Semin Reprod Med 2007; 25(5): 344-351
DOI: 10.1055/s-2007-984740
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Neuroendocrine Changes with Reproductive Aging in Women

Janet E. Hall1
  • 1Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
Further Information

Publication History

Publication Date:
20 August 2007 (online)

ABSTRACT

Aging has dramatic effects on the reproductive system in women. Undoubtedly, the most notable changes in the neuroendocrine axis arise from the loss of ovarian function, and thus, the loss of negative feedback on the hypothalamus and pituitary. Progressive decreases in inhibin B and inhibin A result in an early increase in follicle-stimulating hormone (FSH), which initially maintains folliculogenesis and estradiol secretion. Over time, regular ovulatory cycles give way to inconsistent folliculogenesis and ovulation, dramatic swings in estradiol and gonadotropin levels, and markedly irregular cycles. Changes in estrogen positive feedback may contribute to cycle disruption. Studies in younger and older postmenopausal women indicate that changes in the neuroendocrine axis occur with aging that are independent of the changing ovarian hormonal milieu of the menopausal transition. Luteinizing hormone and FSH decrease progressively after the menopause, as does gonadotropin-releasing hormone (GnRH) pulse frequency. However, the overall amount of GnRH increases with aging, consistent with a significant degree of adaptability in the aging brain in women, and suggesting that aging alters pituitary responsiveness to GnRH. Estrogen negative feedback is not altered by aging; studies of the effects of aging on estrogen positive feedback are ongoing.

REFERENCES

  • 1 Hall J E. Neuroendocrine control of the menstrual cycle. In: Strauss JF, Barbieri RL Yen and Jaffe's Reproductive Endocrinology. 5th ed. Philadelphia, PA; Elsevier 2004: 195-211
  • 2 Bedecarrats G Y, Kaiser U B. Differential regulation of gonadotropin subunit gene promoter activity by pulsatile gonadotropin-releasing hormone (GnRH) in perifused L beta T2 cells: role of GnRH receptor concentration.  Endocrinology. 2003;  144 1802-1811
  • 3 Block E. Quantitative morphological investigations of the follicular system in women: variations at different ages.  Acta Anat (Basel). 1952;  14 108-123
  • 4 Richardson S J. The biological basis of the menopause.  Baillieres Clin Endocrinol Metab. 1993;  7 1-16
  • 5 Gougeon A, Ecochard R, Thalabard J C. 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;  50 653-663
  • 6 Hendriks D J, Mol B W, Bancsi L F, te Velde E R, Broekmans F J. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal follicle-stimulating hormone level.  Fertil Steril. 2005;  83 291-301
  • 7 Muttukrishna S, McGarrigle H, Wakim R, Khadum I, Ranieri D M, Serhal P. Antral follicle count, anti-mullerian hormone and inhibin B: predictors of ovarian response in assisted reproductive technology?.  BJOG. 2005;  112 1384-1390
  • 8 Schwartz D, Mayaux M J. Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS.  N Engl J Med. 1982;  306 404-406
  • 9 Menken J, Trussell J, Larsen U. Age and infertility.  Science. 1986;  233 1389-1394
  • 10 Visser J A, de Jong F H, Laven J S, Themmen A P. Anti-Mullerian hormone: a new marker for ovarian function.  Reproduction. 2006;  131 1-9
  • 11 Welt C K, McNicholl D J, Taylor A E, Hall J E. Female reproductive aging is marked by decreased secretion of dimeric inhibin.  J Clin Endocrinol Metab. 1999;  84 105-111
  • 12 Hall J E, Welt C K, Cramer D W. Inhibin A and inhibin B reflect ovarian function in assisted reproduction but are less useful at predicting outcome.  Hum Reprod. 1999;  14 409-415
  • 13 Welt C K, Schneyer A L. Differential regulation of inhibin B and inhibin a by follicle-stimulating hormone and local growth factors in human granulosa cells from small antral follicles.  J Clin Endocrinol Metab. 2001;  86 330-336
  • 14 Reame N E, Wyman T L, Phillips D J, de Kretser D M, Padmanabhan V. Net increase in stimulatory input resulting from a decrease in inhibin B and an increase in activin A may contribute in part to the rise in follicular phase follicle-stimulating hormone of aging cycling women.  J Clin Endocrinol Metab. 1998;  83 3302-3307
  • 15 Klein N A, Battaglia D E, Fujimoto V Y, Davis G S, Bremner W J, Soules M R. Reproductive aging: accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women.  J Clin Endocrinol Metab. 1996;  81 1038-1045
  • 16 Santoro N, Adel T, Skurnick J H. Decreased inhibin tone and increased activin A secretion characterize reproductive aging in women.  Fertil Steril. 1999;  71 658-662
  • 17 Muttukrishna S, Child T, Lockwood G M, Groome N P, Barlow D H, Ledger W L. Serum concentrations of dimeric inhibins, activin A, gonadotrophins and ovarian steroids during the menstrual cycle in older women.  Hum Reprod. 2000;  15 549-556
  • 18 Klein N A, Battaglia D E, Woodruff T K et al.. Ovarian follicular concentrations of activin, follistatin, inhibin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-2 (IGFBP-2), IGFBP-3, and vascular endothelial growth factor in spontaneous menstrual cycles of normal women of advanced reproductive age.  J Clin Endocrinol Metab. 2000;  85 4520-4525
  • 19 Baccarelli A, Morpurgo P S, Corsi A et al.. Activin A serum levels and aging of the pituitary-gonadal axis: a cross-sectional study in middle-aged and elderly healthy subjects.  Exp Gerontol. 2001;  36 1403-1412
  • 20 Schneyer A L, Rzucidlo D A, Sluss P M, Crowley Jr W F. Characterization of unique binding kinetics of follistatin and activin or inhibin in serum.  Endocrinology. 1994;  135 667-674
  • 21 Welt C K, Jimenez Y, Sluss P M, Smith P C, Hall J E. Control of estradiol secretion in reproductive ageing.  Hum Reprod. 2006;  21 2189-2193
  • 22 Santoro N, Isaac B, Neal-Perry G et al.. Impaired folliculogenesis and ovulation in older reproductive aged women.  J Clin Endocrinol Metab. 2003;  88 5502-5509
  • 23 Hansen K R, Thyer A C, Sluss P M, Bremner W J, Soules M R, Klein N A. Reproductive ageing and ovarian function: is the early follicular phase FSH rise necessary to maintain adequate secretory function in older ovulatory women?.  Hum Reprod. 2005;  20 89-95
  • 24 Piltonen T, Koivunen R, Ruokonen A, Tapanainen J S. Ovarian age-related responsiveness to human chorionic gonadotropin.  J Clin Endocrinol Metab. 2003;  88 3327-3332
  • 25 Mushayandebvu T, Castracane V D, Gimpel T, Adel T, Santoro N. Evidence for diminished midcycle ovarian androgen production in older reproductive aged women.  Fertil Steril. 1996;  65 721-723
  • 26 Durlinger A L, Gruijters M J, Kramer P et al.. Anti-Mullerian hormone attenuates the effects of FSH on follicle development in the mouse ovary.  Endocrinology. 2001;  142 4891-4899
  • 27 Josso N, Racine C, di Clemente N, Rey R, Xavier F. The role of anti-Mullerian hormone in gonadal development.  Mol Cell Endocrinol. 1998;  145 3-7
  • 28 Burger H G, Dudley E C, Hopper J L et al.. Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population-based cohort of women.  J Clin Endocrinol Metab. 1999;  84 4025-4030
  • 29 Welt C K, Smith Z A, Pauler D K, Hall J E. Differential regulation of inhibin A and inhibin B by luteinizing hormone, follicle-stimulating hormone, and stage of follicle development.  J Clin Endocrinol Metab. 2001;  86 2531-2537
  • 30 Treloar A E, Boynton R E, Behn B G, Brown B W. Variation of the human menstrual cycle through reproductive life.  Int J Fertil. 1967;  12 77-126
  • 31 Klein N A, Harper A J, Houmard B S, Sluss P M, Soules M R. Is the short follicular phase in older women secondary to advanced or accelerated dominant follicle development?.  J Clin Endocrinol Metab. 2002;  87 5746-5750
  • 32 Soules M R, Sherman S, Parrott E et al.. Executive summary: Stages of Reproductive Aging Workshop (STRAW).  Fertil Steril. 2001;  76 874-878
  • 33 Burger H G, Cahir N, Robertson D M et al.. Serum inhibins A and B fall differentially as FSH rises in perimenopausal women.  Clin Endocrinol (Oxf). 1998;  48 809-813
  • 34 Burger H G, Dudley E, Mamers P, Groome N, Robertson D M. Early follicular phase serum FSH as a function of age: the roles of inhibin B, inhibin A and estradiol.  Climacteric. 2000;  3 17-24
  • 35 Davison S L, Bell R, Donath S, Montalto J G, Davis S R. Androgen levels in adult females: changes with age, menopause, and oophorectomy.  J Clin Endocrinol Metab. 2005;  90 3847-3853
  • 36 Overlie I, Moen M H, Morkrid L, Skjaeraasen J S, Holte A. The endocrine transition around menopause-a five years prospective study with profiles of gonadotropins, estrogens, androgens and SHBG among healthy women.  Acta Obstet Gynecol Scand. 1999;  78 642-647
  • 37 Randolph Jr J F, Sowers M, Bondarenko I V, Harlow S D, Luborsky J L, Little R J. Change in estradiol and follicle-stimulating hormone across the early menopausal transition: effects of ethnicity and age.  J Clin Endocrinol Metab. 2004;  89 1555-1561
  • 38 Landgren B M, Collins A, Csemiczky G, Burger H G, Baksheev L, Robertson D M. Menopause transition: annual changes in serum hormonal patterns over the menstrual cycle in women during a nine-year period prior to menopause.  J Clin Endocrinol Metab. 2004;  89 2763-2769
  • 39 Santoro N, Brown J R, Adel T, Skurnick J H. Characterization of reproductive hormonal dynamics in the perimenopause.  J Clin Endocrinol Metab. 1996;  81 1495-1501
  • 40 Wise P M, Krajnak K M, Kashon M L. Menopause: the aging of multiple pacemakers.  Science. 1996;  273 67-70
  • 41 van Look P F, Lothian H, Hunter W M, Michie E A, Baird D T. Hypothalamic-pituitary-ovarian function in perimenopausal women.  Clin Endocrinol (Oxf). 1977;  7 13-31
  • 42 Fujimoto V Y, Spencer S J, Rabinovici J, Plosker S, Jaffe R B. Endogenous catecholamines augment the inhibitory effect of opioids on luteinizing hormone secretion during the midluteal phase.  Am J Obstet Gynecol. 1993;  169 1524-1530
  • 43 Weiss G, Skurnick J H, Goldsmith L T, Santoro N F, Park S J. Menopause and hypothalamic-pituitary sensitivity to estrogen.  JAMA. 2004;  292 2991-2996
  • 44 Keye Jr W R, Jaffe R B. Strength-duration characteristics of estrogen effects on gonadotropin response to gonadotropin-releasing hormone in women. I. Effects of varying duration of estradiol administration.  J Clin Endocrinol Metab. 1975;  41 1003-1008
  • 45 Young J R, Jaffe R B. Strength-duration characteristics of estrogen effects on gonadotropin response to gonadotropin-releasing hormone in women. II. Effects of varying concentrations of estradiol.  J Clin Endocrinol Metab. 1976;  42 432-442
  • 46 Taylor A E, Whitney H, Hall J E, Martin K, Crowley Jr W F. Midcycle levels of sex steroids are sufficient to recreate the follicle-stimulating hormone but not the luteinizing hormone midcycle surge: evidence for the contribution of other ovarian factors to the surge in normal women.  J Clin Endocrinol Metab. 1995;  80 1541-1547
  • 47 Shideler S E, DeVane G W, Kalra P S, Benirschke K, Lasley B L. Ovarian-pituitary hormone interactions during the perimenopause.  Maturitas. 1989;  11 331-339
  • 48 Friedman C I, Danforth D R, Herbosa-Encarnacion C, Arbogast L, Alak B M, Seifer D B. Follicular fluid vascular endothelial growth factor concentrations are elevated in women of advanced reproductive age undergoing ovulation induction.  Fertil Steril. 1997;  68 607-612
  • 49 Wise P M, Kashon M L, Krajnak K M et al.. Aging of the female reproductive system: a window into brain aging.  Recent Prog Horm Res. 1997;  52 279-303
  • 50 Stewart D A, Blackman M R, Kowatch M A, Danner D B, Roth G S. Discordant effects of aging on prolactin and luteinizing hormone-beta messenger ribonucleic acid levels in the female rat.  Endocrinology. 1990;  126 773-778
  • 51 Brito A N, Sayles T E, Krieg Jr R J, Matt D W. Relation of attenuated proestrous luteinizing hormone surges in middle-aged female rats to in vitro pituitary gonadotropin-releasing hormone responsiveness.  Eur J Endocrinol. 1994;  130 540-544
  • 52 Krieg Jr R J, Brito A N, Sayles T E, Matt D W. Luteinizing hormone secretion by dispersed anterior pituitary gland cells from middle-aged rats.  Neuroendocrinology. 1995;  61 318-325
  • 53 Zheng W, Jimenez-Linan M, Rubin B S, Halvorson L M. Anterior pituitary gene expression with reproductive aging in the female rat.  Biol Reprod. 2007;  76 1091-1102
  • 54 Hall J E, Lavoie H B, Marsh E E, Martin K A. Decrease in gonadotropin-releasing hormone (GnRH) pulse frequency with aging in postmenopausal women.  J Clin Endocrinol Metab. 2000;  85 1794-1800
  • 55 Wide L, Naessen T. 17 beta-oestradiol counteracts the formation of the more acidic isoforms of follicle-stimulating hormone and luteinizing hormone after menopause.  Clin Endocrinol (Oxf). 1994;  40 783-789
  • 56 Hall J E, Sluss P M, Eriksson K, Sharpless J L, Wide L. Less basic isoforms of endogenous luteinizing hormone (LH) in postmenopausal women result in prolonged plasma disappearance. The Endocrine Society 81st Annual Meeting.  1999;  292 P2-5
  • 57 Sharpless J L, Supko J G, Martin K A, Hall J E. Disappearance of endogenous luteinizing hormone is prolonged in postmenopausal women.  J Clin Endocrinol Metab. 1999;  84 688-694
  • 58 Srouji S, Histed S, Gill S, Sluss P, Hall J E. LH half-life in postmenopausal women is prolonged by both estrogen withdrawal and aging. Endocrine Society 88th Annual Meeting.  2006;  186 P1-102
  • 59 Moenter S M, Caraty A, Locatelli A, Karsch F J. Pattern of gonadotropin-releasing hormone (GnRH) secretion leading up to ovulation in the ewe: existence of a preovulatory GnRH surge.  Endocrinology. 1991;  129 1175-1182
  • 60 Clarke I J. Two decades of measuring GnRH secretion.  Reprod Suppl. 2002;  59 1-13
  • 61 Alexander S E, Aksel S, Hazelton J M, Yeoman R R, Gilmore S M. The effect of aging on hypothalamic function in oophorectomized women.  Am J Obstet Gynecol. 1990;  162 446-449
  • 62 Lambalk C B, De Boer L, Schoute E, Popp-Snyders C, Schoemaker J. Post-menopausal and chronological age have divergent effects on pituitary and hypothalamic function in episodic gonadotrophin secretion.  Clin Endocrinol (Oxf). 1997;  46 439-443
  • 63 Santoro N, Banwell T, Tortoriello D, Lieman H, Adel T, Skurnick J. Effects of aging and gonadal failure on the hypothalamic-pituitary axis in women.  Am J Obstet Gynecol. 1998;  178 732-741
  • 64 Hayes F J, McNicholl D J, Schoenfeld D, Marsh E E, Hall J E. Free alpha-subunit is superior to luteinizing hormone as a marker of gonadotropin-releasing hormone despite desensitization at fast pulse frequencies.  J Clin Endocrinol Metab. 1999;  84 1028-1036
  • 65 Hall J E, Taylor A E, Martin K A, Rivier J, Schoenfeld D A, Crowley Jr W F. Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women.  Proc Natl Acad Sci USA. 1994;  91 6894-6898
  • 66 Pagan Y L, Srouji S S, Jimenez Y, Emerson A, Gill S, Hall J E. Inverse relationship between luteinizing hormone and body mass index in polycystic ovarian syndrome: investigation of hypothalamic and pituitary contributions.  J Clin Endocrinol Metab. 2006;  91 1309-1316
  • 67 Gill S, Sharpless J L, Rado K, Hall J E. Evidence that GnRH decreases with gonadal steroid feedback but increases with age in postmenopausal women.  J Clin Endocrinol Metab. 2002;  87 2290-2296
  • 68 Chongthammakun S, Claypool L E, Terasawa E. Ovariectomy increases in vivo luteinizing hormone-releasing hormone release in pubertal, but not prepubertal, female rhesus monkeys.  J Neuroendocrinol. 1993;  5 41-50
  • 69 Rance N E, Uswandi S V. Gonadotropin-releasing hormone gene expression is increased in the medial basal hypothalamus of postmenopausal women.  J Clin Endocrinol Metab. 1996;  81 3540-3546
  • 70 Dalkin A C, Haisenleder D J, Ortolano G A, Ellis T R, Marshall J C. The frequency of gonadotropin-releasing-hormone stimulation differentially regulates gonadotropin subunit messenger ribonucleic acid expression.  Endocrinology. 1989;  125 917-924
  • 71 Haisenleder D J, Ortolano G A, Yasin M, Dalkin A C, Marshall J C. Regulation of gonadotropin subunit messenger ribonucleic acid expression by gonadotropin-releasing hormone pulse amplitude in vitro.  Endocrinology. 1993;  132 1292-1296
  • 72 Genazzani A D, Petraglia F, Sgarbi L et al.. Difference of LH and FSH secretory characteristics and degree of concordance between postmenopausal and aging women.  Maturitas. 1997;  26 133-138
  • 73 Rossmanith W G, Scherbaum W A, Lauritzen C. Gonadotropin secretion during aging in postmenopausal women.  Neuroendocrinology. 1991;  54 211-218
  • 74 Hall J E, Gill S. Neuroendocrine aspects of aging in women.  Endocrinol Metab Clin North Am. 2001;  30 631-646
  • 75 Gill S, Lavoie H B, Bo-Abbas Y, Hall J E. Negative feedback effects of gonadal steroids are preserved with aging in postmenopausal women.  J Clin Endocrinol Metab. 2002;  87 2297-2302
  • 76 Chongthammakun S, Terasawa E. Negative feedback effects of estrogen on luteinizing hormone-releasing hormone release occur in pubertal, but not prepubertal, ovariectomized female rhesus monkeys.  Endocrinology. 1993;  132 735-743
  • 77 Moenter S M, Caraty A, Karsch F J. The estradiol-induced surge of gonadotropin-releasing hormone in the ewe.  Endocrinology. 1990;  127 1375-1384

Janet E HallM.D. 

Reproductive Endocrine Unit, BHX-5, Massachusetts General Hospital

55 Fruit Street, Boston, MA 02114

Email: hall.janet@mgh.harvard.edu

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