Gonadotropin

Last updated
Glycoprotein hormone
Identifiers
SymbolHormone_6
Pfam PF00236
InterPro IPR000476
PROSITE PDOC00623
SCOP2 1hcn / SCOPe / SUPFAM

Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. [1] [2] [3] 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), [3] 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. [4] LH and FSH are secreted by the anterior pituitary gland, while hCG and eCG are secreted by the placenta in pregnant humans and mares, respectively. [5] The gonadotropins act on the gonads, controlling gamete and sex hormone production.

Contents

Gonadotropin is sometimes abbreviated Gn. The alternative spelling gonadotrophin which inaccurately implies a nourishing mechanism [6] is also used.

There are various preparations of gonadotropins for therapeutic use, mainly as fertility medication. There are also fad diet or quack preparations, which are illegal in various countries.

Natural types and subunit structure

The two principal gonadotropins in vertebrates are luteinizing hormone (LH) and follicle-stimulating hormone (FSH), although primates produce a third gonadotropin called chorionic gonadotropin (CG). LH and FSH are heterodimers consisting of two peptide chains, an alpha chain and a beta chain. LH and FSH share nearly identical alpha chains (about 100 amino acids long), whereas the beta chain provides specificity for receptor interactions. These subunits are heavily modified by glycosylation.

The alpha subunit is common to each protein dimer (well conserved within species, but differing between them), [4] and a unique beta subunit confers biological specificity. [7] The alpha chains are highly conserved proteins of about 100 amino acid residues which contain ten conserved cysteines all involved in disulfide bonds, [8] as shown in the following schematic representation.

                       +---------------------------+            +----------+|             +-------------|--+            |          ||             |             |  |        xxxxCxCxxxxxxCxCCxxxxxxxxxxxxxCCxxxxxxxxxxCxCxxCx              |      |                 |          |              +------|-----------------+          |                     |                            |                     +----------------------------+

'C': conserved cysteine involved in a disulphide bond.

Intracellular levels of free alpha subunits are greater than those of the mature glycoprotein, implying that hormone assembly is limited by the appearance of the specific beta subunits, and hence that synthesis of alpha and beta is independently regulated. [7]

Another human gonadotropin is human chorionic gonadotropin (hCG), produced by the placenta during pregnancy.

Mechanism

gonadotropin-releasing hormone Gonadotropin releasing hormone3d.png
gonadotropin-releasing hormone

Gonadotropin receptors are embedded in the surface of the target cell membranes and coupled to the G-protein system. Signals triggered by binding to the receptor are relayed within the cells by the cyclic AMP second messenger system.

Gonadotropins are released under the control of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus and preoptic area of the hypothalamus. The gonads — testes and ovaries — are the primary target organs for LH and FSH. The gonadotropins affect multiple cell types and elicit multiple responses from the target organs. As a simplified generalization, LH stimulates the Leydig cells of the testes and the theca cells of the ovaries to produce testosterone (and indirectly estradiol), whereas FSH stimulates the spermatogenic tissue of the testes and the granulosa cells of ovarian follicles, as well as stimulating production of estrogen by the ovaries.

Although gonadotropins are secreted in a pulsatile manner (as a result of pulsatile GnRH release), unlike the case of GnRH and GnRH agonists, constant/non-pulsatile activation of the gonadotropin receptors by the gonadotropins does not produce functional inhibition. This can be seen during the first 7–10 weeks of pregnancy, where constantly high and progressively-increasing levels of hCG circulate and mediate production of estrogen and progesterone by the corpus luteum until the placenta takes over the production of these hormones. [9]

Diseases

Gonadotropin deficiency due to pituitary disease results in hypogonadism, which can lead to infertility. Treatment includes administered gonadotropins, which, therefore, work as fertility medication. Such can either be produced by extraction and purification from urine or be produced by recombinant DNA.

Failure or loss of the gonads usually results in elevated levels of LH and FSH in the blood. [10] [11]

LH insensitivity, which results in Leydig cell hypoplasia in males, and FSH insensitivity, are conditions of insensitivity to LH and FSH, respectively, caused by loss-of-function mutations in their respective signaling receptors. Another closely related condition to these is GnRH insensitivity.

Pharmaceutical preparations

There are various preparations of gonadotropins for therapeutic use, mainly as fertility medication. For example, the so-called menotropins (also called human menopausal gonadotropins) consist of LH and FSH extracted from the urine of menopausal women. [12] There are also recombinant variants. Besides the aforementioned legitimate pharmaceutical drugs, there are fad diet or quack preparations, which are illegal in various countries.

See also

Related Research Articles

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 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).

Human chorionic gonadotropin Hormone

Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo, which eventually forms the placenta after implantation. The presence of hCG is detected in some pregnancy tests. Some cancerous tumors produce this hormone; therefore, elevated levels measured when the patient is not pregnant may lead to a cancer diagnosis and, if high enough, paraneoplastic syndromes, however, it is not known whether this production is a contributing cause, or an effect of carcinogenesis. The pituitary analog of hCG, known as luteinizing hormone (LH), is produced in the pituitary gland of males and females of all ages.

Follicle-stimulating hormone Gonadotropin that regulates the development of reproductive processes

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

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 of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

Gonadotropin-releasing hormone 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.

Hypothalamic–pituitary–gonadal axis

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.

Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of hypogonadotropic hypogonadism (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.

The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin-releasing hormone (GnRH). The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate.

GNRHR Protein-coding gene in the species Homo sapiens

Gonadotropin-releasing hormone receptor is a protein that in humans is encoded by the GNRHR gene.

Glycoprotein hormones, alpha polypeptide

Glycoprotein hormones, alpha polypeptide is a protein that in humans is encoded by the CGA gene.

FSHB

Follitropin subunit beta also known as follicle-stimulating hormone beta subunit (FSH-B) is a protein that in humans is encoded by the FSHB gene. Alternative splicing results in two transcript variants encoding the same protein.

Luteinizing hormone beta polypeptide

Luteinizing hormone subunit beta also known as lutropin subunit beta or LHβ is a polypeptide that in association with an alpha subunit common to all gonadotropin hormones forms the reproductive signaling molecule luteinizing hormone. In humans it is encoded by the LHB gene.

Hypothalamic–pituitary hormones are hormones that are produced by the hypothalamus and pituitary gland. Although the organs in which they are produced are relatively small, the effects of these hormones cascade throughout the body. They can be classified as a hypothalamic–pituitary axis of which the adrenal (HPA), gonadal (HPG), thyroid (HPT), somatotropic (HPS), and prolactin (HPP) axes are branches.

Equine chorionic gonadotropin is a gonadotropic hormone produced in the chorion of pregnant mares. Previously referred to as pregnant mare's serum gonadotropin (PMSG), the hormone is commonly used in concert with progestogen to induce ovulation in livestock prior to artificial insemination.

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.

Fertile eunuch syndrome Medical condition

The fertile eunuch syndrome or Pasqualini syndrome is a cause of hypogonadotropic hypogonadism caused by a luteinizing hormone deficiency. It is characterized by hypogonadism with spermatogenesis. Pasqualini and Bur published the first case of eunuchoidism with preserved spermatogenesis in 1950 in la Revista de la Asociación Médica Argentina. The hypoandrogenism with spermatogenesis syndrome included:

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.

Pulsatile secretion is a biochemical phenomenon observed in a wide variety of cell and tissue types, in which chemical products are secreted in a regular temporal pattern. The most common cellular products observed to be released in this manner are intercellular signaling molecules such as hormones or neurotransmitters. Examples of hormones that are secreted pulsatilely include insulin, thyrotropin, TRH, gonadotropin-releasing hormone (GnRH) and growth hormone (GH). In the nervous system, pulsatility is observed in oscillatory activity from central pattern generators. In the heart, pacemakers are able to work and secrete in a pulsatile manner. A pulsatile secretion pattern is critical to the function of many hormones in order to maintain the delicate homeostatic balance necessary for essential life processes, such as development and reproduction. Variations of the concentration in a certain frequency can be critical to hormone function, as evidenced by the case of GnRH agonists, which cause functional inhibition of the receptor for GnRH due to profound downregulation in response to constant (tonic) stimulation. Pulsatility may function to sensitize target tissues to the hormone of interest and upregulate receptors, leading to improved responses. This heightened response may have served to improve the animal's fitness in its environment and promote its evolutionary retention.

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

  1. ↑ Parhar, Ishwar S. (2002). Gonadotropin-releasing Hormone: Molecules and Receptors. Amsterdam: Elsevier. ISBN   0-444-50979-8.
  2. ↑ Pierce JG, Parsons TF (1981). "Glycoprotein hormones: structure and function". Annual Review of Biochemistry. 50: 465–95. doi:10.1146/annurev.bi.50.070181.002341. PMID   6267989.
  3. 1 2 Stockell Hartree A, Renwick AG (November 1992). "Molecular structures of glycoprotein hormones and functions of their carbohydrate components". The Biochemical Journal. 287 ( Pt 3) (Pt 3): 665–79. doi:10.1042/bj2870665. PMC   1133060 . PMID   1445230.
  4. 1 2 Godine JE, Chin WW, Habener JF (July 1982). "alpha Subunit of rat pituitary glycoprotein hormones. Primary structure of the precursor determined from the nucleotide sequence of cloned cDNAs". The Journal of Biological Chemistry. 257 (14): 8368–71. doi: 10.1016/S0021-9258(18)34340-0 . PMID   6177696.
  5. ↑ Golos TG, Durning M, Fisher JM (June 1991). "Molecular cloning of the rhesus glycoprotein hormone alpha-subunit gene". DNA and Cell Biology. 10 (5): 367–80. doi:10.1089/dna.1991.10.367. PMID   1713773.
  6. ↑ Stewart J, Li CH (August 1962). "On the use of -tropin or -trophin in connection with anterior pituitary hormones". Science. 137 (3527): 336–7. Bibcode:1962Sci...137..336S. doi:10.1126/science.137.3527.336. PMID   13917136. S2CID   9747521.
  7. 1 2 Goodwin RG, Moncman CL, Rottman FM, Nilson JH (October 1983). "Characterization and nucleotide sequence of the gene for the common alpha subunit of the bovine pituitary glycoprotein hormones". Nucleic Acids Research. 11 (19): 6873–82. doi:10.1093/nar/11.19.6873. PMC   326420 . PMID   6314263.
  8. ↑ Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE, Machin KJ, et al. (June 1994). "Crystal structure of human chorionic gonadotropin". Nature. 369 (6480): 455–61. Bibcode:1994Natur.369..455L. doi:10.1038/369455a0. PMID   8202136. S2CID   4263358.
  9. ↑ Laurence A. Cole (21 September 2010). Human Chorionic Gonadotropin (hCG). Elsevier. pp. 205–. ISBN   978-0-12-384908-3.
  10. ↑ Basaria S (April 2014). "Male hypogonadism". Lancet. 383 (9924): 1250–63. doi:10.1016/S0140-6736(13)61126-5. PMID   24119423. S2CID   30479724.
  11. ↑ Rothman MS, Wierman ME (2008). "Female hypogonadism: evaluation of the hypothalamic-pituitary-ovarian axis". Pituitary. 11 (2): 163–9. doi:10.1007/s11102-008-0109-3. PMID   18404388. S2CID   6666672.
  12. ↑ Menotropins at the US National Library of Medicine Medical Subject Headings (MeSH)
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