GLYCOPROTEIN HORMONES

Glycoprotein hormones are complex protein hormones that have a carbohydrate

chain. They are heterodimers consisting of a common α subunit and a hormone-
specific β-subunit. The α subunit is coded by same genes in a given species and
has 92 or 96 amino acid sequences whereas the β-subunit is assumed to confer
the hormone specificity. The α- and β-subunits contain a Cysteine-knot motif and
several N-linked glycosylation sites, which are important for biological activity of
the hormone.

The classic Glyco Protein hormone (GPH) family consists of four members: FSH
(Follicle Stimulating Hormone), LH (Luteinizing Hormone), and TSH (Thyroid
Stimulating Hormone) secreted from the pituitary, and hCG (human Chorionic
Gonadotropin) secreted from the placenta. FSH, LH, and CG have gonadotropic
activity, and TSH have thyrotropic activity. The glycoprotein hormones are
characterized by their heavy glycosylation and are cystine rich molecules with 5
conserved disulphides in alpha and 6 in beta chain.

Coming to the molecular mechanism of action, the very first step in GPH action is
their binding to specific receptors (GPHRs) at the plasma membrane level of
gonadal cells. GPHRs are seven transmembrane domain (7-TMD) receptors with a
very large extracellular domain (ECD) containing numerous leucine-rich repeats
(LRR) with a horseshoe shape that accommodate GPH binding. Following high-
affinity and specific binding with the receptor’s ECD, an interaction with the 7-
TMD must occur to promote a transconformation that is detected by the
intracellular partners, essentially the heterotrimeric G-protein Gs but also, in
certain situations, other pathways 

Thyroid Stimulating Hormone (TSH)

Thyroid-stimulating hormone, also known as TSH, is a glycoprotein hormone
produced by the anterior pituitary. It consists of two chains: an alpha chain and a
beta chain. It has a molecular mass of approximately 28,000Da. It is the primary
stimulus for thyroid hormone production by the thyroid gland. It also exerts
growth effects on thyroid follicular cells leading to enlargement of the thyroid.
The hypothalamic-pituitary axis regulates TSH release. Specifically, neurons in
the hypothalamus release TRH, or thyroid-releasing hormone, which stimulates
thyrotrophs of the anterior pituitary to secrete TSH. TSH, in turn, stimulates
thyroid follicular cells to release thyroid hormones in the form of T3 or T4.
TSH binds to and activates the TSH receptor (TSHR), which is a G-protein
coupled receptor (GPCR) on the basolateral surface of thyroid follicular cells.
TSHR is coupled to both Gs and Gq G-proteins, activating both the cAMP
pathway (via Gsa) and the phosphoinositol/calcium (IP/Ca2+; via Gq) second
messenger signaling cascades. The Gs pathway activates iodide uptake, thyroid
hormone secretion, and gland growth and differentiation. The Gq pathway is rate-
limiting for hormone synthesis by stimulating iodide organification. A gain in
function mutation of the TSH receptor results in hyperthyroidism, while a loss in
function mutation results in hypothyroidism. TSH stimulates thyroid hormone
secretion through enhancing iodide uptake, thyroglobulin synthesis, and
thyroperoxidase activity. Additionally, TSH also increases blood flow to the
thyroid gland and stimulates hypertrophy and hyperplasia of thyroid follicular
cells to exert growth effects on the thyroid gland.

Follicle Stimulating Hormone (FSH)

Follicle-stimulating hormone (FSH) is a hormone produced by the anterior
pituitary in response to gonadotropin-releasing hormone (GnRH) from the
hypothalamus. FSH is a glycoprotein dimer with alpha and beta subunits. FSH
displays an α subunit, common to other gonadotropins and to thyrotropin, and a
β subunit specifically binding to its G protein-coupled receptor (GPCR), namely
FSHR.
 GnRH stimulates FSH release. The hypothalamus produces GnRH, and it is
released into the hypophyseal portal circulation to act on G-protein-coupled
receptors at gonadotropic cells of the anterior pituitary. Those gonadotropic cells
produce FSH and luteinizing hormone (LH) and release them into the peripheral
circulation.

In the ovary, FSH regulates folliculogenesis, oocyte selection, and the synthesis
of sex steroid hormones, thus preparing the reproductive tract for fertilization,
implantation, and pregnancy. FSH stimulates granulosa cells in the ovarian
follicles to synthesize aromatase, which converts androgens produced by the
thecal cells to estradiol which later converts to estrogen. During the follicular
phase of the menstrual cycle, FSH stimulates the maturation of ovarian follicles.
As a dominant follicle takes over and secretes estradiol and inhibin, FSH
secretion is suppressed. FSH peaks at the same time as the LH surge that causes
ovulation. FSH then remains low throughout the luteal phase, preventing the
development of new follicles. In males FSH, along with testosterone, is necessary
for maintaining normal sperm count and function. Studies have shown that FSH
deprivation not only lowers sperm count but also affects the quality of the
remaining sperm.

Luteinizing Hormone (LH)

Luteinizing hormone (LH) is a glycoprotein hormone which is co-secreted along
with follicle stimulating hormone by the gonadotropin cells in the anterior
pituitary. Luteinizing hormone is a part of a neurological pathway comprised of
the hypothalamus, the pituitary gland, and gonads.
In this pathway, LH release is stimulated by gonadotropin-releasing hormone
(GnRH) and inhibited by estrogen in females and testosterone in males. LH has
various functions and they differ between women and men. In both sexes, LH
contributes to the maturation of primordial germ cells. In men, LH causes the
Leydig cells of the testes to produce testosterone. In women, LH triggers the
creation of steroid hormones from the ovaries. Additionally, it helps to regulate
the length and order of the menstrual cycle in females by playing roles in both
ovulation and implantation of an egg in the uterus.
Luteinizing hormone acts by binding to a G-protein coupled receptor which in
turn activates Adenylyl cyclase. Adenylyl cyclase, an enzyme, then goes on to
produce cyclic-AMP, thus increasing its intracellular concentration, which then
activates a kinase molecule called protein kinase A (PKA). PKA then
phosphorylates specific intracellular proteins that then go on to achieve the end
physiologic actions of LH like steroid production and ovulation.

Human Chorionic Gonadotropin (hCG)

Human chorionic gonadotropin (hCG) is produced primarily by differentiated
syncytiotrophoblasts, and represents a key embryonic signal that is essential for
the maintenance of pregnancy. As a 237 amino acid heterodimer, hCG is
comprised of α-(93-amino acid, 14.5 kD) and β-(145-amino acid, 22.2 kD) subunits
that are non-covalently linked by charge interactions and contain a total of eight
carbohydrate side chains. hCG is also involved in important clinical functions
ranging from diagnosis and monitoring of pregnancy, early detection of
pregnancy-related disorders, prenatal aneuploidy screening, detection of
gynecological cancers, and treatment of infertility.
In early pregnancy, human chorionic gonadotropin (hCG) is produced primarily
by differentiated syncytiotrophoblasts, and represents a key embryonic signal
essential for the maintenance of pregnancy. During the initial six weeks of
pregnancy, hCG promotes secretion of progesterone, estradiol, and estrone via
transformation of the post-ovulatory ovary into the gravid corpus luteum
Furthermore, hCG binds to its receptor to perform specialized roles in promoting
angiogenesis in the uterine endothelium, maintaining myometrial quiescence, as
well as fostering immunomodulation via alteration of activity of dendritic cells,
the reduction of T-cell activation and cytokine production, promotion of T
regulatory (Treg) cell recruitment, and an increase in proliferation of uterine
natural killer (NK) cells at the maternal-fetal interface. Metabolism of hCG by the
placenta, liver, blood, and kidney determines its steady-state levels.
Measurements of serum or urine hCG levels provide important information in a
variety of clinical situations, such as diagnosis and monitoring of pregnancy and
pregnancy-related disorders, prenatal screening, and gynecological cancers.

hCG can activate various signaling cascades including mothers against

decapentaplegic homolog 2 (Smad2), protein kinase C (PKC), and/or protein
kinase A (PKA) in several cells types by binding to luteinizing hormone/chorionic
gonadotropin receptor (LHCGR) or potentially by direct/indirect interaction with
transforming growth factor beta receptor (TGFβR). The molecule displays
specialized roles in promoting angiogenesis in the uterine endothelium,
maintaining myometrial quiescence, as well as fostering immunomodulation at
the maternal-fetal interface. It is a member of the glycoprotein hormone family
that includes luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and
follicle-stimulating hormone (FSH). The α-subunit of hCG displays homologies
with TSH, LH, and FSH, whereas the β subunit is 80–85% homologous to LH. The
hCG molecule is produced by a variety of organs, exists in various forms.

REFERENCES
 Cahoreau C, Klett D, Combarnous Y. Structure-function relationships of
glycoprotein hormones and their subunits' ancestors. Front Endocrinol (Lausanne).
2015;6:26. Published 2015 Feb 26. doi:10.3389/fendo.2015.00026

 Nedresky D, Singh G. Physiology, Luteinizing Hormone. [Updated 2020 Aug 16].

In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan
https://www.ncbi.nlm.nih.gov/books/NBK539692/
 Pirahanchi Y, Toro F, Jialal I. Physiology, Thyroid Stimulating Hormone (TSH)
[Updated 2020 Jun 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls
Publishing; 2020 Jan
https://www.ncbi.nlm.nih.gov/books/NBK499850/
 Nwabuobi C, Arlier S, Schatz F, Guzeloglu-Kayisli O, Lockwood CJ, Kayisli UA.
hCG: Biological Functions and Clinical Applications. Int J Mol Sci. 2017;18(10):2037.
Published 2017 Sep 22. doi:10.3390/ijms18102037