EXTRA PITUITARY GONADOTROPINS 

Pashu Sandesh, 09 Feb 2022

Sriti Pandey, Abhishek Rajput

Extra pituitary gonadotropins are those gonadotropins that are secreted from tissue other than the pituitary gland. It comprises placental/chorionic gonadotropins as equine chorionic gonadotropin (eCG)/ pregnant mare serum gonadotropins (PMSG) and human chorionic gonadotropin (hCG).

Equine Chorionic Gonadotropin (eCG) 

The hormone is commonly used in concert with progestogen to induce ovulation in livestock prior to artificial insemination. It is previously referred to as pregnant mare's serum gonadotropin (PMSG). eCG was discovered more than 80 years ago as a factor found in the circulation of the pregnant mare during the first third of gestation. It is a variant of equine luteinizing hormone (LH), differentially glycosylated by the equine trophoblast cells. It has the peculiar property of provoking both follicle-stimulating hormone (FSH) and LH activity in non-equid species. The biological basis for this dual activity is believed to be the result of promiscuity of the mammalian FSH receptors, imparting the capacity to respond to this equine LH-like hormone. The best approximation of the role of eCG in the mare is that it induces accessory corpora lutea to better support early gestation. There are numerous applications for eCG in domestic species, including induction of puberty, reversal of anestrus, superovulation and, most recently, improvement of fertility.

The cognate embryonic glycoprotein, human chorionic gonadotropin (hCG) is the fetal signal for the rescue of the corpus luteum from demise, thus maintaining gestation in the human species. Although several roles have been proposed for eCG in the mare (Murphy and Martinuk, 1991) none has been confirmed with any degree of certainty. The equine LH receptor shows elevated homology with other mammalian LH receptors, as well as the capability to bind LH from other species (Saint-Dizier et al., 2011). While eCG interacts exclusively with the equine LH receptor in the horse, it displays only a fraction of the LH bioactivity of equine LH (Saint-Dizier et al., 2004b), for reasons that are currently unclear. This notwithstanding, eCG binds to the equine corpus luteum during early gestation (Saint-Dizier et al., 2004a), and thus, may provide gonadotropin support to maintain pregnancy. At approximately day 40 of gestation, accessory luteal structures appear in the ovary of the mare, coincident with, or not long after, the initiation of secretion of eCG from the endometrial cups (Amoroso et al., 1948). These appear to be the result of accessory ovulations, as their initiation has been shown to be accompanied by the occurrence of oocytes in the oviduct (Amoroso et al., 1948), and by concurrent increases in circulating progesterone. The temporal relationship between these two events suggests eCG may induce supplementary ovulations and support the second wave of corpora lutea (Allen, 2001), thereby ensuring sufficient hormonal support for the continuation of gestation. Inbred horses hysterectomies during early pregnancy, accessory corpora lutea fail to appear (Squires et al., 1974), further suggesting that eCG is the stimulus for supplementary ovulations. In hybrid gestations of a donkey sire and horse dam, eCG production is remarkably diminished (Allen, 1975), with a concurrent increase in the frequency of abortion during early pregnancy (Boeta and Zarco, 2010). A second purported function of eCG in the mare has been stated to be isolation of the semi allogenic fetus from recognition by the maternal immune system. Mammalian trophoblast in general has this capacity, first by suppression of the maternal immune system and then by alteration of maternal immune cells to participate in, rather than antagonize, implantation. Equine trophoblast, and, in particular, the chorionic girdle cells, have this capability, as demonstrated by persistence following allogeneic transplantation to non-pregnant mares (de Mestre et al., 2011). There is no evidence that eCG participates in this immuno-isolation, indeed, paternal antigens are recognized by the maternal immune system as early as day 45 of gestation (Baker et al., 2000).

Human Chorionic Gonadotropin (hCG) 

hCG is a hormone produced by the embryo after implantation. It is a heterodimeric glycoprotein composed of 237 amino acids with a molecular mass of 25.7 kDa, with an α (alpha) subunit identical to that of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and β (beta) subunit that is unique to hCG. The α-subunit is 92 amino acids long and β-subunit contains 145 amino acids. The two subunits create a small hydrophobic core surrounded by a high surface-area-to-volume ratio: 2.8 times that of a sphere. The vast majority of the outer amino acids are hydrophilic (Lapthorn et al., 1994). Naturally, it is produced in the human placenta by the syncytiotrophoblast. Like other gonadotropins, they can be extracted from the urine of pregnant women or produced from cultures of genetically modified cells using recombinant DNA technology. 

Human chorionic gonadotropin interacts with the LHCG receptor of the ovary and promotes the maintenance of the corpus luteum during the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone during the first trimester. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus^. Due to its highly negative charge, hCG may repel the immune cells of the mother, protecting the fetus during the first trimester. It has also been hypothesized that hCG may be a placental link for the development of local maternal immunotolerance. For example, hCG-treated endometrial cells induce an increase in T cell apoptosis (dissolution of T cells). These results suggest that hCG may be a link in the development of peri trophoblastic immune tolerance, and may facilitate the trophoblast invasion, which is known to expedite fetal development in the endometrium (Kayisli et al., 2003).  

Because of its similarity to LH, hCG can also be used clinically to induce ovulation in the ovaries as well as testosterone production in the testes. As the most abundant biological source is women who are presently pregnant, some organizations collect urine from pregnant women to extract hCG for use infertility treatment.  Human chorionic gonadotropin also plays a role in cellular differentiation/proliferation and may activate apoptosis.

Human chorionic gonadotropin can be used as a tumour marker, as its β subunit is secreted by some cancers including seminoma, choriocarcinoma, germ cell tumours, hydatidiform mole formation, teratoma with elements of choriocarcinoma, and islet cell tumour. For this reason, a positive result in males can be a test for testicular cancer. The normal range for men is between 0-5 mIU/mL. Combined with alpha-fetoprotein, β-HCG is an excellent tumour marker for the monitoring of germ cell tumours.

Human chorionic gonadotropin is extensively used parenterally for final maturation induction in lieu of luteinizing hormone. In the presence of one or more mature ovarian follicles, ovulation can be triggered by the administration of HCG. As ovulation will happen between 38 and 40 hours after a single HCG injection, procedures can be scheduled to take advantage of this time sequence, such as intrauterine insemination or sexual intercourse. Also, patients that undergo IVF, in general, receive HCG to trigger the ovulation process but have an oocyte retrieval performed at about 34 to 36 hours after injection by, a few hours before the eggs actually would be released from the ovary. As HCG supports the corpus luteum, the administration of HCG is used in certain circumstances to enhance the production of progesterone.

In males, hCG injections are used to stimulate the Leydig cells to synthesize testosterone. The intratesticular testosterone is necessary for spermatogenesis from the Sertoli cells. Typical uses for HCG in men include hypogonadism and fertility treatment.

CONCLUSION

A better understanding of extra-pituitary gonadotropins is important as they play a crucial role in the maintenance of pregnancy as well as early detection of pregnancy in some species. These hormones have been successfully used for various aspects of reproduction as induction of puberty, estrus synchronization and so on in various farm animals.

REFERENCES

William T. Moore, Jr. and Darrell N. Ward. 1980. Pregnant Mare Serum Gonadotropin rapid chromatographic procedures for the purification of intact hormone and isolation of subunits. The journal of biological chemistry 255 (14): 6923-6929.

Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE, Machin KJ, Morgan FJ, Isaacs NW. (1994). "Crystal structure of human chorionic gonadotropin". Nature 369 (6480): 455–61.

Kayisli U, Selam B, Guzeloglu-Kayisli O, Demir R, Arici A. (2003). "Human chorionic gonadotropin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas-Fas ligand system". J. Immunol. 171 (5): 2305–13.

"Tumor Markers Found in Blood or Urine". American Cancer Society. Retrieved 21 January 2014.

Gordon, Ian R. (2004). Reproductive technologies in farm animals. CABI. ISBN 978-0-85199-862-6.