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{{protein | Name = Luteinizing hormone beta polypeptide| caption = LH (green line) surges at ovulation | image = Estradiol Cycle.jpg | width = 300 | HGNCid = 6584 | Symbol = LHB | AltSymbols = | EntrezGene = 3972 | OMIM = 152780 | RefSeq = NM_000894 | UniProt = P01229 | PDB = | ECnumber = | Chromosome = 19 | Arm = q | Band = 13.3 | LocusSupplementaryData =  }}
{{infobox protein
{{SI}}
| Name = [[Chorionic gonadotropin alpha]]
{{CMG}}
| caption =
| image =
| width =
| HGNCid = 1885
| Symbol = [[Chorionic gonadotropin alpha|CGA]]
| AltSymbols = HCG, GPHa, GPHA1
| EntrezGene = 1081
| OMIM = 118850
| RefSeq = NM_000735
| UniProt = P01215
| PDB =
| ECnumber =
| Chromosome = 6
| Arm = q
| Band = 14
| LocusSupplementaryData = -q21
}}
{{infobox protein
| Name = [[Luteinizing hormone beta polypeptide]]
| caption =  
| image =
| width = 500
| HGNCid = 6584
| Symbol = [[Luteinizing hormone beta polypeptide|LHB]]
| AltSymbols =  
| EntrezGene = 3972
| OMIM = 152780
| RefSeq = NM_000894
| UniProt = P01229
| PDB =  
| ECnumber =  
| Chromosome = 19
| Arm = q
| Band = 13.3  
| LocusSupplementaryData =   
}}
'''Luteinizing hormone''' ('''LH''', also known as '''lutropin''' and sometimes '''lutrophin'''<ref>{{cite journal | vauthors = Ujihara M, Yamamoto K, Nomura K, Toyoshima S, Demura H, Nakamura Y, Ohmura K, Osawa T | title = Subunit-specific sulphation of oligosaccharides relating to charge-heterogeneity in porcine lutrophin isoforms | journal = Glycobiology | volume = 2 | issue = 3 | pages = 225–31 | date = June 1992 | pmid = 1498420 | doi = 10.1093/glycob/2.3.225 }}</ref>) is a [[hormone]] produced by [[gonadotropic cell]]s in the [[anterior pituitary gland]]. In females, an acute rise of LH ("'''LH surge'''") triggers [[ovulation]]<ref name="Georgia">{{GeorgiaPhysiology|5/5ch9/s5ch9_5}}</ref> and development of the [[corpus luteum]]. In males, where LH had also been called '''interstitial cell–stimulating hormone''' ('''ICSH'''),<ref>{{cite journal | vauthors = Louvet JP, Harman SM, Ross GT | title = Effects of human chorionic gonadotropin, human interstitial cell stimulating hormone and human follicle-stimulating hormone on ovarian weights in estrogen-primed hypophysectomized immature female rats | journal = Endocrinology | volume = 96 | issue = 5 | pages = 1179–86 | date = May 1975 | pmid = 1122882 | doi = 10.1210/endo-96-5-1179 }}</ref> it stimulates [[Leydig cell]] production of [[testosterone]].<ref name="Georgia" /> It acts synergistically with [[Follicle-stimulating hormone|FSH]].


==Overview==
== Structure ==
'''Luteinizing hormone''' ('''LH''', also known as '''lutropin'''<ref>{{eMedicineDictionary|lutropin}}</ref>) is a [[hormone]] synthesized and secreted by [[gonadotrope]]s in the [[anterior pituitary|anterior lobe]] of the [[pituitary gland]].<ref name="Colorado">[http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/lhfsh.html Gonadotropins: Luteinizing and Follicle Stimulating Hormones at colostate.edu]</ref> In concert with the other pituitary gonadotropin [[follicle stimulating hormone]] ([[Follicle-stimulating hormone|FSH]]) it is necessary for proper [[reproduction|reproductive]] function:


* In the ''female'', an acute rise of LH – the ''LH surge'' – triggers [[ovulation]]. <ref>{{GeorgiaPhysiology|5/5ch9/s5ch9_5}}</ref>
LH is a hetero[[protein dimer|dimer]]ic [[glycoprotein]]. Each [[monomer]]ic unit is a  [[glycoprotein]] molecule; one alpha and one beta subunit make the full, functional protein.


* In the ''male'', where LH had also been called '''Interstitial Cell Stimulating Hormone''' ('''ICSH'''),<ref>{{cite journal |author=Louvet J, Harman S, Ross G |title=Effects of human chorionic gonadotropin, human interstitial cell stimulating hormone and human follicle-stimulating hormone on ovarian weights in estrogen-primed hypophysectomized immature female rats |journal=Endocrinology |volume=96 |issue=5 |pages=1179-86 |year=1975 |pmid=1122882}}</ref> it stimulates [[Leydig cell]] production of [[testosterone]]. <ref>{{GeorgiaPhysiology|5/5ch8/s5ch8_5}}</ref>
Its structure is similar to that of the other glycoprotein hormones, [[follicle-stimulating hormone]] (FSH), [[thyroid-stimulating hormone]] (TSH), and [[human chorionic gonadotropin]] (hCG). The protein dimer contains 2 glycopeptidic subunits, labeled alpha and beta subunits, that are non-covalently associated (i.e., without any disulfide bridge linking them):<ref name="pmid24001578">{{cite journal | vauthors = Jiang X, Dias JA, He X | title = Structural biology of glycoprotein hormones and their receptors: insights to signaling | journal = Molecular and Cellular Endocrinology | volume = 382 | issue = 1 | pages = 424–51 | date = January 2014 | pmid = 24001578 | doi = 10.1016/j.mce.2013.08.021 }}</ref>


==Structure==
* The ''[[Alpha subunit of glycoprotein hormones|alpha subunits]]'' of LH, FSH, TSH, and hCG are identical, and contain 92 [[amino acids]] in human but 96 [[amino acids]] in almost all other vertebrate species (glycoprotein hormones do not exist in invertebrates).
LH  is a [[glycoprotein]]. Each monomeric unit is a [[protein]] molecule with a sugar attached to it; two of these make the full, functional protein.
* The ''beta subunits'' vary. LH has a beta subunit of 120 amino acids (LHB) that confers its specific biologic action and is responsible for the specificity of the interaction with the [[LH receptor]]. This beta subunit contains an amino acid sequence that exhibits large homologies with that of the beta subunit of [[Human chorionic gonadotropin|hCG]] and both stimulate the same receptor.  However, the hCG beta subunit contains an additional 24 amino acids, and the two hormones differ in the composition of their sugar moieties.


Its structure is similar to the other glycoproteins, [[follicle-stimulating hormone]] (FSH), [[thyroid-stimulating hormone]] (TSH), and [[human chorionic gonadotropin]] (hCG). The protein dimer contains 2 [[polypeptide]] units, labeled alpha and beta subunits that are connected by two [[disulfide bridge]]s:
The different composition of these [[oligosaccharide]]s affects bioactivity and speed of degradation. The biologic [[half-life]] of LH is 20 minutes, shorter than that of  FSH (3–4 hours) and hCG (24 hours).{{Citation needed|date=November 2008}}


* The ''[[Alpha subunit of glycoprotein hormones|alpha subunits]]'' of LH, FSH, TSH, and hCG are identical, and contain 92 [[amino acids]].
== Genes ==


* The ''beta subunits'' vary. LH has a beta subunit of  121 amino acids (LHB) that confers its specific biologic action and is responsible for interaction with the [[LH receptor]]. This beta subunit contains the same amino acids in sequence as the beta sub unit of [[Human chorionic gonadotropin|hCG]] and both stimulate the same receptor, however, the hCG beta subunit contains an additional 24 amino acids, and both hormones differ in the composition of their sugar moieties.  
The [[gene]] for the ''alpha subunit'' is located on [[chromosome 6]]q12.21.


The different composition of these [[oligosaccharide]]s affects bioactivity and speed of degradation. The biologic [[half-life]] of LH is 20 minutes, shorter than that of FSH (3-4 hours) or hCG (24 hours).<sup>[citation needed]</sup>
The luteinizing hormone ''beta subunit'' gene is localized in the LHB/CGB gene cluster on [[chromosome 19]]q13.32. In contrast to the alpha gene activity, beta LH subunit gene activity is restricted to the pituitary gonadotropic cells. It is regulated by the [[gonadotropin-releasing hormone]] from the [[hypothalamus]]. [[Inhibin]], [[activin]], and [[sex hormone]]s do not affect genetic activity  for the beta subunit production of LH.


==Genes==
== Function ==
The [[gene]] for the ''alpha subunit'' is located on [[chromosome 6]]q12.21.
[[File:Figure 28 03 01.jpg|thumb|Effects of LH on the body|500px]]


The luteinizing hormone ''beta subunit'' gene is localized in the LHB/CGB gene cluster on [[chromosome 19]]q13.32. In contrast to the alpha gene activity, beta LH subunit gene activity is restricted to the pituitary gonadotropic cells. It is regulated by the [[gonadotropin releasing hormone]] from the  [[hypothalamus]]. [[Inhibin]], [[activin]], and [[sex hormone]]s do not affect genetic activity  for the beta subunit production of LH.
In females: ovulation, maintaining of corpus luteum and secretion of progesterone.  


==Activity==
In males: testosterone secretion.  
In both males and females, LH is essential for reproduction.  


* In ''females'', at the time of menstruation, FSH initiates follicular growth, specifically affecting [[granulosa cell]]s.<ref name="Colorado"> </ref> With the rise in estrogens, LH  receptors are also expressed on the maturing follicle that produces an increasing amount of [[estradiol]]. Eventually at the time of the maturation of the follicle, the estrogen rise leads via the hypothalamic interface to the “positive feed-back” effect,  a release of LH  over a 24-48 hour period. This 'LH surge' triggers [[ovulation]] hereby not only releasing the egg, but also initiating the conversion of the residual follicle into a [[corpus luteum]] that, in turn, produces [[progesterone]] to prepare the [[endometrium]] for a possible [[implantation]]. LH is necessary to maintain luteal function for the first two weeks. In case of a [[pregnancy]] luteal function will be further maintained by the action of hCG from the newly established pregnancy. LH supports [[thecal cell]]s in the ovary that provide [[androgen]]s and hormonal precursors for estradiol production.
===Effects in females===


* In the male, LH acts upon the Leydig cell of the [[testis]] and is responsible for the production of [[testosterone]], the “male hormone” that exerts both endocrine activity and intratesticular activity such as [[spermatogenesis]].
LH supports [[theca cell]]s in the ovaries that provide [[androgen]]s and hormonal precursors for [[estradiol]] production. At the time of [[menstruation]], FSH initiates [[Ovarian follicle|follicular]] growth, specifically affecting [[granulosa cell]]s.<ref name="Colorado">{{cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/lhfsh.html|title=Gonadotropins: Luteinizing and Follicle Stimulating Hormones|last=Bowen|first=R.|date=13 May 2004|publisher=Colorado State University|accessdate=12 March 2012}}</ref> With the rise in [[oestrogen|estrogen]]s, LH receptors are also expressed on the maturing follicle, which causes it to produce more [[estradiol]]. Eventually, when the follicle has fully matured, a spike in [[17α-hydroxyprogesterone]] production by the follicle inhibits the production of [[oestrogen|estrogen]]s, leading to a decrease in estrogen-mediated [[negative feedback]] of [[GnRH]] in the [[hypothalamus]], which then stimulates the release of LH from the [[anterior pituitary]].<ref>{{cite journal | vauthors = Mahesh VB | title = Hirsutism, virilism, polycystic ovarian disease, and the steroid-gonadotropin-feedback system: a career retrospective | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 302 | issue = 1 | pages = E4-E18 | date = January 2012 | pmid = 22028409 | pmc = 3328092 | doi = 10.1152/ajpendo.00488.2011 }}</ref> However another theory of the LH peak is a positive feedback mechanism from [[estradiol]]. The levels keep rising through the follicular phase and when they reach an unknown threshold, this results in the peak of the LH.<ref>Guyton and Hall Textbook of Medical Physiology 2006 page 1021</ref> This effect is opposite from the usual negative feedback mechanism presented at lower levels. In other words, the mechanism(s) are not yet clear.
The increase in LH production only lasts for 24 to 48 hours. This "LH surge" triggers [[ovulation]], thereby not only releasing the egg from the follicle, but also initiating the conversion of the residual follicle into a [[corpus luteum]] that, in turn, produces [[progesterone]] to prepare the [[endometrium]] for a possible [[Implantation (human embryo)|implantation]]. LH is necessary to maintain luteal function for the second two weeks of the menstrual cycle. If [[pregnancy]] occurs, LH levels will decrease, and luteal function will instead be maintained by the action of hCG ([[human chorionic gonadotropin]]), a hormone very similar to LH but secreted from the new placenta.


The release of LH at the pituitary gland is controlled by pulses of [[gonadotropin-releasing hormone]] (GnRH) from the hypothalamus. Those pulses, in turn, are subject to the estrogen feedback from the gonads.
===Effects in males ===
LH acts upon the [[Leydig cells]] of the [[testis]] and is regulated by [[GnRH | gonadotropin-releasing hormone]] (GnRH).<ref name="fert">{{cite web|url=http://www.testosteronetherapy.com/low_testosterone_treatment/male-fertility-treatment-hcg-lh-recombinant-fsh.html |title=Male Medical Fertility Treatment: HCG + LH + Recombinant FSH To Increase Sperm Count Through Spermatogenisis |accessdate=6 April 2015 |deadurl=yes |archiveurl=https://web.archive.org/web/20150219164931/http://www.testosteronetherapy.com/low_testosterone_treatment/male-fertility-treatment-hcg-lh-recombinant-fsh.html |archivedate=February 19, 2015 }}{{MEDRS|date=May 2015}}</ref> The Leydig cells produce [[testosterone]] (T) under the control of LH, which regulates the expression of the enzyme [[17β-hydroxysteroid dehydrogenase]] that is used to convert androstenedione, the hormone produced by the testes, to testosterone,<ref name="onset">{{cite web | url = https://www.boundless.com/biology/mammalian-reproduction/hormones-in-the-male-reproductive-system/role-of-hormones-in-controlling-male-reproductive-system/ |title=The onset of puberty is controlled by two major hormones: FSH initiates spermatogenesis and LH signals the release of testosterone. |accessdate=6 April 2015}}{{MEDRS|date=May 2015}}</ref> an [[androgen]] that exerts both endocrine activity and intratesticular activity on [[spermatogenesis]].


==Normal levels==
LH is released from the pituitary gland, and is controlled by pulses of [[GnRH | gonadotropin-releasing hormone]]. When T levels are low, GnRH is released by the [[hypothalamus]], stimulating the pituitary gland to release LH.<ref name="fert"/> As the levels of T increase, it will act on the hypothalamus and pituitary through a negative feedback loop and inhibit the release of GnRH and LH consequently.<ref name="onset"/> Androgens (T, DHT) inhibit monoamine oxidase (MAO) in pineal, leading to increased melatonin and reduced LH and FSH by melatonin-induced increase of GnIH synthesis and secretion. T can also be aromatized into [[estradiol]] (E2) to inhibit LH. E2 decreases pulse amplitude and responsiveness to GnRH from the hypothalamus onto the pituitary.<ref name="Pitteloud">{{cite journal | vauthors = Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF, Hayes FJ | title = Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 93 | issue = 3 | pages = 784–91 | date = March 2008 | pmid = 18073301 | pmc = 2266963 | doi = 10.1210/jc.2007-2156 }}</ref>
LH levels are normally low during childhood and, in women, high after [[menopause]].  


During the reproductive years typical levels are  between 5-20 mIU/ml.  
Gonadal steroids ([[oestrogen|estrogen]]s and androgens) generally have negative feedback effects on GnRH-1 release at the level of the hypothalamus and at the gonadotropes, reducing their sensitivity to GnRH. Positive feedback by estrogens also occurs in the gonadal axis of female mammals and is responsible for the midcycle surge of LH that stimulates ovulation. Although estrogens inhibit [[kisspeptin]] (Kp) release from kiss1 neurons in the ARC, estrogens stimulate Kp release from the Kp neurons in the AVPV. As estrogens' levels gradually increase the positive effect predominates, leading to the LH surge. [[gamma-Aminobutyric acid|GABA]]-secreting neurons that innervate GnRH-1 neurons also can stimulate GnRH-1 release. These GABA neurons also possess ERs and may be responsible for the GnRH-1 surge. Part of the inhibitory action of endorphins on GnRH-1 release is through inhibition of these GABA neurons. Rupture of the ovarian follicle at ovulation causes a drastic reduction in estrogen synthesis and a marked increase in secretion of progesterone by the corpus luteum in the ovary, reinstating a predominantly negative feedback on hypothalamic secretion of GnRH-1.<ref>{{cite book |last1=Norris |first1=David O. |last2=Carr |first2=James A. |date=2013 |title=Vertebrate Endocrinology |url=https://books.google.com/books?id=F_NaW1ZcSSAC&printsec=frontcover#v=onepage&q&f=false |publisher=Academic Press |location= |page=126 |isbn=978-0-12-396465-6 | name-list-format = vanc }}</ref>


Physiologic high LH levels are seen during the LH surge (v.s.); typically they last 48 hours.
Changes in LH and testosterone (T) blood levels and pulse secretions are induced by changes in [[sexual arousal]] in human males.<ref name="Stoleru">{{cite journal | vauthors = Stoléru SG, Ennaji A, Cournot A, Spira A | title = LH pulsatile secretion and testosterone blood levels are influenced by sexual arousal in human males | journal = Psychoneuroendocrinology | volume = 18 | issue = 3 | pages = 205–18 | year = 1993 | pmid = 8516424 | doi = 10.1016/0306-4530(93)90005-6 }}</ref>


[[Image:ovulatietest.jpg|thumb|left]]
== Normal levels ==


==Ovulation predictor kit (LH kit)==
[[File:Luteinizing hormone (LH) during menstrual cycle.png|thumb|450px|[[Reference ranges for blood tests|Reference ranges for the blood content]] of luteinizing hormone (LH) during the [[menstrual cycle]].<ref name="Häggström2014">{{cite journal|last1=Häggström|first1=Mikael|title=Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle|journal=WikiJournal of Medicine|volume=1|issue=1|year=2014|issn=2002-4436|doi=10.15347/wjm/2014.001}}</ref>
The detection of the LH surge has become useful for people who want to know when ovulation occurs. LH can be detected by urinary ovulation predictor kits (OPK, also LH-kit) that are performed daily around the time ovulation may be expected.<ref>{{cite journal |author=Nielsen M, Barton S, Hatasaka H, Stanford J |title=Comparison of several one-step home urinary luteinizing hormone detection test kits to OvuQuick |journal=Fertil Steril |volume=76 |issue=2 |pages=384-7 |year=2001 |pmid=11476792}}</ref> The conversion from a negative to a positive reading would suggest that ovulation is about to occur within 24-48 hours. Couples who plan to [[Conceive a child|conceive]] would time intercourse accordingly.<ref>[http://www.pinelandpress.com/faq/opk.html Ovulation Predictor Kit information at pinelandpress.com]</ref>
{{bulleted list|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.}}]]


As sperm can stay viable in the woman for several days, such tests are not recommended for [[contraceptive]] practices.
LH levels are normally low during [[childhood]] and, in women, high after [[menopause]]. As LH is secreted as pulses, it is necessary to follow its concentration over a sufficient period of time to get proper information about its blood level.


==Disease states==
During the reproductive years, typical levels are  between 1–20 IU/L. Physiologic high LH levels are seen during the LH surge (v.s.); typically they last 48 hours.
=== Relative elevations ===
 
In males over 18 years of age, reference ranges have been estimated to be 1.8–8.6 IU/L.<ref>[http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/8663 Mayo Medical Laboratories - Test ID: LH, Luteinizing Hormone (LH), Serum], retrieved December 2012</ref>
 
LH is measured in [[International Units|international units]] (IU). When quantifying the amount of LH in a sample in IUs, it is important to know which international standard your lot of LH was calibrated against, as they can vary broadly from year to year.  For human urinary LH, one IU is most recently defined as 1/189th of an ampule denoted 96/602 and distributed by the [[NIBSC]], corresponding to approximately 0.04656µg of LH protein for a single IU, but older standard versions are still widely in use.<ref>[http://apps.who.int/iris/bitstream/10665/68388/1/WHO_BS_03.1983.pdf World Health Organization Proposed International Standard for Luteinizing Hormone.] WHO Expert Committee on Biological Standardization. [[World Health Organization]]. Geneva. 2003.</ref><ref>[http://www.nibsc.org/documents/ifu/96-602.pdf WHO International Standard, Luteinizing Hormone, Human, Recombinant.] National Institute for Biological Standards and Control.</ref>
 
[[Image:ovulatietest.jpg|thumb]]
 
== Predicting ovulation ==
 
The detection of a surge in release of luteinizing hormone indicates impending [[ovulation]]. LH can be detected by [[urinary]] ovulation predictor kits (OPK, also LH-kit) that are performed, typically daily, around the time ovulation may be expected.<ref>{{cite journal | vauthors = Nielsen MS, Barton SD, Hatasaka HH, Stanford JB | title = Comparison of several one-step home urinary luteinizing hormone detection test kits to OvuQuick | journal = Fertility and Sterility | volume = 76 | issue = 2 | pages = 384–7 | date = August 2001 | pmid = 11476792 | doi = 10.1016/S0015-0282(01)01881-7 }}</ref>  A conversion from a negative to a positive reading would suggest that ovulation is about to occur within 24–48 hours, giving women two days to engage in [[sexual intercourse]] or [[artificial insemination]] with the intention of [[conceiving]].<ref>{{cite web|url=http://www.pinelandpress.com/faq/opk.html |title=Ovulation Predictor Kit Frequently Asked Questions |publisher=Fertility Plus |accessdate=12 March 2012 |deadurl=yes |archiveurl=https://web.archive.org/web/20120312021506/http://www.pinelandpress.com/faq/opk.html |archivedate=March 12, 2012 }}{{MEDRS|date=May 2015}}</ref>
 
Tests may be read manually using a colour-change paper strip, or digitally with the assistance of reading electronics.
 
Tests for luteinising hormone may be combined with testing for [[estradiol]] in tests such as the Clearblue [[fertility monitor]].<ref>{{cite web|url=http://opregnancy.com/how-to-get-pregnant/ |title=How to Get Pregnant |year=2009 |publisher=OPregnancy.com |accessdate=12 March 2012 |deadurl=yes |archiveurl=https://web.archive.org/web/20120312065154/http://opregnancy.com/how-to-get-pregnant/ |archivedate=March 12, 2012 }}{{MEDRS|date=May 2015}}</ref>
 
The sensitivity of LH tests are measured in [[milli international unit]], with tests commonly available in the range 10–40 m.i.u. (the lower the number, the higher the sensitivity).{{Citation needed|date=August 2009}}
 
As sperm can stay viable in the woman for several days, LH tests are not recommended for [[contraceptive]] practices, as the LH surge typically occurs after the beginning of the fertile window.
 
== Disease states ==
 
=== Excess ===


In children with [[precocious puberty]] of pituitary or central origin, LH and FSH levels may be in the reproductive range instead of the low levels typical for their age.
In children with [[precocious puberty]] of pituitary or central origin, LH and FSH levels may be in the reproductive range instead of the low levels typical for their age.


During the reproductive years, relatively elevated LH is frequently seen in patients with the [[polycystic ovary syndrome]]; however it would be unusual for them to have LH levels outside of the normal reproductive range.
During the reproductive years, relatively elevated LH is frequently seen in patients with [[polycystic ovary syndrome]]; however, it would be unusual for them to have LH levels outside of the normal reproductive range.


===High LH levels===
Persistently high LH levels are indicative of situations where the normal restricting feedback from the gonad is absent, leading to a pituitary production of  both LH and FSH. While this is typical in menopause, it is abnormal in the reproductive years. There it may be a sign of:
Persistently high LH levels are indicative of situations where the normal restricting feedback from the gonad is absent, leading to an unrestricted pituitary production of  both LH and FSH. While this is typical in the menopause, it is abnormal in the reproductive years. There it may be a sign of:
# [[Premature menopause]]
# [[Premature menopause]]
# [[Gonadal dysgenesis]], [[Turner syndrome]]
# [[Gonadal dysgenesis]], [[Turner syndrome]]
# [[Castration]]
# [[Castration]]
# [[Swyer syndrome]]
# [[Swyer syndrome]]
# Certain forms of [[CAH]]
# [[Polycystic ovary syndrome]]
# Testicular failure
# Certain forms of [[congenital adrenal hyperplasia]]
# [[Hypergonadotropic hypogonadism|Testicular failure]]
# Pregnancy - BetaHCG can mimic LH so tests may show elevated LH
 
Note: A medical drug for inhibiting luteinizing hormone secretion is [[Butinazocine]].<ref>{{US patent|4406904}}</ref>
 
=== Deficiency ===


=== Deficient LH activity ===
Diminished secretion of LH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. In females, [[amenorrhea]]  is commonly observed. Conditions with very low LH secretions include:
Diminished secretion of LH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. In females, [[amenorrhea]]  is commonly observed.
# [[Fertile eunuch syndrome|Pasqualini syndrome]]<ref>{{cite journal | vauthors = Weiss J, Axelrod L, Whitcomb RW, Harris PE, Crowley WF, Jameson JL | title = Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone | journal = The New England Journal of Medicine | volume = 326 | issue = 3 | pages = 179–83 | date = January 1992 | pmid = 1727547 | doi = 10.1056/NEJM199201163260306 }}</ref><ref>{{cite journal | vauthors = Valdes-Socin H, Salvi R, Daly AF, Gaillard RC, Quatresooz P, Tebeu PM, Pralong FP, Beckers A | title = Hypogonadism in a patient with a mutation in the luteinizing hormone beta-subunit gene | journal = The New England Journal of Medicine | volume = 351 | issue = 25 | pages = 2619–25 | date = December 2004 | pmid = 15602022 | doi = 10.1056/NEJMoa040326 }}</ref><ref>{{cite journal | vauthors = Valdes-Socin H, Daly AF, Beckers A | title = Luteinizing Hormone Deficiency: Historical Views and Future Perspectives. | journal = Austin Andrology | date = 2017 | volume = 2 | issue = 1 | pages = 1015 | url = http://austinpublishinggroup.com/andrology/download.php?file=fulltext/andrology-v2-id1015.pdf }}</ref>
Conditions with very low LH secretions are:
# [[Kallmann syndrome]]
# [[Kallmann syndrome]]
# [[Hypothalamic suppression]]
# [[Hypothalamic suppression]]
# [[Hypopituitarism]]
# [[Hypopituitarism]]
# [[Eating disorder]]
# [[Eating disorder]]
# [[Female athlete triad]]
# [[Hyperprolactinemia]]
# [[Hyperprolactinemia]]
# [[Gonadotropin deficiency]]
# [[Hypogonadism]]
# Gonadal suppression therapy  
# Gonadal suppression therapy  
##[[GnRH antagonist]]
##[[GnRH antagonist]]
##[[GnRH agonist]] ([[downregulation]])
##[[GnRH agonist]] (inducing an initial stimulation (flare up) followed by permanent blockage of the GnRH pituitary receptor)
 
== As a medication ==
 
LH  is available mixed with FSH in the form of [[menotropin]], and other forms of urinary [[gonadotropins]]. More purified forms of urinary gonadotropins may reduce the LH portion in relation to FSH. Recombinant LH is available as lutropin alfa (Luveris).<ref>[http://www.fertilitylifelines.com/serono/products/luveris/index.jsp Luveris information]{{MEDRS|date=May 2015}} {{webarchive |url=https://web.archive.org/web/20060618151316/http://www.fertilitylifelines.com/serono/products/luveris/index.jsp |date=June 18, 2006 }}</ref>  All these medications have to be given parenterally. They are commonly used in infertility therapy to stimulate follicular development, the notable one being in [[IVF]] therapy.


==Availability==
Often, HCG medication is used as an LH substitute because it activates the same receptor. Medically used hCG is derived from urine of pregnant women, is less costly, and has a longer half-life than LH.
LH is available mixed with FSH in the form of [[Pergonal]], and other forms of urinary [[gonadotropins]] . More purified forms of urinary gonadotropins may reduce the LH portion in relation to FSH. Recombinant LH is available as lutropin alfa (Luveris®).<ref>[http://www.fertilitylifelines.com/serono/products/luveris/index.jsp Luveris information]</ref> All these medications have to be given parenterally. They are commonly in infertility therapy to stimulate follicular development, notably in [[IVF]] therapy.


Often, hCG medication is used as an LH substitute as it activates the same receptor. Medically used hCG is derived from urine of pregnant women, less costly, and has a longer half-life than LH.
== References ==
{{reflist|33em}}


==References==
== External links ==
{{reflist|2}}
* {{MeshName|Luteinizing+Hormone}}


{{Gonadotropins and GnRH}}
{{Hormones}}
{{Hormones}}
{{Peptidergics}}


{{DEFAULTSORT:Luteinizing Hormone}}
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Revision as of 07:03, 25 August 2017

Chorionic gonadotropin alpha
Identifiers
SymbolCGA
Alt. symbolsHCG, GPHa, GPHA1
Entrez1081
HUGO1885
OMIM118850
RefSeqNM_000735
UniProtP01215
Other data
LocusChr. 6 q14-q21
Luteinizing hormone beta polypeptide
Identifiers
SymbolLHB
Entrez3972
HUGO6584
OMIM152780
RefSeqNM_000894
UniProtP01229
Other data
LocusChr. 19 q13.3

Luteinizing hormone (LH, also known as lutropin and sometimes lutrophin[1]) is a hormone produced by gonadotropic cells in the anterior pituitary gland. In females, an acute rise of LH ("LH surge") triggers ovulation[2] and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH),[3] it stimulates Leydig cell production of testosterone.[2] It acts synergistically with FSH.

Structure

LH is a heterodimeric glycoprotein. Each monomeric unit is a glycoprotein molecule; one alpha and one beta subunit make the full, functional protein.

Its structure is similar to that of the other glycoprotein hormones, follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG). The protein dimer contains 2 glycopeptidic subunits, labeled alpha and beta subunits, that are non-covalently associated (i.e., without any disulfide bridge linking them):[4]

  • The alpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92 amino acids in human but 96 amino acids in almost all other vertebrate species (glycoprotein hormones do not exist in invertebrates).
  • The beta subunits vary. LH has a beta subunit of 120 amino acids (LHB) that confers its specific biologic action and is responsible for the specificity of the interaction with the LH receptor. This beta subunit contains an amino acid sequence that exhibits large homologies with that of the beta subunit of hCG and both stimulate the same receptor. However, the hCG beta subunit contains an additional 24 amino acids, and the two hormones differ in the composition of their sugar moieties.

The different composition of these oligosaccharides affects bioactivity and speed of degradation. The biologic half-life of LH is 20 minutes, shorter than that of FSH (3–4 hours) and hCG (24 hours).[citation needed]

Genes

The gene for the alpha subunit is located on chromosome 6q12.21.

The luteinizing hormone beta subunit gene is localized in the LHB/CGB gene cluster on chromosome 19q13.32. In contrast to the alpha gene activity, beta LH subunit gene activity is restricted to the pituitary gonadotropic cells. It is regulated by the gonadotropin-releasing hormone from the hypothalamus. Inhibin, activin, and sex hormones do not affect genetic activity for the beta subunit production of LH.

Function

File:Figure 28 03 01.jpg
Effects of LH on the body

In females: ovulation, maintaining of corpus luteum and secretion of progesterone.

In males: testosterone secretion.

Effects in females

LH supports theca cells in the ovaries that provide androgens and hormonal precursors for estradiol production. At the time of menstruation, FSH initiates follicular growth, specifically affecting granulosa cells.[5] With the rise in estrogens, LH receptors are also expressed on the maturing follicle, which causes it to produce more estradiol. Eventually, when the follicle has fully matured, a spike in 17α-hydroxyprogesterone production by the follicle inhibits the production of estrogens, leading to a decrease in estrogen-mediated negative feedback of GnRH in the hypothalamus, which then stimulates the release of LH from the anterior pituitary.[6] However another theory of the LH peak is a positive feedback mechanism from estradiol. The levels keep rising through the follicular phase and when they reach an unknown threshold, this results in the peak of the LH.[7] This effect is opposite from the usual negative feedback mechanism presented at lower levels. In other words, the mechanism(s) are not yet clear. The increase in LH production only lasts for 24 to 48 hours. This "LH surge" triggers ovulation, thereby not only releasing the egg from the follicle, but also initiating the conversion of the residual follicle into a corpus luteum that, in turn, produces progesterone to prepare the endometrium for a possible implantation. LH is necessary to maintain luteal function for the second two weeks of the menstrual cycle. If pregnancy occurs, LH levels will decrease, and luteal function will instead be maintained by the action of hCG (human chorionic gonadotropin), a hormone very similar to LH but secreted from the new placenta.

Effects in males

LH acts upon the Leydig cells of the testis and is regulated by gonadotropin-releasing hormone (GnRH).[8] The Leydig cells produce testosterone (T) under the control of LH, which regulates the expression of the enzyme 17β-hydroxysteroid dehydrogenase that is used to convert androstenedione, the hormone produced by the testes, to testosterone,[9] an androgen that exerts both endocrine activity and intratesticular activity on spermatogenesis.

LH is released from the pituitary gland, and is controlled by pulses of gonadotropin-releasing hormone. When T levels are low, GnRH is released by the hypothalamus, stimulating the pituitary gland to release LH.[8] As the levels of T increase, it will act on the hypothalamus and pituitary through a negative feedback loop and inhibit the release of GnRH and LH consequently.[9] Androgens (T, DHT) inhibit monoamine oxidase (MAO) in pineal, leading to increased melatonin and reduced LH and FSH by melatonin-induced increase of GnIH synthesis and secretion. T can also be aromatized into estradiol (E2) to inhibit LH. E2 decreases pulse amplitude and responsiveness to GnRH from the hypothalamus onto the pituitary.[10]

Gonadal steroids (estrogens and androgens) generally have negative feedback effects on GnRH-1 release at the level of the hypothalamus and at the gonadotropes, reducing their sensitivity to GnRH. Positive feedback by estrogens also occurs in the gonadal axis of female mammals and is responsible for the midcycle surge of LH that stimulates ovulation. Although estrogens inhibit kisspeptin (Kp) release from kiss1 neurons in the ARC, estrogens stimulate Kp release from the Kp neurons in the AVPV. As estrogens' levels gradually increase the positive effect predominates, leading to the LH surge. GABA-secreting neurons that innervate GnRH-1 neurons also can stimulate GnRH-1 release. These GABA neurons also possess ERs and may be responsible for the GnRH-1 surge. Part of the inhibitory action of endorphins on GnRH-1 release is through inhibition of these GABA neurons. Rupture of the ovarian follicle at ovulation causes a drastic reduction in estrogen synthesis and a marked increase in secretion of progesterone by the corpus luteum in the ovary, reinstating a predominantly negative feedback on hypothalamic secretion of GnRH-1.[11]

Changes in LH and testosterone (T) blood levels and pulse secretions are induced by changes in sexual arousal in human males.[12]

Normal levels

File:Luteinizing hormone (LH) during menstrual cycle.png
Reference ranges for the blood content of luteinizing hormone (LH) during the menstrual cycle.[13]
  • 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.

LH levels are normally low during childhood and, in women, high after menopause. As LH is secreted as pulses, it is necessary to follow its concentration over a sufficient period of time to get proper information about its blood level.

During the reproductive years, typical levels are between 1–20 IU/L. Physiologic high LH levels are seen during the LH surge (v.s.); typically they last 48 hours.

In males over 18 years of age, reference ranges have been estimated to be 1.8–8.6 IU/L.[14]

LH is measured in international units (IU). When quantifying the amount of LH in a sample in IUs, it is important to know which international standard your lot of LH was calibrated against, as they can vary broadly from year to year. For human urinary LH, one IU is most recently defined as 1/189th of an ampule denoted 96/602 and distributed by the NIBSC, corresponding to approximately 0.04656µg of LH protein for a single IU, but older standard versions are still widely in use.[15][16]

Predicting ovulation

The detection of a surge in release of luteinizing hormone indicates impending ovulation. LH can be detected by urinary ovulation predictor kits (OPK, also LH-kit) that are performed, typically daily, around the time ovulation may be expected.[17] A conversion from a negative to a positive reading would suggest that ovulation is about to occur within 24–48 hours, giving women two days to engage in sexual intercourse or artificial insemination with the intention of conceiving.[18]

Tests may be read manually using a colour-change paper strip, or digitally with the assistance of reading electronics.

Tests for luteinising hormone may be combined with testing for estradiol in tests such as the Clearblue fertility monitor.[19]

The sensitivity of LH tests are measured in milli international unit, with tests commonly available in the range 10–40 m.i.u. (the lower the number, the higher the sensitivity).[citation needed]

As sperm can stay viable in the woman for several days, LH tests are not recommended for contraceptive practices, as the LH surge typically occurs after the beginning of the fertile window.

Disease states

Excess

In children with precocious puberty of pituitary or central origin, LH and FSH levels may be in the reproductive range instead of the low levels typical for their age.

During the reproductive years, relatively elevated LH is frequently seen in patients with polycystic ovary syndrome; however, it would be unusual for them to have LH levels outside of the normal reproductive range.

Persistently high LH levels are indicative of situations where the normal restricting feedback from the gonad is absent, leading to a pituitary production of both LH and FSH. While this is typical in menopause, it is abnormal in the reproductive years. There it may be a sign of:

  1. Premature menopause
  2. Gonadal dysgenesis, Turner syndrome
  3. Castration
  4. Swyer syndrome
  5. Polycystic ovary syndrome
  6. Certain forms of congenital adrenal hyperplasia
  7. Testicular failure
  8. Pregnancy - BetaHCG can mimic LH so tests may show elevated LH

Note: A medical drug for inhibiting luteinizing hormone secretion is Butinazocine.[20]

Deficiency

Diminished secretion of LH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. In females, amenorrhea is commonly observed. Conditions with very low LH secretions include:

  1. Pasqualini syndrome[21][22][23]
  2. Kallmann syndrome
  3. Hypothalamic suppression
  4. Hypopituitarism
  5. Eating disorder
  6. Female athlete triad
  7. Hyperprolactinemia
  8. Hypogonadism
  9. Gonadal suppression therapy
    1. GnRH antagonist
    2. GnRH agonist (inducing an initial stimulation (flare up) followed by permanent blockage of the GnRH pituitary receptor)

As a medication

LH is available mixed with FSH in the form of menotropin, and other forms of urinary gonadotropins. More purified forms of urinary gonadotropins may reduce the LH portion in relation to FSH. Recombinant LH is available as lutropin alfa (Luveris).[24] All these medications have to be given parenterally. They are commonly used in infertility therapy to stimulate follicular development, the notable one being in IVF therapy.

Often, HCG medication is used as an LH substitute because it activates the same receptor. Medically used hCG is derived from urine of pregnant women, is less costly, and has a longer half-life than LH.

References

  1. ↑ Ujihara M, Yamamoto K, Nomura K, Toyoshima S, Demura H, Nakamura Y, Ohmura K, Osawa T (June 1992). "Subunit-specific sulphation of oligosaccharides relating to charge-heterogeneity in porcine lutrophin isoforms". Glycobiology. 2 (3): 225–31. doi:10.1093/glycob/2.3.225. PMID 1498420.
  2. ↑ 2.0 2.1 Essentials of Human Physiology by Thomas M. Nosek. Section 5/5ch9/s5ch9_5.
  3. ↑ Louvet JP, Harman SM, Ross GT (May 1975). "Effects of human chorionic gonadotropin, human interstitial cell stimulating hormone and human follicle-stimulating hormone on ovarian weights in estrogen-primed hypophysectomized immature female rats". Endocrinology. 96 (5): 1179–86. doi:10.1210/endo-96-5-1179. PMID 1122882.
  4. ↑ Jiang X, Dias JA, He X (January 2014). "Structural biology of glycoprotein hormones and their receptors: insights to signaling". Molecular and Cellular Endocrinology. 382 (1): 424–51. doi:10.1016/j.mce.2013.08.021. PMID 24001578.
  5. ↑ Bowen, R. (13 May 2004). "Gonadotropins: Luteinizing and Follicle Stimulating Hormones". Colorado State University. Retrieved 12 March 2012.
  6. ↑ Mahesh VB (January 2012). "Hirsutism, virilism, polycystic ovarian disease, and the steroid-gonadotropin-feedback system: a career retrospective". American Journal of Physiology. Endocrinology and Metabolism. 302 (1): E4–E18. doi:10.1152/ajpendo.00488.2011. PMC 3328092. PMID 22028409.
  7. ↑ Guyton and Hall Textbook of Medical Physiology 2006 page 1021
  8. ↑ 8.0 8.1 "Male Medical Fertility Treatment: HCG + LH + Recombinant FSH To Increase Sperm Count Through Spermatogenisis". Archived from the original on February 19, 2015. Retrieved 6 April 2015.[unreliable medical source?]
  9. ↑ 9.0 9.1 "The onset of puberty is controlled by two major hormones: FSH initiates spermatogenesis and LH signals the release of testosterone". Retrieved 6 April 2015.[unreliable medical source?]
  10. ↑ Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF, Hayes FJ (March 2008). "Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men". The Journal of Clinical Endocrinology and Metabolism. 93 (3): 784–91. doi:10.1210/jc.2007-2156. PMC 2266963. PMID 18073301.
  11. ↑ Norris DO, Carr JA (2013). Vertebrate Endocrinology. Academic Press. p. 126. ISBN 978-0-12-396465-6.
  12. ↑ Stoléru SG, Ennaji A, Cournot A, Spira A (1993). "LH pulsatile secretion and testosterone blood levels are influenced by sexual arousal in human males". Psychoneuroendocrinology. 18 (3): 205–18. doi:10.1016/0306-4530(93)90005-6. PMID 8516424.
  13. ↑ Häggström, Mikael (2014). "Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle". WikiJournal of Medicine. 1 (1). doi:10.15347/wjm/2014.001. ISSN 2002-4436.
  14. ↑ Mayo Medical Laboratories - Test ID: LH, Luteinizing Hormone (LH), Serum, retrieved December 2012
  15. ↑ World Health Organization Proposed International Standard for Luteinizing Hormone. WHO Expert Committee on Biological Standardization. World Health Organization. Geneva. 2003.
  16. ↑ WHO International Standard, Luteinizing Hormone, Human, Recombinant. National Institute for Biological Standards and Control.
  17. ↑ Nielsen MS, Barton SD, Hatasaka HH, Stanford JB (August 2001). "Comparison of several one-step home urinary luteinizing hormone detection test kits to OvuQuick". Fertility and Sterility. 76 (2): 384–7. doi:10.1016/S0015-0282(01)01881-7. PMID 11476792.
  18. ↑ "Ovulation Predictor Kit Frequently Asked Questions". Fertility Plus. Archived from the original on March 12, 2012. Retrieved 12 March 2012.[unreliable medical source?]
  19. ↑ "How to Get Pregnant". OPregnancy.com. 2009. Archived from the original on March 12, 2012. Retrieved 12 March 2012.[unreliable medical source?]
  20. ↑ U.S. Patent 4,406,904
  21. ↑ Weiss J, Axelrod L, Whitcomb RW, Harris PE, Crowley WF, Jameson JL (January 1992). "Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone". The New England Journal of Medicine. 326 (3): 179–83. doi:10.1056/NEJM199201163260306. PMID 1727547.
  22. ↑ Valdes-Socin H, Salvi R, Daly AF, Gaillard RC, Quatresooz P, Tebeu PM, Pralong FP, Beckers A (December 2004). "Hypogonadism in a patient with a mutation in the luteinizing hormone beta-subunit gene". The New England Journal of Medicine. 351 (25): 2619–25. doi:10.1056/NEJMoa040326. PMID 15602022.
  23. ↑ Valdes-Socin H, Daly AF, Beckers A (2017). "Luteinizing Hormone Deficiency: Historical Views and Future Perspectives" (PDF). Austin Andrology. 2 (1): 1015.
  24. ↑ Luveris information[unreliable medical source?] Archived June 18, 2006, at the Wayback Machine.

External links

Template:Gonadotropins and GnRH

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