo-
retically possible that hCG and LH may have distinct functions
as a result of unique conformational changes that they might
induce in the same receptor molecule.
hCG belongs to the glycoprotein hormone and cystine knot
growth factor families. The former consists of LH, FSH, TSH
and the latter consists of transforming growth factors e b,
platelet derived growth factor and nerve growth factor.
Belonging to the same family implies overlapping functions by
these diverse set of molecules.
Although CG is only found in humans and subhuman pri-
mates, its functional analog, LH, is present in all species,
regardless of the pregnancy. Structurally similar CG and/or LH
molecules have been found in unicellular organisms, fish and
nematodes,10
but they may not perform the same functions.
It has been a mystery for decades why only humans and
subhuman primates have CG, when they already have a
functionally similar LH. The best guess is that evolutionary
and selection pressures may have led to the appearance of CG.
These pressures could have been that pregnancies in humans
and primates may have faced unusual hurdles during evolu-
tion and to overcome them, sturdier, longer lasting and
multifunctional molecule such as CG, might have been
required.11
The newly evolved CG probably then used the
same receptors and signaling systems as LH.
The identification of hCG dates back to more than 50 years.
Most of that time, it was known for its actions to rescue corpus
luteum from regression in a fertile cycle.7,8
Corpus luteum is
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2. needed for progesterone secretion, which maintains preg-
nancy. The progesterone secretion progressively shifts from
corpus luteum to placenta and is completed by about the 9th
week of pregnancy. This completion obviates the need for the
corpus luteum for pregnancy continuation. However, both
corpus luteum and hCG are maintained throughout preg-
nancy. It does not make sense for continued hCG secretion,
when it has no functions during the remainder of the preg-
nancy. The chances are that hCG has other functions, but we
simply did not know anything about them. Indeed, the
research in the past 20 years has shown that hCG has many
other functions through regulating several non-gonadal tis-
sues listed below (Table 1).7,8,12
hCG receptors, which bind LH as previously mentioned, are
also present in non-gonadal tissues of males.4,6
These tissues
include those that are common to both genders as well as
gender specific tissues/cells, such as sperm, secondary sex
organs (prostate, epididymis, and seminal vesicles) and
penis.7,8,13,14
The evolutionary significance of CG in males is
not known. However, it is possible that these receptors are
primarily meant for LH, which acquired the capacity to regu-
late male non-gonadal tissues for some unknown evolu-
tionary advantages.
The hCG actions in the non-gonadal tissues is context,
tissue and cell type dependent. The sum of all the hCG actions
can be summarized into five categories: those that favor
pregnancy initiation, pregnancy maintenance, safeguard
fetus from rejection, support fetal growth and development
and allow delivery when fetus is sufficiently mature for its
survival outside the womb.4,5
The probable evolutionary sig-
nificance of hCG actions is to safeguard pregnancy against all
the odds during primates evolution. This could also include
providing a relief from maladies that could potentially
threaten the successful completion of pregnancy. These
maladies, for example, could be rheumatoid arthritis, certain
pathogenic infections and other conditions which may chal-
lenge pregnancy continuation. In view of the above discus-
sion, it is easy to understand why hCG has such broad
regulatory roles in the body.
This leads to a next question of whether the broad regu-
latory roles of hCG are totally unexpected. As it turns out
many other hormones, such as prolactin, FSH, gonadotropin
releasing hormone, oxytocin, relaxin, etc, have multiple sites
of action beyond their conventional targets. Thus it should not
be surprising to find that hCG and LH can also regulate many
non conventional target tissues. The multiple uses of hor-
mones may have been conserved because of the environment
and mode of life changes during the evolution of organisms.
Finally multiple hormone uses could be a functional redun-
dancy and efficiency. In summary, the evolutionary and se-
lection pressures, environmental and mode of life changes
could have led to the hCG appearance and multiplicity of its
actions in humans. This functional multiplicity has led to a
wind fall of new therapeutic possibilities in reproductive
health and in other areas of medicine.7,8,12
r e f e r e n c e s
1. Vinson GP. On the origin of hormones. Endocrinologist. 2009/
10;94:8.
2. Taubert S, Ward JD, Yamamoto KR. Nuclear hormone
receptors in nematodes: evolution and function. Mol Cell
Endocrinol. 2010;334:49e55.
3. Hillier S. Endocrine evolution. Endocrinologist. 2009/10;94:9.
4. Krasowski MD, Ni A, Hagey LR, Ekins S. Evolution of
promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR,
and CAR. Mol Cell Endocrinol. 2010;334:39e44.
5. Freamat M, Sower SA. Functional divergence of glycoprotein
hormone receptors. Integ Comp Biol. 2010;50:110e123.
6. Maston GA, Ruvolo M. Chorionic gonadotropin has a recent
origin within primates and an evolutionary history of
selection. Mol Biol Evol. 2002;19:320e335.
7. Rao CV. Nongonadal actions of LH and hCG in reproductive
biology and medicine. Sem Reprod Med (Guest Editor). 2001;vol.
19:1e119.
8. Rao CV, Lei ZM. The past, present and future of nongonadal
LH/hCG actions in reproductive biology and medicine. Mol Cell
Endocrinol. 2007;269:2e8.
9. Pierce JG, Parsons TF. Glycoprotein hormones: structure and
function. Annu Rev Biochem. 1981;50:465e495.
10. Hsu SY, Nakanayashi K, Bhalla A. Evolution of
glycoprotein hormone subunit genes in bilateral metazoa:
identification of two novel human glycoprotein hormone
subunit family genes, GPA2 and GPB5. Mol Endocrinol.
2002;16:1538e1551.
11. Diamond J. The Third Chimpanzee, Chapters 3e6. New York, NY:
Harper Collins Publishers; 1993.
12. Rahman N, Rao CV. Recent progress in luteinizing hormone/
human chorionic gonadotropin hormone research. Mol Hum
Reprod. 2009;15:703e711.
13. Kokk K, Kuuslahti M, Keisala T, et al. Expression of luteinizing
hormone receptors in the mouse penis. J Androl.
2011;32:49e54.
Table 1 e Non-gonadal tissue targets of hCG/LH actions in females.
Targets
Oocyte
Early embryo
Human embryonic stem cells
Fallopian tubes
Uterus
Cervix
Placenta
Decidua
Cells of immune system
Fetal membranes
Several brain regions, including pineal
gland
Spinal cord
Neural retina
Adrenal cortex
Skin
Mammary glands
Bone
Adipose tissue
Urinary bladder
Target tissue vasculature
Umbilical cord
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3. 14. Parrott AM, Sriram G, Liu Y, Matthews MB. Expression of type
II chorionic gonadotropin genes supports a role in the male
reproductive system. Mol Cell Biol. 2010;2:287e299.
C.V. Rao*
Professor of Cell Biology, Department of Cellular Biology and
Pharmacology, Herbert Wertheim College of Medicine, Florida
International University, Miami, FL 33199, USA
Carlo Ticconi
Academic Department of Biomedicine and Prevention, Section of
Gynecology and Obstetrics, Tor Vergata University, Rome, Italy
Clinical Department of Surgery, Division of Gynecology and
Obstetrics, University Hospital Policlinico Tor Vergata, Rome, Italy
*Corresponding author. Molecular Human Genetics and
Obstetrics and Gynecology, Director of Reproduction
Development Program, 1120 SW 8th St. GL 495C, Miami, FL
33199, USA. Tel.: þ1 305 348 0659; fax: þ1 305 348 1577.
E-mail address: crao@fiu.edu
Available online 2 October 2014
http://dx.doi.org/10.1016/j.jrhm.2014.09.001
2214-420X/Copyright © 2014, Reed Elsevier India Pvt. Ltd. All
rights reserved.
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