関: follitropin alpha

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/04/28 13:52:38」(JST)

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For other uses of the term FSH, see FSH (disambiguation).

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.^[1] FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) act synergistically in reproduction. Specifically, an increase in FSH secretion by the anterior pituitary causes ovulation.

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, thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG, a hormone produced in pregancy). 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 111 amino acids (FSH β), which confers its specific biologic action and is responsible for interaction with the FSH-receptor. The sugar part of the hormone is composed of fucose, galactose, mannose, galactosamine, glucosamine, and sialic acid, the latter being critical for its biologic half-life. The half-life of FSH is 3–4 hours.

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.

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.^[2]
- 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 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.^[3]

(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 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.^[4]

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, 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,^[5] 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.

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 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:

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.
Klinefelter syndrome

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

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.)

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).^[6]

References

^ "Follicle-Stimulating Hormone".
^ 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.
^ 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.
^ 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.
^ Boulpaep EL, Boron WF (2005). Medical physiology: a cellular and molecular approach. St. Louis, Mo: Elsevier Saunders. p. 1125. ISBN 1-4160-2328-3.
^ 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.

External links

Day 3 FSH levels From the Infertility Blog by Dr. Fred Licciardi
High FSH: an excuse to send patients away From the Infertility Blog by Dr. Fred Licciardi
FSH and Estradiol
Causes & Symptoms of High FSH
Information on high FSH compiled by a woman with high FSH
High FSH Levels background information
Getting Pregnant with High FSH by Julia Indichova, author of Inconceivable (Doubleday 2001) and The Fertile Female (Adell Press 2007)

UpToDate Contents

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1. 排卵誘発の概要 overview of ovulation induction
2. 体外受精（IFV） in vitro fertilization
3. 患者情報：ゴナドトロピンによる不妊治療（詳細） infertility treatment with gonadotropins beyond the basics

English Journal

A large, multicentre, observational, post-marketing surveillance study of the 2:1 formulation of follitropin alfa and lutropin alfa in routine clinical practice for assisted reproductive technology.

Bühler K, Naether OG, Bilger W.Author information Centre for Gynaecology, Endocrinology and Reproductive Medicine, Ulm and Stuttgart D-70174, Germany. buehler.kf@t-online.de.AbstractBACKGROUND: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) both have a role to play in follicular development during the natural menstrual cycle. LH supplementation during controlled ovarian stimulation (COS) for assisted reproductive technology (ART) is used for patients with hypogonadotropic hypogonadism. However, the use of exogenous LH in COS in normogonadotropic women undergoing ART is the subject of debate. The aim of this study was to investigate characteristics of infertile women who received the 2:1 formulation of follitropin alfa and lutropin alfa (indicated for stimulation of follicular development in women with severe LH and FSH deficiency) in German clinical practice.
Reproductive biology and endocrinology : RB&E.Reprod Biol Endocrinol.2014 Jan 14;12(1):6. doi: 10.1186/1477-7827-12-6.
BACKGROUND: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) both have a role to play in follicular development during the natural menstrual cycle. LH supplementation during controlled ovarian stimulation (COS) for assisted reproductive technology (ART) is used for patients with hypog
PMID 24423045

Clinical efficacy and cost-effectiveness of HP-human FSH (Fostimon®) versus rFSH (Gonal-F®) in IVF-ICSI cycles: a meta-analysis.

Gerli S, Bini V, Favilli A, Di Renzo GC.Author information Department of Obstetrics and Gynecology, University of Perugia, Perugia, Italy. gerber@unipg.itAbstractClinical efficacy of human-derived follicle-stimulating hormone (FSH) versus recombinant FSH (rFSH) in IVF-ICSI cycles has long been compared, but no clear evidence of the superiority of a preparation over the other has been found. Human gonadotropins have been often grouped together, but a different glycosylation may be present in each preparation, therefore influencing the specific bioactivity. To exclude confounding factors, a meta-analysis and a cost-effectiveness analysis were designed to compare effectiveness and cost-effectiveness of a specific highly purified human FSH (HP-hFSH) (Fostimon®) versus rFSH (Gonal-F®) in IVF/ICSI cycles. Research methodology filters were applied in MEDLINE, Current Contents and Web of Science from 1980 to February 2012. Eight randomized trials met selection criteria. The meta-analysis showed no significant differences between rFSH and HP-hFSH treatment in live-birth rate (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.63-1.11), clinical pregnancy rate (OR 0.85, 95% CI 0.68-1.07), number of oocytes retrieved, number of mature oocytes and days of stimulation. The cost-effectiveness ratio was € 7174 in the rFSH group and € 2056 in the HP-hFSH group. HP-hFSH is as effective as rFSH in ovarian stimulation for IVF-ICSI cycles, but the human preparation is more cost-effective.
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.Gynecol Endocrinol.2013 Jun;29(6):520-9. doi: 10.3109/09513590.2012.758703. Epub 2013 Jan 28.
Clinical efficacy of human-derived follicle-stimulating hormone (FSH) versus recombinant FSH (rFSH) in IVF-ICSI cycles has long been compared, but no clear evidence of the superiority of a preparation over the other has been found. Human gonadotropins have been often grouped together, but a differen
PMID 23356335

What are biosimilars and are they important?

[No authors listed]AbstractAll prescribers will be familiar with the issues associated with the use of branded and generic 'chemical' medicines.(1) For biological products (e.g. epoetin, filgrastim), a biosmilar medicine is a new biological product that is similar to a medicine that has already been authorised to be marketed in the EU (the biological reference medicine).(2) Six biosimilar medicinal products are currently marketed in the UK-three versions of filgrastim (▾Nivestim, ▾Tevagrastim and Zarzio),(3-5) two versions of epoetin (Binocrit and Retacrit)(6,7) and one version of somatropin (Omnitrope).(8) Applications for biosimilar versions of follitropin alfa and infliximab are under evaluation by the European Medicine's Agency (EMA) Committee for Medicinal Products for Human Use.(9) In the future there may also be biosimilar versions of insulins, recombinant vaccines, interferons and monoclonal antibodies such as rituximab and trastuzumab.(10) It is estimated that about 50% of the current UK market for biological medicines by spend may be subject to biosimilar competition by 2019. In this article, we will consider the background to developing biosimilar medicines, how and why they differ from traditional generic medicines in their licensing requirements and the issues that may arise as they are introduced to clinical practice.
Drug and therapeutics bulletin.Drug Ther Bull.2013 May;51(5):57-60. doi: 10.1136/dtb.2013.5.0181.
All prescribers will be familiar with the issues associated with the use of branded and generic 'chemical' medicines.(1) For biological products (e.g. epoetin, filgrastim), a biosmilar medicine is a new biological product that is similar to a medicine that has already been authorised to be marketed
PMID 23657197

Japanese Journal

リコンビナントFSHの基礎 (特集排卵誘発Update)

石原理,鈴木元晴,菊地真理子 [他]
産科と婦人科 79(7), 854-858, 2012-07
NAID 40019366139

Recombinant follicle-stimulating hormone (follitropin alfa) versus purified urinary follicle-stimulating hormone in a low-dose step-up regimen to induce ovulation in Japanese women with anti-estrogen-ineffective oligo- or anovulatory infertility : results of a single-blind Phase III study

TAKETANI Yuji,KELLY Eduardo,YOSHIMURA Yasunori,HOSHIAI Hiroshi,IRAHARA Minoru,MIZUNUMA Hideki,SAITO Hidekazu,ANDOH Kazumichi,YANAIHARA Takumi
Reproductive medicine and biology 9(2), 99-106, 2010-06-01
NAID 10027050407

Recombinant follicle-stimulating hormone (follitropin alfa) for ovulation induction in Japanese patients with anti-estrogen-ineffective oligo- or anovulatory infertility : results of a phase II dose-response study

TAKETANI Yuji,KELLY Eduardo,YOSHIMURA Yasunori,HOSHIAI Hiroshi,IRAHARA Minoru,MIZUNUMA Hideki,SAITO Hidekazu,ANDOH Kazumichi,BEBIA Zourab,YANAIHARA Takumi
Reproductive medicine and biology 9(2), 91-97, 2010-06-01
NAID 10027050391

Related Pictures

★リンクテーブル★

リンク元	「ホリトロピンアルファ」「フォリトロピンアルファ」「follitropin alpha」
関連記事	「alfa」

「ホリトロピンアルファ」

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