Luteinizing hormone

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).

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

Effects of LH on the body

In both males and females, LH is essential for reproduction.

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 17-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 first 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 GnRH.^[8] The Leydig cells produce testosterone (T) under the control of LH, which regulates the expression of the enzyme 17-β hydroxysteroid dehydrogenase that is used to convert androstenedione, the hormone produced by the gonads, 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 (GnRH). 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 (MOA) in pineal, leading to increased melatonin and reduced LH & FSH by melatonin-induced increase of GnIH synthesis and secretion. T can also be aromatized into Estradiol (E2) in order 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

Reference ranges for the blood content of luteinizing hormone (LH) during the menstrual cycle.

• 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 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.

In males over 18 years of age, reference ranges have been estimated to be 1.8-8.6 IU/L.^[13]

LH is measured in International Units (IU). For Human Urinary LH, one IU is defined as the amount of LH that has an activity corresponding to 0.13369 mg of pure Human Urinary LH.^[14]

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.^[15] 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.^[16]

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.^[17]

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)

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 the 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 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. 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

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: LH isolated deficiency^[18][19]
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).^[20] 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

External links

• Luteinizing Hormone at the US National Library of Medicine Medical Subject Headings (MeSH)