Skip to main content
SpringerLink
Log in

Why are We Waiting to Start Large Scale Clinical Testing of Human Chorionic Gonadotropin for the Treatment of Preterm Births?

  • Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Preterm births are an expensive global health problem. Despite the basic science and clinical research advances to better understand and prevent preterm births, the rates are increasing. There are several therapeutic options. While some options such as progestins work for selected women, others such as magnesium sulfate can only be used for delaying births for 24 to 48 hours so that the patients can be treated with corticosteroids to promote fetal lung maturity. Based on the scientific and clinical evidence, we recommend testing human chorionic gonadotropin in a large multicenter, randomized, double-blind, and placebo-controlled clinical trials in women with active preterm labor and those with a previous history of preterm births. Human chorionic gonadotropin is not only inexpensive but also has not shown any side effects so far in the infants or in the mothers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Martin JAPreterm births-United States, 2006 and 2010; Centers for Disease Control and Prevention. MMWR Surveill Summ. 2013;62(suppl 3):136–138.

    Google Scholar 

  2. Centers for Disease Control and Prevention. Preterm Births. Web site. http://www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm. Updated October 28, 2015. Accessed November 2015.

  3. Baker B. Evidence-based practice to improve outcomes for late preterm infants. J Obstet Gynecol Neonatal Nurs. 2015;44(1):127–134.

    Article  PubMed  Google Scholar 

  4. Maitre NL, Ballard RA, Ellenberg JH, Greenberg JM, Hamvas A, Pryhuber GS. State-of- the-art. Respiratory consequences of prematurity: evolution of a diagnosis and development of a comphehensive approach. J Perinatol. 2015;35(5):1–9.

    Article  Google Scholar 

  5. Theplib A, Phupong V. Success rate of terbuline in inhibiting pre-term labor for 48 h. J Matern Fetal Neonatal Med. 2015:1–4.

  6. Bennett P, Edwards V. Use of magnesium sulfate in obstetrics. Lancet. 1997;350(9090):1491.

    Article  CAS  PubMed  Google Scholar 

  7. Lei ZM, Rao CV. Endocrinology of the trophoblast tissue. In: Becker K Principles and Practice of Endocrinology and Metbaolism, 3rd Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 1096–1102.

  8. Licht P, Cao H, Lei ZM, Rao ChV, Merz WM. Novel self-regulation of human chorionic gonadotropin biosynthesis in term pregnancy human placenta. Endocrinology. 1993;133(6):3014–3025.

    Article  CAS  PubMed  Google Scholar 

  9. Fritz MC, Speroff L. Chapter 8, Endocrinology of Pregnancy, In: Clinical Gynecologic Endocrinology and Infertility. 8th edition. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011: 269–330.

    Google Scholar 

  10. Lin J, Lojun S, Lei ZM, Wu WX, Peiper SC, Rao ChV. Lymphocytes from pregnant women express human chorionic gonadotropin / luteinizing hormone receptor gene. Mol Cell Endocrinol. 1995;111(1):r13–r17.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang YM, Lei ZM, Rao ChV. Functional importance of human monocyte luteinizing hormone and chorionic gonadotropin receptors. J Soc Gynecol Invest. 1999;6(suppl 1):Abstr 46.

    Google Scholar 

  12. Rao CV. Nongonadal actions of LH and hCG in reproductive biology and medicine. Sem Reprod Med. 2001l;(Guest editor);19(1):1–119.

    Google Scholar 

  13. Zhang YM, Rao ChV, Lei ZM. Macrophages in human reproductive tissues contain luteinizing hormone/chorionic gonadotropin receptors. Am J Reprod Immunol. 2003;49(2):93–100.

    Article  CAS  PubMed  Google Scholar 

  14. Yoshimura T, Inaba M, Suguira K, et al. Analyses of dendritic cell subsets in pregnancy. Am J Reprod Immunol. 2003;50(2):137–145.

    Article  CAS  PubMed  Google Scholar 

  15. Rao CV, Lei ZM. The past, present and future of nongonadal LH/hCG actions in reproductive biology and medicine. Mol Cell Endocrinol. 2007;269(1–2):2–8.

    Article  CAS  PubMed  Google Scholar 

  16. Rahman N, Rao CV. Recent progress in luteinizing hormone/human chorionic gonadotropin hormone research. Mol Human Reprod. 2009;15(11):703–711.

    Article  CAS  Google Scholar 

  17. Tsampalas M, Gridelet V, Berndt S, Foidart J-M, Geenen V, d’Hauterive SP. Human chorionic gonadotropin: a hormone with immunological and angiogenic properties. J Reprod Immunol. 2010;85(1):93–98.

    Article  CAS  PubMed  Google Scholar 

  18. Ambrus G, Rao ChV. Novel regulation of pregnant human myometrial smooth muscle cell gap junctions by human chorionic gonadotropin. Endocrinology. 1994;135(6):2772–2779.

    Article  CAS  PubMed  Google Scholar 

  19. Eta E, Ambrus G, Rao ChV. Direct regulation of human myometrial contractions by human chorionic gonadotropin. J Clin Endocrinol Metab. 1994;79(6):1582–1586.

    CAS  PubMed  Google Scholar 

  20. Slattery MM, Brennan C, O’Leary MJ, Morrison JJ. Human chorionic gonadotropin inhibition of pregnant human myometrial contractility. Brit J Obstet Gynaecol. 2001;108(7):704–708.

    CAS  Google Scholar 

  21. Rao ChV. Novel concepts in neuroendocrine regulation of reproductive tract functions. In: Bazer FW Endocrinology of Pregnancy. Totowa, NJ: The Human Press Inc, 1998: chapter 5:125–144.

    Chapter  Google Scholar 

  22. Reshef E, Lei ZM, Rao ChV, Pridham DD, Chegini N, Luborsky JL. The presence of gonadotropin receptors in nonpregnant human uterus, human placenta, fetal membranes and decidua. J Clin Endocrinol Metab. 1990;70(2):421–430.

    Article  CAS  PubMed  Google Scholar 

  23. Körneyei JL, Lei ZM, Rao ChV. Human myometrial smooth muscle cells are novel targets of direct regulation by human chorionic gonadotropin. Biol Reprod. 1993;49(6):1149–1157.

    Article  Google Scholar 

  24. Toth P, Li X, Rao ChV, et al. Expression of functional human chorionic gonadotropin/human luteinizing hormone receptor gene in human uterine arteries. J Clin Endocrinol Metab. 1994;79(1): 307–315.

    CAS  PubMed  Google Scholar 

  25. Zuo J, Lei ZM, Rao ChV. Human myometrial chorionic gonadotropin/luteinizing hormone receptors in preterm and term deliveries. J Clin Endocrinol Metab. 1994;79(3):907–911.

    CAS  PubMed  Google Scholar 

  26. Kurtzman J, Wilson H, Rao ChV. A proposed role for hCG in clinical obstetrics. Sem Reprod Med. 2001;19(1):63–68.

    Article  CAS  Google Scholar 

  27. Ticconi C, Piccione E, Belmonte A, Rao Ch V. HCG - A new kid on the block in the prematurity prevention. J Matern Fetal Neonatal Med. 2006;19(11):687–692

    Article  CAS  PubMed  Google Scholar 

  28. Toppozada MK. Does hCG have a direct effect on the human myometrium? abstract. Fertil Steril 1998;70:s68.

    Google Scholar 

  29. Europe-Finner GN, Phaneuf S, Watson SP, Lopez Bernal A. Identification and expression of G-proteins in human myometrium: upregulation of G alpha in pregnancy. Endocrinology. 1993();132(6):2484–2490.

    Article  CAS  PubMed  Google Scholar 

  30. Lin DX, Lei ZM, Rao ChV. Dependence of uterine cyclooxygenase2 expression on luteinizing hormone signaling. Biol Reprod. 2005;73(2):256–260.

    Article  CAS  PubMed  Google Scholar 

  31. Belmonte A, Ticconi C, Dolci S, et al. Regulation of phosphodiesterase 5 expression and activity in human pregnant and non-pregnant myometrial cells by human chorionic gonadotropin. J Soc Gynecol Invest. 2005;12(8):570–577.

    Article  CAS  Google Scholar 

  32. Ticconi C, Zicari A, Belmonte A, Realacci M, Rao ChV, Piccione E. Pregnancy – promoting actions of hCG in human myometrium and fetal membranes. Placenta. 2007;28(suppl a):s137–s143.

    Article  PubMed  CAS  Google Scholar 

  33. Mehats C, Schmitz T, Breuiller-Fouche M, Leroy M-J, Cabrol D. Should phosphodiesterase 5 selective inhibitors be used for uterine relaxation? Am J Obstet Gynecol. 2006;195(1):184–185.

    Article  CAS  PubMed  Google Scholar 

  34. Doheny HC, Houlihan DD, Ravikumar N, Smith TJ, Morrison JJ. Human chorionic gonadotropin relaxation of human pregnant myometrium and activation of the BKca channel. J Clin Endocrinol Metab. 2003;88(9):4310–4315.

    Article  CAS  PubMed  Google Scholar 

  35. Lin DX, Lei ZM, Li X, Rao ChV. Targeted disruption of LH receptor gene revealed the importance of uterine LH signaling. Mol Cell Endocrinol. 2005;234(1–2):105–116.

    Article  CAS  PubMed  Google Scholar 

  36. Zuo J, Lei ZM, Rao ChV, Pietrantoni M, Cook VD. Differential cyclooxygenase-1 and -2 gene expression in human myometria from preterm and term deliveries. J Clin Endocrinol Metab. 1994;79(3):894–899.

    CAS  PubMed  Google Scholar 

  37. Toth P. Clinical data supporting the importance of vascular LH/hCG receptors of uterine blood vessels. Sem Reprod Med. 2001;19(1):55–61.

    Article  CAS  Google Scholar 

  38. Lin PC, Li X, Lei ZM, Rao ChV. Human cervix contains functional luteinizing hormone/ human chorionic gonadotropin receptors. J Clin Endocrinol Metab. 2003;88(7):3409–3414.

    Article  CAS  PubMed  Google Scholar 

  39. Ticconi C, Belmonte A, Piccione E, Rao CV. Feto-placental communication system with myometrium in pregnancy and parturition: the role of hormones, neurohormones, inflammatory mediators, and locally active factors. J Mat Fetal Neonat Med. 2006;19(3):125–133.

    Article  CAS  Google Scholar 

  40. Bao S, Rai J, Schreiber J. Expression of nitric oxide synthase isoforms in human pregnant myometrium at term. J Soc Gynecol Invest. 2002;9(6):351–356.

    Article  CAS  Google Scholar 

  41. Flowers B, Ziecik AJ, Caruolo EV. Effects of human chorionic gonadotropin on contractile activity of steroid-primed pig myometrium in vitro. J Reprod Fertil. 1991;92(2):425–432.

    Article  CAS  PubMed  Google Scholar 

  42. Angioni S, Spedicato M, Rizzo A, et al. In vitro activity of human chorionic gonadotropin (hCG) on myometrium contractility. Gynecol Endocrinol. 2011;27(3);180–184.

    Article  CAS  PubMed  Google Scholar 

  43. Mukherjee D, Manna PR, Bhattacharya S. Functional relevane of luteinizing hormone receptor in mouse uterus. Eur J Endocrinol. 1994;131(1):103–108.

    Article  CAS  PubMed  Google Scholar 

  44. Debnath S, Mukherjee D, Bhattacharya SP. Stimulation of preg-nenolone metabolism and aromatase activity by luteinizing hormone in mouse uterus. Eur J Endocrinol. 2000;143(6):799–807.

    Article  CAS  PubMed  Google Scholar 

  45. Zheng M, Shi H, Segaloff DL, Van Voorhis J. Expression and localization of luteinizing hormone receptor in the female mouse reproductive tract. Biol Reprod. 2001;64(1):179–187.

    Article  CAS  PubMed  Google Scholar 

  46. Kaga N, Katsuki Y, Obata M, Shibutani Y. Repeated administration of low-dose lipopolysaccharide induces preterm delivery in mice: a model for human preterm parturition and for assessment of the therapeutic ability of drugs against preterm delivery. Am J Obstet Gynecol. 1996;174(2):754–759.

    Article  CAS  PubMed  Google Scholar 

  47. Elovitz MA, Mrinalini C. The use of progestational agents for pre-term birth: Lessons from a mouse model. Am J Obstet Gynecol. 2006;195(4):1004–1010.

    Article  CAS  PubMed  Google Scholar 

  48. Kemp MW, Saito M, Newnham JP, Nitsos I, Okamura K, Kallapur SG. Preterm birth, infection, and inflammation advances from the study of animal models. Reprod Sci. 2010;17(7):619–628.

    Article  PubMed  Google Scholar 

  49. Bezold KY, Karjalainen MK, Hallman M, Teramo K, Muglia LJ. The genomics of preterm birth: from animal models to human studies. Genome Med. 2013;5(4):34.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kurtzman JT, Spinnato JT, Goldsmith LJ, et al. Human chorionic gonadotropin exhibits potent inhibition of preterm delivery in a small animal model. Am J Obstet Gynecol. 1999;181(4):853–857.

    Article  CAS  PubMed  Google Scholar 

  51. Rao ChV. Differential properties of human chorionic gonadotropin and human luteinizing hormone binding to plasma membranes of bovine corpora lutea. Acta Endocrinol. 1979;90(4):696–710.

    Article  CAS  Google Scholar 

  52. Kurtzman J, Jones E, Goldsmith LJ, et al. Inhibition of preterm delivery by human chorionic gonadotropin is associated with down-regulation of myometrial gap junctions. Am J Obstet Gynecol. 2000;182:s201.

    Google Scholar 

  53. Ali AFM, Fateen B, Ezzet A, Badawy H, Ramadan A, El-tobge A. Treatment of preterm labor with human chorionic gonadotropin: a new modality. Am J Obstet Gynecol. 2000;95(4 suppl 1):s61.

    Google Scholar 

  54. Than NG, Itakura A, Rao CV, et al. Clinical applications of pregnancy-related proteins – a workshop report. Placenta. 2003; 24(suppl. a):s60–s64.

    Article  PubMed  CAS  Google Scholar 

  55. Lorzadeh N, Dehnoori A, Momennasab M. Human chorionic gonadotropin (hCG) versus magnesium sulfate to arrest preterm. Yafteh. 2004;5(3):41–46.

    Google Scholar 

  56. Sakhavar N, Mirteimoori M, Teimoori B. Magnesium sulfate versus hCG (Human Chorionic Gonadotropin) in suppression of pre-term labor. Shiraz E-Med J. 2008;9(3):134–140.

    Google Scholar 

  57. Rani VU, Reddy AM, Singh A, Malathi P. Role of hCG in preventing preterm labour in comparison with vaginal progesterone. Indian Pract. 2012;65:1–6.

    Google Scholar 

  58. Suhag A, Saccone G, Berghella V. Vaginal progesterone for maintenance tocolysis: a systematic review and meta-analysis of randomized trials. Am J Obstet Gynecol. 2015;213(4):479–487.

    Article  CAS  PubMed  Google Scholar 

  59. Meis PJ, Klebanoff M, Thorn E, et al. Prevention of recurrent pre-term delivery by 17 alpha-hydroxyprogesterone caproate. New Engl J Med. 2003;348(24):2379–2385.

    Article  CAS  PubMed  Google Scholar 

  60. Rozenberg P, Chauveaud A, Deruelle P, et al. Prevention of pre-term delivery after successful tocolysis in preterm labor by 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Am J Obstet Gynecol. 2012;206(3):206e1–206e9

    Article  CAS  Google Scholar 

  61. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo-controlled double blind study. Am J Obstet Gynecol. 2003;188(2):419–424.

    Article  PubMed  CAS  Google Scholar 

  62. Martinez de Tejada B, Karolinski A, Ocampo MC, et al. Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): randomized doubled-blind placebo-controlled trial. Brit J Obstet Gynecol. 2015;122(1):80–91.

    Article  CAS  Google Scholar 

  63. Keirse MJ. Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynaecol. 1990;97(2):149–154.

    Article  CAS  PubMed  Google Scholar 

  64. Anderson L, Martin W, Higgins C, Nelson SM, Norman JE. The effect of progesterone on myometrial contractility, potassium channels, and tocolytic efficacy. Reprod Sci. 2009;16(11):1052–1061.

    Article  CAS  PubMed  Google Scholar 

  65. Mesiano S, Welsh TN. Steroid hormone control of myometrial contractility and parturition. Semin Cell Dev Biol. 2007;18(3):321–331.

    Article  CAS  PubMed  Google Scholar 

  66. O’Brien JM. The safety of preogesterone and 17-hydroxyprogesterone caproate administration for the prevention of preterm birth: an evidence-based assessment. Am J Perinatol. 2012;29(9):665–672.

    Article  PubMed  Google Scholar 

  67. Deeks ED.17 α-Hydroxyprogesterone caproate (Makena) in the prevention of preterm birth. Paediatr Drugs. 2011;13(5):337–345.

    Article  PubMed  Google Scholar 

  68. Hines M, Lyseng-Williamson KA, Deeks ED. 17 α-hydroxyprogesterone caproate (Makena), A guide to its use in the prevention of preterm births. Clin Drug Invest. 2013;33(3):223–227.

    Article  CAS  Google Scholar 

  69. Merlob P, Stahl B, Klinger G. 17α Hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth. Reprod Toxicol. 2012;33(1):15–19.

    Article  CAS  PubMed  Google Scholar 

  70. Christian MS, Brent RL, Calda P. Embryo-fetal toxicity signals for 17 α-hydroxyprogesterone caproate in high-risk pregnancies: a review of the non-clinical literature for embryo-fetal toxicity with progestins. J Mat Fetal Neonat Med. 2007;20(2):89–112.

    Article  CAS  Google Scholar 

  71. Rebarber A, Istwan NB, Russo-Stieglitz K, et al. Increased incidence of gestational diabetes in women receiving prophylactic 17 α-hydroxyprogesterone caproate for prevention of recurrent preterm delivery. Diabetes Care. 2007;30(9):2277–2280.

    Article  CAS  PubMed  Google Scholar 

  72. Carmicheal SL, Shaw GM, Laurent C, Croughan MS, Olnet RS, Lammer EJ. Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med. 2005;159(10):957–962.

    Article  Google Scholar 

  73. Phillips RJ, Tyson-Capper AJ, Bailey J, Robson SC, Europe-Finner GN. Regulation of expression of the chorionic gonadotropin/luteinizing hormone receptor gene in the human myometrium: Involvement of specificity protein-1 (Sp1), Sp3, Sp4, Sp-like proteins, and histone deacetylases. J Clin Endocrinol Metab. 2005;90(6):3479–3490.

    Article  CAS  PubMed  Google Scholar 

  74. Condon JC, Jeyasuria P, Faust JM, Wilson JW, Mendelson CR. A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition. Proc Natl Acad Sci U S A. 2003;100(16):9518–9523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Cellular Biology and Pharmacology, Molecular and Human Genetics and Obstetrics and Gynecology, Reproduction and Development Program, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, GL 495 C, 33199, Miami, FL, USA

    C. V. Rao PhD

Authors
  1. C. V. Rao PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. V. Rao PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rao, C.V. Why are We Waiting to Start Large Scale Clinical Testing of Human Chorionic Gonadotropin for the Treatment of Preterm Births?. Reprod. Sci. 23, 830–837 (2016). https://doi.org/10.1177/1933719115620498

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719115620498

Keywords

Search

Navigation