Follicle-stimulating hormone (FSH) is a
gonadotropin, a
glycoprotein polypeptide hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
. FSH is synthesized and secreted by the
gonadotropic cells of the
anterior pituitary gland
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...
and regulates the development, growth,
pubertal maturation, and reproductive processes of the body. FSH and
luteinizing hormone (LH) work together in the
reproductive system
The reproductive system of an organism, also known as the genital system, is the biological system made up of all the anatomical organs involved in sexual reproduction. Many non-living substances such as fluids, hormones, and pheromones are ...
.
Structure
FSH is a 35.5 kDa
glycoprotein heterodimer, consisting of two
polypeptide units, alpha and beta. Its structure is similar to those of
luteinizing hormone (LH),
thyroid-stimulating hormone
Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism ...
(TSH), and
human chorionic gonadotropin
Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantatio ...
(hCG). The
alpha subunits of the glycoproteins LH, FSH, TSH, and hCG are identical and consist of 96
amino acids, while the beta subunits vary.
Both subunits are required for biological activity. FSH has a beta subunit of 111 amino acids (FSH β), which confers its specific biologic action, and is responsible for interaction with the
follicle-stimulating hormone receptor
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 hormo ...
.
The sugar portion of the hormone is covalently bonded to
asparagine
Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
, and is composed of
N-acetylgalactosamine,
mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylat ...
,
N-acetylglucosamine,
galactose, and
sialic acid.
Genes
In humans, the gene for the
alpha subunit is located at cytogenetic location 6q14.3. 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
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual c ...
, and enhanced by
activin
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual ...
.
Activity/functions
FSH regulates the development, growth, pubertal maturation and reproductive processes of the human body.
* In both ''males'' and ''females'', FSH stimulates the maturation of
primordial germ cells.
* In ''males'', FSH induces
Sertoli cells to secrete
androgen-binding proteins (ABPs), regulated by
inhibin
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual c ...
's
negative feedback mechanism on the
anterior pituitary
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...
. Specifically, activation of Sertoli cells by FSH sustains spermatogenesis and stimulates inhibin B secretion.
* 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.
Control of FSH release from the pituitary gland is unknown. Low frequency
gonadotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...
(GnRH) pulses increase FSH mRNA levels in the rat, but is not directly correlated with an increase in circulating FSH. GnRH has been shown to play an important role in the secretion of FSH, with hypothalamic-pituitary disconnection leading to a cessation of FSH. GnRH administration leads to a return of FSH secretion. FSH is subject to oestrogen feed-back from the gonads via the hypothalamic pituitary gonadal axis.
Effects in females
FSH stimulates the growth and recruitment of immature
ovarian follicle
An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with ...
s 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
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual c ...
B to lower FSH serum levels.
In addition, there is evidence that
gonadotropin surge-attenuating factor Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anteri ...
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.
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
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...
of FSH receptors occurs and by postmenopause any remaining small secondary follicles no longer have FSH nor LH 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
Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chorionic ...
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.
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.
Effects in males
FSH stimulates primary
spermatocytes to undergo the first division of
meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately ...
, 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,
and is critical for the initiation of
spermatogenesis.
Measurement
Follicle stimulating hormone is typically measured in the early
follicular phase
The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle (or, in primates for example, the menstrual cycle) during which follicles in the ovary mature from primary follicle to a fully ...
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.
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. For recombinant FSH, one IU corresponds to approximately 0.065 to 0.075
µg of a "fill-by-mass" product.
The mean values for women before
ovulation are around (3.8-8.8) mUI/mL. After ovulation these levels drop to between (1.8-5.1) mUI/mL. At the mid of the
menstrual cycle it reaches its highest value, between (4.5-22.5) mIU / mL. During
menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
, the values goes up even more, between (16.74-113.59) mIU / mL.
For men, the mean values are around (16.74-113.59 mUI/mL).
Disease states
FSH levels are normally low during
childhood and, in females, high after
menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
.
High FSH levels
The most common reason for high serum FSH concentration is in a female who is undergoing or has recently undergone
menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
. 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.
If high FSH levels occur during the reproductive years, it is abnormal. Conditions with high FSH levels include:
#
Premature menopause
Primary ovarian insufficiency (POI) (also called premature ovarian insufficiency, premature menopause, and premature ovarian failure) is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of fol ...
also known as Premature Ovarian Failure
#
Poor ovarian reserve also known as Premature Ovarian Aging
#
Gonadal dysgenesis,
Turner syndrome
Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low h ...
,
Klinefelter syndrome
#
Castration
Castration is any action, surgical, chemical, or otherwise, by which an individual loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical castration uses pharm ...
#
Swyer syndrome
# Certain forms of
CAH
# Testicular failure
#
Lupus
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:
#
Polycystic Ovarian Syndrome
#
Polycystic Ovarian Syndrome + Obesity + Hirsutism + Infertility
#
Kallmann syndrome
#
Hypothalamic suppression
#
Hypopituitarism
#
Hyperprolactinemia
#
Gonadotropin deficiency
# Gonadal suppression therapy
##
GnRH antagonist
Gonadotropin-releasing hormone antagonists (GnRH antagonists) are a class of medications that antagonize the gonadotropin-releasing hormone receptor (GnRH receptor) and thus the action of gonadotropin-releasing hormone (GnRH). They are used in ...
##
GnRH agonist (
downregulation
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...
).
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.
[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]
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
Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chor ...
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).
See also
*
EFSH, a follicle-stimulating hormone obtained from equine species
References
External links
FSH- Lab Tests Online
{{DEFAULTSORT:Follicle-Stimulating Hormone
Recombinant proteins
Glycoproteins
Peptide hormones
Sex hormones
Human hormones
In vitro fertilisation
Hormones of the hypothalamus-pituitary-gonad axis
Anterior pituitary hormones
Human female endocrine system