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You may include any references to papers as in: the use of JSmol in Proteopedia [1] or to the article describing Jmol [2] to the rescue.
Background
FSH, also referred to as follicle-stimulating hormone, belongs to the family of glycoprotein hormones (GPH) which are very complex proteins mostly involved in hormonal activity. The follicle-stimulating hormone, in particular, is one of the gonadotropic hormones, the other one being LH or luteinizing hormone, and these both play many roles in the human body, the most important being their role in the reproductive system. FSH is essential and deeply involved in pubertal development and also in the functions of ovaries and testes in men and women respectively.
Function
In women this hormone can have many functions like regulating the menstrual cycle, stimulating the growth of ovarian follicles in the ovary before the release of the eggs during ovulation. FSH can also increase the production of oestradiol, which is a steroid hormone made from cholesterol that acts to mature and maintain the female reproductive system. On the other hand, in men, it has the function of partly stimulating sperm production during spermatogenesis by acting in Sertoli cells. These Sertoli cells are cells in the testicles that are part of the seminiferous tubule and provide aid for the spermatogenesis process. They are activated by the follicle-stimulating hormone which is secreted by the adenohypophysis and contains FSH receptors on their membranes.
One of the main functions of a structure in the brain called the hypothalamus is to regulate and control the endocrine system, and the hypothalamic hormones control the synthesis, release, and inhibition of hormones from the anterior pituitary gland to the bloodstream. For the activation of the FSH hormone, the hypothalamus first releases a hormone called Gonadotropin-releasing hormone (GnRH), then, this hypothalamic hormone binds specific receptors and stimulates the anterior pituitary gland to produce both FSH and LH, causing the levels of estrogen to rise. FSH is released at a rhythmic pace every 60 to 120 minutes.
The hormone released by the anterior pituitary gland is mostly regulated by antagonistic enhancing and inhibiting molecules, and the release and production of FSH are mainly regulated by the levels of a certain number of specific circulating hormones that are released by the ovaries and testes. The whole system itself receives the name of the hypothalamic-pituitary-gonadal axis. The released FSH is then carried into the general circulation where it will bind to receptors in the testes and ovaries in order to control their functions.
Structure
Regarding the structure of this hormone, research has shown that FSH acts through a G-protein which is coupled to a receptor located on the surface of the target cell which stimulates both ovarian and testicular functions. Glycoprotein hormones and this one in particular are disulfide-rich heterodimers that are consistent on two non-covalently bonded alpha and beta subunits and FSH is around 35.5 kDa.
This structure contains three main components with the colors grey, pink and purple. The grey portion is a G-protein coupled receptor which is a seven transmembrane domain receptor. G-protein receptors are cell surface signaling molecules involved in many essential physiological processes in the human body and its activation is essential for the functioning of FSH. The receptor is composed of 695 amino acids and possesses a molecular mass of 76 kDa, with transmembrane helices. On the other hand the extracellular part of the receptor is glycosylated and has leucine-rich repeats.
This structure also had two different subdomains, the signal specificity subdomain and the hormone-binding subdomain. The transmembrane domain instead contains two cysteine residues that form disulfide bonds in order to stabilize the structure. The purple and pink residues which are found closer together are the hormone itself.
The alpha‐subunit peptide sequence and disulfide bond pattern are very similar in all glycoprotein hormones but the beta‐subunit determines the function of the hormone and dictates the binding to its specific receptor. Both subunits are folded into non-globular cystine structures with three loops that extend from the core motifs and consist of disulfide bridges. The alpha-subunit is always composed of 96 amino acids, and FSH has a beta-subunit of 111 amino acids (FSH β), which provides the hormone with its biological activity that will later use for the interaction with the follicle-stimulating hormone receptors. The sugar portion of FSH is bonded with a covalent bond to the amino acid asparagine and is made of N-acetylgalactosamine, mannose, N-acetylglucosamine, and sialic acid. The different proteins presented in human FSH hormones differ in their degree of glycosylation and sialic acid content.
Relevance
Females experience a decrease in hormone levels at the end of their menstrual cycle which can be detected by the cells of the hypothalamus. These cells will then produce more GnRH that will activate the pituitary gland to produce higher levels of FSH and LH. Due to the rise of the follicle-stimulating hormone a follicle will grow in the ovary which will produce other hormones like inhibin or oestradiol. The hypothalamus will also detect the production of these hormones and decrease the amount of GnRH produced so the FSH can be released. As the follicle keeps growing in the ovary more oestrogen will be produced and this will end in the release of an egg from the mature follicle during ovulation.
Women also experience a rise in FSH hormone levels and secretion during their menstrual cycle, especially during the first half of the cycle, which stimulates the growth of the follicle. After ovulation, the used follicle forms what is called a corpus luteum which is in charge of producing progesterone, and this process will prevent or inhibit more FSH production in the pituitary gland. At the end of the menstrual cycle the levels of progesterone decrease when the corpus luteum is broken down. The next menstrual cycle will only begin when the levels of the follicle-stimulating hormone start to rise again.
The involvement of FSH in men’s biological functions is different than in females. In men the levels and production of FSH are regulated by the levels of inhibin and testosterone which are both produced in the testicles. When testosterone levels begin to rise, the hypothalamus cell detects it and starts decreasing the amount of GnRH production and release. On the other hand when testosterone levels are low the opposite process occurs and larger amounts of GnRH are produced. This process is referred to as negative feedback control and it keeps the levels of testosterone stable.
FSH plays a very important role in fertility, and very high or low levels of FSH can be a sign of ovary or testes malfunction. If the negative feedback process is disrupted and the gonads are able to produce enough testosterone, oestrogen or inhibin, the levels of FSH will rise dramatically, causing a condition called hypergonadotropic-hypogonadism which is associated with ovary and testicle problems like for example Turner’s syndrome in women.
On the other hand, very low levels of FSH in women can also lead to damaging effects like ovary malfunction and failure to complete puberty. This occurs when the follicles in the ovaries fail to grow correctly and are not able to release the egg causing infertility. Hypogonadotropic-hypogonadism is the name used to refer to the condition when FSH levels are too low. Men basically suffer from the same problem because FSH is also required for the production of sperm, so low levels or lack of FSH in men can also cause some conditions like infertility or delayed puberty.
Infertility is a condition that affects around 6 million couples in the United States, meaning that it’s very common. And as it has been mentioned previously in the essay gonadotropin hormones, in concrete FSH play an essential role in the regulation of follicular development and ovulation. This is the reason why in the past two or three decades FSH in both of its forms, highly purified urinary or urinary human menopausal gonadotropin, have been the main focus for the treatment of infertility of ovary malfunction conditions. These kinds of researches propose the idea of ovarian stimulation strategies in anovulatory women in order to activate or stimulate the growth and ovulation of a single dominant follicle (Pang, S. C. 2005).
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References
- ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
- ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
Fan, Q. R., & Hendrickson, W. A. (2005). Structure of human follicle-stimulating hormone in complex with its receptor. Nature, 433(7023), 269–277. https://doi.org/10.1038/nature03206
Pardue, A., Dvoretz, I., Wright, C., Custard, A., Barbara, E. and Langat, D. (2017), Follicle Stimulating Hormone and Reproductive Aging. The FASEB Journal, 31: 935.3-935.3. https://doi.org/10.1096/fasebj.31.1_supplement.935.3
Hoffmann, A. B. (2011). Sex Hormones: Development, Regulation and Disorders. Nova Science Publishers, Inc
Bank, R. (n.d.). FSH:4ay9. Retrieved March 28, 2021, from http://www.rcsb.org/3d-view/4AY9/1
Follicle-stimulating hormone (FSH). (n.d.). Retrieved March 29, 2021, from https://www.yourhormones.info/hormones/follicle-stimulating-hormone/
Pang, S. C. (2005). Use of Follicle-Stimulating Hormone for the Treatment of Female Infertility – Current Concepts. Women’s Health, 87–95. https://doi.org/10.1517/17455057.1.1.087
