Follicle-stimulating hormone
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For other uses of the term FSH, see FSH (disambiguation).
glycoprotein hormones, alpha polypeptide
Identifiers
Symbol
CGA
Entrez
1081
HUGO
1885
OMIM
118850
RefSeq
NM_000735
UniProt
P01215
Other data
Locus
Chr. 6 q14-q21
follicle stimulating hormone, beta polypeptide
Follicle-Stimulating Hormone
Identifiers
Symbol
FSHB
Entrez
2488
HUGO
3964
OMIM
136530
RefSeq
NM_000510
UniProt
P01225
Other data
Locus
Chr. 11 p13
Follicle-stimulating hormone (FSH) is a hormone found in humans and other animals.
It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH
regulates the development, growth, pubertal maturation, and reproductive processes of
the body. FSH and Luteinizing hormone (LH) act synergistically in reproduction.
Contents









1 Structure
2 Genes
3 Activity
o 3.1 Effects in females
o 3.2 Effects in males
4 Measurement
5 Disease states
o 5.1 High FSH levels
o 5.2 Low FSH levels
6 Availability
7 Potential role in vascularization of solid tumors
8 References
9 External links
[edit] Structure
FSH is a glycoprotein. Each monomeric unit is a protein molecule with a sugar attached
to it; two of these make the full, functional protein. Its structure is similar to those of LH,
TSH, and hCG. The protein dimer contains 2 polypeptide units, labeled alpha and beta
subunits. The alpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92
amino acids. The beta subunits vary. FSH has a beta subunit of 118 amino acids (FSH β),
which confers its specific biologic action and is responsible for interaction with the FSHreceptor. The sugar part of the hormone is composed of fucose, galactose, mannose,
galactosamine, glucosamine, and sialic acid, the latter being critical for its biologic halflife. The half-life of FSH is 3–4 hours.
The 92-amino-acid-long FSH alpha subunit in humans has the following sequence:
NH2 – Ala – Pro – Asp – Val – Gln – Asp – Cys – Pro – Glu – Cys – Thr – Leu – Gln –
Glu – Asn – Pro – Phe – Phe – Ser – Gln – Pro – Gly – Ala – Pro – Ile – Leu – Gln –
Cys – Met – Gly – Cys – Cys – Phe – Ser – Arg – Ala – Tyr – Pro – Thr – Pro – Leu –
Arg – Ser – Lys – Lys – Thr – Met – Leu – Val – Gln – Lys – Asn – Val – Thr – Ser –
Glu – Ser – Thr – Cys – Cys – Val – Ala – Lys – Ser – Tyr – Asn – Arg – Val – Thr –
Val – Met – Gly – Gly – Phe – Lys – Val – Glu – Asn – His – Thr – Ala – Cys – His –
Cys – Ser – Thr – Cys – Tyr – Tyr – His – Lys – Ser – OH

Note: The carbohydrate moiety is linked to the asparagine at positions 52 and 78.
The 118-amino-acid-long FSH beta subunit in humans has the following sequence:
NH2 – Asn – Ser – Cys – Glu – Leu – Thr – Asn – Ile – Thr – Ile – Ala – Ile – Glu –
Lys – Glu – Glu – Cys – Arg – Phe – Cys – Ile – Ser – Ile – Asn – Thr – Thr – Trp –
Cys – Ala – Gly – Tyr – Cys – Tyr – Thr – Arg – Asp – Leu – Val – Tyr – Lys – Asp –
Pro – Ala – Arg – Pro – Lys – Ile – Gln – Lys – Thr – Cys – Thr – Phe – Lys – Glu –
Leu – Val – Tyr – Glu – Thr – Val – Arg – Val – Pro – Gly – Cys – Ala – His – His –
Ala – Asp – Ser – Leu – Tyr – Thr – Tyr – Pro – Val – Ala – Thr – Gln – Cys – His –
Cys – Gly – Lys – Cys – Asp – Ser – Asp – Ser – Thr – Asp – Cys – Thr – Val – Arg –
Gly – Leu – Gly – Pro – Ser – Tyr – Cys – Ser – Phe – Gly – Glu – Met – Lys – Glu –
OH

Note: The carbohydrate moiety is linked to the asparagine at positions 7 and 24.
[edit] Genes
The gene for the alpha subunit is located on chromosome 6p21.1-23. It is expressed in
different cell types. The gene for the FSH beta subunit is located on chromosome 11p13,
and is expressed in gonadotropes of the pituitary cells, controlled by GnRH, inhibited by
inhibin, and enhanced by activin.
[edit] Activity
FSH regulates the development, growth, pubertal maturation, and reproductive processes
of the human body.



In both males and females, FSH stimulates the maturation of germ cells.
In males, FSH induces Sertoli cells to secrete inhibin and stimulates the formation of
sertoli-sertoli tight junctions (zonula occludens).
In females, FSH initiates follicular growth, specifically affecting granulosa cells.
With the concomitant rise in inhibin B, FSH levels then decline in the late follicular
phase. This seems to be critical in selecting only the most advanced follicle to
proceed to ovulation. At the end of the luteal phase, there is a slight rise in FSH that
seems to be of importance to start the next ovulatory cycle.
Like its partner LH, FSH release at the pituitary gland is controlled by pulses of
gonadotropin-releasing hormone (GnRH). Those pulses, in turn, are subject to the
oestrogen feed-back from the gonads.
Reference ranges for the blood content of follicle-stimulating hormone levels during the
menstrual cycle. [1]
- The ranges denoted By biological stage may be used in closely monitored menstrual
cycles in regard to other markers of its biological progression, with the time scale being
compressed or stretched to how much faster or slower, respectively, the cycle progresses
compared to an average cycle.
- The ranges denoted Inter-cycle variability are more appropriate to use in nonmonitored cycles with only the beginning of menstruation known, but where the woman
accurately knows her average cycle lengths and time of ovulation, and that they are
somewhat averagely regular, with the time scale being compressed or stretched to how
much a woman's average cycle length is shorter or longer, respectively, than the average
of the population.
- The ranges denoted Inter-woman variability are more appropriate to use when the
average cycle lengths and time of ovulation are unknown, but only the beginning of
menstruation is given.
[edit] Effects in females
FSH stimulates the growth and recruitment of immature Ovarian follicles in the ovary. In
early (small) antral follicles, FSH is the major survival factor that rescues the small antral
follicles (2-5 mm in diameter for humans) from apoptosis (programmed death of the
somatic cells of the follicle and oocyte). In the luteal-follicle phase transition period the
serum levels of progesterone and estrogen (primarily estradiol) decrease and no longer
suppress the release of FSH, consequently FSH peaks at about day three (day one is the
first day of menstrual flow). The cohort of small antral follicles is normally sufficiently in
number to produce enough Inhibin B to lower FSH serum levels.
In addition, there is evidence that gonadotrophin surge-attenuating factor produced by
small follicles during the first half of the follicle phase also exerts a negative feedback on
pulsatile luteinizing hormone (LH) secretion amplitude, thus allowing a more favorable
environment for follicle growth and preventing premature luteinization.[2]
(As a woman nears perimenopause, the number of small antral follicles recruited in each
cycle diminishes and consequently insufficient Inhibin B is produced to fully lower FSH
and the serum level of FSH begins to rise. Eventually the FSH level becomes so high that
down regulation of FSH receptors occurs and by menopause any remaining small
secondary follicles no longer have FSH receptors.)
When the follicle matures and reaches 8–10 mm in diameter it starts to secrete significant
amounts of estradiol. Normally in humans only one follicle becomes dominant and
survives to grow to 18–30 mm in size and ovulate, the remaining follicles in the cohort
undergo atresia. The sharp increase in estradiol production by the dominant follicle
(possibly along with a decrease in gonadotrophin surge-attenuating factor) cause a
positive effect on the hypothalamus and pituitary and rapid GnRH pulses occur and an
LH surge results.
The increase in serum estradiol levels cause a decrease in FSH production by inhibiting
GnRH production in the hypothalamus.[3]
The decrease in serum FSH level causes the smaller follicles in the current cohort to
undergo atresia as they lack sufficient sensitivity to FSH to survive. Occasionally two
follicles reach the 10 mm stage at the same time by chance and as both are equally
sensitive to FSH both survive and grow in the low FSH environment and thus two
ovulations can occur in one cycle possibly leading to non identical (dizygotic) twins.
[edit] Effects in males
FSH stimulates primary spermatocytes to undergo the first division of meiosis, to form
secondary spermatocytes.
FSH enhances the production of androgen-binding protein by the Sertoli cells of the
testes by binding to FSH receptors on their basolateral membranes,[4] and is critical for
the initiation of spermatogenesis.
[edit] Measurement
Follicle stimulating hormone is typically measured in the early follicular phase of the
menstrual cycle, typically day three to five, counted from last menstruation. At this time,
the levels of estradiol (E2) and progesterone are at the lowest point of the menstrual cycle.
FSH levels in this time is often called basal FSH levels, to distinguish from the increased
levels when approaching ovulation.
[edit] Disease states
This section does not cite any references or sources. Please help improve
this section by adding citations to reliable sources. Unsourced material may be
challenged and removed. (September 2010)
FSH levels are normally low during childhood and, in females, high after menopause.
[edit] High FSH levels
The most common reason for high serum FSH concentration is in a female who is
undergoing or has recently undergone menopause. High levels of Follicle-Stimulating
Hormone indicate that the normal restricting feedback from the gonad is absent, leading
to an unrestricted pituitary FSH production.
If high FSH levels occur during the reproductive years, it is abnormal. Conditions with
high FSH levels include:
1.
2.
3.
4.
5.
6.
7.
Premature menopause also known as Premature Ovarian Failure
Poor ovarian reserve also known as Premature Ovarian Aging
Gonadal dysgenesis, Turner syndrome
Castration
Swyer syndrome
Certain forms of CAH
Testicular failure.
Most of these conditions are associated with subfertility and/or infertility. Therefore high
FSH levels are an indication of subfertility and/or infertility.
[edit] Low FSH levels
Diminished secretion of FSH can result in failure of gonadal function (hypogonadism).
This condition is typically manifested in males as failure in production of normal
numbers of sperm. In females, cessation of reproductive cycles is commonly observed.
Conditions with very low FSH secretions are:
1.
2.
3.
4.
5.
6.
7.
8.
Polycystic Ovarian Syndrome
Polycystic Ovarian Syndrome + Obesity + Hirsutism + Infertility
Kallmann syndrome
Hypothalamic suppression
Hypopituitarism
Hyperprolactinemia
Gonadotropin deficiency
Gonadal suppression therapy
1. GnRH antagonist
2. GnRH agonist (downregulation).
[edit] Availability
FSH is available mixed with LH activity in various menotropins including more purified
forms of urinary gonadotropins such as Menopur, as well as without LH activity as
recombinant FSH (Gonal F, Follistim, Follitropin alpha). It is used commonly in
infertility therapy to stimulate follicular development, notably in IVF therapy, as well as
with interuterine insemination (IUI). (See Gonadotropin Preparations.)
[edit] Potential role in vascularization of solid tumors
Elevated FSH receptor levels have been detected in the endothelia of tumor vasculature
in a very wide range of solid tumors. FSH binding is thought to upregulate
neovascularization via at least two mechanisms - one in the VEGF pathway, and the other
VEGF independent - related to the development of umbilical vasculature when
physiological. This presents possible use of FSH and FSH-receptor antagonists as an anti
tumor angiogenesis therapy (cf. avastin for current anti-VEGF approaches).[5]
[edit] References
1. ^ References and further description of values are given in image page in Wikimedia
Commons at Commons:File:Follicle-stimulating hormone (FSH) during menstrual
cycle.png.
2. ^ Fowler PA, Sorsa-Leslie T, Harris W, Mason HD (December 2003). "Ovarian
gonadotrophin surge-attenuating factor (GnSAF): where are we after 20 years of
research?". Reproduction 126 (6): 689–99. doi:10.1530/rep.0.1260689. PMID 14748688.
3. ^ Dickerson LM, Shrader SP, Diaz VA (2008). "Chapter 8: Contraception". In Wells BG,
DiPiro JT, Talbert RL, Yee GC, Matzke GR. Pharmacotherapy: a pathophysiologic
approach. McGraw-Hill Medical. pp. 1313–28. ISBN 0-07-147899-X.
4. ^ Boulpaep EL, Boron WF (2005). Medical physiology: a cellular and molecular
approach. St. Louis, Mo: Elsevier Saunders. pp. 1125. ISBN 1-4160-2328-3.
5. ^ Radu A, Pichon C, Camparo P, Antoine M, Allory Y, Couvelard A, Fromont G, Hai
MT, Ghinea N (October 2010). "Expression of follicle-stimulating hormone receptor in
tumor blood vessels". N. Engl. J. Med. 363 (17): 1621–30. doi:10.1056/NEJMoa1001283.
PMID 20961245.
FSH-receptor
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Follicle stimulating hormone receptor
PDB rendering based on 1xwd.
Available structures
Identifiers
Symbols FSHR; FSHRO; LGR1; MGC141667;
MGC141668; ODG1
External OMIM: 136435 MGI: 95583 HomoloGene: 117
IDs
GeneCards: FSHR Gene
Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species
Human
Mouse
Entrez
2492
14309
Ensembl ENSG00000170820 ENSMUSG00000032937
UniProt P23945
RefSeq
P35378
NM_000145.3
NM_013523.3
NP_000136.2
NP_038551.3
(mRNA)
RefSeq
(protein)
Location Chr 2:
Chr 17:
(UCSC) 49.19 – 49.38 Mb
89.38 – 89.6 Mb
PubMed [1]
[2]
search
The follicle-stimulating hormone receptor or FSH-receptor (FSHR) is a
transmembrane receptor that interacts with the follicle-stimulating hormone (FSH) and
represents a G protein-coupled receptor (GPCR). Its activation is necessary for the
hormonal functioning of FSH. FSHRs are found in the ovary, testis, and uterus.
Contents





1 FSHR gene
2 Receptor structure
3 Ligand binding and signal transduction
o 3.1 Phosphorylation by cAMP-dependent protein kinases
4 Action
5 Receptor regulation
o 5.1 Upregulation
o
o
o






5.2 Desensitization
5.3 Downregulation
5.4 Modulators
6 FSHR abnormalities
7 History
8 See also
9 References
10 Further reading
11 External links
[edit] FSHR gene
The gene for the FSHR is found on chromosome 2 p21 in humans. The gene sequence of
the FSHR consists of about 2,080 nucleotides.[1]
[edit] Receptor structure
The seven transmembrane α-helix structure of a G protein-coupled receptor such as
FSHR
The FSHR consists of 695 amino acids and has a molecular mass of about 76 kDa.[1] Like
other GPCRs, the FSH-receptor possesses seven membrane-spanning domains or
transmembrane helices.

The extracellular domain of the receptor is glycosylated.

The transmembrane domain contains two highly conserved cysteine residues that
build disulfide bonds to stabilize the receptor structure. A highly conserved Asp-ArgTyr triplet motif is present and may be of importance to transmit the signal.

The C-terminal domain is intracellular and brief, rich in serine and threonine residues
for possible phosphorylation.
[edit] Ligand binding and signal transduction
Upon binding FSH externally to the membrane, a transduction of the signal that activates
the G protein that is bound to the receptor internally takes place. With FSH attached, the
receptor shifts conformation and, thus, mechanically activates the G protein, which
detaches from the receptor and activates the cAMP system.
It is believed that a receptor molecule exists in a conformational equilibrium between
active and inactive states. The binding of FSH to the receptor shifts the equilibrium
between active and inactive receptors. FSH and FSH-agonists shift the equilibrium in
favor of active states; FSH antagonists shift the equilibrium in favor of inactive states.
For a cell to respond to FSH, only a small percentage (~1%) of receptor sites need to be
activated.
[edit] Phosphorylation by cAMP-dependent protein kinases
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal
chain coming from the G protein (that was activated by the FSH-receptor) via adenylate
cyclase and cyclic AMP (cAMP).
These protein kinases are present as tetramers with two regulatory units and two catalytic
units. Upon binding of cAMP to the regulatory units, the catalytic units are released and
initiate the phosphorylation of proteins, leading to the physiologic action. The cyclic
AMP-regulatory dimers are degraded by phosphodiesterase and release 5’AMP. DNA in
the cell nucleus binds to phosphorylated proteins through the cyclic AMP response
element (CRE), which results in the activation of genes.[1]
The signal is amplified by the involvement of cAMP and the resulting phosphorylation.
The process is modified by prostaglandins. Other cellular regulators are participate are
the intracellular calcium concentration modified by phospholipase, nitric acid, and other
growth factors.
The FSH receptor can also activate the extracellular signal-regulated kinases (ERK).[2] In
a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the
receptor remains active, the more kinases are activated, the more receptors are
phosphorylated.
[edit] Action
In the ovary, the FSH receptor is necessary for follicular development and expressed on
the granulosa cells.[1]
In the male, the FSH receptor has been identified on the Sertoli cells that are critical for
spermatogenesis.[3]
The FSHR is expressed during the luteal phase in the secretory endometrium of the
uterus.[4]
FSH receptor is selectively expressed on the surface of the blood vessels of a wide range
of carcinogenic tumors.[5]
[edit] Receptor regulation
[edit] Upregulation
Upregulation refers to the increase in the number of receptor site on the membrane.
Estrogen upregulates FSH receptor sites. In turn, FSH stimulates granulosa cells to
produce estrogens. This synergistic activity of estrogen and FSH allows for follicle
growth and development in the ovary.
[edit] Desensitization
The FSHR become desensitized when exposed to FSH for some time. A key reaction of
this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor
domain by protein kinases. This process uncouples Gs protein from the FSHR. Another
way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.
[edit] Downregulation
Downregulation refers to the decrease in the number of receptor sites. This can be
accomplished by metabolizing bound FSHR sites. The bound FSH-receptor complex is
brought by lateral migration to a "coated pit," where such units are concentrated and then
stabilized by a framework of clathrins. A pinched-off coated pit is internalized and
degraded by lysosomes. Proteins may be metabolized or the receptor can be recycled.
Use of long-acting agonists will downregulate the receptor population.
[edit] Modulators
Antibodies to FSHR can interfere with FSHR activity.
[edit] FSHR abnormalities
Some patients with ovarian hyperstimulation syndrome may have mutations in the gene
for FSHR, making them more sensitive to gonadotropin stimulation.[6]
Women with 46 XX gonadal dysgenesis experience primary amenorrhea with
hypergonadotropic hypogonadism. There are forms of 46 xx gonadal dysgenesis wherein
abnormalities in the FSH-receptor have been reported and are thought to be the cause of
the hypogonadism.[7]
Polymorphism may affect FSH receptor populations and lead to poorer responses in
infertile women receiving FSH medication for IVF.[8]
[edit] History
Alfred G. Gilman and Martin Rodbell received the 1994 Nobel Prize in Medicine and
Physiology for the discovery of the G Protein System.
[edit] See also

Luteinizing hormone/choriogonadotropin receptor
[edit] References
1.
2.
3.
4.
5.
6.
7.
8.
^ a b c d Simoni M, Gromoll J, Nieschlag E (December 1997). "The follicle-stimulating hormone
receptor: biochemistry, molecular biology, physiology, and pathophysiology". Endocr. Rev. 18 (6):
739–73. doi:10.1210/er.18.6.739. PMID 9408742.
^ Piketty V, Kara E, Guillou F, Reiter E, Crepieux P (2006). "Follicle-stimulating hormone (FSH)
activates extracellular signal-regulated kinase phosphorylation independently of beta-arrestin- and
dynamin-mediated FSH receptor internalization". Reprod. Biol. Endocrinol. 4: 33.
doi:10.1186/1477-7827-4-33. PMC 1524777. PMID 16787538.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1524777.
^ Asatiani K, Gromoll J, Eckardstein SV, Zitzmann M, Nieschlag E, Simoni M (June 2002).
"Distribution and function of FSH receptor genetic variants in normal men". Andrologia 34 (3):
172–6. doi:10.1046/j.1439-0272.2002.00493.x. PMID 12059813.
^ La Marca A, Carducci Artenisio A, Stabile G, Rivasi F, Volpe A (December 2005). "Evidence
for cycle-dependent expression of follicle-stimulating hormone receptor in human endometrium".
Gynecol. Endocrinol. 21 (6): 303–6. doi:10.1080/09513590500402756. PMID 16390776.
^ Radu A, Pichon C, Camparo P, Antoine M, Allory Y, Couvelard A, Fromont GX, Hai MT,
Ghinea N (October 2010). "Expression of Follicle-Stimulating Hormone Receptor in Tumor Blood
Vessels". N Engl J Med 363 (17): 1621–1630. doi:10.1056/NEJMoa1001283. PMID 20961245.
^ Delbaere A, Smits G, De Leener A, Costagliola S, Vassart G (April 2005). "Understanding
ovarian hyperstimulation syndrome". Endocrine 26 (3): 285–90. doi:10.1385/ENDO:26:3:285.
PMID 16034183.
^ Aittomäki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R,
Sankila EM, Lehväslaiho H, Engel AR, Nieschlag E, Huhtaniemi I, de la Chapelle A (September
1995). "Mutation in the follicle-stimulating hormone receptor gene causes hereditary
hypergonadotropic ovarian failure". Cell 82 (6): 959–68. doi:10.1016/0092-8674(95)90275-9.
PMID 7553856.
^ Loutradis D, Patsoula E, Minas V, Koussidis GA, Antsaklis A, Michalas S, Makrigiannakis A
(April 2006). "FSH receptor gene polymorphisms have a role for different ovarian response to
stimulation in patients entering IVF/ICSI-ET programs". J. Assist. Reprod. Genet. 23 (4): 177–84.
doi:10.1007/s10815-005-9015-z. PMID 16758348.