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| [[File:Hypothalamic–pituitary–gonadal_axis.svg|thumb|upright=1.5x|HPG axis]] | | [[File:Hypothalamic–pituitary–gonadal_axis.svg|thumb|upright=1.5x|HPG axis]] |
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| The '''hypothalamic–pituitary–gonadal axis''' ('''HPG axis''') refers to the [[hypothalamus]], [[pituitary gland]], and [[gonad|gonadal glands]] as if these individual [[endocrine gland]]s were a single entity. Because these glands often act in concert, [[physiology|physiologists]] and [[endocrinology|endocrinologists]] find it convenient and descriptive to speak of them as a single system.
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| The HPG axis plays a critical part in the development and regulation of a number of the body's systems, such as the reproductive and immune systems. Fluctuations in this axis cause changes in the hormones produced by each gland and have various local and systemic effects on the body.
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| The axis controls development, reproduction, and aging in animals. [[Gonadotropin-releasing hormone]] (GnRH) is secreted from the [[hypothalamus]] by [[GnRH Neuron|GnRH-expressing neurons]]. The anterior portion of the [[pituitary gland]] produces [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH), and the gonads produce [[estrogen]] and [[testosterone]].
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| In [[oviparous]] organisms (e.g. fish, reptiles, amphibians, birds), the HPG axis is commonly referred to as the hypothalamus-pituitary-gonadal-liver axis (HPGL-axis) in females. Many egg-yolk and chorionic proteins are synthesized heterologously in the liver, which are necessary for oocyte growth and development. Examples of such necessary liver proteins are [[vitellogenin]] and choriogenin.
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| The [[hypothalamic–pituitary–adrenal axis|HPA]], HPG, and [[hypothalamic–pituitary–thyroid axis|HPT]] axes are three pathways in which the hypothalamus and pituitary direct neuroendocrine function.
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| == Location and regulation ==
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| [[File:Hypothalamus-Hypophysis-Testicle-Hormone-Axis (engl.).svg|thumb|right|HPG regulation in males, with the inhibin/activin system playing a similar role on GnRH-producing cells.]] | | [[File:Hypothalamus-Hypophysis-Testicle-Hormone-Axis (engl.).svg|thumb|right|HPG regulation in males, with the inhibin/activin system playing a similar role on GnRH-producing cells.]] |
| The [[hypothalamus]] is located in the brain and secretes GnRH.<ref name="pmid15082521">{{cite journal |vauthors=Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR | title = Gonadotropin-releasing hormone receptors | journal = Endocr. Rev. | volume = 25 | issue = 2 | pages = 235–75 |date=April 2004 | pmid = 15082521 | doi = 10.1210/er.2003-0002| url = | issn = }}</ref> GnRH travels down the anterior portion of the pituitary via the [[hypophyseal portal system]] and binds to receptors on the secretory cells of the [[adenohypophysis]].<ref name="pmid18601683">{{cite journal | author = Charlton H | title = Hypothalamic control of anterior pituitary function: a history | journal = J. Neuroendocrinol. | volume = 20 | issue = 6 | pages = 641–6 |date=June 2008 | pmid = 18601683 | doi = 10.1111/j.1365-2826.2008.01718.x | url = | issn = }}</ref> In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream.<ref name="pmid15723162">{{cite journal |vauthors=Vadakkadath Meethal S, Atwood CS | title = The role of hypothalamic-pituitary-gonadal hormones in the normal structure and functioning of the brain | journal = Cell. Mol. Life Sci. | volume = 62 | issue = 3 | pages = 257–70 |date=February 2005 | pmid = 15723162 | doi = 10.1007/s00018-004-4381-3 | url = | issn = }}</ref>
| | '''Hypothalamic–pituitary–gonadal axis''' ('''HPG axis''') refers collectively to the [[hypothalamus]], [[pituitary gland]], and [[gonads]] ([[ovaries]] in females, [[testes]] in males) as a single interconnected endocrine system. This functional axis plays a crucial role in regulating reproduction, development, growth, and aging. |
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| These two hormones play an important role in communicating to the gonads. In females FSH and LH act primarily to activate the [[ovaries]] to produce estrogen and inhibin and to regulate the [[menstrual cycle]] and [[ovarian cycle]]. Estrogen forms a [[negative feedback loop]] by inhibiting the production of GnRH in the hypothalamus. [[Inhibin]] acts to inhibit [[activin]], which is a peripherally produced hormone that positively stimulates GnRH-producing cells. [[Follistatin]], which is also produced in all body tissue, inhibits activin and gives the rest of the body more control over the axis. In males LH stimulates the interstitial cells located in the [[testes]] to produce testosterone, and FSH plays a role in [[spermatogenesis]]. Only small amounts of estrogen are secreted in males. Recent research has shown that a neurosteroid axis exists, which helps the cortex to regulate the hypothalamus’s production of GnRH.<ref name="pmid19493163">{{cite journal |vauthors=Meethal SV, Liu T, Chan HW, Ginsburg E, Wilson AC, Gray DN, Bowen RL, Vonderhaar BK, Atwood CS | title = Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors | journal = J. Neurochem. | volume = 110 | issue = 3 | pages = 1014–27 |date=August 2009 | pmid = 19493163 | pmc = 2789665 | doi = 10.1111/j.1471-4159.2009.06192.x | url = | issn = }}</ref>
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| In addition, [[leptin]] and [[insulin]] have stimulatory effects and [[ghrelin]] has inhibitory effects on [[gonadotropin-releasing hormone]] (GnRH) secretion from the [[hypothalamus]].<ref>{{Cite journal | doi = 10.1093/humupd/dmt033| title = The relationship between gut and adipose hormones, and reproduction| journal = Human Reproduction Update| volume = 20| issue = 2| pages = 153–74| year = 2013| last1 = Comninos | first1 = A. N.| last2 = Jayasena | first2 = C. N.| last3 = Dhillo | first3 = W. S. | pmid=24173881}}</ref> [[Kisspeptin]] also influences GnRH secretion.<ref name="SkorupskaiteGeorge2014">{{cite journal|last1=Skorupskaite|first1=K.|last2=George|first2=J. T.|last3=Anderson|first3=R. A.|title=The kisspeptin-GnRH pathway in human reproductive health and disease|journal=Human Reproduction Update|volume=20|issue=4|year=2014|pages=485–500|issn=1355-4786|doi=10.1093/humupd/dmu009|pmid=24615662|pmc=4063702}}</ref>
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| == Function ==
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| === Reproduction ===
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| One of the most important functions of the HPG axis is to regulate reproduction by controlling the uterine and ovarian cycles.<ref name="ReferenceA">{{cite book |author1=Katja Hoehn |author2=Marieb, Elaine Nicpon | title = Human anatomy & physiology | edition = | language = | publisher = Pearson Benjamin Cummings | location = San Francisco | year = 2007 | origyear = | pages = 1090–1110 | quote = | isbn = 0-8053-5909-5 | oclc = | doi = | url = | accessdate = }}</ref> In females, the [[positive feedback]] loop between estrogen and luteinizing hormone help to prepare the follicle in the ovary and the uterus for ovulation and implantation. When the egg is released, the empty follicle sac begins to produce progesterone to inhibit the hypothalamus and the anterior pituitary thus stopping the estrogen-LH positive feedback loop. If conception occurs, the placenta will take over the secretion of progesterone; therefore the mother cannot ovulate again. If conception does not occur, decreasing excretion of progesterone will allow the hypothalamus to restart secretion of GnRH. These hormone levels also control the uterine (menstrual) cycle causing the proliferation phase in preparation for ovulation, the secretory phase after ovulation, and menstruation when conception does not occur. The activation of the HPG axis in both males and females during puberty also causes individuals to acquire secondary sex characteristics.
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| In males, the production of GnRH, LH, and FSH are similar, but the effects of these hormones are different.<ref name="Veldhuis, J. D. 2009">{{cite journal |vauthors=Veldhuis JD, Keenan DM, Liu PY, Iranmanesh A, Takahashi PY, Nehra AX | title = The aging male hypothalamic-pituitary-gonadal axis: pulsatility and feedback | journal = Mol. Cell. Endocrinol. | volume = 299 | issue = 1 | pages = 14–22 |date=February 2009 | pmid = 18838102 | pmc = 2662347 | doi = 10.1016/j.mce.2008.09.005 | url = | issn = }}</ref> FSH stimulates [[sustentacular cell]]s to release [[androgen-binding protein]], which promotes [[testosterone]] binding. LH binds to the interstitial cells, causing them to secrete testosterone. Testosterone is required for normal spermatogenesis and inhibits the hypothalamus. Inhibin is produced by the spermatogenic cells, which, also through inactivating activin, inhibits the hypothalamus. After puberty these hormones levels remain relatively constant.
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| === Life cycle ===
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| The activation and deactivation of the HPG axis also helps to regulate life cycles.<ref name="ReferenceA"/> At birth FSH and LH levels are elevated, and females also have a lifetime supply of primary oocytes. These levels decrease and remain low through childhood. During [[puberty]] the HPG axis is activated by the secretions of estrogen from the ovaries or testosterone from the [[testes]]. This activation of [[estrogen]] and testosterone causes physiological and psychological changes. Once activated, the HPG axis continues to function in men for the rest of their life but becomes deregulated in women, leading to [[menopause]]. This deregulation is caused mainly by the lack of oocytes that normally produce estrogen to create the positive feedback loop. Over several years, the activity the HPG axis decreases and women are no longer fertile.<ref name="pmid19063938">{{cite journal |vauthors=Downs JL, Wise PM | title = The role of the brain in female reproductive aging | journal = Mol. Cell. Endocrinol. | volume = 299 | issue = 1 | pages = 32–8 |date=February 2009 | pmid = 19063938 | pmc = 2692385 | doi = 10.1016/j.mce.2008.11.012 | url = | issn = }}</ref>
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| Although males remain fertile until death, the activity of the HPG axis decreases. As males age, the [[testes]] begin to produce less testosterone, leading to a condition known as post-pubertal [[hypogonadism]].<ref name="Veldhuis, J. D. 2009"/> The cause of the decreased testosterone is unclear and a current topic of research. Post-pubertal hypogonadism results in progressive muscle mass decrease, increase in visceral fat mass, loss of libido, impotence, decreased attention, increased risk of fractures, and abnormal sperm production.
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| === Sexual dimorphism and behavior ===
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| [[Sex steroids]] also affect behavior, because sex steroids affect the brains structure and functioning. During development, hormones help determine how neurons [[synapse]] and [[neuron migration|migrate]] to result in [[sexual dimorphism]]s.<ref name="pmid7134329">{{cite journal | author = Hines M | title = Prenatal gonadal hormones and sex differences in human behavior | journal = Psychol Bull | volume = 92 | issue = 1 | pages = 56–80 |date=July 1982 | pmid = 7134329 | doi = 10.1037/0033-2909.92.1.56| url = | issn = }}</ref> These physical differences lead to differences in behavior. While GnRH has not been shown to have any direct influence on regulating brain structure and function, gonadotropins, sex steroids, and activin have been shown to have such effects. It is thought that FSH may have an important role in brain development and differentiation.
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| Testosterone levels have been shown to relate to [[prosocial behavior]].<ref>{{cite journal |vauthors=Wibral M, Dohmen T, Klingmüller D, Weber B, Falk A | year = 2012 | title = Testosterone Administration Reduces Lying in Men | journal = PLoS ONE | volume = 7 | issue = 10| page = e46774 | doi = 10.1371/journal.pone.0046774 | pmid=23071635 | pmc=3468628}}</ref> This helps create synaptogenesis by promoting neurite development and migration. Activin promotes neural plasticity throughout the lifespan and regulates the neurotransmitters of peripheral neurons. Environment can also affect hormones and behavior interaction.<ref name="pmid19250945">{{cite journal |vauthors=Shepard KN, Michopoulos V, Toufexis DJ, Wilson ME | title = Genetic, epigenetic and environmental impact on sex differences in social behavior | journal = Physiol. Behav. | volume = 97 | issue = 2 | pages = 157–70 |date=May 2009 | pmid = 19250945 | pmc = 2670935 | doi = 10.1016/j.physbeh.2009.02.016 | url = | issn = }}</ref> Women have more connections between areas of language better enabling them to communicate than men. On average men outperform women on [[spatial visualization ability|spatial reasoning tests]], which is theorized to result from sexual differences.{{citation needed|date=October 2015}} Testosterone has been linked to aggression and sex drive; therefore men tend to be more competitive or aggressive than women.{{citation needed|date=September 2014}} There is also a large amount of individual diversity within all these traits and hormone levels.
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| == Clinical relevance ==
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| ===Disorders===
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| Disorders of the hypothalamic–pituitary–gonadal axis are classified by the World Health Organization (WHO) as:<ref>[https://books.google.com/books?id=fh2hJDiLOyAC&pg=PA54 Page 54] in: {{cite book |author1=Guillebaud, John |author2=Enda McVeigh |author3=Roy Homburg |title=Oxford handbook of reproductive medicine and family planning |publisher=Oxford University Press |location=Oxford [Oxfordshire] |year=2008 |pages= |isbn=0-19-920380-6 |oclc= |doi= |accessdate=}}</ref>
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| *WHO group I of [[ovulation disorder]]s: ''Hypothalamic–pituitary failure''
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| *WHO group II of [[ovulation disorder]]s: ''Hypothalamic–pituitary dysfunction''. WHO group II is the most common cause of ovulation disorders, and the most common causative member is [[polycystic ovary syndrome]] (PCOS).<ref>{{Cite journal | last1 = Baird | first1 = D. T. | last2 = Balen | first2 = A. | last3 = Escobar-Morreale | first3 = H. F. | last4 = Evers | first4 = J. L. H. | last5 = Fauser | first5 = B. C. J. M. | last6 = Franks | first6 = S. | last7 = Glasier | first7 = A. | last8 = Homburg | first8 = R. | last9 = La Vecchia | first9 = C. | last10 = Devroey | doi = 10.1093/humupd/dms019 | first10 = P. | last11 = Diedrich | first11 = K. | last12 = Fraser | first12 = L. | last13 = Gianaroli | first13 = L. | last14 = Liebaers | first14 = I. | last15 = Sunde | first15 = A. | last16 = Tapanainen | first16 = J. S. | last17 = Tarlatzis | first17 = B. | last18 = Van Steirteghem | first18 = A. | last19 = Veiga | first19 = A. | last20 = Crosignani | first20 = P. G. | last21 = Evers | first21 = J. L. H. | title = Health and fertility in World Health Organization group 2 anovulatory women | journal = Human Reproduction Update | volume = 18 | issue = 5 | pages = 586–599 | year = 2012 | pmid = 22611175| pmc = }}</ref>
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| ==== Gene mutations ====
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| Genetic mutations and chromosomal abnormalities are two sources of HPG axis alteration.<ref name="pmid18404386">{{cite journal |vauthors=Isidori AM, Giannetta E, Lenzi A | title = Male hypogonadism | journal = Pituitary | volume = 11 | issue = 2 | pages = 171–80 | year = 2008 | pmid = 18404386 | doi = 10.1007/s11102-008-0111-9 | url = | issn = }}</ref> Single mutations usually lead to changes in binding ability of the hormone and receptor leading to inactivation or over activation. These mutations can occur in the genes coding for GnRH, LH, and FSH or their receptors. Depending on which hormone and receptor are unable to bind different effects occur but all alter the HPG axis.
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| For example, the male mutation of the GnRH coding gene could result in hypogonadotrophic hypogonadism. A mutation that cause a gain of function for LH receptor can result in a condition known as testotoxicosis, which cause puberty to occur between ages 2–3 years. Loss of function of LH receptors can cause male pseudohermaphroditism. In females mutations would have analogous effects. Hormone replacement can be used to initiate puberty and continue if the gene mutation occurs in the gene coding for the hormone. Chromosomal mutations tend to affect the androgen production rather than the HPG axis.
| | == Structure and Function == |
| | The HPG axis comprises three main components: |
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| === Suppression ===
| | * '''[[Hypothalamus]]''': Contains specialized neurons that produce and secrete [[gonadotropin-releasing hormone]] (GnRH). |
| The HPG axis can be suppressed by [[hormonal birth control]] administration. Although often described as preventing pregnancy by mimicking the pregnancy state, hormonal birth control is effective because it works on the HPG axis to mimic the luteal phase of a woman's cycle. The primary active ingredients are synthetic [[progestins]], which mimic biologically derived progesterone. The synthetic progestin prevents the hypothalamus from releasing GnRH and the pituitary from releasing LH and FSH; therefore it prevents the ovarian cycle from entering the menstrual phase and prevents follicle development and ovulation. Also as a result, many of the side effects are similar to the symptoms of pregnancy. Alzheimer's has been shown to have a hormonal component, which could possibly be used as a method to prevent the disease.<ref name="pmid18439297">{{cite journal |vauthors=Haasl RJ, Ahmadi MR, Meethal SV, Gleason CE, Johnson SC, Asthana S, Bowen RL, Atwood CS | title = A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E epsilon4 allele | journal = BMC Med. Genet. | volume = 9| pages = 37 | year = 2008 | pmid = 18439297 | pmc = 2396156 | doi = 10.1186/1471-2350-9-37 | url = | issn = }}</ref> [[Male contraceptive]]s utilizing sex hormones approach the problem in a similar way.
| | * '''[[Anterior pituitary gland]]''': Responds to GnRH by secreting two key hormones: |
| | ** [[Luteinizing hormone]] (LH) |
| | ** [[Follicle-stimulating hormone]] (FSH) |
| | * '''[[Gonads]]''': Includes ovaries (in females) and testes (in males), which respond to LH and FSH by producing sex hormones: |
| | ** [[Estrogen]] and [[progesterone]] in females |
| | ** [[Testosterone]] in males |
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| The HPG axis can also be suppressed by [[GnRH antagonist]]s or continuous administration of [[GnRH agonist]], such as in the following applications | | == Physiological Roles == |
| *[[Breast cancer management#Ovarian suppression|Ovarian suppression]] as breast cancer management, to prevent the body's formation of estrogen which may stimulate breast cancer cells. This is generally done by continuous administration of [[GnRH agonist]].
| | The HPG axis controls numerous physiological processes, including: |
| *[[Controlled ovarian hyperstimulation#Ovulation suppression|Ovulation suppression]] as part of [[controlled ovarian hyperstimulation]] in [[in vitro fertilisation|''in vitro'' fertilization]], in order to prevent the spontaneous ovulation of ovarian follicles before they can be harvested.
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| ===Stimulation===
| | * Development of reproductive organs and secondary sexual characteristics |
| [[Ovulation induction]] is usually initially performed by giving an [[antiestrogen]] such as [[clomifene citrate]] or [[letrozole]] in order to decrease negative feedback on the pituitary gland, resulting in an increase in FSH with the aim of increasing [[folliculogenesis]]. It is the main initial medical treatment for [[anovulation]]. | | * Regulation of [[menstrual cycle]] and ovulation in females |
| | * [[Spermatogenesis]] and sexual behavior in males |
| | * Influence on immune function and systemic metabolic processes |
| | * Modulation of aging and overall endocrine health |
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| == Environment factors == | | == Hormonal Regulation == |
| | Hormonal regulation occurs through a tightly controlled feedback loop: |
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| Environment can have large impact on the HPG axis. One example is women with eating disorders suffer from oligomenorrhea and secondary amenorrhea. Starvation from anorexia nervosa or bulimia causes the HPG axis to deactivate causing women's ovarian and uterine cycles to stop. Stress, physical exercise, and weight loss have been correlated with oligomenorrhea and secondary amenorrhea.<ref name="pmid17230292">{{cite journal |vauthors=Wiksten-Almströmer M, Hirschberg AL, Hagenfeldt K | title = Menstrual disorders and associated factors among adolescent girls visiting a youth clinic | journal = Acta Obstet Gynecol Scand | volume = 86 | issue = 1 | pages = 65–72 | year = 2007 | pmid = 17230292 | doi = 10.1080/00016340601034970 | url = | issn = }}</ref> Similarly environmental factors can also affect men such as stress causing [[impotence]]. Prenatal exposure to alcohol can affect the hormones regulating fetal development resulting in foetal alcohol spectrum disorder.<ref name="pmid18266938">{{cite journal |vauthors=Weinberg J, Sliwowska JH, Lan N, Hellemans KG | title = Prenatal alcohol exposure: fetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome | journal = J. Neuroendocrinol. | volume = 20 | issue = 4 | pages = 470–88 |date=April 2008 | pmid = 18266938 | doi = 10.1111/j.1365-2826.2008.01669.x | url = | issn = }}</ref>
| | # The hypothalamus secretes GnRH. |
| | # GnRH stimulates the anterior pituitary to release LH and FSH. |
| | # LH and FSH stimulate the gonads to produce sex hormones (estrogen, progesterone, testosterone). |
| | # Rising levels of these sex hormones provide negative feedback to both the hypothalamus and pituitary, controlling further release of GnRH, LH, and FSH. |
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| == Comparative anatomy == | | == Clinical Significance == |
| | Abnormalities or disruptions in the HPG axis can result in: |
| | * Disorders of sexual development and fertility |
| | * Hormonal imbalances such as [[hypogonadism]] or precocious puberty |
| | * Menstrual irregularities and infertility |
| | * Systemic issues related to immune and metabolic dysfunction |
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| The HPG axis is highly conserved in the animal kingdom.<ref name="pmid19084529">{{cite journal |vauthors=Sower SA, Freamat M, Kavanaugh SI | title = The origins of the vertebrate hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-thyroid (HPT) endocrine systems: new insights from lampreys | journal = Gen. Comp. Endocrinol. | volume = 161 | issue = 1 | pages = 20–9 |date=March 2009 | pmid = 19084529 | doi = 10.1016/j.ygcen.2008.11.023 | url = | issn = }}</ref> While reproductive patterns may vary, the physical components and control mechanisms remain the same. The same hormones are used with some minor evolutionary modifications. Much of the research is done on animal models, because they mimic so well the control mechanism of humans. It is important to remember humans are the only species to hide their fertile period, but this effect is a difference in the effect of the hormones rather than a difference in the HPG axis.
| | Understanding the HPG axis is essential in clinical fields including [[endocrinology]], reproductive medicine, and developmental biology. |
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| == See also == | | == See also == |
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