Molecular and Cellular Endocrinology 383 (2014) 203213

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Molecular and Cellular Endocrinology

journal homepage: www.elsevier.com/locate/mce

Review

Luteinizing hormone and human chorionic gonadotropin: Origins

of difference
Janet Choi a,, Johan Smitz b,1
a
The Center for Womens Reproductive Care at Columbia University, New York, NY, United States
b
UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are widely recognized for their roles
Received 25 September 2013 in ovulation and the support of early pregnancy. Aside from the timing of expression, however, the dif-
Received in revised form 6 December 2013 ferences between LH and hCG have largely been overlooked in the clinical realm because of their similar
Accepted 12 December 2013
molecular structures and shared receptor. With technologic advancements, including the development of
Available online 21 December 2013
highly puried and recombinant gonadotropins, researchers now appreciate that these hormones are not
as interchangeable as once believed. Although they bind to a common receptor, emerging evidence sug-
Keywords:
gests that LH and hCG have disparate effects on downstream signaling cascades. Increased understanding
Gonadotropin
Lutropin
of the inherent differences between LH and hCG will foster more effective diagnostic and prognostic
Luteinizing hormone assays for use in a variety of clinical contexts and support the individualization of treatment strategies
Human chorionic gonadotropin for conditions such as infertility.
Luteinizing hormone/choriogonadotropin 2013 The Authors. Published by Elsevier Ireland Ltd. Open access under CC BY-NC-SA license.
receptor
Luteinizing hormone receptor

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
2. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
3. Molecular structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
3.1. Gonadotropin variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
4. Circulating forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
4.1. Luteinizing hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
4.2. Human chorionic gonadotropin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
5. Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
6. Receptor binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
6.1. Luteinizing hormone/choriogonadotropin receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
6.2. Signaling pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
6.3. Extragonadal LHCGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
7. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

Corresponding author. Address: The Center for Womens Reproductive Care at Columbia University, 1790 Broadway, 2nd Floor, New York, NY 10019, United States. Tel.:
+1 646 756 8282; fax: +1 646 756 8280.
E-mail addresses: jmc30@columbia.edu (J. Choi), johan.smitz@uzbrussel.be (J. Smitz).
1
Address: UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Tel.: +32 2 477 50 52; fax: +32 2 477 50 60.

0303-7207 2013 The Authors. Published by Elsevier Ireland Ltd. Open access under CC BY-NC-SA license.
http://dx.doi.org/10.1016/j.mce.2013.12.009
204 J. Choi, J. Smitz / Molecular and Cellular Endocrinology 383 (2014) 203213
1. Introduction
It is well established that luteinizing hormone (LH) and human
chorionic gonadotropin (hCG) play key roles in the reproductive
cycle. Textbooks recognize the disparate endogenous functions of
these hormones, underscoring the role of LH in follicular matura-
tion and ovulation induction, while acknowledging the essential
role of hCG in early pregnancy survival. During early pregnancy,
hCG is vital to support secretion of progesterone by the corpus lut-
eum, without which a pregnancy cannot persist (Fritz and Speroff,
2011; Mesiano, 2009). Nonetheless, LH and hCG are frequently de-
picted as interchangeable, with one contemporary text stating that
the b subunits [of human LH (hLH) and hCG] confer identical bio-
logic activities when associated with the a subunit (Bulun, 2011).
Although similar in structure and function, LH and hCG are dis-
tinct molecular entities with divergent patterns of expression and
physiologic functions. LH and hCG share a common receptor, yet
each hormone triggers a unique cascade of events following recep-
tor binding (Casarini et al., 2012; Gupta et al., 2012). Moreover,
within the same hormone family, individual isoforms exhibit un-
ique characteristics regarding half-life and biologic functions.
Emerging data suggest that these differences between LH and
hCG have functional signicance. Identifying the unique roles of
LH and hCG is key to understanding both normal physiologic pro-
cesses (e.g., reproduction, placentation) and dysfunctional states
(e.g., infertility, gestational and non-gestational neoplasms). Ad-
vances in gonadotropin purication and recombinant technology
have helped to differentiate the varied actions of LH and hCG. In
turn, this has improved the diagnosis and treatment of human dis-
ease, most signicantly in the context of infertility.
2. Materials and methods
A comprehensive literature review of LH and hCG was con-
ducted, focusing on differentiation in terms of hormone structure,
expression, modication, receptor activation, and clinical use. Sci-
entic literature was identied via interrogation of the MEDLINE
database using relevant search terms, including but not limited
to: gonadotropin, human chorionic gonadotropin, luteinizing
hormone, luteinizing hormone/choriogonadotropin receptor,
lutropin, and lutropin receptor. Results were limited to articles
published in English. Additional resources were extracted from
clinical texts and review articles. Article inclusion was predicated
on relevance to the topic without use of an objective set of criteria,
given that the review is descriptive rather than systematic in
nature.
3. Molecular structure
Both LH and chorionic gonadotropin (CG) are heterodimeric gly-
coproteins comprised of a and b subunits. Along with thyroid-
stimulating hormone (TSH) and follicle-stimulating hormone
(FSH), they share a common 92-amino acid a subunit, whose gene
resides on chromosome 6q12q21 in humans (Bulun, 2011; Naylor
et al., 1983). The unique functions and receptor-binding capacity of
each of these hormones stem from differences among the b sub-
units (Table 1). Transcription of the b-subunit is the rate-limiting
step in LH and CG production (Nagirnaja et al., 2010). The genes
for the LH and hCG b subunits are located within a cluster of seven
similar sequences on human chromosome 19q13.32 (Boorstein
et al., 1982; Jameson and Hollenberg, 1993). One of those se-
quences encodes the b-subunit of LH (LHB); four are hCG b-subunit
coding genes (CGB, CGB5, CGB7, and CGB8), and the remaining two
are pseudogenes (CGB1, CGB2).
Table 1
Characteristics of hLHa and hCGb.
hLH hCG
Molecular weight (Da) 30,000 36,000c
a Subunit
Gene location 6q12q21 6q12q21
Size of mature subunit (no. of amino acids) 92 92
b Subunit
Gene location 19q13.32 19q13.32
Size of mature subunit (no. of amino acids) 121 145
hLH, human luteinizing hormone; hCG, human chorionic gonadotropin.
a
Bulun (2011).
b
Cole (2010).
c
Molecular weight of hyperglycosylated form is 40,00041,000 Da.
The high degree of sequence conservation among CGB genes,
combined with the fact that CG is detected only in equine and pri-
mate species (whereas LH is found in all vertebrates) suggests that
CG is a relatively recent evolutionary derivative of LH. The amino
acid sequences of human LH (hLH) and hCG are highly conserved,
sharing 82% homology (Bulun, 2011). hCG retains the full
145 amino-acid complement in its b-subunit. In contrast, the
b-subunit of LH undergoes cleavage of its 24-amino acid leader se-
quence to generate its nal 121-amino acid sequence.
As a result of structural differences and post-translational mod-
ications, hCG is more stable and has a longer circulating half-life
than LH. The half-lives of these molecules typically are expressed
as a range (on the order of minutes for LH and hours for hCG),
reecting the heterogeneity of circulating isoforms. The shorter
half-life of LH is physiologically important, as it allows for the pro-
duction of LH pulses. The longer half-life of hCG and its greater
receptor binding afnity make it more biologically active than
hLH (Rahman and Rao, 2009; Rao, 1979).
3.1. Gonadotropin variants
In the endogenous state, LH and hCG consists of isohormone
mixtures that result from (1) post-translational modication of
the native proteins; (2) metabolism to form truncated or nicked
intermediates; and (3) natural sequence variants (Bergendah and
Veldhuis, 2001; Cole, 2009; Stanton et al., 1993). Post-translational
modication chiey consists of the addition of various carbohy-
drate side chains, including sialic and sulfonic acid moieties, thus
creating a variety of isoforms (upwards of 30 for LH and 15 for
hCG) that differ with respect to half-life, bioactivity, and signaling
properties (Arey and Lopez, 2011; Bergendah and Veldhuis, 2001;
Cole, 2009; Stanton et al., 1993). Obviously, the number of isoform
classes for each hormone is determined by our capacity for analyt-
ical discrimination. Because glycosylation affects the size and con-
formation of the molecule as well as access to binding sites,
differences in interactions with their cognate receptor are to be ex-
pected (Arey and Lopez, 2011).
Naturally occurring variants of both LH and hCG have been
characterized. A variant of LH that has an additional glycosylation
site compared with wild-type LH is relatively common within cer-
tain populations (Lamminen and Huhtaniemi, 2001; Nilsson et al.,
1997). Data have been collected showing that variant LH differs
from normal LH in its biological effects (Haavisto et al., 1995). This
LH variant has been associated with unexplained infertility and
subfertility due to ovulatory dysfunction in females, and with slo-
wed pubertal progression in males (Raivio et al., 1996; Takahashi
et al., 1998, 1999). Preliminary data also suggest that the variant
LH is more prevalent among women who demonstrate resistance
to ovarian stimulation with recombinant human FSH, compared
 J. Choi, J. Smitz / Molecular and Cellular Endocrinology 383 (2014) 203213
with those who exhibit moderate or strong responses (Alviggi
et al., 2011). Men with one or two copies of the variant allele have
lower circulating LH levels compared with homozygotes for the
wild-type allele (Huhtaniemi et al., 2010). However, the ratio of
biological-to-immunological activity (a measure of relative LH
biopotency) for variant LH is greater than that of wild-type LH
(Haavisto et al., 1995).
A less common LH variant resulting in a single amino acid sub-
stitution in the b subunit (serine for glycine at amino acid 102) has
been associated with menstrual disorders and male infertility
(Hashad et al., 2012; Ramanujam et al., 1999, 2000). Little is known
about how this rare variant affects the functionality of LH. Based on
in vivo experiments, Wide et. al. showed that an extra glycosylation
site on variant LH compared to the wild type, allows for greater
sialylation and results in a longer half-life in serum. Granulosa
cells are triggered typically by distinct pulses of LH; however,
because of its prolonged residence in serum, granulosa cells are
exposed to decreased pulse amplitudes of variant LH. Thus, Wide,
et. al. proposed that the longer half-life of variant LH may be a
contributing factor to the reproductive disorders observed (Wide
et al., 2010).
Although hCG polymorphisms with functional signicance are
generally rare, variants in the b subunit of hCG with putative
protective or detrimental effects on recurrent miscarriage risk have
been identied (Nagirnaja et al., 2012; Rull et al., 2008). The se-
quence changes associated with increased risk of recurrent miscar-
riage occur in the most commonly transcribed hCG b-subunit
genes, CGB5 and CGB8, and result in conformational changes to
the proteins structure (Nagirnaja et al., 2012). One of the b-subunit
missense mutations in particular-hCG b p.Val56Leu adversely im-
pacts its ability to bind efciently with its a-subunit with only
10% forming the complete hCG heterodimer. However, additional
studies show increased bioactivity of this resultant variant hCG
(possibly due to subtle conformational changes) when bound to
LHCGR, increasing the impact of this more sparsely produced var-
iant hCG. The paucity of polymorphisms that have been identied
in hCG imply that only modest changes in CGB5 and CGB8 are
compatible with a successful pregnancy outcome.
4. Circulating forms
4.1. Luteinizing hormone
Gonadotrophic cells of the anterior pituitary produce LH, which
regulates ovulation. Over the course of a normal menstrual cycle, a
surge in LH spurs ovulation from the dominant follicle. This pro-
cess initiates during the mid-follicular phase, when LH stimulates
androgen production in thecal cells. These androgens are aroma-
tized in the granulosa cells to estrogen. Prolonged, sustained estro-
gen levels generate positive feedback on the pituitary gland and
the subsequent LH surge that results in ovulation (Liu and Yen,
1983) Post-ovulation, LH promotes progesterone production, sup-
porting development of the corpus luteum (Van de Wiele et al.,
1970).
The composition of LH isoforms, their longevity, and their bio-
activity vary throughout the menstrual cycle. The ratio of biologi-
cal-to-immunological activity is lowest during the luteal phase,
rising slowly during the follicular phase to a peak at mid-cycle
(Anobile et al., 1998). This corresponds with the pinnacle of LH
sialylation and a marked trough in sulfonation (Wide and Eriksson,
2013). Earlier studies had established that sialylation prolongs LH
half-life, whereas sulfonation hastens protein elimination (Burgon
et al., 1996; Wide et al., 2009). Changes in the extent of glycosyla-
tion during the menstrual cycle appear to be regulated by the
pituitary gland, under the inuence of such factors as gonadotro-
205
pin-releasing hormone (GnRH), estradiol, and testosterone
(Bergendah and Veldhuis, 2001; Lambert et al., 1998; Wide and
Bakos, 1993).
Variations in LH isoform composition are also observed during
the reproductive life cycle. In general, LH isoforms with shorter
half-lives but increased biopotency are present in younger post-
pubertal women, whereas longer-lived LH species are the predom-
inant form detected in post-menopausal women (Reader et al.,
1983; Wide, 1985). LH in the latter group also has an increased ra-
tio of biological-to-immunological activity (Marrama et al., 1983).
Interestingly, women with polycystic ovarian syndrome (PCOS)
an endocrine condition associated with reduced fertilityappear
to predominantly secrete LH isoforms that have a high ratio of bio-
logical-to-immunological activity (Ding and Huhtaniemi, 1991;
Ropelato et al., 1999). Molecular analysis of LH in women with
PCOS has revealed a substantial decrease in sulfonation at midcy-
cle, accompanied by a slight increase in sialylation compared with
non-affected individuals (Wide et al., 2007). The net result is an
increase in basic LH isoforms relative to women without PCOS
(Ropelato et al., 1999; Wide et al., 2007). It is unclear what inu-
ence, if any, these changes have on the half-life of LH. It is known
that that basic LH isoforms are, in general, cleared more rapidly
than acidic isoforms, yet based on ndings regarding the specic
effects of sialylation vs. sulfonation on LH half-life (Burgon et al.,
1996; Wide et al., 2009), the changes observed in women with
PCOS would be expected to increase LH residence time in circula-
tion. This question is made more complex by the apparent effect of
body mass index (BMI) on the LH prole of women with PCOS
(Srouji et al., 2007). Current dogma posits that increased basal
secretion of LH plays a greater role than altered post-translational
modication in the elevated serum LH concentrations that have
been observed among women with PCOS.
In men, LH stimulates testosterone production by Leydig cells of
the testis. The degree of LH sialylation and the ratio of biological-
to-immunological activity of LH are generally greater in men than
in pre-menopausal women (Bergendah and Veldhuis, 2001; Wide
et al., 2007). Unlike women, however, the biological-to-immuno-
logical activity ratio of LH decreases with age in men (Marrama
et al., 1984; Warner et al., 1985). A shift toward more LH species
that have a shorter serum half-life has been described in obese
men, which may be a source of the reduced testosterone levels
reported in those individuals (Castro-Fernandez et al., 2000).
4.2. Human chorionic gonadotropin
At least four physiologically important isoforms of hCG have
been described, including regular hCG, hyperglycosylated hCG (h-
hCG), hyperglycosylated free hCG b subunit, and pituitary hCG. Dif-
ferent cell types produce these isoforms, which have unique,
although sometimes overlapping, functions. Each of the four vari-
ants shares a common protein sequence (at least for the b subunit),
but each is modied differently, resulting in isoforms with dispa-
rate half-lives and biologic functions. The distribution and quantity
of hCG isoforms varies over the course of pregnancy and in the con-
text of aberrant development or disease. For example, in early
pregnancy, an abnormally low proportion of h-hCG to total hCG
(<50%) indicates a failing pregnancy, (Kovalevskaya et al., 2002;
Sasaki et al., 2008), while decreased rst trimester serum free b-
hCG levels have been associated with ectopic pregnancies (Borrelli
et al., 2003). Conversely, elevated h-hCG can indicate choriocarci-
noma or Down syndrome pregnancy (Cole et al., 1999; Elliott
et al., 1997; Palomaki et al., 2007).
Regular hCG is secreted by fused and differentiated syncytio-
trophoblasts. It is the predominant hCG species measured in serum
during pregnancy, after the initial early surge of h-hCG (Cole,
2010). The chief role of hCG historically has been the promotion
206 J. Choi, J. Smitz / Molecular and Cellular Endocrinology 383 (2014) 203213

Table 2
Production and biological functions of hCG isoforms.

Isoform (source) Function(s)

hCG (syncytiotrophoblast cells)
Hyperglycosylated hCG (cytotrophoblast cells normal and
malignant cells)
Free b-hCG (non-trophoblastic malignancies)
Pituitary hCG (gonadotroph cells of the anterior pituitary)
 Promotes corpus luteum progesterone secretion
 Stimulates angiogenesis within pregnant uterus
 Differentiates cytotrophoblasts and may stimulate cytotrophoblast metalloproteinases, facilitating
pregnancy implantation
 Inhibits immune response and macrophage phagocytosis at utero-placental junction
 Relaxes uterine muscle contraction and permits uterine growth during pregnancy
 May promote differentiation and development of umbilical cord and fetal organs
 Blastocyst cross-talk with endometrium prior to implantation
 LHCG receptors found in sperm and fallopian tubes suggesting pre-pregnancy communication roles
 hCG receptors in hippocampus, hypothalamus and brain stem suggests its role in hyperemesis
gravidarum
 Promotes implantation via cytotrophoblast invasion; also inhibits apoptosis and stimulates invasion
by choriocarcinoma cells
 Inhibits non-trophoblastic malignancies apoptosis; promotes cancer cell growth
 Mimics LH functions during the normal menstrual cycle

hCG, human chorionic gonadotropin; LH, luteinizing hormone. Adapted from Cole (2010).

of progesterone secretion by the corpus luteum in early pregnancy.
However, as noted by Cole, hCG levels continue to increase after
hCG is no longer needed for progesterone production, suggesting
other functions for this hormone during pregnancy (Cole, 2009).
It is now believed that hCG is involved in placentation through
activities such as maintaining angiogenesis of the uterine vascula-
ture and promoting differentiation of cytotrophoblasts into syncy-
tiotrophoblasts (Rao and Alsip, 2001; Shi et al., 1993; Zygmunt
et al., 2002). Emerging evidence also suggests roles for regular
hCG in fostering implantation, preventing fetal rejection, coordi-
nating uterine and fetal growth, and, potentially, growth and
development of fetal organs (Cole, 2010). The varieties of estab-
lished and putative functions for regular hCG are listed in Table 2.
Secreted by root or extravillous cytotrophoblasts, h-hCG con-
centrations peak early in the rst trimester. The percentage of
hCG in the form of h-hCG subsequently declines, becoming a minor
component of total hCG measurement during the last two trimes-
ters. The key differentiator between regular hCG and h-hCG is the
complexity of the oligosaccharide side chains: h-hCG tends toward
oligosaccharides with a greater number of sugar residues. Conse-
quently, the molecular weight of h-hCG is in the range of
40,00041,000 Da, whereas that of regular hCG is approximately
36,000 Da. The additional sugar moieties prevent normal protein
folding, thus exposing alternative receptor binding sites and alter-
ing the hormones functionality (Cole, 2010). Indeed, results of re-
cent experiments by Berndt and colleagues indicate that h-hCG-
mediated angiogenesis may occur independent of activation of its
cognate receptor (Berndt et al., 2013).
The association between pregnancy loss and low h-hCG levels
supports a key role for this variant in implantation (Kovalevskaya
et al., 2002; Sasaki et al., 2008). The importance of h-hCG in
implantation/invasion is also evident in the context of choriocarci-
noma, as a pathologic process (Cole, 2010). Current data suggest
that h-hCG and hCG act in conjunction to forewarn the endome-
trium of impending implantation, to foster growth and differentia-
tion of trophoblast cells, and to establish placental villous
structures.
During pregnancy, the amount of total and h-hCG in serum and
urine demonstrates a high degree of inter-individual variability
(Cole, 2010). This endogenous variation may be normalized at
the receptor level via downregulation in the presence of high
hCG concentrations, or through the spare receptor concept, which
generates the same response regardless of the proportion of recep-
tors activated. The end result is that, unless the hCG level is insuf-
cient to support its basic functionality, variation is compatible
with normal pregnancy.
Hyperglycosylated free hCG b subunits are found at low levels
during normal pregnancy and are also produced by non-tropho-
blastic malignancies (Butler et al., 2000; Cole, 2009; Cole et al.,
1988; Iles et al., 1990). Akin to h-hCG, the hyperglycosylated free
b subunit is characterized by N- and O-linked oligosaccharides
containing a large number of sugar residues. Free b subunits are
not only a biomarker of malignancy but are also believed to play
an active role in cancer development by preventing apoptosis
and promoting carcinogenesis (Butler et al., 2000; Cole and Butler,
2008). Indeed, elevated levels of free b-hCG in urine samples of pa-
tients with malignancies increase the likelihood for metastasis and
mortality (Butler et al., 2000; Iles et al., 1996). The anti-apoptotic
effects of free b-hCG may result from antagonistic inhibition of
other growth factor receptors, rather than interaction with the
canonical receptor (Butler and Iles, 2004). Because it lacks the a
subunit, free b-hCG cannot bind to the lutropin receptor (Cole,
2009).
Pituitary hCG is secreted by gonadotrophic cells of the anterior
pituitary. The higher number of sulfonated side chains of pituitary
hCG gives it a shorter half-life than its placental counterpart (Bir-
ken et al., 1996). Pituitary hCG is present in all adults, including
men and pre-/post-menopausal women, and is suppressed with
GnRH agonist treatment (Odell and Grifn, 1987, 1989). During a
regular menstrual cycle, pituitary hCG secretion parallels that of
LH, although the half-life of pituitary hCG is shorter than that of
LH. As much as one-third of follicular-stage LH activity may derive
from hCG during a natural menstrual cycle (Cole, 2010). The func-
tion of pituitary hCG is generally not known, but its concomitant
temporal appearance with LH during the menstrual cycle and com-
mon receptor suggest that its functionality may mimic LHstimu-
lating follicular maturation, inducing ovulation, and supporting
progesterone production during the luteal phase (Cole, 2010). In
contrast, expression of the LHB gene is down-regulated in preg-
nancy (Rull and Laan, 2005) suggesting that while hCG might have
a functional role during the normal menstrual cycle, LH cannot
substitute for hCG in supporting pregnancy.
5. Metabolism
Gonadotropins undergo a series of metabolic conversions be-
fore ultimately being excreted in urine (Braunstein, 2011; Cole,
2009; OConnor et al., 1998). This process has been well character-
ized for hCG. One of the initial steps in hCG degradation is proteo-
lytic cleavage of the b subunit (possibly by human leukocyte
elastase), which generates a nicked form of the protein. Nicked
 J. Choi, J. Smitz / Molecular and Cellular Endocrinology 383 (2014) 203213
hCG rapidly dissociates into its component a and b subunits.
(Alternately, hCG that has not been nicked may slowly dissociate
prior to enzymatic cleavage.) Therefore, h-hCG dissociates more
readily than regular hCG in this context. The nicked b subunit is
further degraded, predominantly in the kidneys, resulting in a b-
core fragment. A comparable LH b-core fragment has been isolated
from human pituitary and urine samples (OConnor et al., 1998).
Given the array of glycosylated hCG forms and the potential for
nicked and dissociated varieties therein, a multitude of hCG degra-
dation products are detected in the urine of pregnant women, of
which the b-core fragment is most prevalent from 7 weeks gesta-
tion onward (Cole, 2009). In total, more than 30 hLH isoforms and
15 variants of hCG have been identied from serum and urine sam-
ples (Cole, 2009; Stanton et al., 1993).
The extent of gonadotropin glycosylation dictates molecular
charge, which, in turn, governs clearance rate, such that more acidic
isoforms have a longer half-life in vivo (Lambert et al., 1998). Inves-
tigators have also noted that the sialic acid content of LH positively
correlates with metabolic clearance rate (Burgon et al., 1996). In
other words, a greater degree of sialylation increases LH retention
in circulation. This observation holds true in the context of GnRH
receptor blockade as well. In response to GnRH receptor blockade,
LH levels decrease and the overall glycosylation prole shifts: the
mean number of sialic acid residues per molecule increases and
the number of sulfonated residues decreases (Wide et al., 2009).
The more sialylated and less sulfonated LH isoforms have longer
circulating half-lives. A similar effect occurs naturally via an LH
polymorphism that results in an extra site for glycosylation. This
LH variant has an increased number of sialic acid residues per mol-
ecule, resulting in a circulating half-life approximately 40% longer
than wild-type LH in humans (Wide et al., 2010).
hCG glycosylation also affects its longevity in circulation. Meta-
bolic clearance rates of deglycosylated, b-core fragment, and desi-
alylated hCG are all faster relative to hCG, with the greatest degree
of acceleration observed for desialylated hCG (Liu et al., 1989; Rosa
et al., 1984). The effects of naturally occurring hCG polymorphisms
on metabolic clearance rate or protein half-life have yet to be
described.
As a valuable early marker of pregnancy as well as various dis-
ease states, the ability to accurately measure hCG in its myriad
forms is particularly important. Beyond pregnancy detection,
hCG measurement is useful for identifying gestational trophoblas-
tic disease, risk of failing or abnormal pregnancy, and non-gesta-
tional malignancies. The predominant hCG species characteristic
of each of these conditions differs. In early pregnancy and gesta-
tional trophoblastic disease, h-hCG is the dominant form, whereas
elevated free b-subunit production is characteristic of certain
cancers (Cole et al., 1988; Elliott et al., 1997; Hoermann et al.,
1992; Iles et al., 1990; Mock et al., 2000). Abnormalities in h-
hCG are also used to assess pregnancy-related riskselevated
maternal blood levels during the rst and second trimester are
associated with fetal aneuploidy risk such as Down syndrome
while low h-hCG in the latter stages of pregnancy is emerging
as a putative marker of preeclampsia risk (Bahado-Singh et al.,
2002; Cole, 2009).
In the case of both LH and hCG, the multiple circulating forms
complicate their measurement in blood and urine (Cole, 2009;
OConnor et al., 1998). For example, total hCG assays, which are
the preferred measurement tool used by clinical laboratories, are
effective for quantifying regular hCG, but are generally suboptimal
for detecting h-hCG (Cole, 2009). Moreover, in addition to differ-
ences in glycosylation and degradation rates, genetic variants have
been found to impede detection of LH by immunoassay (OConnor
et al., 1998; Pettersson and Soderholm, 1991). Detection limits must
also be taken into account when assessing gonadotropin presence or
absence in clinical testing. Extremes in gonadotropin concentrations
207
that occur within certain clinical contexts may generate erroneous
results. It is important, therefore, to be aware of the limitations for
a particular assay when interpreting laboratory ndings.
6. Receptor binding
6.1. Luteinizing hormone/choriogonadotropin receptor
LH and hCG bind to and activate a common receptor, the LH/
choriogonadotropin receptor (LHCGR), also known as the LH or
lutropin receptor (LHR) (Ascoli et al., 2002; Puett et al., 2007). This
675-amino-acid, G-protein-coupled receptor is a member of the
rhodopsin subfamily of glycoprotein hormone receptors, as are
the FSH and TSH receptors. Like all G-protein coupled receptors,
LHCGR is anchored within the cell membrane by seven transmem-
brane domains. The unusually large extracellular domain of LHCGR
is characterized by leucine-rich repeats and multiple sites for gly-
cosylation (Fig. 1). The human LHCGR gene is located on chromo-
some 2p21, in the same general region as the FSH receptor
(Rousseau-Merck et al., 1993, 1990).
Consistent with its role in female reproduction, LHCGR is ex-
pressed by multiple cell types in the ovary, including thecal, luteal,
interstitial, and differentiated granulosa cells (Ascoli et al., 2002).
Expression of LHCGR in these cell types during the ovarian cycle
is dynamic rather than constitutive, reecting changes in the hor-
monal milieu (Menon and Menon, 2012; Menon et al., 2010).
LHCGR is downregulated transiently after the pre-ovulatory LH
surge, reaches a maximum at mid-luteal phase, and decreases with
corpus luteum regression. This pattern is the inverse of what has
been observed for bioactive LH isoforms, wherein peak biologic-
to-immunologic activity occurs at midcycle and reaches its lowest
point during the luteal phase (Anobile et al., 1998). The mecha-
nisms that govern temporal changes in LHCGR expression are not
yet fully elucidated but are generally believed to involve transcrip-
tional as well as post-transcriptional regulation (Ascoli et al., 2002;
Menon and Menon, 2012). Induction of LHCGR expression in differ-
entiating granulosa cells in response to FSH is an example of pre-
dominantly transcriptional control, whereas desensitization of
LHCGR in response to LH or hCG exposure includes an element of
post-transcriptional regulation. Agonist-mediated desensitization
of LHCGR involves a reduction in cell surface receptor concentra-
tion, as well as diminished mRNA abundance. The decrease in
mRNA has been attributed to increased transcript degradation
rather than suppressed transcription (Lu et al., 1993).
Through a series of studies involving rat and human ovarian
models, Menon and colleagues identied a binding protein, meva-
lonate kinase, which appears to regulate LHCGR expression by has-
tening degradation of LHCGR mRNA (Menon et al., 2010). An
inverse correlation was observed between LHCGR mRNA and mev-
alonate kinase activity: when one was elevated, the other was de-
creased (Nair et al., 2002). Moreover, inhibition of mevalonate
kinase prevented downregulation of LHCGR in response to hCG,
whereas overexpression of mevalonate kinase ameliorated induc-
tion of LHCGR in the presence of FSH and estradiol (Ikeda et al.,
2008; Wang et al., 2007).
Alternative splicing of LHCGR mRNA has been implicated in reg-
ulation of the ovarian cycle and luteolysis (Dickinson et al., 2009;
Minegishi et al., 2007). Splice variants differ in exon content and,
consequently, in their ability to bind or respond to LH or hCG.
Using human corpora lutea obtained at various stages of the ovar-
ian cycle, investigators have demonstrated quantitative, but not
qualitative, differences in the prole of LHCGR splice variants, indi-
cating that the relative abundance of mRNA species changes
throughout the ovarian cycle but their identity did not (Dickinson
et al., 2009; Madhra et al., 2004).
208 J. Choi, J. Smitz / Molecular and Cellular Endocrinology 383 (2014) 203213

Fig. 1. Glycoprotein hormone receptor structure. (A) Illustration of the short intracellular, 7-pass transmembrane, and large extracellular domains characteristic of
glycoprotein hormone receptors (e.g., the luteinizing hormone/choriogonadotropin receptor). (B) Three-dimensional schematic of the leucine-rich repeats (LRRs) within the
extracellular domain. (C) Structure of an individual LRR, wherein X represents any amino acid. Reproduced with permission from Vassart et al. (2004).

In vitro evidence suggests that gonadotropin signaling through
LHCGR inuences the expression of individual splice variants
(Dickinson et al., 2009). Previous experiments had shown that
one of the identied LHCGR splice variants forms complexes with
LHCGR or the FSH receptor, inuencing receptor expression and
preventing the latter from reaching the cell surface (Nakamura
et al., 2004; Yamashita et al., 2005). More recently, a truncated
form of LHCGR lacking transmembrane or carboxyterminal do-
mains negatively regulated the expression and activity of the
full-length protein (Dickinson et al., 2009). Further study is needed
to elucidate the physiologic signicance of LHCGR splice variants.
Frank mutations in LHCGR are associated with developmental
and reproductive abnormalities, including psuedohermaphrodism,
micropenis, hypospadias, and infertility (Ascoli et al., 2002; Menon
and Menon, 2012). Emerging data also suggest that polymorphisms
in the LHCGR sequence contribute to risk for conditions associated
with infertility, including PCOS. A genome-wide association study
that detected a link between a polymorphic marker in the region
of LHCGR and PCOS in Han Chinese women (which was conrmed
in a subsequent case-control cohort) spurred several similar investi-
gations in other ethnic groups (Chen et al., 2011; Shi et al., 2012). The
specic polymorphic marker associated with PCOS in the Han Chi-
nese population failed to correlate with PCOS in European popula-
tions (Eriksen et al., 2012; Mutharasan et al., 2013); however,
linkage within the genomic region of LHCGR was maintained upon
ne mapping in one study (Mutharasan et al., 2013).
Utilizing an actual LHCGR sequence variant rather than a neigh-
boring polymorphic marker, Capalbo and colleagues reported a cor-
relation between the 312N LHCGR allele and increased risk for PCOS
in women of Sardinian origin (Capalbo et al., 2012). A dose-depen-
dent effect was observed for this polymorphism, such that homozy-
gosity of the 312N allele was associated with a further elevated risk

Table 3
Half-life in serum and differential downstream effects of r-hLH and r-hCG binding to LHCGR.

Cell type r-hLH r-hCG

Half-life
t1/2a, range of mean, hrs 0.61.3a,b 3.95.5c
t1/2b, range of mean, hrs 912a,b 2331c
Response
ED50 (pM) COS-7/LHCGRe 530.0 51.2 107.1 14.3
Time to maximal cAMP accumulationd COS-7/LHCGRe 10 min 1h
ERK1/2 activationf hGLC Strong Weak
AKT activationf hGLC Strong Minimal
Neuregulin 1 inhibition in presence of ERK1/2 and AKT pathway blockade hGLC Abrogated Unaffected
CYP19A1 expression in presence of ERK1/2 pathway blockade hGLC Increased Unaffected

ERK1/2, extracellular signal-regulated protein kinases 1 and 2; r-hLH, recombinant human luteinizing hormone; r-hCG, recombinant human chorionic gonadotropin; LHCGR,
luteinizing hormone/choriogonadotropin receptor; hGLC, human granulosa cells; t1/2a = distribution (initial) half-life; t1/2b = elimination (terminal) half-life
a
Le Cotonnec et al. (1998a)
b
Le Cotonnec et al. (1998b)
c
Trinchard-Lugan et al. (2002)
d
Doses used were consistent with ED50 for r-hLH and for r-hCG in COS-7/LHCGR cells.
e
COS-7/LHCGR cells constitutively express LHCGR. LHCGR expression in hGLC cells is under physiologic regulation.
f
100 pM dose used for both r-hLH and r-hCG (Casarini et al., 2012).
 J. Choi, J. Smitz / Molecular and Cellular Endocrinology 383 (2014) 203213 209

Fig. 2. Response of human granulosa cells (hGLC) to long-term stimulation with recombinant human luteinizing hormone (r-hLH) or recombinant human chorionic
gonadotropin (r-hCG). Intracellular cyclic adenosine monophosphate (cAMP) (bars) and extracellular progesterone (lines) concentrations during chronic exposure to 500 pM
r-hLH or 100 pM r-hCG in the presence of a non-selective phosphodiesterase inhibitor (IBMX 500 lM); control cells were not exposed to gonadotropins. Panels illustrate 3
time ranges: (A) 012 h; (B) 1324 h; and (C) 2536 h. Extracellular accumulation of cAMP continued to increase during the 36-h evaluation period (D). Reproduced with
permission from Casarini et al. (2012).
210 J. Choi, J. Smitz / Molecular and Cellular Endocrinology 383 (2014) 203213
Fig. 3. Theoretical pathways for the divergence in receptor-mediated signaling
between luteinizing hormone (LH) and human chorionic gonadotropin (hCG).
Although acting on the same receptor, accumulating evidence suggests that LH
binding (A) has a greater impact (thicker arrow) on AKT and extracellular signal-
regulated protein kinase (ERK1/2) phosphorylation than hCG does, whereas binding
of hCG (B) generates a greater intracellular accumulation (thicker arrow) of cAMP
than does LH (Casarini et al., 2012; Gupta et al., 2012). Pathway components
derived from Arey and Lopez (2011). AC, adenylate cyclase; ATP, adenosine
triphosphate; cAMP, cyclic adenosine monophosphate; Gs/Gq, G proteins; IP3,
inositol triphosphate; LHCGR, luteinizing hormone/choriogonadotropin receptor;
PKA, protein kinase A; PLC, phospholipase C; PKC, protein kinase C.
of PCOS beyond that of a single copy. Interestingly, the 312N allele
has been found to be less common among men with maldescended
testes compared with unaffected controls (Simoni et al., 2008).
6.2. Signaling pathways
LHCGR is capable of binding LH, hCG, and h-hCG, but not hCG
free b-subunit (Cole, 2009, 2010). Nicked hCG binds LHCGR, but
with a substantially lower afnity (Cole et al., 1991). Experiments
using hCG and ovine LH indicate that binding of these hormones to
LHCGR differentially inuences receptor interaction with plasma
membrane proteins (Roess et al., 1997), which may contribute to
the subsequent divergence in signaling pathway activation. The
intricacies of LHCGR signaling are a subject of active investigation,
with many components and interfaces not yet dened. It is gener-
ally understood that the cyclic adenosine monophosphate/protein
kinase A (cAMP/PKA) pathway is a signicant effector of down-
stream events that lead to ovulation and steroid biosynthesis.
The effects of gonadotropin binding appear to be regulated by
both temporal and spatial control of cAMP-mediated signaling
(Weedon-Fekjaer and Tasken, 2012). This cascade begins when
LHCGR binds LH or hCG. This induces a conformational change in
LHCGR, leading to the activation of the stimulatory G-protein Gs
(Puett et al., 2007). Gs, in turn, activates adenylate cyclase, which
increases the intracellular pool of cAMP.
Acting through an independent mechanism, LHCGR stimulation
also activates the phospholipase C/inositol phosphate (PLC/IP) sig-
naling pathway (Gilchrist et al., 1996). Given the high levels of LH
or hCG required to activate PLC via LHCGR, it has been suggested
that PLC-based signaling only occurs during the pre-ovulatory LH
surge and during pregnancy (Gudermann et al., 1992). Consistent
with this role, investigators have recently identied PLC as a medi-
ator of nal granulosa cell differentiation in response to LH (Dona-
deu et al., 2011).
Other signaling molecules/pathways including extracellular sig-
nal-regulated protein kinases 1 and 2 (ERK1/2) and AKT have been
identied as major downstream players in LHCGR-mediated sig-
naling, with putative roles in cell proliferation, differentiation,
and survival (Ben-Ami et al., 2009; Noma et al., 2011; Palaniappan
and Menon, 2010; Shiraishi and Ascoli, 2007). Together with cAMP/
PKA, the ERK1/2, and AKT pathways contribute to the regulation of
oocyte and follicle maturation (Brown et al., 2010; Reizel et al.,
2010).
Although both hLH and hCG bind to LHCGR, emerging evidence
suggests that the downstream effects differ. Much like LH and hCG
were considered to be functionally equivalent, the result of recep-
tor binding was traditionally presumed to be alike. New data, how-
ever, suggest that this is not true. Advances in gonadotropin
purication and recombinant technology have allowed investiga-
tors to explore hormone-specic signaling cascades, with
thought-provoking results.
Casarini and colleagues performed a series of experiments
examining changes in gene and protein expression/activation in
response to recombinant hLH (r-hLH) or recombinant hCG
(r-hCG) exposure in COS-7 cells constitutively expressing LHCGR
(COS-7/LHCGR) and in human granulosa cells (hGLC) (Casarini
et al., 2012). Recombinant hCG was found to be ve times more
potent than hLH with respect to cAMP production, with a com-
mensurate lower ED50 (Table 3). cAMP concentration reached its
maximum more quickly with r-hLH than with r-hCG in COS-7/
LHCGR cells (10 minutes and 1 hour, respectively). During ex-
tended gonadotropin exposure in hGLC cells, in which LHCGR
expression was physiologically regulated, cAMP levels cycled, with
a period of approximately 45 h (Fig. 2). Interestingly, extracellu-
lar cAMP levels were not cyclical. Peak intracellular cAMP levels
were generally higher with r-hCG than with r-hLH. Nonetheless,
progesterone production was similar, with supernatant concentra-
tions continuing to increase throughout the 36-hour evaluation
period. In addition, recombinant hLH stimulation of hGLC cells
strongly activated ERK1/2 and AKT, but hCG only weakly affected
these pathways (Table 3). Blockage of the ERK1/2 and/or AKT
pathways inuenced downstream gene expression in hGLC ex-
posed to r-hLH but not those stimulated with r-hCG. To exclude
the possibility that these ndings were specic to recombinant
gonadotropins that do not undergo post-translational modication
of native proteins, the authors repeated the dose-response exper-
iments using extractive hLH and hCG, with results comparable to
that of r-hLH and r-hCG.
Disparate effects on signaling between LH and hCG also have
been described in goat ovarian granulosa cells (Gupta et al.,
2012). In this model, sustained exposure in cell culture led to sig-
nicantly greater cAMP accumulation with hCG vs. ovine LH
(p < 0.05). Long-term culture in the presence of LH supported
growth and proliferation of granulosa cells; hCG, on the other
 J. Choi, J. Smitz / Molecular and Cellular Endocrinology 383 (2014) 203213
hand, had the opposite effect, slowing growth and increasing cell
doubling time. Consistent with the previously described experi-
ments using human granulosa cells, phospho-ERK1/2 levels were
greater after long-term exposure to LH compared with hCG.
Using the aforementioned data in combination with known ele-
ments of LHCGR signaling, we have constructed a schematic illus-
trating potential differences between LH- and hCG-mediated
signaling pathways (Fig. 3). This diagram is an acknowledged sim-
plication of the complex interactions between diverse cascades
that coordinately regulate gonadotropin response. Further explora-
tion in different cell types and physiologic conditions is needed to
fully characterize the unique aspects of signaling via LH or hCG.
6.3. Extragonadal LHCGR
Detection of LHCGR in regions other than ovarian cell types and
Leydig cells of the testes, including the decidua, uterine vascula-
ture, umbilical cord, fetal organs, cytotrophoblast cells, and adrenal
cortex, has spurred ongoing debate regarding the potential role for
gonadotropins in extragonadal locations (Cole, 2010; Pakarainen
et al., 2007; Rao, 2010). It has been suggested that the absence of
overt non-gonadal phenotypes in individuals with naturally occur-
ring LHCGR mutations indicates that LH and hCG have only modest
effects on the normal physiologic activity of these tissues (Ascoli
et al., 2002). Moreover, the extragonadal phenotypes in LHCGR-
knockout and hCG overexpressing mice have been attributed
chiey to changes in gonadal function rather than a physiologic
role for LHCGR in non-gonadal tissue (Pakarainen et al., 2007;
Rahman and Rao, 2009). It should be noted, however, that CG is
not a native constituent of the mouse genome; yet it is hCG for
which the strongest evidence of extragonadal activity has been
unearthed.
As previously discussed, the enduring presence of hCG beyond
the time period associated with luteal support implies additional
functionality. hCG is implicated in multiple modes of supporting
pregnancy in addition to promoting progesterone production.
Implantation, trophoblast invasion, placentation, uterine growth
control, growth and differentiation of fetal organs, as well as a host
of other putative or known functions of hCG that are listed in
Table 2 (Banerjee and Fazleabas, 2011; Cole, 2010). While it seems
clear that extragonadal LHCGR has functional signicance, further
study is needed to clarify its role in normal and aberrant cellular
processes and to characterize the individual effects of various
isoforms.
7. Conclusions
The signicance of differences between LH and hCG in terms of
structure, expression, regulation, and function is just beginning to
be fully realized. It has long been known that LH and hCG funda-
mentally differ in their expression patterns; however, we now
appreciate that categorization based on this attribute alone fails
to adequately describe the complexity and unique aspects of these
hormones. Moreover, an array of isoforms exists within a single
hormone family, the composition of which uctuates during the
course of the ovarian cycle and pregnancy as well as throughout
the lifespan in both men and women. Emerging evidence suggests
that these diverse isoforms have distinct, though often overlap-
ping, functions that are reected by their relative abundance in
normal and aberrant physiologic processes. The importance of
quantitative and qualitative distinctions in signaling cascades acti-
vated by LH and hCG and the clinical relevance of extragonadal
activity are nascent areas of study that merit further exploration.
All of these advances in knowledge broaden the ability to utilize
LH and hCG as diagnostic and prognostic biomarkers, as well as
211
therapeutic tools to help manage clinical conditions such as
infertility.
Disclosure statement
J.C. has nothing to disclose, J.S. has nothing to disclose.
Acknowledgements
Financial support for manuscript development was provided by
Ferring Pharmaceuticals, Inc.
The authors thank Crystal Murcia, PhD, and Jill McCollam,
PharmD, of The JB Ashtin Group, Inc., for assistance in preparing
this manuscript for publication based on the authors initial draft
and direction.
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