Follicle-stimulating hormone

Last updated

glycoprotein hormones, alpha polypeptide
FSHA+B+receptor 1XWD.png
FSH (α-FSH (green), β-FSH (orange)) with receptors (blue)
Identifiers
Symbol CGA
NCBI gene 1081
HGNC 1885
OMIM 118850
RefSeq NM_000735
UniProt P01215
Other data
Locus Chr. 6 q14-q21
Search for
Structures Swiss-model
Domains InterPro
Follicle-stimulating hormone, beta polypeptide
Protein FSHB PDB 1fl7.png
Follicle-stimulating hormone
Identifiers
Symbol FSHB
NCBI gene 2488
HGNC 3964
OMIM 136530
RefSeq NM_000510
UniProt P01225
Other data
Locus Chr. 11 p13
Search for
Structures Swiss-model
Domains InterPro

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. [1] FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland [2] and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system. [3]

Contents

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 (TSH), and human chorionic gonadotropin (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. [4] [5] 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. [6] The sugar portion of the hormone is covalently bonded to asparagine, and is composed of N-acetylgalactosamine, mannose, N-acetylglucosamine, galactose, and sialic acid.

Genes

In humans, the gene for the alpha subunit is located at cytogenetic location 6q14.3. [7] 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. [8]

Activity and functions

FSH regulates the development, growth, pubertal maturation and reproductive processes of the human body. [9]

Control of FSH release from the pituitary gland is unknown. Low frequency gonadotropin-releasing hormone (GnRH) pulses increase FSH mRNA levels in the rat, [10] but is not directly correlated with an increase in circulating FSH. [11] 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.

Reference ranges for the blood content of follicle-stimulating hormone levels during the menstrual cycle. - 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 non-monitored 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. Follicle-stimulating hormone (FSH) during menstrual cycle.png
Reference ranges for the blood content of follicle-stimulating hormone levels during the menstrual cycle.
- 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 non-monitored 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.

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.[ citation needed ]

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. [13]

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. [14]

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 causes a decrease in FSH production by inhibiting GnRH production in the hypothalamus. [15]

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.[ citation needed ]

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, [16] 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. [17]

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. [18] For recombinant FSH, one IU corresponds to approximately 0.065 to 0.075  μg of a "fill-by-mass" product. [19] The mean values for women before ovulation are around (3.8-8.8) IU/L. After ovulation these levels drop to between (1.8-5.1) IU/L. At the mid of the menstrual cycle it reaches its highest value, between (4.5-22.5) IU/L. During menopause, the values goes up even more, between (16.74-113.59) IU/L. For men, the mean values are around (16.74-113.59) IU/L.

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. [20]

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, Klinefelter syndrome
  4. Castration
  5. Swyer syndrome
  6. Certain forms of congenital adrenal hyperplasia
  7. Testicular failure
  8. Lupus [21]

Most of these conditions are associated with subfertility or infertility. Therefore, high FSH levels are an indication of subfertility 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.[ citation needed ] Conditions with very low FSH secretions are:

  1. Polycystic Ovarian Syndrome [22]
  2. Polycystic ovarian syndrome + obesity + hirsutism + infertility
  3. Kallmann syndrome
  4. Aromatase excess syndrome
  5. Hypothalamic suppression
  6. Hypopituitarism
  7. Hyperprolactinemia
  8. Gonadotropin deficiency
  9. 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. [23]

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). [24]

See also

Related Research Articles

<span class="mw-page-title-main">Luteinizing hormone</span> Gonadotropin secreted by the adenohypophysis

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

<span class="mw-page-title-main">Gonadotropin-releasing hormone</span> Mammalian protein found in Homo sapiens

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 from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

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 gonadotropins, human chorionic gonadotropin (hCG) and equine chorionic gonadotropin (eCG), as well as at least two forms of fish gonadotropins. These hormones are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. LH and FSH are secreted by the anterior pituitary gland, while hCG and eCG are secreted by the placenta in pregnant women and mares, respectively. The gonadotropins act on the gonads, controlling gamete and sex hormone production.

Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.

<span class="mw-page-title-main">Folliculogenesis</span> Process of maturation of primordial follicles

In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an immature oocyte. Folliculogenesis describes the progression of a number of small primordial follicles into large preovulatory follicles that occurs in part during the menstrual cycle.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

<span class="mw-page-title-main">Follicular phase</span> Phase of the estrous or menstrual cycle

The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle during which follicles in the ovary mature from primary follicle to a fully mature graafian follicle. It ends with ovulation. The main hormones controlling this stage are secretion of gonadotropin-releasing hormones, which are follicle-stimulating hormones and luteinising hormones. They are released by pulsatile secretion. The duration of the follicular phase can differ depending on the length of the menstrual cycle, while the luteal phase is usually stable, does not really change and lasts 14 days.

<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

<span class="mw-page-title-main">Gonadotropin-releasing hormone antagonist</span> Class of medications

Gonadotropin-releasing hormone antagonists are a class of medications that antagonize the gonadotropin-releasing hormone receptor and thus the action of gonadotropin-releasing hormone (GnRH). They are used in the treatment of prostate cancer, endometriosis, uterine fibroids, female infertility in assisted reproduction, and for other indications.

The theca folliculi comprise a layer of the ovarian follicles. They appear as the follicles become secondary follicles.

Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval for use in in vitro fertilisation (IVF), or be given time to ovulate, resulting in superovulation which is the ovulation of a larger-than-normal number of eggs, generally in the sense of at least two. When ovulated follicles are fertilised in vivo, whether by natural or artificial insemination, there is a very high risk of a multiple pregnancy.

Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure may represent a continuum of premature ovarian senescence. It is usually accompanied by high FSH levels.

Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH)deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

Follicle-stimulating hormone (FSH) insensitivity, or ovarian insensitivity to FSH in females, also referable to as ovarian follicle hypoplasia or granulosa cell hypoplasia in females, is a rare autosomal recessive genetic and endocrine syndrome affecting both females and males, with the former presenting with much greater severity of symptomatology. It is characterized by a resistance or complete insensitivity to the effects of follicle-stimulating hormone (FSH), a gonadotropin which is normally responsible for the stimulation of estrogen production by the ovaries in females and maintenance of fertility in both sexes. The condition manifests itself as hypergonadotropic hypogonadism, reduced or absent puberty, amenorrhea, and infertility in females, whereas males present merely with varying degrees of infertility and associated symptoms.

The hormone of gonadotropins secreted by the anterior hypophyse gland effects on the gonads and play a crucial role in the process of gonadal development and function in vertebrates. In birds and mammals, luteinizinghormone (LH) regulates sex steroid production as well as ovulation, whereas follicle stimulating hormone (FSH) promotes spermatogenesis and ovarian follicle maturation. Since the isolation of gonadotropin-releasing hormone (GnRH), a hypothalamic decapeptide, from mammalian brain in the early 1970s, several other GnRHs have been identified in the brains of other vertebrates. Based on extensive studies in vertebrates, it was generally believed that GnRH is the only hypothalamic regulator of the release of pituitary gonadotropins. Some neurochemicals and peripheral hormones [e.g.gamma-aminobutyric acid (GABA), opiates, gonadal sex steroids, inhibin] can modulate gonadotropin release, but GnRH was considered to have no hypothalamic antagonist.

<span class="mw-page-title-main">Gonadotropin-releasing hormone modulator</span> Type of medication which modulates the GnRH receptor

A GnRH modulator, or GnRH receptor modulator, also known as an LHRH modulator or LHRH receptor modulator, is a type of medication which modulates the GnRH receptor, the biological target of the hypothalamic hormone gonadotropin-releasing hormone. They include GnRH agonists and GnRH antagonists. These medications may be GnRH analogues like leuprorelin and cetrorelix – peptides that are structurally related to GnRH – or small-molecules like elagolix and relugolix, which are structurally distinct from and unrelated to GnRH analogues.

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 anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.

References

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  2. ↑ "Follicle-Stimulating Hormone". WebMD.
  3. ↑ Bowen R. "Luteinizing and Follicle Stimulating Hormones". www.vivo.colostate.edu. Retrieved 2019-05-06.
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  6. ↑ Jiang X, Liu H, Chen X, Chen PH, Fischer D, Sriraman V, et al. (July 2012) [Published online ahead of print 2012-07-16]. Hendrickson WA (ed.). "Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor". Proceedings of the National Academy of Sciences of the United States of America. 109 (31): 12491–6. Bibcode:2012PNAS..10912491J. doi: 10.1073/pnas.1206643109 . eISSN   1091-6490. PMC   3411987 . PMID   22802634.
  7. ↑ Online Mendelian Inheritance in Man (OMIM): Chorionic Gonadotropin, Alpha Chain; CGA - 118850
  8. ↑ Bernard DJ, Fortin J, Wang Y, Lamba P (May 2010). "Mechanisms of FSH synthesis: what we know, what we don't, and why you should care". Fertility and Sterility. 93 (8): 2465–2485. doi:10.1016/j.fertnstert.2010.03.034.
  9. ↑ Ulloa-Aguirre A, Reiter E, Crépieux P (August 2018). "FSH Receptor Signaling: Complexity of Interactions and Signal Diversity". Endocrinology. 159 (8): 3020–3035. doi: 10.1210/en.2018-00452 . PMID   29982321.
  10. ↑ Dalkin AC, Haisenleder DJ, Gilrain JT, Aylor K, Yasin M, Marshall JC (February 1999). "Gonadotropin-releasing hormone regulation of gonadotropin subunit gene expression in female rats: actions on follicle-stimulating hormone beta messenger ribonucleic acid (mRNA) involve differential expression of pituitary activin (beta-B) and follistatin mRNAs". Endocrinology. 140 (2) (published 1999-02-01): 903–8. doi: 10.1210/endo.140.2.6483 . eISSN   1945-7170. PMID   9927322.
  11. ↑ Sharma TP, Nett TM, Karsch FJ, Phillips DJ, Lee JS, Herkimer C, et al. (June 2012) [Published online before print 2012-03-14]. "Neuroendocrine control of FSH secretion: IV. Hypothalamic control of pituitary FSH-regulatory proteins and their relationship to changes in FSH synthesis and secretion". Biology of Reproduction. 86 (6) (published 2012-06-01): 171. doi: 10.1095/biolreprod.111.098442 . PMC   3386145 . PMID   22423050.
  12. ↑ Häggström M (2014-03-25) [Last updated 2017-04-04]. "Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle". WikiJournal of Medicine. 1 (1) (published 2014-03-26). doi: 10.15347/wjm/2014.001 . ISSN   2002-4436.
  13. ↑ 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. CiteSeerX   10.1.1.516.1420 . doi: 10.1530/rep.0.1260689 . eISSN   1741-7899. PMID   14748688.
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  20. ↑ Zhu D, Li X, Macrae VE, Simoncini T, Fu X (August 2018). "Extragonadal Effects of Follicle-Stimulating Hormone on Osteoporosis and Cardiovascular Disease in Women during Menopausal Transition" (PDF). Trends in Endocrinology and Metabolism. 29 (8): 571–580. doi:10.1016/j.tem.2018.06.001. hdl: 20.500.11820/93f9b1f9-3c0d-4d4f-b18c-63842d2d075d . PMID   29983231. S2CID   51602238.
  21. ↑ Li J, May W, McMurray RW (December 2005). "Pituitary hormones and systemic lupus erythematosus". Arthritis and Rheumatism. 52 (12): 3701–12. doi:10.1002/art.21436. PMID   16320320.
  22. ↑ "Polycystic ovary syndrome: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2019-05-06.
  23. ↑ 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
  24. ↑ Radu A, Pichon C, Camparo P, Antoine M, Allory Y, Couvelard A, et al. (October 2010). "Expression of follicle-stimulating hormone receptor in tumor blood vessels". The New England Journal of Medicine. 363 (17): 1621–30. doi: 10.1056/NEJMoa1001283 . PMID   20961245.
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