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JRMH article

  1. 1. Editorial Why does human chorionic gonadotropin have such a broad regulatory roles in the body and are they totally unexpected? Hormones are chemical messengers that nature has evolved them primarily for internal communication in living organ- isms. Both hydrophilic protein hormones and hydrophobic steroid hormones are present in animal and plant kingdoms throughout the evolutionary history and these molecules probably evolved around 4000 million years ago. Reproductive and endocrine systems have likely been evolved with hor- mones from the early living organisms. Hormones require cognate receptors, which in turn require signaling molecules to complete their actions. This would mean a co-evolution of all three molecular entities more or less simultaneously. Thus, hormones, receptors and signaling molecules have also been identified in primitive unicellular organisms, primitive fish, and nematodes such as Caenorhabditis elegans (C. elegans) and round worms.1e5 For example, the simple genome of C. elegans contains six times more nuclear hormone receptor encoding genes than vertebrates.2 It is not known, however, why its genome has such a large number of nuclear hormone receptor encoding genes? This preface leads to human chorionic gonadotropin (hCG). It is commonly known as a pregnancy hormone and widely used for pregnancy testing. Chorionic gonadotropin is also found in subhuman primates.6 Human placenta secretes large quantities and a number of normal and cancer tissues can secrete small quantities of hCG.7,8 The difference is non- placental source of hCG has a shorter circulatory half-life than placental hCG, which has a half-life of about 12 h. Placental hCG is quite heterogeneous and in fact, it is a collection of molecules differing in protein and carbohydrate structures, function and circulatory half-lives. hCG is a protein that contains large amounts of carbohy- drate, especially when it is derived from placenta. Hence, it is called a glycoprotein hormone. It contains two non-covalently bound a- and b-subunits. The a-subunit is encoded by a single gene and highly conserved among luteinizing hormone (LH), follicle stimulating hormone (FSH) and thyroid stimulating hormone (TSH). In fact, the same gene encodes the a-subunit of all four hormones. Gonadotropes in anterior pituitary gland secretes LH and FSH, and thyrotropes secrete TSH. The b-subunit is hormone specific, which bears a significant homology between hCG and LH. Single genes encode b- subunits of LH, FSH and TSH. A six gene cluster, containing pseudogenes, encodes the hCG-b subunit. Not all of them are equally expressed and, moreover, contribution of each of the six to mature hCG, may vary with the pregnancy states. Nevertheless, the cluster is likely to have been evolved from a single LH-b-subunit gene, through a process of duplication and mutations, which probably shifted the transcription start site and c-terminus extension. Because there is only one re- ceptor for hCG and LH, they mimic each other's functions. However, these functions differ quantitatively, which is pri- marily due to the differences in their circulatory half-lives. Due to a lower abundance of carbohydrate residues, LH has a shorter circulatory half-life than hCG.9 In addition, LH has a lower binding affinity than hCG for the receptor.7,8 It is theo- retically possible that hCG and LH may have distinct functions as a result of unique conformational changes that they might induce in the same receptor molecule. hCG belongs to the glycoprotein hormone and cystine knot growth factor families. The former consists of LH, FSH, TSH and the latter consists of transforming growth factors e b, platelet derived growth factor and nerve growth factor. Belonging to the same family implies overlapping functions by these diverse set of molecules. Although CG is only found in humans and subhuman pri- mates, its functional analog, LH, is present in all species, regardless of the pregnancy. Structurally similar CG and/or LH molecules have been found in unicellular organisms, fish and nematodes,10 but they may not perform the same functions. It has been a mystery for decades why only humans and subhuman primates have CG, when they already have a functionally similar LH. The best guess is that evolutionary and selection pressures may have led to the appearance of CG. These pressures could have been that pregnancies in humans and primates may have faced unusual hurdles during evolu- tion and to overcome them, sturdier, longer lasting and multifunctional molecule such as CG, might have been required.11 The newly evolved CG probably then used the same receptors and signaling systems as LH. The identification of hCG dates back to more than 50 years. Most of that time, it was known for its actions to rescue corpus luteum from regression in a fertile cycle.7,8 Corpus luteum is Available online at ScienceDirect journal homepage: j o u r n a l o f r e p r o d u c t i v e h e a l t h a n d m e d i c i n e 1 ( 2 0 1 5 ) 1 e3
  2. 2. needed for progesterone secretion, which maintains preg- nancy. The progesterone secretion progressively shifts from corpus luteum to placenta and is completed by about the 9th week of pregnancy. This completion obviates the need for the corpus luteum for pregnancy continuation. However, both corpus luteum and hCG are maintained throughout preg- nancy. It does not make sense for continued hCG secretion, when it has no functions during the remainder of the preg- nancy. The chances are that hCG has other functions, but we simply did not know anything about them. Indeed, the research in the past 20 years has shown that hCG has many other functions through regulating several non-gonadal tis- sues listed below (Table 1).7,8,12 hCG receptors, which bind LH as previously mentioned, are also present in non-gonadal tissues of males.4,6 These tissues include those that are common to both genders as well as gender specific tissues/cells, such as sperm, secondary sex organs (prostate, epididymis, and seminal vesicles) and penis.7,8,13,14 The evolutionary significance of CG in males is not known. However, it is possible that these receptors are primarily meant for LH, which acquired the capacity to regu- late male non-gonadal tissues for some unknown evolu- tionary advantages. The hCG actions in the non-gonadal tissues is context, tissue and cell type dependent. The sum of all the hCG actions can be summarized into five categories: those that favor pregnancy initiation, pregnancy maintenance, safeguard fetus from rejection, support fetal growth and development and allow delivery when fetus is sufficiently mature for its survival outside the womb.4,5 The probable evolutionary sig- nificance of hCG actions is to safeguard pregnancy against all the odds during primates evolution. This could also include providing a relief from maladies that could potentially threaten the successful completion of pregnancy. These maladies, for example, could be rheumatoid arthritis, certain pathogenic infections and other conditions which may chal- lenge pregnancy continuation. In view of the above discus- sion, it is easy to understand why hCG has such broad regulatory roles in the body. This leads to a next question of whether the broad regu- latory roles of hCG are totally unexpected. As it turns out many other hormones, such as prolactin, FSH, gonadotropin releasing hormone, oxytocin, relaxin, etc, have multiple sites of action beyond their conventional targets. Thus it should not be surprising to find that hCG and LH can also regulate many non conventional target tissues. The multiple uses of hor- mones may have been conserved because of the environment and mode of life changes during the evolution of organisms. Finally multiple hormone uses could be a functional redun- dancy and efficiency. In summary, the evolutionary and se- lection pressures, environmental and mode of life changes could have led to the hCG appearance and multiplicity of its actions in humans. This functional multiplicity has led to a wind fall of new therapeutic possibilities in reproductive health and in other areas of medicine.7,8,12 r e f e r e n c e s 1. Vinson GP. On the origin of hormones. Endocrinologist. 2009/ 10;94:8. 2. Taubert S, Ward JD, Yamamoto KR. Nuclear hormone receptors in nematodes: evolution and function. Mol Cell Endocrinol. 2010;334:49e55. 3. Hillier S. Endocrine evolution. Endocrinologist. 2009/10;94:9. 4. Krasowski MD, Ni A, Hagey LR, Ekins S. Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR. Mol Cell Endocrinol. 2010;334:39e44. 5. Freamat M, Sower SA. Functional divergence of glycoprotein hormone receptors. Integ Comp Biol. 2010;50:110e123. 6. Maston GA, Ruvolo M. Chorionic gonadotropin has a recent origin within primates and an evolutionary history of selection. Mol Biol Evol. 2002;19:320e335. 7. Rao CV. Nongonadal actions of LH and hCG in reproductive biology and medicine. Sem Reprod Med (Guest Editor). 2001;vol. 19:1e119. 8. Rao CV, Lei ZM. The past, present and future of nongonadal LH/hCG actions in reproductive biology and medicine. Mol Cell Endocrinol. 2007;269:2e8. 9. Pierce JG, Parsons TF. Glycoprotein hormones: structure and function. Annu Rev Biochem. 1981;50:465e495. 10. Hsu SY, Nakanayashi K, Bhalla A. Evolution of glycoprotein hormone subunit genes in bilateral metazoa: identification of two novel human glycoprotein hormone subunit family genes, GPA2 and GPB5. Mol Endocrinol. 2002;16:1538e1551. 11. Diamond J. The Third Chimpanzee, Chapters 3e6. New York, NY: Harper Collins Publishers; 1993. 12. Rahman N, Rao CV. Recent progress in luteinizing hormone/ human chorionic gonadotropin hormone research. Mol Hum Reprod. 2009;15:703e711. 13. Kokk K, Kuuslahti M, Keisala T, et al. Expression of luteinizing hormone receptors in the mouse penis. J Androl. 2011;32:49e54. Table 1 e Non-gonadal tissue targets of hCG/LH actions in females. Targets Oocyte Early embryo Human embryonic stem cells Fallopian tubes Uterus Cervix Placenta Decidua Cells of immune system Fetal membranes Several brain regions, including pineal gland Spinal cord Neural retina Adrenal cortex Skin Mammary glands Bone Adipose tissue Urinary bladder Target tissue vasculature Umbilical cord j o u r n a l o f r e p r o d u c t i v e h e a l t h a n d m e d i c i n e 1 ( 2 0 1 5 ) 1 e32
  3. 3. 14. Parrott AM, Sriram G, Liu Y, Matthews MB. Expression of type II chorionic gonadotropin genes supports a role in the male reproductive system. Mol Cell Biol. 2010;2:287e299. C.V. Rao* Professor of Cell Biology, Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA Carlo Ticconi Academic Department of Biomedicine and Prevention, Section of Gynecology and Obstetrics, Tor Vergata University, Rome, Italy Clinical Department of Surgery, Division of Gynecology and Obstetrics, University Hospital Policlinico Tor Vergata, Rome, Italy *Corresponding author. Molecular Human Genetics and Obstetrics and Gynecology, Director of Reproduction Development Program, 1120 SW 8th St. GL 495C, Miami, FL 33199, USA. Tel.: þ1 305 348 0659; fax: þ1 305 348 1577. E-mail address: Available online 2 October 2014 2214-420X/Copyright © 2014, Reed Elsevier India Pvt. Ltd. All rights reserved. j o u r n a l o f r e p r o d u c t i v e h e a l t h a n d m e d i c i n e 1 ( 2 0 1 5 ) 1 e3 3