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Gonadotropins and the Uterus: Is There a Gonad-Independent Pathway?

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Abstract

In the gonads, LH and hCG act via the same receptor to stimulate the production of progesterone in the luteal phase of the menstrual cycle and in early pregnancy. There are numerous reports that these two hormones can have direct actions on the uterus in addition to their indirect actions via stimulation of ovarian steroid hormones. However, unlike the situation in the gonads, various uterine tissues have been shown to respond to the related hormones FSH and TSH or the α-subunit common to these hormones. These additional actions cannot be mediated by the gonadal LH/hCG receptor. There have also been a series of reports that the uterus contains LH/hCG receptors. Attempts to characterize the molecular structure of these receptors have been difficult; thus, the possibility of a variant receptor cannot be excluded. The possibility also exists of a nonhomologous receptor, which would explain the differences in ligand specificity in uterine tissues. I will review the evidence regarding gonadotropin action in nongonadal tissues, primarily the uterus. In addition, the data regarding receptors will be reviewed. Finally, the clinical areas informed by this information will be explored.

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References

  1. Lapthorn AJ, Harris DC, Littlejohn A, et al. Crystal structure of human chorionic gonadotropin [see comments]. Nature 1994; 369:455–61.

    Article  CAS  PubMed  Google Scholar 

  2. Wu H, Lustbader JW, Liu Y, Canfield RE, Hendrickson WA. Structure of human chorionic gonadotropin at 2.6 A resolution from MAD analysis of the selenomethionyl protein. Structure 1994; 2:545–58.

    Article  CAS  PubMed  Google Scholar 

  3. Patel DJ. Glycoprotein hormones. A clasped embrace. Nature 1994; 369:438–9.

    Article  CAS  PubMed  Google Scholar 

  4. Pierce JG, Parsons TF. Glycoprotein hormones: Structure and function. Annu Rev Biochem 1981; 50:465–95.

    Article  CAS  PubMed  Google Scholar 

  5. Landy H, Schneyer AL, Whitcomb RW, Crowley WF Jr. Validation of highly specific and sensitive radioimmunoassays for Iutropin, follitropin, and free alpha subunit in unextracted urine. Clin Chem 1990; 36:340–4.

    Article  CAS  PubMed  Google Scholar 

  6. Dufau ML. Ovarian and testicular LH/hCG receptors. In: Chin WW, Biome I, eds. Glycoprotein hormones: Structure, synthesis, and biologic function. Norwell, Massachusetts: Serono Symposia, 1990:367–76.

    Google Scholar 

  7. Milius RP, Midgley AR Jr, Birken S. Preferential masking by the receptor of immunoreactive sites on the alpha subunit of human choriogonadotropin. Proc Natl Acad Sci U S A 1983; 80:7375–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ashitaka Y, Nishimura R, Futamura K, Oashi M, Tojo S. Serum and chorionic tissue concentrations of human chorionic gonadotropin and its subunits during pregnancy. Endocrinol Jpn 1974; 21:547–50.

    Article  CAS  PubMed  Google Scholar 

  9. Berkowitz R, Ozturk M, Goldstein D, Bernstein M, Hill L, Wands JR. Human chorionic gonadotropin and free subunits’ serum levels in patients with partial and complete hydatidiform moles. Obstet Gynecol 1989; 74:212–6.

    CAS  PubMed  Google Scholar 

  10. Oppenheim DS, Bikkal H, Crowley WF Jr, Klibanski A. Effects of chronic GnRH analogue administration on gonadotrophin and alpha-subunit secretion in post-menopausal women. Clin Endocrinol (Oxf) 1992; 36:559–64.

    Article  CAS  Google Scholar 

  11. Begeot M, Hemming FJ, Dubois PM, Combamous Y, Dubois MP, Aubert ML. Induction of pituitary lactotrope differentiation by luteinizing hormone alpha subunit. Science 1984; 226:566–8.

    Article  CAS  PubMed  Google Scholar 

  12. Kendall SK, Samuelson LC, Saunders TL, Wood RI, Camper SA. Targeted disruption of the pituitary glycoprotein hormone alpha-subunit produces hypogonadal and hypothyroid mice. Genes Dev 1995; 9:2007–19.

    Article  CAS  PubMed  Google Scholar 

  13. Nowak RA, Rein MS, Heffner LJ, Friedman AJ, Tashjian AH Jr. Production of prolactin by smooth muscle cells cultured from human uterine fibroid tumors. J Clin Endocrinol Metab 1993; 76:1308–13.

    CAS  PubMed  Google Scholar 

  14. Rosenberg SM, Bhatnagar AS. Sex steroid and human chorionic gonadotropin modulation of in vitro prolactin production by human term decidua. Am J Obstet Gynecol 1984; 148:461–5.

    Article  CAS  PubMed  Google Scholar 

  15. Stewart EA, Rein MS, Friedman AJ, Zuchowski L, Nowak RA. Glycoprotein hormones and their common alpha-subunit stimulate prolactin production by explant cultures of human leiomyoma and myometrium. Am J Obstet Gynecol 1994; 170:677–83.

    Article  CAS  PubMed  Google Scholar 

  16. Stewart EA, Jain P, Penglase MD, Friedman AJ, Nowak RA. The myometrium of postmenopausal women produces prolactin in response to human chorionic gonadotropin and alpha-subunit in vitro. Fertil Steril 1995; 64:972–6.

    Article  CAS  PubMed  Google Scholar 

  17. Kornyei JL, Lei ZM, Rao CV. Human myometrial smooth muscle cells are novel targets of direct regulation by human chorionic gonadotropin. Biol Reprod 1993; 49:1149–57.

    Article  CAS  PubMed  Google Scholar 

  18. Ambrus G, Rao CV. Novel regulation of pregnant human myo-metrial smooth muscle cell gap junctions by human chorionic gonadotropin. Endocrinology 1994; 135:2772–9.

    Article  CAS  PubMed  Google Scholar 

  19. Eta E, Ambrus G, Rao CV. Direct regulation of human myo-metrial contractions by human chorionic gonadotropin. J Clin Endocrinol Metab 1994; 79:1582–6.

    CAS  PubMed  Google Scholar 

  20. Han SW, Lei ZM, Rao CV. Up-regulation of cyclooxygenase-2 gene expression by chorionic gonadotropin during the differentiation of human endometrial stromal cells into decidua. Endocrinology 1996; 137:1791–7.

    Article  CAS  PubMed  Google Scholar 

  21. Blithe DL, Richards RG, Skarulis MC. Free alpha molecules from pregnancy stimulate secretion of prolactin from human decidual cells: A novel function for free alpha in pregnancy. Endocrinology 1991; 129:2257–9.

    Article  CAS  PubMed  Google Scholar 

  22. Moy E, Kimzey LM, Nelson LM, Bhthe DL. Glycoprotein hormone alpha-subunit functions synergistically with progesterone to stimulate differentiation of cultured human endometrial stromal cells to decidualized cells: A novel role for free alpha-subunit in reproduction. Endocrinology 1996; 137:1332–9.

    Article  CAS  PubMed  Google Scholar 

  23. Fazleabas AT, Donnelly KM, Srinivasan S, Fortman JD, Miller JB. Modulation of the baboon (Papio anubis) uterine endometrium by chorionic gonadotrophin during the period of uterine receptivity. Proc Nad Acad Sci U S A 1999; 96:2543–8.

    Article  CAS  Google Scholar 

  24. Segaloff DL, Ascoli M. The lutropin/choriogonadotropin receptor … 4 years later. Endocr Rev 1993; 14:324–47.

    CAS  PubMed  Google Scholar 

  25. Minegishi T, Nakamura K, Takakura Y, Ibuki Y, Igarashi M, Minegish T. Cloning and sequencing of human FSH receptor cDNA [published erratum appears in Biochem Biophys Res Commun 1994 Jun 15; 201:1057]. Biochem Biophys Res Com-mun 1991; 175:1125–30.

    Article  CAS  Google Scholar 

  26. Nagayama Y, Kaufman KD, Seto P, Rapoport B. Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor. Biochem Biophys Res Commun 1989; 165:1184–90.

    Article  CAS  PubMed  Google Scholar 

  27. Minegishi T, Nakamura K, Takakura Y, et al. Cloning and sequencing of human LH/hCG receptor cDNA [published erratum appears in Biochem Biophys Res Commun 1994 Jun 15; 201:1057]. Biochem Biophys Res Commun 1990; 172:1049–54.

    Article  CAS  PubMed  Google Scholar 

  28. McFarland KC, Sprengel R, Phillips HS, et al. Lutropin-cho-riogonadotropin receptor: An unusual member of the G protein-coupled receptor family. Science 1989; 245:494–9.

    Article  CAS  PubMed  Google Scholar 

  29. Segaloff DL, Ascoli M. The gonadotrophin receptors: Insights from the cloning of their cDNAs. Oxf Rev Reprod Biol 1992; 14:141–68.

    CAS  PubMed  Google Scholar 

  30. Nothacker HP, Grimmelikhuijzen CJ. Molecular cloning of a novel, putative G protein-coupled receptor from sea anemones structurally related to members of the FSH, TSH, LH/CG receptor family from mammals. Biochem Biophys Res Commun 1993; 197:1062–9.

    Article  CAS  PubMed  Google Scholar 

  31. Grover S, Woodward SR, Caticha O, Carrell DT, Odell WD. Partial nucleotide sequence of the Xanthomonas maltophilia chorionic gonadotropin-like receptor. Biochem Biophys Res Commun 1993; 190:371–6.

    Article  CAS  PubMed  Google Scholar 

  32. Nishimori K, Dunkel L, Hsueh AJ, Yamoto M, Nakano R. Expression of luteinizing hormone and chorionic gonadotropin receptor messenger ribonucleic acid in human corpora lutea during menstrual cycle and pregnancy. J Clin Endocrinol Metab 1995; 80:1444–8.

    CAS  PubMed  Google Scholar 

  33. Ziecik AJ, Stanchev PD, Tilton JE. Evidence for the presence of luteinizing hormone/human chorionic gonadotropin-binding sites in the porcine uterus. Endocrinology 1986; 119:1159–63.

    Article  CAS  PubMed  Google Scholar 

  34. Reshef E, Lei ZM, Rao CV, 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; 70:421–30.

    Article  CAS  PubMed  Google Scholar 

  35. Lei ZM, Rao CV, Ackerman DM, Day TG. The expression of human chorionic gonadotropin/human luteinizing hormone receptors in human gestational trophoblastic neoplasms. J Clin Endocrinol Metab 1992; 74:1236–41.

    CAS  PubMed  Google Scholar 

  36. Lei ZM, Rao CV, Lincoln SR, Ackermann DM. Increased expression of human chorionic gonadotropin/human luteinizing hormone receptors in adenomyosis. J Clin Endocrinol Metab 1993; 76:763–8.

    CAS  PubMed  Google Scholar 

  37. Toth P, Li X, Rao CV, et al. Expression of functional human chorionic gonadotropin/human luteinizing hormone receptor gene in human uterine arteries. J Clin Endocrinol Metab 1994; 79:307–15.

    CAS  PubMed  Google Scholar 

  38. Zuo J, Lei ZM, Rao CV. Human myometrial chorionic gonadotropin/luteinizing hormone receptors in preterm and term deliveries. J Clin Endocrinol Metab 1994; 79:907–11.

    CAS  PubMed  Google Scholar 

  39. Singh M, Zuo J, Li X, et al. Decreased expression of functional human chorionic gonadotropin/luteinizing hormone receptor gene in human uterine leiomyomas. Biol Reprod 1995; 53: 591–7.

    Article  CAS  PubMed  Google Scholar 

  40. Lin J, Lei ZM, Lojun S, Rao CV, Satyaswaroop PG, Day TG. Increased expression of luteinizing hormone/human chorionic gonadotropin receptor gene in human endometrial carcinomas. J Clin Endocrinol Metab 1994; 79:1483–91.

    CAS  PubMed  Google Scholar 

  41. Bemardini L, Moretti-Rojas I, Brush M, Rojas FJ, Balmaceda JP. Status of hCG/LH receptor and G proteins in human endometrium during artificial cycles of hormone replacement therapy. J Soc Gynecol Investig 1995; 2:630–5.

    Article  Google Scholar 

  42. Rao CV, Li X, Toth P, Lei ZM, Cook VD. Novel expression of functional human chorionic gonadotropin/luteinizing hormone receptor gene in human umbilical cords. J Clin Endocrinol Metab 1993; 77:1706–14.

    CAS  PubMed  Google Scholar 

  43. Lei ZM, Toth P, Rao CV, Pridham D. Novel coexpression of human chorionic gonadotropin (hCG)/human luteinizing hormone receptors and their ligand hCG in human fallopian tubes. J Clin Endocrinol Metab 1993; 77:863–72.

    CAS  PubMed  Google Scholar 

  44. Lei ZM, Rao CV, Kornyei JL, Licht P, Hiatt ES. Novel expres- sion of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. Endocrinology 1993; 132:2262–70.

    Article  CAS  PubMed  Google Scholar 

  45. Lincoln SR, Lei ZM, Rao CV, Yussman MA. The expression of human chorionic gonadotropin/human luteinizing hormone receptors in ectopic human endometrial implants. J Clin Endocrinol Metab 1992; 75:1140–4.

    CAS  PubMed  Google Scholar 

  46. Lei ZM, Rao CV. Novel presence of luteinizing hormone/ human chorionic gonadotropin (hCG) receptors and the down-regulating action of hCG on gonadotropin- releasing hormone gene expression in immortalized hypothalamic GT1–7 neurons. Mol Endocrinol 1994; 8:1111–21.

    CAS  PubMed  Google Scholar 

  47. Komatsu T, Konishi I, Mandai M, et al. Peritoneal papillary serous carcinoma arising in an infertile woman during ovulation-induction therapy: Immunohistochemical expression of LH/ hCG receptors. Gynecol Oncol 1995; 56:470–4.

    Article  CAS  PubMed  Google Scholar 

  48. Tao YX, Lei ZM, Hofmann GE, Rao CV. Human intermediate trophoblasts express chorionic gonadotropin/luteinizing hormone receptor gene. Biol Reprod 1995; 53:899–904.

    Article  CAS  PubMed  Google Scholar 

  49. Licht P, Cao H, Lei ZM, Rao CV, Merz WE. Novel self-regulation of human chorionic gonadotropin biosynthesis in term pregnancy human placenta. Endocrinology 1993; 133:3014–25.

    Article  CAS  PubMed  Google Scholar 

  50. Lin J, Lojun S, Lei ZM, Wu WX, Peiner SC, Rao CV. Lymphocytes from pregnant women express human chorionic gonadotropin/luteinizing hormone receptor gene. Mol Cell Endocrinol 1995; 111:R13–7.

    Article  CAS  PubMed  Google Scholar 

  51. Stewart EA, Sahakian M, Rhoades A, Van Voorhis BJ, Nowak RA. Messenger ribonucleic acid for the gonadal luteinizing hormone/human chorionic gonadotropin receptor is not present in human endometrium. Fertil Steril 1999; 71:368–72.

    Article  CAS  PubMed  Google Scholar 

  52. Ji IH, Ji TH. Human choriogonadotropin binds to a lutropin receptor with essentially no N-terminal extension and stimulates cAMP synthesis. J Biol Chem 1991; 266:13076–9.

    CAS  PubMed  Google Scholar 

  53. Lei ZM, Mishra S, Zou W, et al. Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene. Mol Endocrinol 2001; 15:184–200.

    Article  CAS  PubMed  Google Scholar 

  54. Nisula BC, Morgan FJ, Canfield PE. Evidence that chorionic gonadotropin has intrinsic thyrotropic activity. Biochem Biophys Res Commun 1974; 59:86–91.

    Article  CAS  PubMed  Google Scholar 

  55. Tomer Y, Huber GK, Davies TF. Human chorionic gonadotropin (hCG) interacts directly with recombinant human TSH receptors. J Clin Endocrinol Metab 1992; 74:1477–9.

    CAS  PubMed  Google Scholar 

  56. Gunji K, Endo T, Ohno M, Minegishi T, Onaya T. Recombinant thyrotropin stimulates cAMP formation in CHO-K1 cells expressing recombinant chorionic gonadotropin receptor. Biochem Biophys Res Commun 1993; 197:1530–5.

    Article  CAS  PubMed  Google Scholar 

  57. Jaffe RB, Lee PA, Midgley AR Jr. Serum gonadotropins before, at the inception of, and following human pregnancy. J Clin Endocrinol Metab 1969; 29:1281–3.

    Article  CAS  PubMed  Google Scholar 

  58. Gonen R, Perez R, David M, Dar H, Merksamer R, Sharf M. The association between unexplained second-trimester maternal serum hCG elevation and pregnancy complications. Obstet Gynecol 1992; 80:83–6.

    CAS  PubMed  Google Scholar 

  59. Hsu CD, Chan DW, Iriye B, Johnson TR, Hong SF, Repke JT. Elevated serum human chorionic gonadotropin as evidence of secretory response in severe preeclampsia. Am J Obstet Gynecol 1994; 170:1135–8.

    Article  CAS  PubMed  Google Scholar 

  60. Adashi EY. The climacteric ovary as a functional gonadotropin-driven androgen- producing gland [published erratum appears in Fertil Steril 1995 Mar; 63:684] [see comments]. Fertil Steril 1994; 62:20–7.

    Article  CAS  PubMed  Google Scholar 

  61. Wimalasena J, Meehan D, Cavallo C. Human epithelial ovarian cancer cell steroid secretion and its control by gonadotropins. Gynecol Oncol 1991; 41:56–63.

    Article  CAS  PubMed  Google Scholar 

  62. Wimalasena J, Dostal R, Meehan D. Gonadotropins, estradiol, and growth factors regulate epithelial ovarian cancer cell growth. Gynecol Oncol 1992; 46:345–50.

    Article  CAS  PubMed  Google Scholar 

  63. Donesky BW, Adashi EY. Surgically induced ovulation in the polycystic ovary syndrome: Wedge resection revisited in the age of laparoscopy [see comments]. Fertil Steril 1995; 63:439–63.

    Article  CAS  PubMed  Google Scholar 

  64. Meldrum DR. Female reproductive aging—ovarian and uterine factors. Fertil Steril 1993; 59:1–5.

    Article  CAS  PubMed  Google Scholar 

  65. Harrison-Woolrych ML, Charnock-Jones DS, Smith SK. Quantification of messenger ribonucleic acid for epidermal growth factor in human myometrium and leiomyomata using reverse transcriptase polymerase chain reaction. J Clin Endocrinol Metab 1994; 78:1179–84.

    CAS  PubMed  Google Scholar 

  66. Stewart EA, Friedman AJ, Peck K, Nowak RA. Relative over-expression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab 1994; 79: 900–6.

    CAS  PubMed  Google Scholar 

  67. Irwin KL, Weiss NS, Lee NC, Peterson HB. Tubal sterilization, hysterectomy, and the subsequent occurrence of epithelial ovarian cancer. Am J Epidemiol 1991; 134:362–9.

    Article  CAS  PubMed  Google Scholar 

  68. Hankinson SE, Hunter DJ, Colditz GA, et al. Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA 1993; 270:2813–8.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Obstetrics, Gynecology and Reproductive Biology, Bngham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts, 02115, USA

    Elizabeth A. Stewart MD

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  1. Elizabeth A. Stewart MD
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Correspondence to Elizabeth A. Stewart MD.

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Supported by National Institutes of Health Grant HD-115301.

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Stewart, E.A. Gonadotropins and the Uterus: Is There a Gonad-Independent Pathway?. Reprod. Sci. 8, 319–326 (2001). https://doi.org/10.1177/107155760100800603

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