Luteinizing hormone
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Luteinizing hormone beta polypeptide
Identifiers
Symbol
LHB
Entrez
3972
HUGO
6584
OMIM
152780
RefSeq
NM_000894
UniProt
P01229
Other data
Locus
Chr. 19 q13.3
Luteinizing hormone (LH, also known as lutropin[1]) is a hormone produced by the
anterior pituitary gland. In females, an acute rise of LH called the 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.[4] It acts synergistically with FSH.
Contents





1 Structure
2 Genes
3 Activity
4 Normal levels
5 Ovulation predictor kit (LH kit)




6 Disease states
o 6.1 Relative elevations
o 6.2 High LH levels
o 6.3 Deficient LH activity
7 Availability
8 References
9 External links
[edit] 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):

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 92-amino acid long LH alpha subunit in humans has the following sequence:
NH2 – Ala – Pro – Asp – Val – Gln – Asp – Cys – Pro – Glu – Cys – Thr – Leu – Gln –
Glu – Asn – Pro – Phe – Phe – Ser – Gln – Pro – Gly – Ala – Pro – Ile – Leu – Gln –
Cys – Met – Gly – Cys – Cys – Phe – Ser – Arg – Ala – Tyr – Pro – Thr – Pro – Leu –
Arg – Ser – Lys – Lys – Thr – Met – Leu – Val – Gln – Lys – Asn – Val – Thr – Ser –
Glu – Ser – Thr – Cys – Cys – Val – Ala – Lys – Ser – Tyr – Asn – Arg – Val – Thr –
Val – Met – Gly – Gly – Phe – Lys – Val – Glu – Asn – His – Thr – Ala – Cys – His –
Cys – Ser – Thr – Cys – Tyr – Tyr – His – Lys – Ser – OH

Note: The carbohydrate moiety is linked to the asparagine at positions 52 and 78.

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.
NH2 – Ser – Arg – Glu – Pro – Leu – Arg – Pro – Trp – Cys – His – Pro – Ile – Asn –
Ala – Ile – Leu – Ala – Val – Glu – Lys – Glu – Gly – Cys – Pro – Val – Cys – Ile –
Thr – Val – AsnThr – Thr – Ile – Cys – Ala – Gly – Tyr – Cys – Pro – Thr – Met – Met –
Arg – Val – Leu – Gln – Ala – Val – Leu – Pro – Pro – Leu – Pro – Gln – Val – Val –
Cys – Thr – Tyr – Arg – Asp – Val – Arg – Phe – Glu – Ser – Ile – Arg – Leu – Pro –
Gly – Cys – Pro – Arg – Gly – Val – Asp – Pro – Val – Val – Ser – Phe – Pro – Val –
Ala – Leu – Ser – Cys – Arg – Cys – Gly – Pro – Cys – Arg – Arg – Ser – Thr – Ser –
Asp – Cys – Gly – Gly – Pro – Lys – Asp – His – Pro – Leu – Thr – Cys – Asp – His –
Pro – Gln – Leu – Ser – Gly – Leu – Leu – Phe – Leu – OH
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]
Reference ranges for the blood content of luteinizing hormone (LH) during the menstrual
cycle. [5]
- 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 nonmonitored 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.
[edit] 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.
[edit] Activity
In both males and females, LH is essential for reproduction.

In females, at the time of menstruation, FSH initiates follicular growth, specifically
affecting granulosa cells.[6] With the rise in oestrogens, 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 oestrogen rise leads via the
hypothalamic interface to the “positive feed-back” effect, a release of LH over a 24to 48-hour period. This 'LH surge' triggers ovulation, thereby 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
(a hormone very similar to LH) from the newly established pregnancy. LH supports
theca cells in the ovary that provide androgens and hormonal precursors for estradiol
production.

In the male, LH acts upon the Leydig cells of the testis and is responsible for the
production of testosterone, an androgen that exerts both endocrine activity and
intratesticular activity on spermatogenesis.
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
oestrogen feedback from the gonads.
[edit] Normal levels
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 a 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.
[edit] Ovulation predictor kit (LH kit)
The detection of the Luteinising hormone surge 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.[7] The 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 intentions of conceiving.[8]
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.[9]
The sensitivity of LH tests are measured in milli international unit, with tests commonly
available in the range 10-40 m.i.u.[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. [note: photo shows "negative" results in the top strip, i.e., no LH surge,
and "positive" results in the bottom strip. *This information needs editing. An LH surge
will cause the test line (on the left) to be darker in colour than the strip on the right
(depending on the brand you buy; follow package insert instructions for interpreting
results). Women with PCOS may have LH in their urine throughout their cycle, causing
their tests to appear coloured throughout the cycle as displayed in the bottom strip. ]
[edit] Disease states
[edit] Relative elevations
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.
[edit] 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 the 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.
5.
6.
7.
Swyer syndrome
Polycystic Ovary Syndrome
Certain forms of CAH
Testicular failure
[edit] 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 are:
1.
2.
3.
4.
5.
6.
7.
8.
Kallmann syndrome
Hypothalamic suppression
Hypopituitarism
Eating disorder
Female athlete triad
Hyperprolactinemia
Gonadotropin deficiency
Gonadal suppression therapy
1. GnRH antagonist
2. GnRH agonist (downregulation)
[edit] Availability
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).[10] [11] [12]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.
[edit] References
1.
2.
3.
4.
5.
6.
^ lutropin at eMedicine Dictionary
^ Physiology at MCG 5/5ch9/s5ch9_5
^ Louvet J, Harman S, Ross G (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.
^ Physiology at MCG 5/5ch8/s5ch8_5
^ References and further description of values are given in image page in Wikimedia Commons at
Commons:File:Luteinizing hormone (LH) during menstrual cycle.png.
^ Gonadotropins: Luteinizing and Follicle Stimulating Hormones at colostate.edu
7.
^ Nielsen M, Barton S, Hatasaka H, Stanford J (2001). "Comparison of several one-step home
urinary luteinizing hormone detection test kits to OvuQuick". Fertil Steril 76 (2): 384–7.
doi:10.1016/S0015-0282(01)01881-7. PMID 11476792.
8. ^ Ovulation Predictor Kit information at pinelandpress.com
9. ^ "Clearblue website". http://www.clearblue.com/uk/HCP/faq.php. Retrieved 2009-08-11.
10. ^ Luveris information
11. ^ Luveris®;
http://www.emdserono.com/cmg.emdserono_us/en/images/Luveris_tcm115_19351.pdf
12. ^ Luveritis, Administration and storage info,
http://www.txfertility.com/forms/Luveris%20instructions.pdf
Luteinizing hormone/choriogonadotropin
receptor
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Luteinizing hormone/choriogonadotropin
receptor
[show]Available structures
Identifiers
LHCGR; FLJ41504; HHG; LCGR; LGR2;
Symbols LH/CG-R; LH/CGR; LHR; LHRHR; LSH-R;
ULG5
External OMIM: 152790 MGI: 96783
IDs
HomoloGene: 37276 GeneCards: LHCGR Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species Human
Mouse
Entrez 3973
16867
Ensembl ENSG00000138039 ENSMUSG00000024107
UniProt P22888
RefSeq
(mRNA)
RefSeq
(protein)
P30730
NM_000233.3
NM_013582.2
NP_000224.2
NP_038610.1
Location Chr 2:
Chr 17:
(UCSC) 48.86 – 48.98 Mb
89.14 – 89.19 Mb
PubMed
search
[1]
[2]
The luteinizing hormone/choriogonadotropin receptor (LHCGR), also
lutropin/choriogonadotropin receptor (LCGR) or luteinizing hormone receptor
(LHR) is a transmembrane receptor found in the ovary, testis and extragonadal organs
like the uterus. The receptor interacts with both luteinizing hormone (LH) and chorionic
gonadotropins (such as hCG in humans) and represents a G protein-coupled receptor
(GPCR). Its activation is necessary for the hormonal functioning during reproduction.
LHCGRs are found in the ovary, testis, and many extragonadal tissues.
Contents









1 LHCGR gene
2 Receptor structure
3 Ligand binding and signal transduction
o 3.1 Phosphorylation by cAMP-dependent protein kinases
4 Action
o 4.1 Ovary
o 4.2 Testis
o 4.3 Extragonadal
5 Receptor regulation
o 5.1 Upregulation
o 5.2 Desensitization
o 5.3 Downregulation
o 5.4 Modulators
6 LHCGR abnormalities
7 History
8 Interactions
9 References


10 Further reading
11 External links
[edit] LHCGR gene
The gene for the LHCGR is found on chromosome 2 p21 in humans, close to the FSH
receptor gene. It consists of 70 kbp (versus 54 kpb for the FSHR).[1] The gene is similar
to the gene for the FSH receptor and the TSH receptor.
[edit] Receptor structure
The LHCGR consists of 674 amino acids and has a molecular mass of about 85–95 kDA
based on the extent of glycosylation.[2]
The seven transmembrane α-helix structure of a G protein-coupled receptor such as
LHCGR
Like other GPCRs, the LHCG receptor possess seven membrane-spanning domains or
transmembrane helices.[3] The extracellular domain of the receptor is heavily
glycosylated. These transmembrane domain contains two highly conserved cysteine
residues, which build disulfide bonds to stabilize the receptor structure. The
transmembrane part is highly homologous with other members of the rhodopsin family of
GPCRs. The C-terminal domain is intracellular and brief, rich in serine and threonine
residues for possible phosphorylation.
[edit] Ligand binding and signal transduction
Upon binding of LH to the external part of the membrane spanning receptor, a
transduction of the signal takes place that activates the G protein that is bound to the
receptor internally. With LH attached, the receptor shifts conformation and thus
mechanically activates the G protein, which detaches from the receptor and activates the
cAMP system.[4]
It is believed that a receptor molecule exists in a conformational equilibrium between
active and inactive states. The binding of LH (or CG) to the receptor shifts the
equilibrium between active and inactive receptors. LH and LH-agonists shift the
equilibrium in favor of active states; LH antagonists shift the equilibrium in favor of
inactive states. For a cell to respond to LH only a small percentage (~1%) of receptor
sites need to be activated.
[edit] Phosphorylation by cAMP-dependent protein kinases
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal
chain coming from the G protein (that was activated by the LHCG-receptor) via
adenylate cyclase and cyclic AMP (cAMP). These protein kinases are present as
tetramers with two regulatory units and two catalytic units. Upon binding of cAMP to the
regulatory units, the catalytic units are released and initiate the phosphorylation of
proteins leading to the physiologic action. The cyclic AMP-regulatory dimers are
degraded by phosphodiesterase and release 5’AMP. DNA in the cell nucleus binds to
phosphorylated proteins through the cyclic AMP response element (CRE), which results
in the activation of genes.[1]
The signal is amplified by the involvement of cAMP and the resulting phosphorylation.
The process is modified by prostaglandins. Other cellular regulators are participate are
the intracellular calcium concentration modified by phospholipase, nitric acid, and other
growth factors.
In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer
the receptor remains active the more kinases are activated and the more receptors are
phosphorylated.
Other pathways of signaling exist for the LHCGR.[2]
[edit] Action
[edit] Ovary
In the ovary, the LHCG receptor is necessary for follicular maturation and ovulation, as
well as luteal function. Its expression requires appropriate hormonal stimulation by FSH
and estradiol. The LHCGR is present on granulosa cells, theca cells, luteal cells, and
interstitial cells[2] The LCGR is restimulated by increasing levels of chorionic
gonadotropins in case a pregnancy is developing. In turn, luteal function is prolonged and
the endocrine milieu is supportive of the nascent pregnancy.
[edit] Testis
In the male the LHCGR has been identified on the Leydig cells that are critical for
testosterone production, and support spermatogenesis.
Normal LHCGR functioning is critical for male fetal development, as the fetal Leydig
cells produce testosterone to induce masculinization.
[edit] Extragonadal
LHCGR have been found in many types of extragonadal tissues, and the physiologic role
of some has remained largely unexplored. Thus receptors have been found in the uterus,
sperm, seminal vesicles, prostate, skin, breast, adrenals, thyroid, neural retina,
neuroendocrine cells, and (rat) brain.[2]
[edit] Receptor regulation
[edit] Upregulation
Upregulation refers to the increase in the number of receptor sites on the membrane.
Estrogen and FSH upregulate LHCGR sites in preparation for ovulation. After ovulation,
the luteinized ovary maintains LHCGR s that allow activation in case there is an
implantation.
[edit] Desensitization
The LHCGRs become desensitized when exposed to LH for some time. A key reaction of
this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor
domain by protein kinases. This process uncouples Gs protein from the LHCGR. Another
way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.
[edit] Downregulation
Downregulation refers to the decrease in the number of receptor sites. This can be
accomplished by metabolizing bound LHCGR sites. The bound LCGR complex is
brought by lateral migration to a coated pit, where such units are concentrated and then
stabilized by a framework of clathrins. A pinched-off coated pit is internalized and
degraded by lysosomes. Proteins may be metabolized or the receptor can be recycled.
Use of long-acting agonists will downregulate the receptor population.
[edit] Modulators
Antibodies to LHCGR can interfere with LHCGR activity.
[edit] LHCGR abnormalities
Loss-of-function mutations in females can lead to infertility. In 46, XY individuals severe
inactivation can cause male pseudohermaphroditism, as fetal Leydig cells during may not
respond and induce masculinization.[5] Less severe inactivation can result in hypospadias
or a micropenis.[2]
[edit] History
Alfred G. Gilman and Martin Rodbell received the 1994 Nobel Prize in Medicine and
Physiology for the discovery of the G Protein System.
[edit] Interactions
Luteinizing hormone/choriogonadotropin receptor has been shown to interact with
GIPC1.[6]
[edit] References
1. ^ a b Simoni M, Gromoll J, Nieschlag E (1997). "The follicle-stimulating hormone
receptor: biochemistry, molecular biology, physiology, and pathophysiology".
Endocr. Rev. 18 (6): 739–73. doi:10.1210/er.18.6.739. PMID 9408742.
2. ^ a b c d e Ascoli M, Fanelli F, Segaloff DL (2002). "The
lutropin/choriogonadotropin receptor, a 2002 perspective". Endocr. Rev. 23 (2):
141–74. doi:10.1210/er.23.2.141. PMID 11943741.
3. ^ Dufau ML (1998). "The luteinizing hormone receptor". Annu. Rev. Physiol. 60:
461–96. doi:10.1146/annurev.physiol.60.1.461. PMID 9558473.
4. ^ Ryu KS, Gilchrist RL, Koo YB, Ji I, Ji TH (1998). "Gene, interaction, signal
generation, signal divergence and signal transduction of the LH/CG receptor".
International journal of gynaecology and obstetrics: the official organ of the
International Federation of Gynaecology and Obstetrics 60 Suppl 1: S9–20.
doi:10.1016/S0020-7292(98)80001-5. PMID 9833610.
5. ^ Wu SM, Chan WY (1999). "Male pseudohermaphroditism due to inactivating
luteinizing hormone receptor mutations". Arch. Med. Res. 30 (6): 495–500.
doi:10.1016/S0188-4409(99)00074-0. PMID 10714363.
6. ^ Hirakawa, Takashi; Galet Colette, Kishi Mikiko, Ascoli Mario (Dec. 2003).
"GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ
domain binding motif, and it regulates the sorting of the internalized human
choriogonadotropin and the density of cell surface hLHR". J. Biol. Chem. (United
States) 278 (49): 49348–57. doi:10.1074/jbc.M306557200. ISSN 0021-9258.
PMID 14507927.