Luteinizing hormone (LH, also known asluteinising hormone,[1]lutropin and sometimeslutrophin[2]) is ahormone produced bygonadotropic cells in theanterior pituitary gland. The production of LH is regulated bygonadotropin-releasing hormone (GnRH) from the hypothalamus.[3] In females, an acute rise of LH known as anLH surge, triggersovulation[4] and development of thecorpus luteum. In males, where LH had also been calledinterstitial cell–stimulating hormone (ICSH),[5] it stimulatesLeydig cell production oftestosterone.[4] It acts synergistically with follicle-stimulating hormone (FSH).
The term luteinizing comes from theLatin "luteus", meaning "yellow".[6] This is in reference to thecorpus luteum, which is a mass of cells that forms in an ovary after an ovum (egg) has been discharged.[7] The corpus luteum is so named because it often has a distinctive yellow color.[7] The process of forming the corpus luteum is known as "luteinization", and thus the hormone that triggers this process is termed the "luteinizing" hormone.
Thealpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92amino acids in human but 96amino acids in almost all other vertebrate species (glycoprotein hormones do not exist in invertebrates).
Thebeta 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 theLH receptor. This beta subunit contains an amino acid sequence that exhibits large homologies with that of the beta subunit ofhCG 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 theseoligosaccharides affects bioactivity and speed of degradation. The biologichalf-life of LH is 20 minutes, shorter than that of FSH (3–4 hours) and hCG (24 hours).[citation needed] The biologicalhalf-life of LH is 23 hours subcutaneous[9] or terminal half life of 10-12 hours.[10]
The luteinizing hormonebeta subunit gene is localized in the LHB/CGB gene cluster onchromosome 19q13.32.[11] In contrast to the alpha gene activity, beta LH subunit gene activity is restricted to the pituitary gonadotropic cells. It is regulated by thegonadotropin-releasing hormone from thehypothalamus.[12] GnRH activates Egr1 which interacts with transcription factors NR5A1 and PITX1 at the gene promoter to up-regulate LHB transcription.[13][14]
LH supportstheca cells in the ovaries that provideandrogens and hormonal precursors forestradiol production. At the time ofmenstruation, FSH initiatesfollicular growth, specifically affectinggranulosa cells.[15] With the rise inestrogens, LH receptors are also expressed on the maturing follicle, which causes it to produce moreestradiol. Eventually, when the follicle has fully matured, a spike in17α-hydroxyprogesterone production by the follicle inhibits the production ofestrogens. Previously, the preovulatory LH surge was attributed to a decrease in estrogen-mediatednegative feedback ofGnRH in thehypothalamus, subsequently stimulating the release of LH from theanterior pituitary.[16] Some studies, however, attribute the LH surge to positive feedback fromestradiol after production by the dominant follicle exceeds a certain threshold. Exceptionally high levels of estradiol induce hypothalamic production ofprogesterone, which stimulates elevated GnRH secretion, triggering a surge in LH.[17] The increase in LH production only lasts for 24 to 48 hours. This "LH surge" triggersovulation, thereby not only releasing the egg from the follicle, but also initiating the conversion of the residual follicle into acorpus luteum that, in turn, produces progesterone to prepare theendometrium for a possibleimplantation. LH is necessary to maintain luteal function for the second two weeks of the menstrual cycle. Ifpregnancy 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.
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 inhibitkisspeptin (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.[18]
LH acts upon theLeydig cells of thetestis and is regulated bygonadotropin-releasing hormone (GnRH).[19] The Leydig cells producetestosterone under the control of LH. LH binds to LH receptors on the membrane surface of Leydig cells. Binding to this receptor causes an increase in cyclic adenosine monophosphate (cAMP), a secondary messenger, which allows cholesterol to translocate into the mitochondria. Within the mitochondria, cholesterol is converted to pregnenolone by CYP11A1.[20] Pregnenolone is then converted to dehydroepiandrosterone (DHEA).[21] DHEA is then converted to androstenedione by 3β-hydroxysteroid dehydrogenase (3β-HSD)[22] and then finally converted to testosterone by17β-hydroxysteroid dehydrogenase (HSD17B). The onset of puberty is controlled by two major hormones: FSH initiates spermatogenesis and LH signals the release of testosterone,[23] anandrogen that exerts both endocrine activity and intratesticular activity onspermatogenesis.
LH is released from the pituitary gland, and is controlled by pulses ofgonadotropin-releasing hormone. When bloodstream testosterone levels are low, the pituitary gland is stimulated to release LH.[19] As the levels of testosterone increase, it will act on the pituitary through a negative feedback loop and inhibit the release of GnRH and LH consequently.[24] Androgens (including testosterone anddihydrotestosterone) inhibit monoamine oxidase (MAO) in the pineal gland, leading to increased melatonin and reduced LH and FSH by melatonin-induced increase of Gonadotropin-Inhibitory Hormone (GnIH)[25] synthesis and secretion. Testosterone can also be aromatized intoestradiol (E2) to inhibit LH. E2 decreases pulse amplitude and responsiveness to GnRH from the hypothalamus onto the pituitary.[26]
Changes in LH and testosterone blood levels and pulse secretions are induced by changes insexual arousal in human males.[27]
Luteinizing hormone receptors are located in areas of the brain associated withcognitive function.[28] The role of LH role in thecentral nervous system (CNS) may be of relevance to understanding and treating post-menopausal cognitive decline.[29]
Some research has observed an inverse relationship between circulating LH and CNS LH levels.[30] After ovariectomy (a procedure used to mimic menopause) in female mice, circulating LH levels surge while CNS levels of LH fall.[28] Treatments that lower circulating LH restore LH levels in the CNS.[28]
The ranges denotedBy 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 denotedInter-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 denotedInter-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 duringchildhood and in women, high aftermenopause. Since 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 reproductive years, typical levels are between 1 and 20 IU/L. Physiologic high LH levels are seen during the LH surge (v.s.) and typically last 48 hours.
In males over 18 years of age, reference ranges have been estimated to be 1.8–8.6 IU/L.[32]
LH is measured ininternational 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 since they can vary broadly from year to year. For human urinary LH, one IU is defined as 1/189th of an ampule denoted 96/602 and distributed by theNIBSC, corresponding to approximately 0.04656 μg of LH protein for a single IU, but older standard versions are still widely in use.[33][34]
Chance offertilization by menstrual cycle day relative to ovulation[35]
The detection of a surge in release of luteinizing hormone indicates impendingovulation. LH can be detected byurinary ovulation predictor kits (OPK, also LH-kit) that are performed, typically daily, around the time ovulation may be expected.[36] 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 insexual intercourse orartificial insemination with the intention ofconceiving.[37]
The recommended testing frequency differs between manufacturers. For example, the Clearblue test is taken daily, and an increased frequency does not decrease the risk of missing an LH surge.[38] On the other hand, the Chinese companyNantong Egens Biotechnology recommends using their test twice per day.[39] If testing once per day, no significant difference has been found between testing LH in the morning versus in the evening, in relation to conception rates,[40] and recommendations of what time in the day to take the test varies between manufacturers and healthcare workers.[41] Tests may be read manually using a color-change paper strip, or digitally with the assistance of reading electronics.
The sensitivity of LH tests are measured inmilli 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 forcontraceptive practices, as the LH surge typically occurs after the beginning of the fertile window.[citation needed]
In children withprecocious 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 withpolycystic 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:
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:
Luteinizing hormone is available mixed with FSH in the form ofmenotropin, and other forms of urinarygonadotropins. More purified forms of urinary gonadotropins may reduce the LH portion in relation to FSH. Recombinant luteinizing hormone is available as lutropin alfa (Luveris).[45]
Phosphorylation is a biochemical process that involves the addition of phosphate to an organic compound.Steroidogenesis entails processes by which cholesterol is converted to biologically active steroid hormones. A study shows that LH via a PKA signaling pathway regulates the phosphorylation and localization of DRP1 within mitochondria of thesteroidogenic cells of the ovary.[46]
^Ujihara M, Yamamoto K, Nomura K, Toyoshima S, Demura H, Nakamura Y, et al. (June 1992). "Subunit-specific sulphation of oligosaccharides relating to charge-heterogeneity in porcine lutrophin isoforms".Glycobiology.2 (3):225–231.doi:10.1093/glycob/2.3.225.PMID1498420.
^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):1179–1186.doi:10.1210/endo-96-5-1179.PMID1122882.
^le Cotonnec JY, Porchet HC, Beltrami V, Munafo A (February 1998). "Clinical pharmacology of recombinant human luteinizing hormone: Part I. Pharmacokinetics after intravenous administration to healthy female volunteers and comparison with urinary human luteinizing hormone".Fertility and Sterility.69 (2):189–194.doi:10.1016/S0015-0282(97)00501-3.PMID9496327.
^Tilbrook AJ, Clarke IJ (March 2001). "Negative feedback regulation of the secretion and actions of gonadotropin-releasing hormone in males".Biology of Reproduction.64 (3):735–742.doi:10.1095/biolreprod64.3.735.PMID11207186.
^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):205–218.doi:10.1016/0306-4530(93)90005-6.PMID8516424.S2CID23595343.
^Martinez AR, Bernardus RE, Vermeiden JP, Schoemaker J (March 1994). "Time schedules of intrauterine insemination after urinary luteinizing hormone surge detection and pregnancy results".Gynecological Endocrinology.8 (1):1–5.doi:10.3109/09513599409028450.PMID8059611.
^Meniru GI (2001).Cambridge Guide to Infertility Management and Assisted Reproduction. Cambridge University Press. p. 67.
^US 4406904, Welle HB, Marko M, "Method of inhibiting luteinizing hormone secretion with 6,7-benzomorphan derivatives", issued 27 September 1983, assigned to ACF Chemiefarma NV.
^Valdes-Socin H, Salvi R, Daly AF, Gaillard RC, Quatresooz P, Tebeu PM, et al. (December 2004). "Hypogonadism in a patient with a mutation in the luteinizing hormone beta-subunit gene".The New England Journal of Medicine.351 (25):2619–2625.doi:10.1056/NEJMoa040326.hdl:2268/23485.PMID15602022.
^ab"Luveris EPAR".European Medicines Agency. 29 November 2000. Retrieved23 July 2024.
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