Skip to main content

Female Reproductive Systems: Hormone Dependence and Receptor Expression

  • Chapter
  • First Online:
Nuclear Receptors in Human Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1390))

Abstract

The female reproductive system which consists of the ovaries, uterus (myometrium, endometrium), Fallopian tubes, cervix and vagina is exquisitely sensitive to the actions of steroid hormones. The ovaries play a key role in the synthesis of bioactive steroids (oestrogens, androgens, progestins) that act both within the tissue (intracrine/paracrine) as well as on other reproductive organs following release into the blood stream (endocrine action). Sex steroid receptors encoded by the oestrogen (ESR1, ESR2), progesterone (PR) and androgen (AR) receptor genes, which are members of the superfamily of ligand activated transcription factors are widely expressed within these tissues. These receptors play critical role(s) in regulation of cell proliferation, ovulation, endometrial receptivity, myometrial cell function and inflammatory cell infiltration. Our understanding of their importance has been informed by studies on human tissues and cells, which have employed immunohistochemistry as well as a wide range of molecular and genetic methods to identify which processes are dependent steroid ligand activation. The development of mice with targeted deletions of each of these receptors has provided complementary data that has extended our appreciation of cell-cell interactions in the fine tuning of reproductive tissue function. This large body of work has formed the basis of new and improved therapeutics to treat conditions such as infertility.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Aghajanova L, Hamilton AE, Giudice LC (2008) Uterine receptivity to human embryonic implantation: histology, biomarkers, and transcriptomics. Semin Cell Dev Biol 19:204–211

    Article  CAS  PubMed  Google Scholar 

  2. Aghajanova L, Velarde MC, Giudice LC (2010) Altered gene expression profiling in endometrium: evidence for progesterone resistance. Semin Reprod Med 28:51–58

    Article  CAS  PubMed  Google Scholar 

  3. Ahn J, Yoon MJ, Hong SH, Cha H, Lee D, Koo HS, Ko JE, Lee J, Oh S, Jeon NL, Kang YJ (2021) Three-dimensional microengineered vascularised endometrium-on-a-chip. Hum Reprod 36:2720–2731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ameer MA, Fagan SE, Sosa-Stanley JN, Peterson DC (2021) Anatomy, abdomen and pelvis, uterus. StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2021, StatPearls Publishing LLC

    Google Scholar 

  5. Anamthathmakula P, Kyathanahalli C, Ingles J, Hassan SS, Condon JC, Jeyasuria P (2019) Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy. EBioMedicine 39:520–530

    Article  PubMed  Google Scholar 

  6. Armstrong GM, Maybin JA, Murray AA, Nicol M, Walker C, Saunders PTK, Rossi AG, Critchley HOD (2017) Endometrial apoptosis and neutrophil infiltration during menstruation exhibits spatial and temporal dynamics that are recapitulated in a mouse model. Sci Rep 7:17416

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Astapova O, Minor BMN, Hammes SR (2019) Physiological and pathological androgen actions in the ovary. Endocrinology 160:1166–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ayehunie S, Islam A, Cannon C, Landry T, Pudney J, Klausner M, Anderson DJ (2015) Characterization of a hormone-responsive Organotypic human vaginal tissue model: morphologic and immunologic effects. Reprod Sci 22:980–990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Beato M, Wright RHG, Dily FL (2020) 90 years of progesterone: molecular mechanisms of progesterone receptor action on the breast cancer genome. J Mol Endocrinol 65:T65–T79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Binder AK, Rodriguez KF, Hamilton KJ, Stockton PS, Reed CE, Korach KS (2013) The absence of ER-beta results in altered gene expression in ovarian granulosa cells isolated from in vivo preovulatory follicles. Endocrinology 154:2174–2187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bozorgmehr M, Gurung S, Darzi S, Nikoo S, Kazemnejad S, Zarnani AH, Gargett CE (2020) Endometrial and menstrual blood mesenchymal stem/stromal cells: biological properties and clinical application. Front Cell Dev Biol 8:497

    Article  PubMed  PubMed Central  Google Scholar 

  12. Brenner RM, Slayden OD (2005) Progesterone receptor antagonists and the endometrial antiproliferative effect. Semin Reprod Med 23:74–81

    Article  CAS  PubMed  Google Scholar 

  13. Brenner RM, Slayden OD, Critchley HO (2002) Anti-proliferative effects of progesterone antagonists in the primate endometrium: a potential role for the androgen receptor. Reproduction 124:167–172

    Article  CAS  PubMed  Google Scholar 

  14. Briceag I, Costache A, Purcarea VL, Cergan R, Dumitru M, Briceag I, Sajin M, Ispas AT (2015) Fallopian tubes–literature review of anatomy and etiology in female infertility. J Med Life 8:129–131

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Brighton PJ, Maruyama Y, Fishwick K, Vrljicak P, Tewary S, Fujihara R, Muter J, Lucas ES, Yamada T, Woods L, Lucciola R, Hou Lee Y, Takeda S, Ott S, Hemberger M, Quenby S, Brosens JJ (2017) Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. elife 6:e31274

    Article  PubMed  PubMed Central  Google Scholar 

  16. Britt KL, Kerr J, O'donnell L, Jones ME, Drummond AE, Davis SR, Simpson ER, Findlay JK (2002) Estrogen regulates development of the somatic cell phenotype in the eutherian ovary. FASEB J 16:1389–1397

    Article  CAS  PubMed  Google Scholar 

  17. Brodie J, Mcewan IJ (2005) Intra-domain communication between the N-terminal and DNA-binding domains of the androgen receptor: modulation of androgen response element DNA binding. J Mol Endocrinol 34:603–615

    Article  CAS  PubMed  Google Scholar 

  18. Brosens JJ, Lam EW (2013) Progesterone and FOXO1 signaling: harnessing cellular senescence for the treatment of ovarian cancer. Cell Cycle 12:1660–1661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bulun SE, Moravek MB, Yin P, Ono M, Coon JST, Dyson MT, Navarro A, Marsh EE, Zhao H, Maruyama T, Chakravarti D, Kim JJ, Wei JJ (2015) Uterine leiomyoma stem cells: linking progesterone to growth. Semin Reprod Med 33:357–365

    Article  CAS  PubMed  Google Scholar 

  20. Bylander A, Lind K, Goksör M, Billig H, Larsson DGJ (2013) The classical progesterone receptor mediates the rapid reduction of fallopian tube ciliary beat frequency by progesterone. Reprod Biol Endocrinol 11:33–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bylander A, Gunnarsson L, Shao R, Billig H, Larsson DGJ (2015) Progesterone-mediated effects on gene expression and oocyte-cumulus complex transport in the mouse fallopian tube. Reprod Biol Endocrinol 13:40

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Cavallini A, Dinaro E, Giocolano A, Caringella AM, Ferreri R, Tutino V, Loverro G (2008) Estrogen receptor (ER) and ER-related receptor expression in normal and atrophic human vagina. Maturitas 59:219–225

    Article  CAS  PubMed  Google Scholar 

  23. Cellai I, DI Stasi V, Comeglio P, Maseroli E, Todisco T, Corno C, Filippi S, Cipriani S, Sorbi F, Fambrini M, Petraglia F, Scavello I, Rastrelli G, Acciai G, Villanelli F, Danza G, Sarchielli E, Guarnieri G, Morelli A, Maggi M, Vignozzi L (2021) Insight on the Intracrinology of menopause: androgen production within the human vagina. Endocrinology 162:bqaa219

    Article  PubMed  CAS  Google Scholar 

  24. Channing CP, Schaerf FW, Anderson LD, Tsafriri A (1980) Ovarian follicular and luteal physiology. Int Rev Physiol 22:117–201

    CAS  PubMed  Google Scholar 

  25. Christin JR, Wang C, Chung CY, Liu Y, Dravis C, Tang W, Oktay MH, Wahl GM, Guo W (2020) Stem cell determinant SOX9 promotes lineage plasticity and progression in basal-like breast cancer. Cell Rep 31:107742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cloke B, Huhtinen K, Fusi L, Kajihara T, Yliheikkila M, Ho KK, Teklenburg G, Lavery S, Jones MC, Trew G, Kim JJ, Lam EW, Cartwright JE, Poutanen M, Brosens JJ (2008) The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium. Endocrinology 149:4462–4474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Coffey K, Robson CN (2012) Regulation of the androgen receptor by post-translational modifications. J Endocrinol 215:221–237

    Article  CAS  PubMed  Google Scholar 

  28. Collins F, Macpherson S, Brown P, Bombail V, Williams AR, Anderson RA, Jabbour HN, Saunders PT (2009) Expression of oestrogen receptors, ERalpha, ERbeta, and ERbeta variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERalpha. BMC Cancer 9:330

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Conneely OM, Mulac-Jericevic B, Demayo F, Lydon JP, O'malley BW (2002) Reproductive functions of progesterone receptors. Recent Prog Horm Res 57:339–355

    Article  CAS  PubMed  Google Scholar 

  30. Couse JF, Yates MM, Rodriguez KF, Johnson JA, Poirier D, Korach KS (2006) The Intraovarian actions of estrogen receptor-{alpha} (ER{alpha}) are necessary to repress the formation of morphological and functional Leydig-like cells in the female gonad. Endocrinology 147:3666–3678

    Article  CAS  PubMed  Google Scholar 

  31. Critchley HO, Saunders PT (2009) Hormone receptor dynamics in a receptive human endometrium. Reprod Sci 16:191–199

    Article  CAS  PubMed  Google Scholar 

  32. Critchley HO, Brenner RM, Henderson TA, Williams K, Nayak NR, Slayden OD, Millar MR, Saunders PT (2001a) Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. J Clin Endocrinol Metab 86:1370–1378

    CAS  PubMed  Google Scholar 

  33. Critchley HO, Kelly RW, Brenner RM, Baird DT (2001b) The endocrinology of menstruation–a role for the immune system. Clin Endocrinol 55:701–710

    Article  CAS  Google Scholar 

  34. Critchley HO, Henderson TA, Kelly RW, Scobie GS, Evans LR, Groome NP, Saunders PT (2002) Wild-type estrogen receptor (ERbeta1) and the splice variant (ERbetacx/beta2) are both expressed within the human endometrium throughout the normal menstrual cycle. J Clin Endocrinol Metab 87:5265–5273

    Article  CAS  PubMed  Google Scholar 

  35. Critchley HOD, Maybin JA, Armstrong GM, Williams ARW (2020) Physiology of the endometrium and regulation of menstruation. Physiol Rev 100:1149–1179

    Article  PubMed  Google Scholar 

  36. Damdimopoulos AE, Spyrou G, Gustafsson JA (2008) Ligands differentially modify the nuclear mobility of estrogen receptors alpha and beta. Endocrinology 149:339–345

    Article  CAS  PubMed  Google Scholar 

  37. Das A, Mantena SR, Kannan A, Evans DB, Bagchi MK, Bagchi IC (2009) De novo synthesis of estrogen in pregnant uterus is critical for stromal decidualization and angiogenesis. Proc Natl Acad Sci U S A 106:12542–12547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Davis HC, Hackney AC (2017) The hypothalamic–pituitary–ovarian Axis and Oral contraceptives: regulation and function. In: Hackney AC (ed) Sex hormones, exercise and women: scientific and clinical aspects. Springer International Publishing, Cham

    Google Scholar 

  39. DE Leo B, Esnal-Zufiaurre A, Collins F, Critchley HOD, Saunders PTK (2017) Immunoprofiling of human uterine mast cells identifies three phenotypes and expression of ERbeta and glucocorticoid receptor. F1000Res 6:667

    Article  PubMed  PubMed Central  Google Scholar 

  40. Demayo FJ, Lydon JP (2020) 90 years of progesterone: new insights into progesterone receptor signaling in the endometrium required for embryo implantation. J Mol Endocrinol 65:T1–T14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Deroo BJ, Rodriguez KF, Couse JF, Hamilton KJ, Collins JB, Grissom SF, Korach KS (2009) Estrogen receptor beta is required for optimal cAMP production in mouse granulosa cells. Mol Endocrinol (Baltimore, Md.) 23:955–965

    Article  CAS  Google Scholar 

  42. Devoto L, Vega M, Kohen P, Castro O, Carvallo P, Palomino A (2002) Molecular regulation of progesterone secretion by the human corpus luteum throughout the menstrual cycle. J Reprod Immunol 55:11–20

    Article  CAS  PubMed  Google Scholar 

  43. Dietrich W, Gaba A, Zhegu Z, Bieglmayer C, Mairhofer M, Mikula M, Tschugguel W, Yotova I (2011) Testosterone dependent androgen receptor stabilization and activation of cell proliferation in primary human myometrial microvascular endothelial cells. Fertil Steril 95:1247–1255.e2

    Article  CAS  PubMed  Google Scholar 

  44. Duffy DM, Wells TR, Haluska GJ, Stouffer RL (1997) The ratio of progesterone receptor isoforms changes in the monkey corpus luteum during the luteal phase of the menstrual cycle. Biol Reprod 57:693–699

    Article  CAS  PubMed  Google Scholar 

  45. Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M (2000) Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 127:4277–4291

    Article  CAS  PubMed  Google Scholar 

  46. Dupont S, Dennefeld C, Krust A, Chambon P, Mark M (2003) Expression of Sox9 in granulosa cells lacking the estrogen receptors, ERalpha and ERbeta. Dev Dyn 226:103–106

    Article  CAS  PubMed  Google Scholar 

  47. Fraser HM, Bell J, Wilson H, Taylor PD, Morgan K, Anderson RA, Duncan WC (2005) Localization and quantification of cyclic changes in the expression of endocrine gland vascular endothelial growth factor in the human corpus luteum. J Clin Endocrinol Metab 90:427–434

    Article  CAS  PubMed  Google Scholar 

  48. Garry R, Hart R, Karthigasu KA, Burke C (2009) A re-appraisal of the morphological changes within the endometrium during menstruation: a hysteroscopic, histological and scanning electron microscopic study. Hum Reprod 24:1393–1401

    Article  CAS  PubMed  Google Scholar 

  49. Gellersen B, Brosens J (2003) Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J Endocrinol 178:357–372

    Article  CAS  PubMed  Google Scholar 

  50. Gellersen B, Brosens JJ (2014) Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev 35:851–905

    Article  CAS  PubMed  Google Scholar 

  51. Giangrande PH, Mcdonnell DP (1999) The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene. Recent Prog Horm Res 54:291–313. discussion 313-4

    CAS  PubMed  Google Scholar 

  52. Gibson E, Mahdy H (2021) Anatomy, abdomen and pelvis, ovary. StatPearls. Treasure Island (FL): StatPearls Publishing, Copyright © 2021, StatPearls Publishing LLC

    Google Scholar 

  53. Gibson DA, Mcinnes KJ, Critchley HO, Saunders PT (2013) Endometrial Intracrinology--generation of an estrogen-dominated microenvironment in the secretory phase of women. J Clin Endocrinol Metab 98:E1802–E1806

    Article  CAS  PubMed  Google Scholar 

  54. Gibson DA, Simitsidellis I, Collins F, Saunders PT (2014) Evidence of androgen action in endometrial and ovarian cancers. Endocr Relat Cancer 21:T203–T218

    Article  CAS  PubMed  Google Scholar 

  55. Gibson DA, Greaves E, Critchley HO, Saunders PT (2015) Estrogen-dependent regulation of human uterine natural killer cells promotes vascular remodelling via secretion of CCL2. Hum Reprod 30:1290–1301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gibson DA, Simitsidellis I, Cousins FL, Critchley HO, Saunders PT (2016) Intracrine androgens enhance Decidualization and modulate expression of human endometrial receptivity genes. Sci Rep 6:19970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gibson DA, Saunders PTK, Mcewan IJ (2018a) Androgens and androgen receptor: above and beyond. Mol Cell Endocrinol 465:1–3

    Article  CAS  PubMed  Google Scholar 

  58. Gibson DA, Simitsidellis I, Kelepouri O, Critchley HOD, Saunders PTK (2018b) Dehydroepiandrosterone enhances decidualization in women of advanced reproductive age. Fertil Steril 109:728–734 e2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gibson DA, Esnal-Zufiaurre A, Bajo-Santos C, Collins F, Critchley HOD, Saunders PTK (2020) Profiling the expression and function of oestrogen receptor isoform ER46 in human endometrial tissues and uterine natural killer cells. Hum Reprod 35:641–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gold JM, Shrimanker I (2021) Physiology, vaginal. StatPearls. Treasure Island (FL): StatPearls Publishing, Copyright © 2021, StatPearls Publishing LLC

    Google Scholar 

  61. Graham JD, Hanson AR, Croft AJ, Fox AH, Clarke CL (2009) Nuclear matrix binding is critical for progesterone receptor movement into nuclear foci. FASEB J 23:546–556

    Article  CAS  PubMed  Google Scholar 

  62. Greaves E, Collins F, Critchley HO, Saunders PT (2013) ERbeta-dependent effects on uterine endothelial cells are cell specific and mediated via Sp1. Hum Reprod 28:2490–2501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Greaves E, Critchley HOD, Horne AW, Saunders PTK (2017) Relevant human tissue resources and laboratory models for use in endometriosis research. Acta Obstet Gynecol Scand 96:644–658

    Article  PubMed  PubMed Central  Google Scholar 

  64. Grimm SL, Hartig SM, Edwards DP (2016) Progesterone Receptor Signaling Mechanisms. J Mol Biol 428:3831–3849

    Article  CAS  PubMed  Google Scholar 

  65. Gu C, Duluc D, Wiest M, Xue Y, Yi J, Gorvel JP, Joo H, Oh S (2021) Cell type-specific expression of estrogen and progesterone receptors in the human vaginal mucosa. Clin Immunol 232:108874

    Article  CAS  PubMed  Google Scholar 

  66. Gulappa T, Menon B, Menon KMJ (2017) LHCGR expression during follicle stimulating hormone-induced follicle growth is negatively regulated by eukaryotic initiation factor 5A. Endocrinology 158:2672–2679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hall JM, Couse JF, Korach KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 276:36869–36872

    Article  CAS  PubMed  Google Scholar 

  68. Henderson TA, Saunders PT, Moffett-King A, Groome NP, Critchley HO (2003a) Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metab 88:440–449

    Article  CAS  PubMed  Google Scholar 

  69. Henderson TA, Saunders PTK, Moffett-King A, Groome NP, Critchley HOD (2003b) Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metabol 88:440–449

    Article  CAS  Google Scholar 

  70. Hild-Petito S, Stouffer RL, Brenner RM (1988) Immunocytochemical localization of estradiol and progesterone receptors in the monkey ovary throughout the menstrual cycle. Endocrinology 123:2896–2905

    Article  CAS  PubMed  Google Scholar 

  71. Horne AW, King AE, Shaw E, Mcdonald SE, Williams AR, Saunders PT, Critchley HO (2009a) Attenuated sex steroid receptor expression in fallopian tube of women with ectopic pregnancy. J Clin Endocrinol Metab 94:5146–5154

    Article  CAS  PubMed  Google Scholar 

  72. Hu J, Zhang Z, Shen WJ, Azhar S (2010) Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metab (Lond) 7:47

    Article  CAS  Google Scholar 

  73. Jackson-Bey T, Colina J, Isenberg BC, Coppeta J, Urbanek M, Kim JJ, Woodruff TK, Burdette JE, Russo A (2020) Exposure of human fallopian tube epithelium to elevated testosterone results in alteration of cilia gene expression and beating. Hum Reprod 35:2086–2096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Jamnongjit M, Hammes SR (2006) Ovarian steroids: the good, the bad, and the signals that raise them. Cell Cycle 5:1178–1183

    Article  CAS  PubMed  Google Scholar 

  75. Jeselsohn R, Cornwell M, Pun M, Buchwalter G, Nguyen M, Bango C, Huang Y, Kuang Y, Paweletz C, Fu X, Nardone A, De Angelis C, Detre S, Dodson A, Mohammed H, Carroll JS, Bowden M, Rao P, Long HW, Li F, Dowsett M, Schiff R, Brown M (2017) Embryonic transcription factor SOX9 drives breast cancer endocrine resistance. Proc Natl Acad Sci U S A 114:E4482–E4491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kagami K, Ono M, Iizuka T, Matsumoto T, Hosono T, Sekizuka-Kagami N, Shinmyo Y, Kawasaki H, Fujiwara H (2020) A novel third mesh-like myometrial layer connects the longitudinal and circular muscle fibers–a potential stratum to coordinate uterine contractions. Sci Rep 10:8274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kajihara T, Tochigi H, Prechapanich J, Uchino S, Itakura A, Brosens JJ, Ishihara O (2012) Androgen signaling in decidualizing human endometrial stromal cells enhances resistance to oxidative stress. Fertil Steril 97:185–191

    Article  CAS  PubMed  Google Scholar 

  78. Kajihara T, Tanaka K, Oguro T, Tochigi H, Prechapanich J, Uchino S, Itakura A, Sucurovic S, Murakami K, Brosens JJ, Ishihara O (2014) Androgens modulate the morphological characteristics of human endometrial stromal cells decidualized in vitro. Reprod Sci 21:372–380

    Article  PubMed  CAS  Google Scholar 

  79. Kim JJ, Buzzio OL, Li S, Lu Z (2005) Role of FOXO1A in the regulation of insulin-like growth factor-binding protein-1 in human endometrial cells: interaction with progesterone receptor. Biol Reprod 73:833–839

    Article  CAS  PubMed  Google Scholar 

  80. Kim JJ, Kurita T, Bulun SE (2013) Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev 34:130–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Knock GA, Tribe RM, Hassoni AA, Aaronson PI (2001) Modulation of potassium current characteristics in human myometrial smooth muscle by 17β-estradiol and Progesterone1. Biol Reprod 64:1526–1534

    Article  CAS  PubMed  Google Scholar 

  82. Kolkova Z, Noskova V, Ehinger A, Hansson S, Casslen B (2010) G protein-coupled estrogen receptor 1 (GPER, GPR 30) in normal human endometrium and early pregnancy decidua. Mol Hum Reprod 16:743–751

    Article  CAS  PubMed  Google Scholar 

  83. Kong CS, Ordonez AA, Turner S, Tremaine T, Muter J, Lucas ES, Salisbury E, Vassena R, Tiscornia G, Fouladi-Nashta AA, Hartshorne G, Brosens JJ, Brighton PJ (2021) Embryo biosensing by uterine natural killer cells determines endometrial fate decisions at implantation. FASEB J 35:e21336

    CAS  PubMed  Google Scholar 

  84. Korach KS, Emmen JM, Walker VR, Hewitt SC, Yates M, Hall JM, Swope DL, Harrell JC, Couse JF (2003) Update on animal models developed for analyses of estrogen receptor biological activity. J Steroid Biochem Mol Biol 86:387–391

    Article  CAS  PubMed  Google Scholar 

  85. Kota SK, Gayatri K, Jammula S, Kota SK, Krishna SVS, Meher LK, Modi KD (2013) Endocrinology of parturition. Indian J Endocrinol Metab 17:50–59

    Article  PubMed  PubMed Central  Google Scholar 

  86. Labrie F (2018) Intracrinology and menopause: the science describing the cell-specific intracellular formation of estrogens and androgens from DHEA and their strictly local action and inactivation in peripheral tissues. Menopause 26:220–224

    Article  Google Scholar 

  87. Labrie F, Martel C, Pelletier G (2017) Is vulvovaginal atrophy due to a lack of both estrogens and androgens? Menopause 24:452–461

    Article  PubMed  Google Scholar 

  88. Lerner A, Owens LA, Coates M, Simpson C, Poole G, Velupillai J, Liyanage M, Christopoulos G, Lavery S, Hardy K, Franks S (2019) Expression of genes controlling steroid metabolism and action in granulosa-lutein cells of women with polycystic ovaries. Mol Cell Endocrinol 486:47–54

    Article  CAS  PubMed  Google Scholar 

  89. Lethaby A, Ayeleke RO, Roberts H (2016) Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2016:Cd001500

    PubMed Central  Google Scholar 

  90. Levin ER (2008) Rapid signaling by steroid receptors. Am J Physiol Regul Integr Comp Physiol 295:R1425–R1430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Li S, O’neill SRS, Zhang Y, Holtzman MJ, Takemaru K-I, Korach KS, Winuthayanon W (2017) Estrogen receptor α is required for oviductal transport of embryos. FASEB J 31:1595–1607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Li S, Herrera GG, Tam KK, Lizarraga JS, Beedle M-T, Winuthayanon W (2018) Estrogen action in the epithelial cells of the mouse vagina regulates neutrophil infiltration and vaginal tissue integrity. Sci Rep 8:11247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Lim H, Ma L, Ma WG, Maas RL, Dey SK (1999) Hoxa-10 regulates uterine stromal cell responsiveness to progesterone during implantation and decidualization in the mouse. Mol Endocrinol 13:1005–1017

    Article  CAS  PubMed  Google Scholar 

  94. Lubahn DB, Brown TR, Simental JA, Higgs HN, Migeon CJ, Wilson EM, French FS (1989) Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci U S A 86:9534–9538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lucas ES, Vrljicak P, Muter J, Diniz-Da-Costa MM, Brighton PJ, Kong CS, Lipecki J, Fishwick KJ, Odendaal J, Ewington LJ, Quenby S, Ott S, Brosens JJ (2020) Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window. Commun Biol 3:37

    Article  PubMed  PubMed Central  Google Scholar 

  96. Lydon JP, Demayo FJ, Conneely OM, O’malley BW (1996) Reproductive phenotpes of the progesterone receptor null mutant mouse. J Steroid Biochem Mol Biol 56:67–77

    Article  CAS  PubMed  Google Scholar 

  97. Maclean A, Bunni E, Makrydima S, Withington A, Kamal AM, Valentijn AJ, Hapangama DK (2020) Fallopian tube epithelial cells express androgen receptor and have a distinct hormonal responsiveness when compared with endometrial epithelium. Hum Reprod 35:2097–2106

    Article  CAS  PubMed  Google Scholar 

  98. Makieva S, Saunders PT, Norman JE (2014) Androgens in pregnancy: roles in parturition. Hum Reprod Update 20:542–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Makieva S, Hutchinson LJ, Rajagopal SP, Rinaldi SF, Brown P, Saunders PT, Norman JE (2016) Androgen-induced relaxation of uterine myocytes is mediated by blockade of both Ca flux and MLC phosphorylation. J Clin Endocrinol Metab 101:jc20152851

    Article  CAS  Google Scholar 

  100. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans R (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Marshall E, Lowrey J, Macpherson S, Maybin JA, Collins F, Critchley HO, Saunders PT (2011) In silico analysis identifies a novel role for androgens in the regulation of human endometrial apoptosis. J Clin Endocrinol Metab 96:E1746–E1755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Martyn F, Mcauliffe FM, Wingfield M (2014) The role of the cervix in fertility: is it time for a reappraisal? Hum Reprod 29:2092–2098

    Article  CAS  PubMed  Google Scholar 

  103. Maseroli E, Cellai I, Filippi S, Comeglio P, Cipriani S, Rastrelli G, Rosi M, Sorbi F, Fambrini M, Petraglia F, Amoriello R, Ballerini C, Lombardelli L, Piccinni MP, Sarchielli E, Guarnieri G, Morelli A, Maggi M, Vignozzi L (2020) Anti-inflammatory effects of androgens in the human vagina. J Mol Endocrinol 65:109–124

    Article  CAS  PubMed  Google Scholar 

  104. Matsuzaki S, Fukaya T, Suzuki T, Murakami T, Sasano H, Yajima A (1999) Oestrogen receptor α and β mRNA expression in human endometrium throughout the menstrual cycle. Mol Hum Reprod 5:559–564

    Article  CAS  PubMed  Google Scholar 

  105. Maybin JA, Duncan WC (2004) The human corpus luteum: which cells have progesterone receptors? Reproduction 128:423–431

    Article  CAS  PubMed  Google Scholar 

  106. Mcclamrock HD, Adashi EY (1992) Gestational hyperandrogenism. Fertil Steril 57:257–274

    Article  CAS  PubMed  Google Scholar 

  107. Mcewan IJ, Mcguinness D, Hay CW, Millar RP, Saunders PT, Fraser HM (2010) Identification of androgen receptor phosphorylation in the primate ovary in vivo. Reproduction 140:93–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Medina-Laver Y, Rodriguez-Varela C, Salsano S, Labarta E, Dominguez F (2021) What do we know about classical and non-classical progesterone receptors in the human female reproductive tract? A review. Int J Mol Sci 22:11278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mehta FF, Son J, Hewitt SC, Jang E, Lydon JP, Korach KS, Chung S-H (2016) Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus. Oncotarget 7:17455–17467

    Article  PubMed  PubMed Central  Google Scholar 

  110. Miller WL, Auchus RJ (2011) The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 32:81–151

    Article  CAS  PubMed  Google Scholar 

  111. Mirkin S, Simon JA, Liu JH, Archer DF, Castro PD, Graham S, Bernick B, Komm B (2021) Evaluation of endometrial progesterone receptor expression after 12 weeks of exposure to a low-dose vaginal estradiol insert. Menopause 28:998–1003

    Article  PubMed  PubMed Central  Google Scholar 

  112. Miyagawa S, Iguchi T (2015) Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina. Proc Natl Acad Sci 112:12986–12991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN (2000) Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci U S A 97:10972–10977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Nutu M, Weijdegård B, Thomas P, Thurin-Kjellberg A, Billig H, Larsson DGJ (2009) Distribution and hormonal regulation of membrane progesterone receptors β and γ in ciliated epithelial cells of mouse and human fallopian tubes. Reprod Biol Endocrinol 7:89

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Okada H, Tsuzuki T, Murata H (2018) Decidualization of the human endometrium. Reprod Med Biol 17:220–227

    Article  PubMed  PubMed Central  Google Scholar 

  116. Owens LA, Kristensen SG, Lerner A, Christopoulos G, Lavery S, Hanyaloglu AC, Hardy K, Yding Andersen C, Franks S (2019) Gene expression in granulosa cells from small antral follicles from women with or without polycystic ovaries. J Clin Endocrinol Metab 104:6182–6192

    Article  PubMed  PubMed Central  Google Scholar 

  117. Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS (1997) Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 277:1508–1510

    Article  CAS  PubMed  Google Scholar 

  118. Pawar S, Laws MJ, Bagchi IC, Bagchi MK (2015) Uterine epithelial estrogen receptor-α controls Decidualization via a paracrine mechanism. Mol Endocrinol (Baltimore, Md.) 29:1362–1374

    Article  CAS  Google Scholar 

  119. Payne AH, Hales DB (2004) Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev 25:947–970

    Article  CAS  PubMed  Google Scholar 

  120. Penning TM, Drury JE (2007) Human aldo-keto reductases: function, gene regulation, and single nucleotide polymorphisms. Arch Biochem Biophys 464:241–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Perusquia M, Navarrete E, Jasso-Kamel J, Montano LM (2005) Androgens induce relaxation of contractile activity in pregnant human myometrium at term: a nongenomic action on L-type calcium channels. Biol Reprod 73:214–221

    Article  CAS  PubMed  Google Scholar 

  122. Pieber D, Allport VC, Bennett PR (2001) Progesterone receptor isoform A inhibits isoform B-mediated transactivation in human amnion. Eur J Pharmacol 427:7–11

    Article  CAS  PubMed  Google Scholar 

  123. Polanski LT, Barbosa MA, Martins WP, Baumgarten MN, Campbell B, Brosens J, Quenby S, Raine-Fenning N (2014) Interventions to improve reproductive outcomes in women with elevated natural killer cells undergoing assisted reproduction techniques: a systematic review of literature. Hum Reprod 29:65–75

    Article  CAS  PubMed  Google Scholar 

  124. Poola I, Abraham J, Baldwin K, Saunders A, Bhatnagar R (2005) Estrogen receptors beta4 and beta5 are full length functionally distinct ERbeta isoforms: cloning from human ovary and functional characterization. Endocrine 27:227–238

    Article  CAS  PubMed  Google Scholar 

  125. Press MF, Greene GL (1988) Localization of progesterone receptor with monoclonal antibodies to the human progestin receptor. Endocrinology 122:1165–1175

    Article  CAS  PubMed  Google Scholar 

  126. Richards JS, Pangas SA (2010) The ovary: basic biology and clinical implications. J Clin Invest 120:963–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Robker RL, Russell DL, Espey LL, Lydon JP, O'malley BW, Richards JS (2000a) Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases. Proc Natl Acad Sci U S A 97:4689–4694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Robker RL, Russell DL, Yoshioka S, Sharma SC, Lydon JP, O'malley BW, Espey LL, Richards JS (2000b) Ovulation: a multi-gene, multi-step process. Steroids 65:559–570

    Article  CAS  PubMed  Google Scholar 

  129. Sanderson PA, Critchley HO, Williams AR, Arends MJ, Saunders PT (2017) New concepts for an old problem: the diagnosis of endometrial hyperplasia. Hum Reprod Update 23:232–254

    PubMed  Google Scholar 

  130. Saunders PTK (2020) What have we learned from animal models of endometriosis and how can we use the knowledge gained to improve treatment of patients? Adv Anat Embryol Cell Biol 232:99–111

    Article  PubMed  Google Scholar 

  131. Saunders PT, Millar MR, Williams K, Macpherson S, Harkiss D, Anderson RA, Orr B, Groome NP, Scobie G, Fraser HM (2000) Differential expression of estrogen receptor-alpha and -beta and androgen receptor in the ovaries of marmosets and humans. Biol Reprod 63:1098–1105

    Article  CAS  PubMed  Google Scholar 

  132. Shaaban AM, Green AR, Karthik S, Alizadeh Y, Hughes TA, Harkins L, Ellis IO, Robertson JF, Paish EC, Saunders PT, Groome NP, Speirs V (2008) Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients. Clin Cancer Res 14:5228–5235

    Article  CAS  PubMed  Google Scholar 

  133. Shynlova O, Nadeem L, Zhang J, Dunk C, Lye S (2020) Myometrial activation: novel concepts underlying labor. Placenta 92:28–36

    Article  CAS  PubMed  Google Scholar 

  134. Simitsidellis I, Saunders PTK, Gibson DA (2018) Androgens and endometrium: new insights and new targets. Mol Cell Endocrinol 465:48–60

    Article  CAS  PubMed  Google Scholar 

  135. Sojka DK, Yang L, Yokoyama WM (2019) Uterine natural killer cells. Front Immunol 10:960–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Springwald A, Lattrich C, Skrzypczak M, Goerse R, Ortmann O, Treeck O (2010) Identification of novel transcript variants of estrogen receptor alpha, beta and progesterone receptor gene in human endometrium. Endocrine 37:415–424

    Article  CAS  PubMed  Google Scholar 

  137. Stener-Victorin E, Padmanabhan V, Walters KA, Campbell RE, Benrick A, Giacobini P, Dumesic DA, Abbott DH (2020) Animal models to understand the etiology and pathophysiology of polycystic ovary syndrome. Endocr Rev 41:bnaa010

    Article  PubMed  PubMed Central  Google Scholar 

  138. Stocco C, Telleria C, Gibori G (2007) The molecular control of corpus luteum formation, function, and regression. Endocr Rev 28:117–149

    Article  CAS  PubMed  Google Scholar 

  139. Thornton JW (2001) Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc Natl Acad Sci U S A 98:5671–5676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Turco MY, Gardner L, Hughes J, Cindrova-Davies T, Gomez MJ, Farrell L, Hollinshead M, Marsh SGE, Brosens JJ, Critchley HO, Simons BD, Hemberger M, Koo BK, Moffett A, Burton GJ (2017) Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat Cell Biol 19:568–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Turner KJ, Macpherson S, Millar MR, Mcneilly AS, Williams K, Cranfield M, Groome NP, Sharpe RM, Fraser HM, Saunders PT (2002) Development and validation of a new monoclonal antibody to mammalian aromatase. J Endocrinol 172:21–30

    Article  CAS  PubMed  Google Scholar 

  142. Tyagi S, Chan EC, Barker D, Mcelduff P, Taylor KA, Riveros C, Singh E, Smith R (2022) Transcriptomic analysis reveals myometrial topologically associated domains linked to onset of human term labor. Mol Hum Reprod 28(3):gaac003

    Article  PubMed  PubMed Central  Google Scholar 

  143. VAN Weerden WM, Bierings HG, VAN Steenbrugge GJ, DE Jong FH, Schroder FH (1992) Adrenal glands of mouse and rat do not synthesize androgens. Life Sci 50:857–861

    Article  PubMed  Google Scholar 

  144. Wada-Hiraike O, Hiraike H, Okinaga H, Imamov O, Barros RP, Morani A, Omoto Y, Warner M, Gustafsson JA (2006) Role of estrogen receptor beta in uterine stroma and epithelium: insights from estrogen receptor beta-/- mice. Proc Natl Acad Sci U S A 103:18350–18355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wagenfeld A, Saunders PT, Whitaker L, Critchley HO (2016) Selective progesterone receptor modulators (SPRMs): progesterone receptor action, mode of action on the endometrium and treatment options in gynecological therapies. Expert Opin Ther Targets 20:1045–1054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Walters KA, Handelsman DJ (2018) Role of androgens in the ovary. Mol Cell Endocrinol 465:36–47

    Article  CAS  PubMed  Google Scholar 

  147. Wang H, Critchley HO, Kelly RW, Shen D, Baird DT (1998) Progesterone receptor subtype B is differentially regulated in human endometrial stroma. Mol Hum Reprod 4:407–412

    Article  CAS  PubMed  Google Scholar 

  148. Wånggren K, Stavreus-Evers A, Olsson C, Andersson E, Gemzell-Danielsson K (2008) Regulation of muscular contractions in the human Fallopian tube through prostaglandins and progestagens. Hum Reprod 23:2359–2368

    Article  PubMed  CAS  Google Scholar 

  149. Weihua Z, Saji S, Mäkinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA (2000) Estrogen receptor (ER) beta, a modulator of ERalpha in the uterus. Proc Natl Acad Sci U S A 3:5936–5941

    Article  Google Scholar 

  150. Welsh T, Johnson M, Yi L, Tan H, Rahman R, Merlino A, Zakar T, Mesiano S (2012) Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium. J Endocrinol 212:227–238

    Article  CAS  PubMed  Google Scholar 

  151. Whitaker LH, Murray AA, Matthews R, Shaw G, Williams AR, Saunders PT, Critchley HO (2017) Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium. Hum Reprod 32:531–543

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Wilkens J, Male V, Ghazal P, Forster T, Gibson DA, Williams AR, Brito-Mutunayagam SL, Craigon M, Lourenco P, Cameron IT, Chwalisz K, Moffett A, Critchley HO (2013) Uterine NK cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil. J Immunol 191:2226–2235

    Article  CAS  PubMed  Google Scholar 

  153. Winuthayanon W, Hewitt SC, Orvis GD, Behringer RR, Korach KS (2010) Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses. Proc Natl Acad Sci U S A 107:19272–19277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Winuthayanon W, Bernhardt ML, Padilla-Banks E, Myers PH, Edin ML, Lih FB, Hewitt SC, Korach KS, Williams CJ (2015) Oviductal estrogen receptor α signaling prevents protease-mediated embryo death. elife 4:e10453–e10453

    Article  PubMed  PubMed Central  Google Scholar 

  155. Winuthayanon W, Lierz SL, Delarosa KC, Sampels SR, Donoghue LJ, Hewitt SC, Korach KS (2017) Juxtacrine activity of estrogen receptor α in uterine stromal cells is necessary for estrogen-induced epithelial cell proliferation. Sci Rep 7:8377–8377

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Yilmaz BD, Bulun SE (2019) Endometriosis and nuclear receptors. Hum Reprod Update 25:473–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Studies exploring the role(s) of steroid hormone receptors on reproductive function conducted in the senior author’s laboratory have been funded by grants from the UK Medical Research Council (MR/N024524/1; G1100356/1).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Philippa T. K. Saunders .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kuan, K.K.W., Saunders, P.T.K. (2022). Female Reproductive Systems: Hormone Dependence and Receptor Expression. In: Campbell, M.J., Bevan, C.L. (eds) Nuclear Receptors in Human Health and Disease. Advances in Experimental Medicine and Biology, vol 1390. Springer, Cham. https://doi.org/10.1007/978-3-031-11836-4_2

Download citation

Publish with us

Policies and ethics