Perimenopause pp 101-118 | Cite as

Dissociation of Endocrine and Gametogenic Ovarian Function

  • Gregory F. Erickson
Part of the Serono Symposia USA book series (SERONOSYMP)


Aging in women is associated with decreased fecundity as a result of the failure of dominant follicles to release eggs that can undergo normal embryonic development (1–4). In vitro fertilization (IVF) studies (5, 6) have demonstrated that this decrease becomes particularly evident in patients after 36 years of age when pregnancy rates (PR) with self-oocytes decrease sharply by ~65%, i.e., from a ~25% per transfer in women ≤ 30 years of age to ~9% per transfer in women after the age of 36 (6). A similar age-related decrease in female fecundity has been found using artificial insemination donor (AID) (7) and gamete intrafallopian transfer (GIFT) (8). The low fecundity rate continues through ~44 years, after which viable pregnancies almost never occur (8–10).


Granulosa Cell Follicular Fluid Ovary Reserve Primordial Follicle Dominant Follicle 
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  1. 1.
    Sauer MV, Paulson RJ, Lobo RA. A preliminary report on oocyte donation extending reproductive potential to women over 40. N Engl J Med 1990; 323:1157–60.PubMedCrossRefGoogle Scholar
  2. 2.
    Navot D, Bergh PA, Williams MA, et al. Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility. Lancet 1991;337:1375–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Sauer MV, Paulson RJ, Lobo RA. Pregnancy after age 50: application of oocyte donation to women after natural menopause. Lancet 1993;341:321–3.PubMedCrossRefGoogle Scholar
  4. 4.
    Sauer MV, Miles RA, Dahmoush L, Paulson RJ, Press M, Moyer D. Evaluating the effect of age on endometrial responsiveness to hormone replacement therapy: a histologic, ultrasonographic, and tissue receptor analysis. J Assist Reprod Genet 1993;10:47–52.PubMedCrossRefGoogle Scholar
  5. 5.
    Padilla SL, Garcia JE. Effect of maternal age and number of in vitro fertilization procedures on pregnancy outcome. Fertil Steril 1989;52:270–3.PubMedGoogle Scholar
  6. 6.
    Piette C, de Mouzon J, Bachelot A, Spira A. In vitro fertilization: influence of women’s age on pregnancy rates. Hum Reprod 1990;5:56–9.PubMedGoogle Scholar
  7. 7.
    Cecos F, Schwartz D, Mayaux MJ. Female fecundity as a function of age. N Engl J Med 1982;306:404–6.CrossRefGoogle Scholar
  8. 8.
    Qasim SM, Karacan M, Corsan GH, Shelden R, Kemmann E. High-order oocyte transfer in gamete intrafallopian transfer patients 40 or more years of age. Fertil Steril 1995;64:107–10.PubMedGoogle Scholar
  9. 9.
    Penzias AS, Thompson IE, Alper MM, Oskowitz SP, Berger MJ. Successful use of gamete intrafallopian transfer does not reverse the decline in fertility in women over 40 years of age. Obstet Gynecol 1991;77:37–9.PubMedGoogle Scholar
  10. 10.
    Wood C, Calderon I, Crombie A. Age and fertility: results of assisted reproductive technology in women over 40 years. J Assist Reprod Genet 1992;9:482–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Sherman BM, Korenman SG. Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest 1975;55:699–707.PubMedCrossRefGoogle Scholar
  12. 12.
    Navot D, Rosenwaks Z, Margolioth EJ. Prognostic assessment of female fecundity. Lancet 1987;2:645–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Lee SJ, Lenton EA, Sexton L, Cooke ID. The effect of age on the cyclical patterns of plasma LH, FSH, oestradiol and progesterone in women with regular menstrual cycles. Hum Reprod 1988;3:851–5.PubMedGoogle Scholar
  14. 14.
    Hughes EG, Robertson DM, Handelsman DJ, Hayward S, Healy DL, DeKretser DM. Inhibin and estradiol responses to ovarian hyperStimulation: effects of age and predictive value for in vitro fertilization outcome. J Clin Endocrinol Metab 1990;70:358–64.PubMedCrossRefGoogle Scholar
  15. 15.
    Munne S, Alikani M, Tomkin G, Grifo J, Cohen J. Embryo morphology, developmental rates, and maternal age are correlated with chromosome abnormalities. Fertil Steril 1995;64:382–91.PubMedGoogle Scholar
  16. 16.
    Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51:651–4.PubMedGoogle Scholar
  17. 17.
    Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992;7:1342–6.PubMedGoogle Scholar
  18. 18.
    Gougeon A, Ecochard R, Thalabard JC. Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol Reprod 1994;50:653–63.PubMedCrossRefGoogle Scholar
  19. 19.
    McKinlay SM, Brambilla DJ, Posner, JG. The normal menopause transition. Maturitas 1992;14:103–15.PubMedCrossRefGoogle Scholar
  20. 20.
    Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Meredith S, Dudenhoffer G, Butcher RL, Sperner SP, Walla T. Unilateral ovariectomy increases loss of primordial follicles and is associated with increased metestrous concentration of follicle stimulating hormone. Biol Reprod 1992;47:162–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Lintern-Moore S. Effect of athymia on the initiation of follicular growth in the rat ovary. Biol Reprod 1977;17:155–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Lintern-Moore S, Everitt AV. The effect of restricted food intake on the size and composition of the ovarian follicle population in the wistar rat. Biol Reprod 1978;19:688–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Howe E, Lintern-Moore S, Moore GPM, Hawkins J. Ovarian development in hypopituitary snell dwarf mice. The size and composition of the follicle population. Biol Reprod 1978;19:959–65.PubMedCrossRefGoogle Scholar
  25. 25.
    Lintern-Moore S, Supasri Y, Pavasuthipaisit K, Sobhon P. Acute and chronic morphine sulfate treatment alters ovarian development in prepubertal rats. Biol Reprod 1979;21:379–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Lintern-Moore S, Moore GPM, Panaretto BA, Robertson D. Follicular development in the neonatal mouse ovary; effect of epidermal growth factor. Acta Endocrinol 1981;96:123–6.PubMedGoogle Scholar
  27. 27.
    Lenton EA, DeKretser DM, Woodward AJ, Robertson DM. Inhibin concentrations throughout the menstrual cycles of normal, infertile, and older women compared with those during spontaneous conception cycles. J Clin Endocrinol Metab 1991;73:1180–90.PubMedCrossRefGoogle Scholar
  28. 28.
    Rivier C, Vale W, Rivier J. Studies of the inhibin family of hormones: a review. Recent Prog Hormone Res 1987;28:104–18.Google Scholar
  29. 29.
    Rivier C, Vale W. Immunoneutralization of endogenous inhibin modified hormone secretion and ovulation rate in the rat. Endocrinology 1989; 125:152–57.PubMedCrossRefGoogle Scholar
  30. 30.
    Muttukrishna S, Fowler PA, Groome NP, Mitchell GG, Robertson WR, Knight PG. Serum concentrations of dimeric inhibin during the spontaneous human menstrual cycle and after treatment with exogenous gonadotropin. Hum Reprod 1994;9:1634–42.PubMedGoogle Scholar
  31. 31.
    Yamoto M, Minami S, Nakano R, Kobayashi M. Immunohistochemical localization of inhibin/activin subunits in human ovarian follicles during the menstrual cycle. J Clin Endocrinol Metab 1992;74:989–93.PubMedCrossRefGoogle Scholar
  32. 32.
    Roberts VJ, Barth S, El-Roeiy A. Expression of inhibin/activin subunits and follistatin messenger ribonucleic acids and proteins in ovarian follicles and the corpus luteum during the human menstrual cycle. J Clin Metab 1993; 77:1402–10.CrossRefGoogle Scholar
  33. 33.
    Illingworth PJ, Reddi K, Smith KB, Baird DT. The source of inhibin secretion during the human menstrual cycle. J Clin Endocrinol Metab 1991;73:667–73.PubMedCrossRefGoogle Scholar
  34. 34.
    Vale W, Rivier J, Vaughan J, et al. Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid. Nature 1986;321:776–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Ling N, Ying S-Y, Ueno N, et al. Pituitary FSH is released by a heterodimer of the β-subunits from the two forms of inhibin. Nature 1986;321:779–82.PubMedCrossRefGoogle Scholar
  36. 36.
    Nakamura T, Asashima M, Eto Y, et al. Isolation and characterization of native activin B. J Biol Chem 1992;267:16385–89.PubMedGoogle Scholar
  37. 37.
    Schwall R, Schmelzer CH, Matsuyama E, Mason AJ. Multiple actions of recombinant activin-A in vivo. Endocrinology 1989;125:1420–23.PubMedCrossRefGoogle Scholar
  38. 38.
    Rivier C, Vale W. Effect of recombinant activin-A on gonadotropin secretion in the female rat. Endocrinology 1991;129:2463–65.PubMedCrossRefGoogle Scholar
  39. 39.
    Carroll RS, Kowash PM, Lofgren JA, Schwall RH, Chin WW. In vivo regulation of FSH synthesis by inhibin and activin. Endocrinology 1991; 129:3299–304.PubMedCrossRefGoogle Scholar
  40. 40.
    Woodruff TK, Krummen LA, Lyon RJ, Stocks DL, Mather JP. Recombinant human inhibin A and recombinant human activin A regulate pituitary and ovarian function in the adult female rat. Endocrinology 1993;132:2332–41.PubMedCrossRefGoogle Scholar
  41. 41.
    DePaolo LV, Bicsak TA, Erickson GF, Shimasaki S, Ling N. Follistatin and activin: a potential intrinsic regulatory system within diverse tissues. Soc Exp Biol Med 1991;198:500–12.Google Scholar
  42. 42.
    Mathews LS. Activin receptors and cellular signaling by the receptor serine kinase family. Endocr Rev 1994;15:310–37.PubMedGoogle Scholar
  43. 43.
    Demura R, Suzuki T, Tajima S, et al. Human plasma free activin and inhibin levels during the menstrual cycle. J Clin Endocrinol Metab 1993;76:1080–2.PubMedCrossRefGoogle Scholar
  44. 44.
    Meunier H, Cajander SB, Roberts VJ, et al. Rapid changes in the expression of inhibin α-, βA-, and βB-subunits in ovarian cell types during the rat estrous cycle. Mol Endocrinol 1988;2:1352–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Meunier H, Roberts VJ, Sawchenko PE, Cajander SB, Hsueh AJW, Vale W. Periovulatory changes in the expression of inhibin α-, βA-, and βB-subunits in hormonally induced immature female rats. Mol Endocrinol 1989;3:2062–69.PubMedCrossRefGoogle Scholar
  46. 46.
    Miyanaga K, Erickson GF, DePaolo LV, Ling N, Shimasaki S. Differential control of activin, inhibin and follistatin proteins in cultured rat granulosa cells. Biochem Biophys Res Commun 1993;194:253–25.PubMedCrossRefGoogle Scholar
  47. 47.
    Feng Z-M, Madigan MB, Chen C-L C. Expression of type II activin receptor genes in the male and female reproductive tissues of the rat. Endocrinology 1993;132:2593–600.PubMedCrossRefGoogle Scholar
  48. 48.
    Nakamura M, Minegishi T, Hasegawa Y, et al. Effect of an activin A on follicle-stimulating hormone (FSH) receptor messenger ribonucleic acid levels and FSH receptor expression in cultured rat granulosa cells. Endocrinology 1993;133:538–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Cameron VA, Nishimura E, Mathews LS, Lewis KA, Sawchenko PE, Vale WW. Hybridization histochemical localization of activin receptor subtypes in rat brain, pituitary, ovary and testis. Endocrinology 1994;134:799–808.PubMedCrossRefGoogle Scholar
  50. 50.
    LaPolt PS, Soto D, Su J-G, et al. Activin stimulation of inhibin secretion and messenger RNA levels in cultured granulosa cells. Mol Endocrinol 1989; 3:1666–73.PubMedCrossRefGoogle Scholar
  51. 51.
    Xiao S, Farnworth PG, Findlay JK. Interaction between activin and of basal inhibin production by cultured rat granulosa cells. Endocrinology 1992; 131:2365–70.PubMedCrossRefGoogle Scholar
  52. 52.
    Woodruff TK, Krummen L, McCray G, Mather JP. In situ ligand binding of recombinant human [125] activin-A and recombinant human [125] inhibin-A to the adult rat ovary. Endocrinology 1993;133:2998–3006.PubMedCrossRefGoogle Scholar
  53. 53.
    Xiao S, Robertson DM, Findlay JK. Effects of activin and follicle-stimulating hormone (FSH)-suppressing protein/follistatin on FSH receptors and differentiation of cultured rat granulosa cells. Endocrinology 1992;131:1009–16.PubMedCrossRefGoogle Scholar
  54. 54.
    Presl J, Pospisil J, Figarova V, Krabec Z. Stage-dependent changes in binding of iodinated FSH during ovarian follicle maturation in rats. Endocrinol Exp 1974;8:291–98.PubMedGoogle Scholar
  55. 55.
    Zeleznik AJ, Schuler HM, Reichert LE. Gonadotropin-binding sites in the rhesus monkey ovary: role of the vasculature in the selective distribution of human chorionic gonadotropin to the preovulatory follicle. Endocrinology 1981;109:356–62.PubMedCrossRefGoogle Scholar
  56. 56.
    Nimrod A, Lamprecht SA. Hormone-induced desensitization of cultured rat granulosa cells to FSH. Biochem Biophys Res Commun 1980;92:905–11.PubMedCrossRefGoogle Scholar
  57. 57.
    Nakamura K, Nakamura M, Igarashi S, et al. Effect of activin on luteinizing hormone-human chorionic gonadotropin receptor messenger ribonucleic acid in granulosa cells. Endocrinology 1994;134:2329–35.PubMedCrossRefGoogle Scholar
  58. 58.
    Miro F, Smyth CD, Hillier SG. Development-related effects of recombinant activin on steroid synthesis in rat granulosa cells. Endocrinology 1991; 129:3388–94.PubMedCrossRefGoogle Scholar
  59. 59.
    Woodruff TK, Lyan RJ, Hansen SE, Rice GC, Mather JP. Inhibin and activin locally regulate rat ovarian folliculogenesis. Endocrinology 1990;127:3196–205.PubMedCrossRefGoogle Scholar
  60. 60.
    Miro F, Smyth CD, Hillier SG. Development-related effects of recombinant activin on steroid synthesis in rat granulosa cells. Endocrinology 1991; 129:3388–94.PubMedCrossRefGoogle Scholar
  61. 61.
    Erickson GF, Kokka S, Rivier C. Activin causes premature superovulation. Endocrinology 1995;136:4804–13.PubMedCrossRefGoogle Scholar
  62. 62.
    Itoh M, Igarashi M, Yamada K, et al. Activin A stimulates meiotic maturation of the rat oocyte in vitro. Biochem Biophys Res Commun 1990;166:1479–84.PubMedCrossRefGoogle Scholar
  63. 63.
    Hillier SG, Yong EL, Illingworth PJ, Baird DT, Schwall RH, Mason J. Effect of recombinant inhibin on androgen synthesis in cultured human thecal cells. Mol Cell Endocrinol 1991;75:Rl-6.CrossRefGoogle Scholar
  64. 64.
    Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51:651–54.PubMedGoogle Scholar
  65. 65.
    Li R, Phillips DM, Mather JP. Activin promotes ovarian follicle development in vitro. Endocrinology 1995;136:849–56.PubMedCrossRefGoogle Scholar
  66. 66.
    Doi M, Igarashi M, Hasegawa Y, et al. In vivo action of activin-A on pituitary-gonadal system. Endocrinology 1992;130:139–44.PubMedCrossRefGoogle Scholar
  67. 67.
    Gougeon A, Ecochard R, Thalabard JC. Age-related changes of the population of human ovarian follicles: increase in the dissappearance rate of non-growing and early-growing follicles in aging women. Biol Reprod 1994;50:653–63.PubMedCrossRefGoogle Scholar
  68. 68.
    Erickson GF. An analysis of follicle development and ovum maturation. Sem Reprod Endocrinol 1986;4:233–54.CrossRefGoogle Scholar

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© Springer-Verlag New York, Inc. 1997

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  • Gregory F. Erickson

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