Physiology, Luteinizing Hormone


Article Author:
Daniel Nedresky


Article Editor:
Gurdeep Singh


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Updated:
4/8/2019 8:03:34 PM

Introduction

Luteinizing hormone (LH) is a glycoprotein hormone which is co-secreted along with follicle stimulating hormone by the gonadotrophin cells in the adenohypophysis (anterior pituitary). Luteinizing hormone is a part of a neurological pathway comprised of the hypothalamus, the pituitary gland, and gonads. In this pathway, LH release is stimulated by gonadotropin-releasing hormone (GnRH) and inhibited by estrogen in females and testosterone in males. LH has various functions, and they differ between women and men. In both sexes, LH contributes to the maturation of primordial germ cells. In men, LH causes the Leydig cells of the testes to produce testosterone. In women, LH triggers the creation of steroid hormones from the ovaries.[1] Additionally, it helps to regulate the length and order of the menstrual cycle in females by playing roles in both ovulation and implantation of an egg in the uterus.[2]

Cellular

Gonadotroph cells in the anterior pituitary gland produce luteinizing hormone. Gonadotroph cells have large round cell body with prominent Golgi apparatus and endoplasmic reticulum. These cells are diffusely spread out and comprise around 10 to 15% of the functional anterior pituitary cell mass. These cells do not react well with acid or basic stains and thus appear either basophilic or chromophobic under the microscope.[3]

LH and FSH are both made from similar genes, and thus have similar properties. They are both glycoproteins made up of an alpha and beta subunit.  The alpha subunit is the same between the two hormones, and the beta subunit of each is different and gives each hormone its biological specificity.[4] Specifically, the alpha subunit of LH is made up of 92 amino acids, and the beta subunit is made up of 120 amino acids. Combined these two subunits have a mass of 28 kDa.[5]

Development

Fetal Development:

Luteinizing hormone and human chorionic gonadotropin (hCG) are two essential hormones in the development of both sexes. Their levels can be seen to fluctuate throughout development. In male fetuses, hCG begins at a high level in the plasma and quickly decreases between weeks 10 and 20 of gestation and then slowly decline after that. In contrast, LH secretion increases by week 10 and reaches a peak before week 20 followed by a gradual decrease after that. Because of increased plasma levels of HCG early on in gestation, it is a more significant contributor to testosterone production by Leydig cells than LH early in the development of a fetus. However, as LH levels rise, the regulation of testosterone formation changes to LH driven by around weeks 15 to 20 of gestation. This change in regulation can be exemplified by anencephalic male fetuses that are deficient in LH. In these fetuses normal development of the male reproductive tract occurs while hCG levels are high initially. However, due to the lack of LH, the development of the external genitalia is impeded when hCG levels decrease around gestational weeks 15 to 20.[6]

In female fetuses, the peak levels of LH are higher than in male fetuses; this has been thought to be due to negative feedback of higher testosterone levels on the hypothalamic-pituitary-gonadal axis in male fetuses. Female fetuses have a lower level of gonadal hormones during gestation because the development of the female reproductive tract is not dependent on circulating levels of LH or hCG. The developing ovary does not even express luteinizing hormone/choriogonadotropin receptors until the 16th week of gestation, thus the reason why there is minimal steroidogenesis in the ovary until after delivery of the fetus.[6]

After Delivery:

After delivery, regardless of sex, a sharp increase in LH levels is seen because of the withdrawal of estrogen from the mother. After this temporary increase in LH levels, they begin to decline and stay at low basal levels until prepuberty starts in both sexes.[6]

Puberty:

In the years leading up to puberty in both sexes, there is a slow increase in the secretion of LH nocturnally. As puberty progresses, LH begins to be secreted less so in a nocturnal pattern followed by a pulsatile pattern throughout the whole day. This increase in gonadotropin secretion helps to stimulate gonadal steroidogenesis important to undergo maturation.[6]

Organ Systems Involved

The primary organ systems that luteinizing hormone is involved with are the central nervous system (hypothalamus and pituitary) and the reproductive organ systems of both males and females (See figure: Hypothalamic-Pituitary-Gonadal Axis).

Hypothalamus secretes GnRH in a pulsatile manner which stimulates secretion of LH. GnRH itself undergoes regulation by multiple neurotransmitters like dopamine, serotonin, norepinephrine, glutamate, opiate, and galanin. Kisspeptin is a key regulator of GnRH; it is an important GnRH secretagogue, encoded by the KISS1 gene. Gonadal steroids, estrogen, progesterone, and testosterone exert negative feedback thus decrease secretion of LH.[7]

Function

In males, LH stimulates testosterone release by the Leydig cells of the testes. In females, LH stimulates steroid release from the ovaries, ovulation, and the release of progesterone after ovulation by the corpus luteum [8].

Ovulation:

Ovulation is made possible due to the combined actions of the hypothalamus, pituitary, and ovary. The hypothalamus begins the process of ovulation by releasing GnRH in a pulsatile fashion. This pulsatile release causes the anterior pituitary, to release LH and FSH which then act on the ovarian follicle. This follicle is made up of 3 essential cells: theca cells, granulosa cells, and the oocyte. LH causes the theca cells to make androstenedione. Androstenedione then converts to estradiol via aromatase which is stimulated by FSH. Upon achieving a critical concentration of estradiol, the negative feedback on LH that normally occurs by estrogen is shut off, and it begins to have positive feedback on LH release, which causes an “LH surge” which initiates ovulation. Once ovulation has occurred, the follicle becomes the corpus luteum. The corpus luteum secretes progesterone and is stimulated by LH or hCG if a pregnancy does occur.[9]

Mechanism

Luteinizing hormone acts by binding to a G-protein coupled receptor which in turn activates adenylyl cyclase. Adenylyl cyclase, an enzyme, then goes on to produce cyclic-AMP, thus increasing its intracellular concentration, which then activates a kinase molecule called protein kinase A (PKA). PKA then phosphorylates specific intracellular proteins that then go on to achieve the end physiologic actions of LH like steroid production and ovulation.[8]

Related Testing

Ovulation predictor kits are used by women to determine the exact time of ovulation while trying to get pregnant. These kits work by quantifying luteinizing hormone levels in the urine.[10]

Clinical Significance

Testicular Dysfunction in Chronic Kidney Disease (CKD):

Low libido, potency, and testicular size are all signs of testicular dysfunction. In end-stage renal disease, all these signs can present. Testosterone concentration in the plasma and how quickly testosterone production takes place are usually low in patients with chronic kidney disease. Spermatogenesis has been noted to be either lowered or completely absent as well. After renal transplantation, the changes noted above can be reversed and return to normal. Studies have shown that this testicular dysfunction and altered testosterone concentration results from by higher levels of LH in the plasma and lower amounts of secretory LH pulses seen in men with end-stage renal disease when compared to healthy subjects or men who underwent a successful renal transplant. This fact is significant because the pulsatile secretion of LH is necessary for gonadotropin receptors of the testes to function properly. Also, sustained high levels of LH in the blood and testes can cause a loss of gonadotropin receptors in the testes.[11]

Infertility and Assisted Reproductive Technology:

Infertility is the inability to become clinically pregnant after at least 12 months of unprotected sexual intercourse. It can be caused by female factors, male factors, or both. In women, it can be the result of ovulatory issues (i.e., anovulation), obstructions of the fallopian tubes, and endometriosis. To become pregnant, many women undergo assisted reproductive technologies (ART), like intrauterine insemination and in vitro fertilization.[12]

Proper development of a follicle and ovulation involve the combined effects of FSH and LH and their activities in the body. This interplay between FSH and LH has also been shown to be important in ART. It has been found that low LH levels in the body can create poor outcomes for assisted reproductive technology (ART). Thus, patients who have low endogenous LH, such as with hypogonadotropic hypogonadism, can have an increase in efficacy of ART with exogenous LH treatment.[13] Also, another study found that with supplementation of LH during the mid-follicular phase, there were better pregnancy results in people who had not responded optimally to conventional ART. This outcome was thought to be due to increased production of 17-beta-estradiol.[2] Also, one study reported that fertilization, implantation, and clinical pregnancy rates were all higher in patients who underwent ART that included the use of recombinant human LH (r-hLH) when compared to patients who underwent ART without the use of r-hLH. A lower apoptosis rate was also present in patients who underwent ART that included r-hLH.[5]

Although there are demonstrable benefits of LH supplementation during ART, research also shows that levels of LH can have unfavorable effects on ART.[13] These adverse effects are thought to result from inhibition of granulosa cell proliferation, atresia of immature follicles, and luteinization of preovulatory follicles before they are supposed to. Besides, increased LH before ovulation has been shown to influence the conception and implantation of the embryo negatively.[2]

Hypogonadotropic Hypogonadism in Males:

Hypogonadism is impaired testicular function; this can occur due to a problem with the testes (primary/hypogonadotropic hypogonadism) or due to a problem with the hypothalamic-pituitary-gonadal axis (secondary/hypogonadotropic hypogonadism). Men with hypogonadotropic hypogonadism have low levels of androgens in the plasma as well as a lack/delay of sexual maturity, which can cause symptoms such as a lack of libido, depression, increase in adipose tissue, and diminished erectile function.[14]

Patients with hypogonadotropic hypogonadism usually have an issue with GnRH signaling which then causes a decrease in FSH and LH secretion. This decrease in FSH and LH contributes to both decreased androgen levels as well as reduced spermatogenesis. Studies have shown that giving these patients pulsatile GnRH or LH (or hCG) and FSH can help increase and maintain spermatogenesis and thus the increase the sperm concentration in the ejaculate. Even then, most couples will need ART to achieve pregnancy.[15]


  • Image 9774 Not availableImage 9774 Not available
    Used with Permission from Professor Peter Koopman, PhD, FAA from http://www.dsdgenetics.org
Attributed To: Used with Permission from Professor Peter Koopman, PhD, FAA from http://www.dsdgenetics.org

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Physiology, Luteinizing Hormone - Questions

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A 60-year-old man presents due to lethargy, decreased muscle strength, and loss of libido. Lab analyses reveal that his calculated total testosterone is below the reference range and his sex hormone binding globulin (SHBG) is elevated. Further blood tests to measure which of the following would most likely aid in determining the etiology of his signs and symptoms?



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Which of the following hormones is associated with first biochemical changes of puberty?



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A 45-year-old male presents to the clinic due to decreased libido, erectile dysfunction, and decreased testicular size over the past year. 2 years ago he was diagnosed with chronic kidney disease (CKD) stage 5 and has been on dialysis since then. In addition, the patient has a history of well-controlled hypertension, hypercholesterolemia, and diabetes mellitus. His most recent hemoglobin A1C was 6.3%, most recent blood pressure was 135/85 mmHg, and most recent total cholesterol level was 190 mg/dL. Which of the following is the most likely cause of this patient's symptoms?



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A 28-year-old female presents to her local Ob/Gyn clinic for questions about infertility. She and her 29-year-old husband have been having unprotected sexual intercourse for the past 2 years and have not been able to achieve a pregnancy. The husband has undergone sperm testing that was negative for any dysfunction. Her last menstrual period was 3 months ago and a pregnancy test done today was negative. The patient states that she has a history of irregular menstrual periods for the past 10 years. Today her BMI is 35 kg/m2, blood pressure is 130/80, and the temperature is 99 degrees Fahrenheit. On pelvic examination, bilateral adnexal masses are palpated. What hormone is being produced at higher than normal levels and is contributing to her infertility?



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A 25-year-old primigravid mother at 19 weeks gestation presents to the clinic for a routine prenatal visit. Her pregnancy has been uncomplicated thus far. The fetus was noted previously to be a male. All routine prenatal testing has been normal. Which plasma hormone in the fetus at this time is predominately contributing to the testosterone production of the fetus?



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Physiology, Luteinizing Hormone - References

References

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Kumar P,Sait SF, Luteinizing hormone and its dilemma in ovulation induction. Journal of human reproductive sciences. 2011 Jan;     [PubMed]
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Ezcurra D,Humaidan P, A review of luteinising hormone and human chorionic gonadotropin when used in assisted reproductive technology. Reproductive biology and endocrinology : RB     [PubMed]
Rodger RS,Morrison L,Dewar JH,Wilkinson R,Ward MK,Kerr DN, Loss of pulsatile luteinising hormone secretion in men with chronic renal failure. British medical journal (Clinical research ed.). 1985 Dec 7;     [PubMed]
Fraietta R,Zylberstejn DS,Esteves SC, Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo, Brazil). 2013;     [PubMed]
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