Skip to main content

The Endocrinology of the Menstrual Cycle

Part of the Methods in Molecular Biology book series (MIMB,volume 1154)

Abstract

The ovulatory menstrual cycle is the result of the integrated action of the hypothalamus, pituitary, ovary, and endometrium. Like a metronome, the hypothalamus sets the beat for the menstrual cycle by the pulsatile release of gonadotropin-releasing hormone (GnRH). GnRH pulses occur every1–1.5 h in the follicular phase of the cycle and every 2–4 h in the luteal phase of the cycle. Pulsatile GnRH secretion stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). The pituitary gland translates the tempo set by the hypothalamus into a signal, LH and FSH secretion, that can be understood by the ovarian follicle. The ovarian follicle is composed of three key cells: theca cells, granulosa cells, and the oocyte. In the ovarian follicle, LH stimulates theca cells to produce androstenedione. In granulosa cells from small antral follicles, FSH stimulates the synthesis of aromatase (Cyp19) which catalyzes the conversion of theca-derived androstenedione to estradiol. A critical concentration of estradiol, produced from a large dominant antral follicle, causes positive feedback in the hypothalamus, likely through the kisspeptin system, resulting in an increase in GnRH secretion and an LH surge. The LH surge causes the initiation of the process of ovulation. After ovulation, the follicle is transformed into the corpus luteum, which is stimulated by LH or chorionic gonadotropin (hCG) should pregnancy occur to secrete progesterone. Progesterone prepares the endometrium for implantation of the conceptus. Estradiol stimulates the endometrium to proliferate. Estradiol and progesterone cause the endometrium to become differentiated to a secretory epithelium. During the mid-luteal phase of the cycle, when progesterone production is at its peak, the secretory endometrium is optimally prepared for the implantation of an embryo. A diagrammatic representation of the intricate interactions involved in coordinating the menstrual cycle is provided in Fig. 1.

Key words

  • Menstrual cycle
  • Estradiol
  • Progesterone
  • Kisspeptin
  • Amphiregulin
  • Theca cells
  • Granulosa cells
  • Oocyte

This is a preview of subscription content, access via your institution.

Buying options

Protocol
USD   49.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4939-0659-8_7
  • Chapter length: 25 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   129.00
Price excludes VAT (USA)
  • ISBN: 978-1-4939-0659-8
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   169.00
Price excludes VAT (USA)
Hardcover Book
USD   279.99
Price excludes VAT (USA)
Fig. 1
Fig. 2
Fig. 3

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Treloar AE, Boynton RE, Borchelt BG et al (1967) Variation of the human menstrual cycle through reproductive life. Int J Fertil 12:77–126

    CAS  PubMed  Google Scholar 

  2. Betsey EM, Pinole AP (1997) Menstrual bleeding patterns in untreated women. Contraception 55:57–65

    CrossRef  Google Scholar 

  3. Rance NE, Young WS, McMullen NT (1994) Topography of neurons expressing luteinizing hormone releasing hormone gene transcripts in the human hypothalamus and basal forebrain. J Comp Neurol 339:573–586

    CAS  PubMed  CrossRef  Google Scholar 

  4. Crowley WF, Pitteloud N, Seminara S (2008) New genes controlling human reproduction and how you find them. Trans Am Clin Climatol Assoc 119:29–38

    PubMed Central  PubMed  Google Scholar 

  5. Martin C, Balasubramanian R, Dwyer AA et al (2011) The role of prokineticin 2 pathway in human reproduction: evidence from the study of human and murine gene mutations. Endocr Rev 32:225–246

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  6. Schally AV, Arimura A, Bowers CY et al (1968) Hypothalamic neurohormones regulating anterior pituitary function. Recent Prog Horm Res 24:497–588

    CAS  PubMed  Google Scholar 

  7. Knobil E (1980) The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 35:53–88

    Google Scholar 

  8. Kesner J, Wilson R, Kaufman J et al (1987) Unexpected responses of the hypothalamic gonadotropin-releasing hormone ‘pulse generator’ to physiological estradiol inputs in the absence of the ovary. Proc Natl Acad Sci 84:8745–8749

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  9. Soules MR, Steiner R, Clifton D et al (1984) Progesterone modulation of pulsatile luteinizing hormone secretion in normal women. J Clin Endocrinol Metab 58:378–383

    CAS  PubMed  CrossRef  Google Scholar 

  10. Nakai Y, Plant TM, Hess D et al (1978) On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey. Endocrinology 102:1008–1014

    CAS  PubMed  CrossRef  Google Scholar 

  11. Karsch FJ, Weick R, Butler W et al (1973) Induced LH surges in the rhesus monkey: strength-duration characteristics of the estrogen stimulus. Endocrinology 92:1740–1747

    CAS  PubMed  CrossRef  Google Scholar 

  12. Levine J, Norman RL, Gliessman P et al (1985) In vivo gonadotropin-releasing hormone release and serum luteinizing hormone measurements in ovariectomized, estrogen-treated rhesus macaques. Endocrinology 117:711–721

    CAS  PubMed  CrossRef  Google Scholar 

  13. Maeda K, Ohkura S, Uenoyama Y et al (2010) Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res 1364:103–115

    CAS  PubMed  CrossRef  Google Scholar 

  14. Chan YM, Butler JP, Pinnell NE et al (2011) Kisspeptin resets the hypothalamic GnRH clock in men. J Clin Endocrinol Metab 96:E908–E915

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  15. Mimri R, Lebenthal Y, Lazar L et al (2011) A novel loss of function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family. J Clin Endocrinol Metab 96:E536–E545

    CrossRef  Google Scholar 

  16. Pitteloud N, Durrani S, Raivio T et al (2010) Complex genetics in idiopathic hypogonadotropic hypogonadism. Front Horm Res 39:142–153

    CAS  PubMed  CrossRef  Google Scholar 

  17. Williams WP, Jarjisian SG, Mikkelsen JD et al (2011) Circadian control of kisspeptin and a gated GnRH response mediate the preovulatory luteinizing hormone surge. Endocrinology 152:595–606

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  18. Williams N, Caston-Balderrama AL, Helmreich D et al (2001) Longitudinal changes in reproductive hormones and menstrual cyclicity in cynomolgus monkeys during strenuous exercise training: abrupt transition to exercise-induced amenorrhea. Endocrinology 142:2381–2389

    CAS  PubMed  Google Scholar 

  19. DeSouz MJ, Toombs RJ, Scheid JL et al (2010) High prevalence of subtle and severe menstrual disturbances in exercising women: confirmation using daily hormone measures. Hum Reprod 25:491–503

    CrossRef  Google Scholar 

  20. Williams NI, Reed JL, Leidy HJ et al (2010) Estrogen and progesterone exposure is reduced in response to energy deficiency in women aged 25 to 40 years. Hum Reprod 25:2328–2339

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  21. Bjorbaek C, Kahn BB (2004) Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 59:305–331

    CAS  PubMed  CrossRef  Google Scholar 

  22. Welt CK, Chan JL, Bullen J et al (2004) Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 351:987–997

    CAS  PubMed  CrossRef  Google Scholar 

  23. Chou SH, Chamberland JP, Liu X et al (2011) Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A 108(16):6585–6590

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  24. Castellano JM, Bentsen AH, Mikkelsen JD et al (2010) Kisspeptins: bridging energy homeostasis and reproduction. Brain Res 1364:129–138

    CAS  PubMed  CrossRef  Google Scholar 

  25. Oktem O, Urman B (2010) Understanding follicle growth in vivo. Hum Reprod 12:2944–2954

    CrossRef  Google Scholar 

  26. Dorrington JH, Armstrong DT (1979) Effects of FSH on gonadal functions. Recent Prog Horm Res 35:301–342

    CAS  PubMed  Google Scholar 

  27. Xu M, Fazleabas AT, Shikanov A et al (2011) In vitro oocyte maturation and preantral follicle culture from the luteal-phase baboon ovary produce mature oocytes. Biol Reprod 84:689–697

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  28. Young JM, McNeilly AS (2010) Theca: the forgotten cell of the ovarian follicle. Reproduction 140:489–504

    CAS  PubMed  CrossRef  Google Scholar 

  29. Galloway SM, Gregan SM, Wilson T et al (2002) Bmp15 mutations and ovarian function. Mol Cell Endocrinol 191:15–18

    CAS  PubMed  CrossRef  Google Scholar 

  30. Chu MX, Liu ZH, Jiao CL et al (2007) Mutations in BMPR-IB and BMP-15 genes associated with litter size in small tailed Han sheep. J Anim Sci 85:598–603

    CAS  PubMed  CrossRef  Google Scholar 

  31. McNatty KP, Smith DM, Makris A et al (1979) The microenvironment of the human antral follicle. J Clin Endocrinol Metab 49:851–860

    CAS  PubMed  CrossRef  Google Scholar 

  32. DiZerega GS, Hodgen GD (1981) Folliculogenesis in the primate ovarian cycle. Endocr Rev 2:27–49

    CAS  PubMed  CrossRef  Google Scholar 

  33. Yoo SW, Savchev S, Sergott L et al (2011) A large network of interconnected signaling pathways in human ovarian follicles is supported by the gene expression activity of the granulosa cells. Reprod Sci 18:476–484

    CAS  PubMed  CrossRef  Google Scholar 

  34. Haadsma ML, Groen H, Fidler V et al (2008) The predictive value of ovarian reserve tests for spontaneous pregnancy in subfertile ovulatory women. Hum Reprod 23:1800–1807

    CAS  PubMed  CrossRef  Google Scholar 

  35. Rodgers RJ, Lavranos TC, van Wezel IL et al (1999) Development of the ovarian follicular epithelium. Mol Cell Endocrinol 151:171–179

    CAS  PubMed  CrossRef  Google Scholar 

  36. Thoroddsen A, Dahm-Kahler P, Lind AK et al (2011) The water permeability channels aquaporins 1 to 3 are differentially expressed in granulosa and theca cells of the preovulatory follicle during precise stages of human ovulation. J Clin Endocrinol Metab 96:1021–1028

    CAS  PubMed  CrossRef  Google Scholar 

  37. Conti M, Hsieh M, Park JY et al (2006) Role of epidermal growth factor network in ovarian follicles. Mol Endocrinol 20:715–723

    CAS  PubMed  CrossRef  Google Scholar 

  38. Zamah AM, Hsieh M, Chen J et al (2010) Human oocyte maturation is dependent on LH-stimulated accumulation of the epidermal growth factor-like growth factor, amphiregulin. Hum Reprod 25:2569–2578

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  39. Ben-Ami I, Komsky A, Bern O et al (2011) In vitro maturation of human germinal vesicle stage oocytes: role of epidermal growth factor-like growth factors in the culture medium. Hum Reprod 26:76–81

    CAS  PubMed  CrossRef  Google Scholar 

  40. Csapo AI, Pulkkinen MO, Wiest WG (1973) Effects of luteectomy and progesterone replacement therapy in early pregnant patients. Am J Obstet Gynecol 115:759–765

    CAS  PubMed  Google Scholar 

  41. Jarvela IY, Ruokonen A, Tekay A (2008) Effect of rising hCG levels on the human corpus luteum during early pregnancy. Hum Reprod 23:2775–2781

    PubMed  CrossRef  Google Scholar 

  42. Kohen P, Castro O, Palomina A et al (2003) The steroidogenic response and corpus luteum expression of the steroidogenic acute regulatory protein after human chorionic administration at different times in the human luteal phase. J Clin Endocrinol Metab 88:3421–3430

    CAS  PubMed  CrossRef  Google Scholar 

  43. Strauss JF, Kallen CB, Christenson LK et al (1999) The steroidogenic acute regulatory protein (StAR) a window into the complexities of intracellular cholesterol trafficking. Recent Prog Horm Res 54:369–394

    CAS  PubMed  Google Scholar 

  44. Kiriakidou M, McAllister JM, Sugawara T et al (1996) Expression of steroidogenic acute regulatory protein (StAR) in the human ovary. J Clin Endocrinol Metab 81:4122–4128

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  CrossRef  Google Scholar 

  46. Andersen CY, Schmidt KT, Kristensen SG et al (2010) Concentrations of AMH and inhibin-B in relation to follicular diameter in normal human small antral follicles. Human Reprod 25:1282–1287

    CAS  CrossRef  Google Scholar 

  47. Hagen CP, Aksglaede L, Sorensen K et al (2010) Serum levels of anti-Mullerian hormone as a marker of ovarian function in 926 health females from birth to adulthood and in 172 Turner syndrome patients. J Clin Endocrinol Metab 95:5003–5010

    CAS  PubMed  CrossRef  Google Scholar 

  48. Ledger WL (2010) Clinical utility of measurement of anti-mullerian hormone in reproductive endocrinology. J Clin Endocrinol Metab 95:5144–5154

    CAS  PubMed  CrossRef  Google Scholar 

  49. Hansen KR, Hodnett GM, Knowlton N et al (2011) Correlation of ovarian reserve tests with histologically determined primordial follicle number. Fertil Steril 95:170–175

    PubMed  CrossRef  Google Scholar 

  50. Broer SL, Dolleman M, Opmeer BC et al (2011) AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis. Hum Reprod Update 17:46–54

    CAS  PubMed  CrossRef  Google Scholar 

  51. Genro VK, Grynberg M, Scheffer JB et al (2011) Serum anti-Mullerian hormone levels are negatively related to follicular output rate (FORT) in normo-cycling women undergoing controlled ovarian hyperstimulation. Hum Reprod 26:671–677

    CAS  PubMed  CrossRef  Google Scholar 

  52. Nelson SM, Yates RW, Lyall H et al (2009) Anti-mullerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod 24:867–875

    CAS  PubMed  CrossRef  Google Scholar 

  53. Al-Azemi M, Killick ST, Duffy S et al (2011) Multi-maker assessment of ovarian reserve predicts oocyte yield after ovulation induction. Hum Reprod 26:414–422

    CAS  PubMed  CrossRef  Google Scholar 

  54. Coxworth JE, Hawkes K (2010) Ovarian follicle loss in humans and mice: lessons from statistical model comparison. Hum Reprod 25:1796–1805

    CAS  PubMed  CrossRef  Google Scholar 

  55. Begum S, Papaioannou VE, Gosden RG (2008) The oocyte population is not renewed in transplanted adult ovaries. Hum Reprod 23:2326–2330

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  56. Gargett CE, Masuda H (2010) Adult stem cells in the endometrium. Mol Hum Reprod 16:818–834

    CAS  PubMed  CrossRef  Google Scholar 

  57. Sonderegger S, Pollheimer J, Knofler M (2010) Wnt signaling in implantation, decidualization and placental differentiation – review. Placenta 31:839–847

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  58. Tulac S, Nayak NR, Kao LC et al (2003) Identification, characterization and regulation of canonical Wnt signaling pathway in human endometrium. J Clin Endocrinol Metab 88:3860–3866

    CAS  PubMed  CrossRef  Google Scholar 

  59. van Amerongen R, Nusse R (2009) Towards an integrated view of Wnt signaling in development. Development 136:3205–3214

    PubMed  CrossRef  Google Scholar 

  60. Tulac S, Overgaard MT, Hamilton AE et al (2006) Dickkopf-1, an inhibitor of Wnt signaling is regulated by progesterone in human endometrial stromal cells. J Clin Endocrinol Metab 91:1453–1461

    CAS  PubMed  CrossRef  Google Scholar 

  61. Cloke B, Huhtinen K, Fusi L et al (2008) The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium. Endocrinology 149:4462–4474

    CAS  PubMed  CrossRef  Google Scholar 

  62. Liu X, Nie J, Guo SW (2011) Elevated immunoreactivity to tissue factor and its association with dysmenorrhea severity and the amount of menses in adenomyosis. Hum Reprod 26:337–345

    CAS  PubMed  CrossRef  Google Scholar 

  63. Nordengren J, Pilka R, Noskova V et al (2004) Differential localization and expression of urokinase plasminogen activator (uPA), its receptor (uPAR) and its inhibitor PAI-1 mRNA and protein in endometrial tissue during the menstrual cycle. Mol Hum Reprod 10:655–663

    CAS  PubMed  CrossRef  Google Scholar 

  64. Dunn CJ, Goa KL (1999) Tranexamic acid: a review of its use in surgery and other indications. Drugs 57:1005–1032

    CAS  PubMed  CrossRef  Google Scholar 

  65. Jensen JT, Parke S, Mellinger U et al (2011) Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest. Obstet Gynecol 117:777–787

    CAS  PubMed  CrossRef  Google Scholar 

  66. Noyes RW, Hertig AT, Rock J (1950) Dating the endometrial biopsy. Fertil Steril 1:3–11

    Google Scholar 

  67. King A (2000) Uterine leukocytes and decidualization. Hum Reprod Update 6:28–36

    CAS  PubMed  CrossRef  Google Scholar 

  68. Norwitz ER, Schust DJ, Fisher SJ (2001) Implantation and the survival of early pregnancy. N Engl J Med 345:1400–1408

    CAS  PubMed  CrossRef  Google Scholar 

  69. Paiva P, Menkhorst E, Salamonsen L et al (2009) Leukemia inhibitory factor and interleukin-11: critical regulators in the establishment of pregnancy. Cytokine Growth Factor Rev 20:319–328

    PubMed  CrossRef  Google Scholar 

  70. Menkhorst E, Zhang JG, Sims NA et al (2011) Vaginally administered PEGylated LIF antagonist blocked embryo implantation and eliminated non-target effects on bone in mice. PLoS One 6:e19665

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  71. Robb L, Li R, Hartley L, Nandurkar HH et al (1998) Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat Med 4:303–308

    CAS  PubMed  CrossRef  Google Scholar 

  72. Cullinan EB, Abbondanzo SJ, Anderson PS et al (1996) Leukemia inhibitory factor and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci 93:3115–3120

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  73. Dominquez F, Simon C, Quinonero A et al (2010) Human endometrial CD98 is essential for blastocyst adhesion. PLoS One 5:e13380

    CrossRef  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert L. Barbieri M.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this protocol

Cite this protocol

Barbieri, R.L. (2014). The Endocrinology of the Menstrual Cycle. In: Rosenwaks, Z., Wassarman, P. (eds) Human Fertility. Methods in Molecular Biology, vol 1154. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0659-8_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-0659-8_7

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-0658-1

  • Online ISBN: 978-1-4939-0659-8

  • eBook Packages: Springer Protocols