An Overview on the Role of Prolactin and its Receptors in the Reproductive System of Women with External Genital Endometriosis

Numerous studies on animal models endow prolactin with multiple functions, both physiological (reproduction, lactation, growth, metabolism, transport and electrolyte behaviour) and pathological (immunity and carcinogenesis). Prolactin is an acidophilic cells hormone of the anterior pituitary gland. For the past decade, there have been many discoveries regarding the functions of prolactin and its receptor (PRL-R). Prolactin has its effect by binding to membrane-bound receptor isoforms, known as long-form and short-form receptors. The PRL-R receptor is expressed in various tissues, such as the mammary gland, prostate gland, ovaries, immune system cells, adipocytes, liver, etc. One of the most well-known functions of prolactin is to stimulate the proliferation and differentiation of breast cells necessary for lactation. Animal models have provided information on the biology of prolactin proteins and give convincing evidence that each prolactin isoform has independent biological functions. It is important to remember that excessive secretion of this hormone is associated with such symptoms as hypogonadism and infertility. Today, up to 40% of all female infertility cases are caused by hyperproduction of prolactin. One of the infertility causes is  a combination of hyperprolactinemia and external genital endometriosis, which is currently not well studied. It remains relevant to determine the role of prolactin and dopamine in the pathogenesis of  infertility in women with external genital endometriosis and the possibility of using dopamine agonists in the treatment of this disease. This review focuses on the role of prolactin and its receptors in the pathogenesis of infertility associated with endometriosis.

prolactin receptors, endometriosis, infertility, prolactin, hyperolactinemia, anovulation

1. Ali S, Pellegrini I, Kelly PA. A prolactin-dependent immune cell line (Nb2) expresses a mutant form of prolactin receptor. J Biol Chem. 1991 Oct 25;266(30):20110-7.

2. Arden KC, Boutin JM, Djiane J, Kelly PA, Cavenee WK. The receptors for prolactin and growth hormone are localized in the same region of human chromosome 5. Cytogenet Cell Genet. 1990;53(2-3):161–5.

3. Bachelot A, Beaufaron J, Servel N, Kedzia C, Monget P, Kelly PA, Gibori G, Binart N. Prolactin independent rescue of mouse corpus luteum life span: identification of prolactin and luteinizing hormone target genes. Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E676–84. doi: 10.1152/ajpendo.91020.2008.

4. Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA. 1990 Sep;87(18):6934–8. doi: 10.1073/pnas.87.18.6934

5. Bernard V, Young J, Chanson P, Binart N. New insights in prolactin: pathological implications. Nature Reviews Endocrinology. 2015 Mar 17;11(5):265–75. doi: 10.1038/nrendo.2015.36

6. Bernard V, Young J, Binart N. Prolactin — a pleiotropic factor in health and disease. Nature Reviews Endocrinology. 2019 Mar 21;15(6):356–65. doi: 10.1038/s41574-019-0194-6

7. Bernichtein S, Touraine P, Goffin V. New concepts in prolactin biology. J Endocrinol. 2010 Jul;206(1):1–11. doi: 10.1677/JOE-10-0069

8. Bethea CL, Neill JD. Lesions of the Suprachiasmatic Nuclei Abolish the Cervically Stimulated Prolactin Surges in the Rat*. Endocrinology. 1980 Jul;107(1):1–5. doi: 10.1210/endo-107-1-1

9. Bouilly J, Sonigo C, Auffret J, Gibori G, Binart N. Prolactin signaling mechanisms in ovary. Molecular and Cellular Endocrinology. 2012 Jun;356(1–2):80–7. doi: 10.1016/j.mce.2011.05.004

10. Boutin JM, Edery M, Shirota M, Jolicoeur C, Lesueur L, Ali S, Gould D, Djiane J, Kelly PA. Identification of a cDNA encoding a long form of prolactin receptor in human hepatoma and breast cancer cells. Mol Endocrinol. 1989 Sep;3(9):1455–61. doi: 10.1210/mend-3-9-1455

11. Brooks CL. Molecular Mechanisms of Prolactin and Its Receptor. Endocrine Reviews. 2012 Aug;33(4):504–25. doi: 10.1210/er.2011-1040

12. Brooks AJ, Waters MJ. The growth hormone receptor: mechanism of activation and clinical implications. Nature Reviews Endocrinology [Internet]. 2010 Sep 1 [cited 2020 Apr 24];6(9):515–525. doi: 10.1038/nrendo.2010.123

13. Cabrera-Reyes EA, Limon-Morales O, RiveroSegura NA, Camacho-Arroyo I, Cerbon M. Prolactin function and putative expression in the brain. Endocrine. 2017 Aug;57(2):199–213. doi: 10.1007/s12020-017-1346-x

14. Chen W, Guo X, Jin Z, Li R, Shen L, Li W1, Cai W. Transcriptional alterations of genes related to fertility decline in male rats induced by chronic sleep restriction. Syst Biol Reprod Med. 2020 Apr;66(2):99–111. doi: 10.1080/19396368.2019.1678694

15. Chen Y, Moutal A, Navratilova E, Kopruszinski C, Yue X, Ikegami M, et al. The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females. Science Translational Medicine. 2020 Feb 5;12(529):eaay7550. doi: 10.1126/scitranslmed.aay7550

16. Clevenger CV, Chang WP, Ngo W, Pasha TL, Montone KT, Tomaszewski JE. Expression of prolactin and prolactin receptor in human breast carcinoma. Evidence for an autocrine/paracrine loop. Am J Pathol. 1995;146(3):695–705.

17. Clevenger CV, Medaglia MV. The protein tyrosine kinase P59fyn is associated with prolactin (PRL) receptor and is activated by PRL stimulation of Tlymphocytes. Mol Endocrinol. 1994 Jun;8(6):674–81. doi: 10.1210/mend.8.6.7935483

18. Clevenger CV, Sillman AL, Hanley-Hyde J, Prystowsky MB. Requirement for prolactin during cell cycle regulated gene expression in cloned Tlymphocytes. Endocrinology. 1992 Jun;130(6):3216–22. doi: 10.1210/endo.130.6.1534539

19. Clevenger CV, Torigoe T, Reed JC. Prolactin induces rapid phosphorylation and activation of prolactin receptor-associated RAF-1 kinase in a Tcell line. J Biol Chem. 1994 Feb 25;269(8):5559–65.

20. Das R, Vonderhaar BK. Transduction of prolactin's (PRL) growth signal through both long and short forms of the PRL receptor. Mol Endocrinol. 1995 Dec;9(12):1750–9. doi: 10.1210/mend.9.12.8614411

21. Esmaeilzadeh S, Mirabi P, Basirat Z, Zeinalzadeh M, Khafri S. Association between endometriosis and hyperprolactinemia in infertile women. Iran J Reprod Med. 2015;13(3):155–60.

22. Eyal O, Jomain JB, Kessler C, Goffin V, Handwerger S. Autocrine prolactin inhibits human uterine decidualization: a novel role for prolactin. Biol Reprod. 2007; 76:777e83. doi: 10.1095/biolreprod.106.053058

23. Gao Y, Shen M, Ma X, Li J, Wang B, Wang J, et al. Seven Hormonal Biomarkers for Diagnosing Endometriosis: Meta-Analysis and Adjusted Indirect Comparison of Diagnostic Test Accuracy. Journal of Minimally Invasive Gynecology. 2019 Sep;26(6):1026-1035.e4. doi: 10.1016/j.jmig.2019.04.004

24. Goffin V, Shiverick KT, Kelly PA, Martial JA. Sequence-Function Relationships Within the Expanding Family of Prolactin, Growth Hormone, Placental Lactogen, and Related Proteins in Mammals*. Endocrine Reviews. 1996 Aug;17(4):385–410. doi: 10.1210/edrv-17-4-385

25. Grattan DR, Kokay IC. Prolactin: a pleiotropic neuroendocrine hormone. J Neuroendocrinol. 2008 Jun;20(6):752–63. doi: 10.1111/j.1365-2826.2008.01736.x.

26. Grattan DR, Szawka RE. Kisspeptin and Prolactin. Semin Reprod Med. 2019 Mar;37(2):93–104. doi: 10.1055/s-0039-3400956.

27. Gregoriou G, Bakas P, Vitoratos N, Papadias K, Goumas K, Chryssicopoulos A, et al. Evaluation of Serum ProlactinLevels in Patients with Endometriosisand Infertility. Gynecologic and Obstetric Investigation. 1999;48(1):48–51. doi: 10.1159/000010133

28. Grosdemouge I, Bachelot A, Lucas A, Baran N, Kelly PA, Binart N. Reproductive Biology and Endocrinology. 2003;1(1):12. doi: 10.1186/1477-7827-1-12

29. Huang C, Snider F, Cross JC. Prolactin Receptor Is Required for Normal Glucose Homeostasis and Modulation of β-Cell Mass during Pregnancy. Endocrinology. 2009 Apr;150(4):1618–26. doi: 10.1210/en.2008-1003

30. Bakowska JC, Morrell JI. The distribution of mRNA for the short form of the prolactin receptor in the forebrain of the female rat. Molecular Brain Research. 2003 Aug;116(1–2):50–8. doi: 10.1016/s0169-328x(03)00213-4

31. Kokay IC, Petersen SL, Grattan DR. Identification of prolactin-sensitive GABA and kisspeptin neurons in regions of the rat hypothalamus involved in the control of fertility. Endocrinology. 2011;152:526e35. doi: 10.1210/en.2010-0668

32. Kokay IC, Wyatt A, Phillipps HR, Aoki M, Ectors F, Boehm U, et al. Analysis of prolactin receptor expression in the murine brain using a novel prolactin receptor reporter mouse. Journal of Neuroendocrinology. 2018 Aug 23;30(9):e12634. doi: 10.1111/jne.12634

33. Ladyman SR, Hackwell ECR, Brown RSE. The role of prolactin in co-ordinating fertility and metabolic adaptations during reproduction. Neuropharmacology. 2020 May 1;167:107911. doi: 10.1016/j.neuropharm.2019.107911.

34. Lesueur L, Edery M, Ali S, Paly J, Kelly PA, Djiane J. Comparison of long and short forms of the prolactin receptor on prolactin-induced milk protein gene transcription. Proc Natl Acad Sci USA. 1991;88(3):824–828. doi: 10.1073/pnas.88.3.824

35. Li R, Kondegowda NG, Filipowska J, Hampton RF, Leblanc S, Garcia-Ocana A, et al. Lactogens Reduce Endoplasmic Reticulum Stress-induced Rodent and Human β-cell Death and Diabetes Incidence in Akita Mice. Diabetes. 2020 Apr 24;db190909. doi: 10.2337/db19-0909

36. Ling C, Svensson L, Oden B, Weijdegard B, Eden B, Eden S. Identification of functional prolactin (PRL) receptor gene expression: PRL inhibits lipoprotein lipase activity in human white adipose tissue. J Clin Endocrinol Metab. 2003;88:1804–8. doi: 10.1210/jc.2002-021137

37. Matalliotakis I, Panidis D, Vlassis G, Vavilis D, Neonaki M, Koumantakis E. PRL, TSH and their response to the TRH test in patients with endometriosis before, during, and after treatment with danazol. Gynecol Obstet Invest. 1996;42:183–86. doi: 10.1159/000291947

38. Mirabi P, Alamolhoda SH, Golsorkhtabaramiri M, Namdari M, Esmaeilzadeh S. Prolactin concentration in various stages of endometriosis in infertile women. JBRA Assist Reprod. 2019 Aug 22;23(3):225–9. doi: 10.5935/1518-0557.20190020

39. Motamedi B, Rafiee-Pour H-A, Khosravi M-R, Kefayat A, Baradaran A, Amjadi E, et al. Prolactin receptor expression as a novel prognostic biomarker for triple negative breast cancer patients. Annals of Diagnostic Pathology. 2020 Jun;46:151507. doi: 10.1016/j.anndiagpath.2020.151507

40. Nagano M, Kelly PA. Tissue distribution and regulation of rat prolactin receptor gene expression. Quantitative analysis by polymerase chain reaction. J Biol Chem. 1994 May 6;269(18):13337–45.

41. Ben-Jonathan N, LaPensee CR, LaPensee EW. What Can We Learn from Rodents about Prolactin in Humans? Endocrine Reviews. 2007 Dec 5;29(1):1–41. doi: 10.1210/er.2007-0017

42. Ben-Jonathan N, Mershon Jl, Allen Dl, Steinmetz RW. Extrapituitary Prolactin: Distribution, Regulation, Functions, and Clinical Aspects. Endocrine Reviews. 1996 Dec;17(6):639–69. doi: 10.1210/edrv-17-6-639

43. Ouhtit A, Morel G, Kelly PA. Visualization of Gene Expression of Short and Long Forms of Prolactin Receptor in Rat Reproductive Tissues. Biology of Reproduction. 1993 Sep 1;49(3):528–36. doi: 10.1095/biolreprod49.3.528

44. Panidis D, Vavilis D, Rousso D, Panidou E, Kalogeropoulos A. Provocative tests of prolactin before, during and after long-term danazol treatment in patients with endometriosis. Gynecological Endocrinology. 1992 Jan;6(1):19–24. doi: 10.3109/09513599209081002

45. Phillipps HR, Yip SH, Grattan DR. Patterns of prolactin secretion. Molecular and Cellular Endocrinology. 2020 Feb;502:110679. doi: 10.1016/j.mce.2019.110679

46. Qazi AM, Tsai-Morris C-H, Dufau ML. LigandIndependent Homo- and Heterodimerization of Human Prolactin Receptor Variants: Inhibitory Action of the Short Forms by Heterodimerization. Molecular Endocrinology. 2006 Aug;20(8):1912–23. doi: 10.1210/me.2005-0291

47. Rivera JC, Aranda J, Riesgo J, Nava G, Thebault S, López-Barrera F, et al. Expression and cellular localization of prolactin and the prolactin receptor in mammalian retina. Experimental Eye Research. 2008 Feb;86(2):314–21. doi: 10.1016/j.exer.2007.11.003

48. Sangeeta Devi Y, Halperin J. Reproductive actions of prolactin mediated through short and long receptor isoforms. Molecular and Cellular Endocrinology. 2014 Jan;382(1):400–10. doi: 10.1016/j.mce.2013.09.016

49. Shirota M, Banville D, Ali S, Jolicoeur C, Boutin J-M, Edery M, et al. Expression of Two Forms of Prolactin Receptor in Rat Ovary and Liver. Molecular Endocrinology. 1990 Aug;4(8):1136–43. doi: 10.1210/mend-4-8-1136

50. Silva JF, Henriques PC, Campideli-Santana AC, Araujo-Lopes R, Aquino NSS, Hipolito LTM, et al. Estradiol Potentiates But Is Not Essential for Prolactin-Induced Suppression of Luteinizing Hormone Pulses in Female Rats. Endocrinology. 2020 Feb 13;161(4). doi: 10.1210/endocr/bqaa022

51. Stevens AM, Yu-Lee LY. Multiple prolactinresponsive elements mediate G1 and S phase expression of the interferon regulatory factor-1 gene. Molecular Endocrinology. 1994 Mar;8(3):345–55. doi: 10.1210/mend.8.3.8015552

52. Thoreau E, Petridou B, Kelly PA, Djiane J, Mornon JP. Structural symmetry of the extracellular domain of the Cytokine/Growth hormone/Prolactin receptor family and Interferon receptors revealed by Hydrophobic Cluster Analysis. FEBS Letters. 1991 Apr 22;282(1):26–31. doi: 10.1016/0014-5793(91)80437-8

53. Toulis KA, Goulis DG, Kolibianakis EM, Venetis CA, Tarlatzis BC, Papadimas I. Risk of gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a metaanalysis. Fertility and Sterility. 2009 Aug;92(2):667–77. doi: 10.1016/j.fertnstert.2008.06.045

54. Tufa DM, Shank T, Yingst AM, Trahan GD, Shim S, Lake J, et al. Prolactin Acts on Myeloid Progenitors to Modulate SMAD7 Expression and Enhance Hematopoietic Stem Cell Differentiation into the NK Cell Lineage. Scientific Reports. 2020 Apr 14;10(1). doi: 10.1038/s41598-020-63346-4

55. Wang H, Gorpudolo N, Behr B. The Role of Prolactin– and Endometriosis-Associated Infertility. Obstetrical & Gynecological Survey. 2009 Aug;64(8):542–7. doi: 10.1097/OGX.0b013e3181ab5479