LH is not necessary for the differentiation of the genitals in the male sense. In fact, in our species, HCG (human chorionic gonadotropin) produced by the placenta, very homologous to LH, will allow the masculinization of the genital organs before birth by acting on the same LHR receptor.
However, after birth, LH is essential for testicular maturation, especially for the proliferation and maturation of Leydig cells, which will acquire the ability to secrete testosterone, allowing pubertal virilization and activation of spermatogenesis.
About 15% of couples are infertile and the origin is male in about half of cases, making it a public health problem. In addition, there is a decrease in the number and quality of spermatozoa in industrialized countries.
In humans, spermatogenesis is triggered at puberty by activating pulsatile secretion, by kisspeptine the hypothalamic peptide GnRH (gonadotropin-releasing hormone) which induces the secretion of two pituitary gonadotropins: LH (luteinizing hormone) and FSH (follicle stimulating hormone).
These two hormones include a common α sub-unit and a specific β sub-unit. LH controls the production of testosterone by Leydig cells, endocrine cells located in the interstitium of the testicles. This hormone is essential for virilization and, together with FSH, triggers spermatogenesis.
The joint action of testosterone and FSH is exerted on the Sertoli cells that delimit the wall of the seminiferous tubes in which the germinal cells will mature until the sperm stage.
In fact, in the human species, there are three waves of proliferation of Leydig cells. Each of these waves is characterized by the production of testosterone by these cells.
The first is prenatal: it occurs after 10 weeks of fetal life and depends on hCG. Fetal testosterone secretion peaks at 14-15 weeks.
The third wave occurs at puberty during activation of the gonadotropic axis in adolescents. Under the action of gonadotropins, the secretion of testosterone is activated.
The alpha subunit of LH is biologically identical to three other hormones: FSH, thyroid stimulating hormone (TSH) and human chorionic gonadotropin (HCG).
The beta subunit is unique and determines the immunological and biological activity of LH. The half-life of the luteinizing hormone is 20 minutes. The corresponding receptor of the hormone is the LH receptor, and receptor mutations can lead to LH inactivity.
In man, both LH and FSH are necessary for spermatogenesis. LH stimulates Leydig cells to convert cholesterol into testosterone. Testosterone and FSH, in turn, modulate Sertoli cells, which serve as “caregiving” cells for spermatogenesis within the light of the seminiferous tubules.
The fertile eunuch syndrome or Pasqualini syndrome is the cause of hypogonadotropic hypogonadism due to luteinizing hormone deficiency.
Characterized by hypogonadism with spermatogenesis, Pasqualini and Bur published in 1950, the first case of eunuchadism with preserved spermatogenesis.
Hypoganadism with spermatogenesis included:
1) eunuchidism, as habit or corporal aspect.
2) testicles with normal spermatogenesis and incomplete volume, with mature sperm in a high proportion of seminiferous tubes and undifferentiated and immature Leydig cells.
3) complete functional compensation by administration of the hormone chorionic gonadotropin, while HCG is administered
- total gonadotropins in urine within normal limits
5) this definition implies the normal activity of the pituitary gland and the absence of congenital malformations in general.
In describing five other similar cases in 1953, McCullagh coined the term fertile eunuch, this term is incorrect and should not be used. In fact, these patients are not really eunuchs.
A first step in understanding Pasqualini syndrome was the absence of luteinizing hormone (LH) in patients’ plasma and urine.
The second advance was the functional and genetic studies that validated the hypothesis of a functional deficit of LH in these men.
Deactivation of luteinizing hormone mutations is also described in some women.
Different groups demonstrated in these cases an LH with different degrees of immune activity but biologically inactive in most patients, due to one or more inactivating mutations in the LHB gene.
Finally, full understanding of Pasqualini syndrome allowed reversing the hypoandrogenic phenotype and restoring fertility in these patients through the use of chorionic gonadotropin and modern in vitro fertility techniques.
Some rare observations, such as mutations in the beta gene of the luteinizing hormone subunit, have contributed substantially to our understanding of male reproductive development and infertility.
A testicular biopsy showed that 82 percent of the seminiferous tubules had complete spermatogenesis, while only Sertoli cells were present in 5 percent.
In the rest of the tubules there were incomplete spermatogenesis and few Leydig cells.
The outstanding features of the syndrome were the presence of spermatogenesis despite a moderate to severe androgenic decision.
Treatment with chorionic gonadotropin increased androgen secretion.
Although more cases of this syndrome could be expected to come to light, the cause of LH deficiency remained uncertain until the advent of the genetic era.
The next breakthrough came with functional and genetic studies that validated the hypothesis of functional LH dysfunction in these men.
In 1992, Weiss et al. identified a hypogonadal male among an inbred family.
He had high levels of FSH and LH, but LH had reduced biological activity. Klinefelter syndrome was ruled out. Sequencing of the LHB gene demonstrated a homozygous mutation, explaining both immunological activity and biologically reduced activity.
Subsequently, a man with a missense homozygous mutation in the LHB subunit gene has been described, which nullified the dimerization of the subunit and made LH biologically and immunologically inactive.
Treatment with human chorionic gonadotropin (hCG) induced almost normalization of testicular structure.
In other cases described, the intracellular export and the secretion of luteinizing hormone by the gonadotropes were affected.
However, the absence or reduction of LH secretion in men with LHB gene mutations affects puberty and alters the proliferation and maturation of Leydig cells.
Men with decient LH have reduced spermatogenesis, from azoospermia to oligospermia, which has been related to the lack of LH stimulation and the low intratesticular action of testosterone.
As more doctors are able to diagnose luteinizing hormone (LH) deficiency, the issue of the best therapeutic strategy to offer these patients has not been resolved.
Although the administration of testosterone may cause secondary sexual characteristics, it does not promote testicular development by abruptly mimicking the state of puberty.
Treatment with gonadotropin may develop the fertility potential of these patients if performed in time for early diagnosis of hypogonadotropic hypogonadism.
This strategy may promote the maturation of Sertoli and Leydig, and may improve spermatogenesis and maximize fertility potential.
More studies in infertile male patients with variants of LH are needed to demonstrate whether recombinant treatment with LH or HCG might be beneficial in selected populations.
Keywords: LH isolated deficit, LH deficiency, Pasqualini syndrome, LH receptor, LH gene, LH alpha fraction, LH beta fraction, LH and Leydig cells, LH and spermatogenesis, LH and puberty, fertile eunuch, LH rectifier mutation, LH pulsatile secretion, LH inactive mutation, delayed puberty and LH, recombinant HCG treatment.