Follicle-stimulating hormone

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein

glycoprotein hormones,
polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells
alpha polypeptide
of the anterior pituitary gland,[1] and regulates the development, growth,
pubertal maturation, and reproductive processes of the body. FSH and luteinizing
hormone (LH) work together in the reproductive system. [2]

Contents
Structure
Genes
Activity/functions FSH (α-FSH (green), β-FSH
Effects in females (orange)) with receptors (blue)
Effects in males Identifiers
Measurement Symbol CGA
Disease states
NCBI 1081 (https://www.ncbi.nl
High FSH levels
Low FSH levels gene m.nih.gov/gene?cmd=retri
eve&dopt=default&list_uid
Use as therapy
s=1081&rn=1)
Potential role in vascularization of solid tumors
HGNC 1885 (https://www.genena
References
mes.org/data/gene-symbol
External links
-report/#!/hgnc_id/HGNC:1
885)

Structure OMIM 118850 (https://omim.org/

118850)
FSH is a 35.5 kDa glycoprotein heterodimer, consisting of two polypeptide
RefSeq NM_000735 (https://geno
units, alpha and beta. Its structure is similar to those of luteinizing hormone
me.ucsc.edu/cgi-bin/hgTra
(LH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin
cks?Submit=Submit&positi
(hCG). The alpha subunits of the glycoproteins LH, FSH, TSH, and hCG are
on=NM_000735&rn=1)
identical and consist of 96 amino acids, while the beta subunits vary.[3][4] Both
subunits are required for biological activity. FSH has a beta subunit of 111 amino UniProt P01215 (https://www.unipr
acids (FSH β), which confers its specific biologic action, and is responsible for ot.org/uniprot/P01215)
interaction with the follicle-stimulating hormone receptor.[5] The sugar portion Other data
of the hormone is covalently bonded to asparagine, and is composed of N- Locus Chr. 6 q14-q21 (https://omi
acetylgalactosamine, mannose, N-acetylglucosamine, galactose, and sialic acid. m.org/search/?index=gene
Map&search=6q14)
Genes
follicle stimulating hormone, beta
In humans, the gene for the alpha subunit is located at
polypeptide
cytogenetic location 6q14.3.[6] It is expressed in two cell types,
most notably the basophils of the anterior pituitary. 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.

Activity/functions
FSH regulates the development, growth, pubertal maturation
and reproductive processes of the human body. [7]

In both males and females, FSH stimulates the

maturation of primordial germ cells.
In males, FSH induces Sertoli cells to secrete Follicle-stimulating hormone
androgen-binding proteins (ABPs), regulated by
inhibin's negative feedback mechanism on the Identifiers
anterior pituitary. Specifically, activation of Sertoli
cells by FSH sustains spermatogenesis and Symbol FSHB
stimulates inhibin B secretion.
NCBI 2488 (https://www.ncbi.nlm.nih.gov/gen
In females, FSH initiates follicular growth, specifically
affecting granulosa cells. With the concomitant rise gene e?cmd=retrieve&dopt=default&list_uids=
in inhibin B, FSH levels then decline in the late 2488&rn=1)
follicular phase. This seems to be critical in selecting
only the most advanced follicle to proceed to HGNC 3964 (https://www.genenames.org/data/g
ovulation. At the end of the luteal phase, there is a ene-symbol-report/#!/hgnc_id/HGNC:396
slight rise in FSH that seems to be of importance to
start the next ovulatory cycle. 4)

Control of FSH release from the pituitary gland is unknown. OMIM 136530 (https://omim.org/136530)
Low frequency gonadotropin-releasing hormone (GnRH) RefSeq NM_000510 (https://genome.ucsc.edu/cg
pulses increase FSH mRNA levels in the rat,[8] but is not i-bin/hgTracks?Submit=Submit&position=
directly correlated with an increase in circulating FSH.[9] NM_000510&rn=1)
GnRH has been shown to play an important role in the UniProt P01225 (https://www.uniprot.org/uniprot/
secretion of FSH, with hypothalamic-pituitary disconnection P01225)
leading to a cessation of FSH. GnRH administration leads to a
Other data
return of FSH secretion. FSH is subject to oestrogen feed-back
from the gonads via the hypothalamic pituitary gonadal axis. Locus Chr. 11 p13 (https://omim.org/search/?ind
ex=geneMap&search=11p13)

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 sufficient in number to produce
enough Inhibin B to lower FSH serum levels.

In addition, there is evidence that gonadotropin 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.[11]

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 downregulation of FSH receptors occurs and by postmenopause any remaining small secondary follicles no
longer have FSH nor LH receptors.[12]
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 Reference ranges for the blood content of follicle-stimulating hormone levels
decrease in gonadotrophin surge- during the menstrual cycle.[10]
attenuating factor) cause a positive - The ranges denoted By biological stage may be used in closely monitored
effect on the hypothalamus and 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,
pituitary and rapid GnRH pulses
respectively, the cycle progresses compared to an average cycle.
occur and an LH surge results.
- The ranges denoted Inter-cycle variability are more appropriate to use in
non-monitored cycles with only the beginning of menstruation known, but
The increase in serum estradiol
where the woman accurately knows her average cycle lengths and time of
levels cause a decrease in FSH
ovulation, and that they are somewhat averagely regular, with the time scale
production by inhibiting GnRH being compressed or stretched to how much a woman's average cycle length
production in the hypothalamus.[13] is shorter or longer, respectively, than the average of the population.
- The ranges denoted Inter-woman variability are more appropriate to use
The decrease in serum FSH level when the average cycle lengths and time of ovulation are unknown, but only
causes the smaller follicles in the the beginning of menstruation is given.
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.

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,[14] and is critical for the initiation of spermatogenesis.

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. [15]

FSH is measured in International Units (IU). For Human Urinary FSH, one IU is defined as the amount of FSH that has an
activity corresponding to 0.11388 mg of pure Human Urinary FSH.[16] For recombinant FSH, one IU corresponds to
approximately 0.065 to 0.075 µg of a "fill-by-mass" product.[17]
Disease states
FSH levels are normally low during childhood and, in females, high after menopause.

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 FSH indicate that the normal restricting feedback from the gonad is absent, leading to an unrestricted
pituitary FSH production.FSH may contribute to postmenopausal osteoporosis and cardiovascular disease. [18]

If high FSH levels occur during the reproductive years, it is abnormal. Conditions with high FSH levels include:

1. Premature menopause also known as Premature Ovarian Failure

2. Poor ovarian reserve also known as Premature Ovarian Aging
3. Gonadal dysgenesis, Turner syndrome
4. Castration
5. Swyer syndrome
6. Certain forms of CAH
7. Testicular failure.
8. Klinefelter syndrome
9. Systemic Lupus Erythematosus also known as Lupus [19]
Most of these conditions are associated with subfertility and/or infertility. Therefore, high FSH levels are an indication of
subfertility and/or infertility.

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. Polycystic Ovarian Syndrome [20]

2. Polycystic Ovarian Syndrome + Obesity + Hirsutism + Infertility
3. Kallmann syndrome
4. Hypothalamic suppression
5. Hypopituitarism
6. Hyperprolactinemia
7. Gonadotropin deficiency
8. Gonadal suppression therapy

1. GnRH antagonist
2. GnRH agonist (downregulation).

Isolated FSH deficiency due to mutations in the gene for β-subunit of FSH is rare with 13 cases reported in the literature up to
2019.[21]

Use as therapy
FSH is used commonly in infertility therapy, mainly for ovarian hyperstimulation as part of IVF. In some cases, it is used in
ovulation induction for reversal of anovulation as well.

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 (Gonapure, Gonal F, Follistim, Follitropin alpha).
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).[22]

References
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it/lhfsh.html). www.vivo.colostate.edu. Retrieved 2019-05-06.
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81). NCBI. Retrieved 2 January 2016.
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online ahead of print 2012-07-16]. Hendrickson WA (ed.). "Structure of follicle-stimulating hormone in complex
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of the National Academy of Sciences of the United States of America. 109 (31): 12491–6.
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FSH-regulatory proteins and their relationship to changes in FSH synthesis and secretion" (https://www.ncbi.nlm.
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6%2Fs0378-5122%2896%2990009-2). PMID 8865134 (https://www.ncbi.nlm.nih.gov/pubmed/8865134).
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WHO Expert Committee on Biological Standardization. Twenty-sixth Report. World Health Organization. Geneva.
1975
17. "Gonadotropin preparations: past, present, and future perspectives". Fertility and Sterility. 90 (5 Suppl): S13–20.
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PMID 19007609 (https://www.ncbi.nlm.nih.gov/pubmed/19007609).
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20. "Polycystic ovary syndrome: MedlinePlus Medical Encyclopedia" (https://medlineplus.gov/ency/article/000369.ht
m). medlineplus.gov. Retrieved 2019-05-06.
21. Misgar RA, Wani AI, Bankura B, Bashir MI, Roy A, Das M (2019) FSH β-subunit mutations in two sisters: the first
report from the Indian sub-continent and review of previous cases. Gynecol Endocrinol 2:1-4
22. 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". The New England Journal of
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External links
FSH (http://labtestsonline.org/understanding/analytes/fsh/tab/test) - Lab Tests Online

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