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Editorial

Why does human chorionic gonadotropin havesuch a broad regulatory roles in the body and arethey 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 4000million 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 threemolecular entitiesmore 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

roundworms.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 LHmay 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 pressuresmay 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

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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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 previouslymentioned, 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 hormonereceptors in nematodes: evolution and function. Mol CellEndocrinol. 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 glycoproteinhormone receptors. Integ Comp Biol. 2010;50:110e123.

6. Maston GA, Ruvolo M. Chorionic gonadotropin has a recentorigin within primates and an evolutionary history ofselection. Mol Biol Evol. 2002;19:320e335.

7. Rao CV. Nongonadal actions of LH and hCG in reproductivebiology and medicine. Sem Reprod Med (Guest Editor). 2001;vol.19:1e119.

8. Rao CV, Lei ZM. The past, present and future of nongonadalLH/hCG actions in reproductive biology and medicine.Mol CellEndocrinol. 2007;269:2e8.

9. Pierce JG, Parsons TF. Glycoprotein hormones: structure andfunction. Annu Rev Biochem. 1981;50:465e495.

10. Hsu SY, Nakanayashi K, Bhalla A. Evolution ofglycoprotein hormone subunit genes in bilateral metazoa:identification of two novel human glycoprotein hormonesubunit 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 HumReprod. 2009;15:703e711.

13. Kokk K, Kuuslahti M, Keisala T, et al. Expression of luteinizinghormone receptors in the mouse penis. J Androl.2011;32:49e54.

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14. Parrott AM, Sriram G, Liu Y, Matthews MB. Expression of typeII chorionic gonadotropin genes supports a role in the malereproductive 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.2014.09.0012214-420X/Copyright © 2014, Reed Elsevier India Pvt. Ltd. All

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