Reproductive ageing in women

The traditional view in respect to female reproduction is that the number of oocytes at birth is fixed and continuously declines towards the point when no more oocytes are available after menopause. In this review we briefly discuss the embryonic development of female germ cells and ovarian follicles. The ontogeny of the hypothalamic‐pituitary‐gonadal axis is then discussed, with a focus on pubertal transition and normal ovulatory menstrual cycles during female adult life. Biochemical markers of menopausal transition are briefly examined. We also examine the effects of age on female fertility, the contribution of chromosomal abnormalities of the oocyte to the observed decline in female fertility with age and the possible biological basis for the occurrence of such abnormalities. Finally, we consider the effects of maternal age on obstetric complications and perinatal outcome. New data that have the potential to revolutionize our understanding of mammalian oogenesis and follicular formation, and of the female reproductive ageing process, are also briefly considered. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[1]  R. Fretts Etiology and prevention of stillbirth. , 2005, American journal of obstetrics and gynecology.

[2]  S. Hamamah,et al.  The occurrence of aneuploidy in human: lessons from the cytogenetic studies of human oocytes. , 2006, European journal of medical genetics.

[3]  L. Wildt,et al.  Control of the rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin-releasing hormone. , 1980, Science.

[4]  S. Yen,et al.  Expression of inhibin/activin subunits and follistatin messenger ribonucleic acids and proteins in ovarian follicles and the corpus luteum during the human menstrual cycle. , 1993, The Journal of clinical endocrinology and metabolism.

[5]  V. Padmanabhan,et al.  Changes in serum inhibin, activin and follistatin concentrations during puberty in girls. , 2000, Human reproduction.

[6]  M. Faddy,et al.  Follicle dynamics during ovarian ageing , 2000, Molecular and Cellular Endocrinology.

[7]  K. Eddleman,et al.  Long-term outcomes in multiple gestations. , 2005, Clinics in perinatology.

[8]  G. Lenaz Role of mitochondria in oxidative stress and ageing. , 1998, Biochimica et biophysica acta.

[9]  I. M. Young,et al.  Constant Pineal Output and Increasing Body Mass Account for Declining Melatonin Levels During Human Growth and Sexual Maturation , 1988, Journal of pineal research.

[10]  P. Sluss,et al.  Age-related analysis of inhibin A, inhibin B, and activin a relative to the intercycle monotropic follicle-stimulating hormone rise in normal ovulatory women. , 2004, The Journal of clinical endocrinology and metabolism.

[11]  J. Studd,et al.  A report on 100 cycles of oocyte donation; factors affecting the outcome. , 1990, Human reproduction.

[12]  R. Berkowitz,et al.  Delayed childbearing and the outcome of pregnancy. , 1990, The New England journal of medicine.

[13]  Tomoko Kaneko,et al.  Corrigendum: Germline stem cells and follicular renewal in the postnatal mammalian ovary , 2004, Nature.

[14]  F. de Zegher,et al.  Acute N-Methyl-D,L-Aspartate Administration Stimulates the Luteinizing Hormone Releasing Hormone Pulse Generator in the Ovine Fetus , 1999, Hormone Research in Paediatrics.

[15]  J. Shay,et al.  Telomerase activity in human germline and embryonic tissues and cells. , 1996, Developmental genetics.

[16]  Ean,et al.  INCREASED MATERNAL AGE AND THE RISK OF FETAL DEATH , 2000 .

[17]  D. Baird,et al.  PULSATILE SECRETION OF LH, FSH, PROLACTIN, OESTRADIOL AND PROGESTERONE DURING THE HUMAN MENSTRUAL CYCLE , 1982, Clinical endocrinology.

[18]  R. Frydman,et al.  Seasonal influence of diurnal rhythms in the onset of the plasma luteinizing hormone surge in women. , 1982, The Journal of clinical endocrinology and metabolism.

[19]  R. Speed The possible role of meiotic pairing anomalies in the atresia of human fetal oocytes , 1988, Human Genetics.

[20]  D. Seifer,et al.  Early follicular serum müllerian-inhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles. , 2002, Fertility and sterility.

[21]  D. Apter,et al.  Gonadotrophin releasing hormone pulse generator activity before and during sexual maturation in girls: new insights. , 1993, Human reproduction.

[22]  M. Birch-Machin,et al.  The role of mitochondria in ageing and carcinogenesis , 2006, Clinical and experimental dermatology.

[23]  D. Skupski,et al.  Multifetal pregnancies , 1995, Current opinion in obstetrics & gynecology.

[24]  R. Edwards,et al.  Test-tube babies, 1981 , 1981, Nature.

[25]  A. Chetrit,et al.  Effect of Very Advanced Maternal Age on Pregnancy Outcome and Rate of Cesarean Delivery , 1998, Obstetrics and gynecology.

[26]  M. Grumbach The neuroendocrinology of human puberty. An ontogenetic perspective , 1990 .

[27]  H. Burger,et al.  Menopause transition: Annual changes in serum hormonal patterns over the menstrual cycle in women during a nine-year period prior to menopause. , 2004, The Journal of clinical endocrinology and metabolism.

[28]  R. Pearl,et al.  Studies on the physiology of reproduction in the domestic fowl. XVIII. Further observations on the anatomical basis of fecundity , 1921 .

[29]  R. Gosden,et al.  Spindles, mitochondria and redox potential in ageing oocytes. , 2004, Reproductive biomedicine online.

[30]  F. Waldhauser,et al.  Pulsatile secretion of gonadotropins in early infancy , 1981, European Journal of Pediatrics.

[31]  L. Gianaroli,et al.  Fertility and ageing. , 2005, Human reproduction update.

[32]  D. Styne,et al.  Puberty : ontogeny, neuroendocrinology, physiology, and disorders , 1998 .

[33]  K. Mogi,et al.  A role of gamma-amino butyric acid (GABA) and glutamate in control of puberty in female rhesus monkeys: effect of an antisense oligodeoxynucleotide for GAD67 messenger ribonucleic acid and MK801 on luteinizing hormone-releasing hormone release. , 1999, Endocrinology.

[34]  M. Aubert,et al.  The ontogenesis of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function. , 1976, Recent progress in hormone research.

[35]  Herng‐Ching Lin,et al.  Association between maternal age and the likelihood of a cesarean section: a population‐based multivariate logistic regression analysis , 2004, Acta obstetricia et gynecologica Scandinavica.

[36]  S. H. Kane Advancing Age and the Primigravida , 1967, Obstetrics and gynecology.

[37]  B. Lasley,et al.  The operating characteristics of the hypothalamic-pituitary system during the menstrual cycle and observations of biological action of somatostatin. , 1975, Recent progress in hormone research.

[38]  M. R. Curtis,et al.  STUDIES ON THE PHYSIOLOGY OF REPRODUCTION IN THE DOMESTIC FOWL: XVI. DOUBLE EGGS , 1916 .

[39]  J. Demaille,et al.  Maternal aging and chromosomal abnormalities: new data drawn from in vitro unfertilized human oocytes , 2003, Human Genetics.

[40]  P. Motta,et al.  Elimination of germ cells during differentiation of the human ovary: an electron microscopic study. , 1986, European journal of obstetrics, gynecology, and reproductive biology.

[41]  E. Terasawa,et al.  Neurobiological mechanisms of the onset of puberty in primates. , 2001, Endocrine reviews.

[42]  M. Soules,et al.  Executive summary: Stages of Reproductive Aging Workshop (STRAW) , 2001, Climacteric : the journal of the International Menopause Society.

[43]  A. Mason,et al.  Localization of inhibin/activin subunit mRNAs within the primate ovary. , 1990, Molecular endocrinology.

[44]  D. Baird,et al.  PULSATILE RELEASE OF LH AND OESTRADIOL DURING THE PERIOVULATORY PERIOD IN WOMEN , 1984, Clinical Endocrinology.

[45]  J. Tilly,et al.  Germline stem cells and follicular renewal in the postnatal mammalian ovary , 2004, Nature.

[46]  C. Lambalk,et al.  The endocrinology of dizygotic twinning in the human , 1998, Molecular and Cellular Endocrinology.

[47]  T. de Lange,et al.  Ending up with the right partner , 1998, Nature.

[48]  E. Thompson The elderly primigravida. , 1951, The Practitioner.

[49]  Burger,et al.  Serum Inhibins A and B fall differentially as FSH rises in perimenopausal women , 1998, Clinical endocrinology.

[50]  S. Kapen,et al.  Human puberty: 24-hour estradiol in pubertal girls. , 1976, The Journal of clinical endocrinology and metabolism.

[51]  N E Morton,et al.  The origin of 47,XXY and 47,XXX aneuploidy: heterogeneous mechanisms and role of aberrant recombination. , 1994, Human molecular genetics.

[52]  M. Racine,et al.  Sex differences in FSH-regulatory peptides in pubertal age boys and girls and effects of sex steroid treatment. , 2004, Human reproduction.

[53]  J. Mills,et al.  Mechanisms of maternal aneuploidy: FISH analysis of oocytes and polar bodies in patients undergoing assisted conception , 2000, Human Genetics.

[54]  O. Djahanbakhch,et al.  A RAPID LUTEINIZING HORMONE RADIOIMMUNOASSAY FOR THE PREDICTION OF OVULATION , 1981, British journal of obstetrics and gynaecology.

[55]  J M Tanner,et al.  Variations in pattern of pubertal changes in girls. , 1969, Archives of disease in childhood.

[56]  N. Klein,et al.  Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. , 1996, Human reproduction.

[57]  D. Apter,et al.  Gonadotropin-releasing hormone pulse generator activity during pubertal transition in girls: pulsatile and diurnal patterns of circulating gonadotropins. , 1993, The Journal of clinical endocrinology and metabolism.

[58]  T. K. Jensen,et al.  Serum inhibin A and inhibin B in healthy prepubertal, pubertal, and adolescent girls and adult women: relation to age, stage of puberty, menstrual cycle, follicle-stimulating hormone, luteinizing hormone, and estradiol levels. , 2000, The Journal of clinical endocrinology and metabolism.

[59]  P. Jacobs,et al.  Trisomy in man. , 1984, Annual review of genetics.

[60]  T. G. Baker,et al.  A QUANTITATIVE AND CYTOLOGICAL STUDY OF GERM CELLS IN HUMAN OVARIES. , 1964, Proceedings of the Royal Society of London. Series B, Biological sciences.

[61]  A. Yahaya,et al.  Pregnancy outcome at age 40 and older , 2001, Archives of Gynecology and Obstetrics.

[62]  M. Forman,et al.  Do Delayed Childbearers Face Increased Risks of Adverse Pregnancy Outcomes After the First Birth? , 1993, Obstetrics and gynecology.

[63]  A. Bukovsky,et al.  Origin of germ cells and formation of new primary follicles in adult human ovaries , 2004, Reproductive biology and endocrinology : RB&E.

[64]  T. Plant,et al.  Puberty in monkeys is triggered by chemical stimulation of the hypothalamus. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[65]  C. Harley,et al.  Telomeres shorten during ageing of human fibroblasts , 1990, Nature.

[66]  E. Knobil,et al.  The neuroendocrine control of the menstrual cycle. , 1980, Recent progress in hormone research.

[67]  M. Grumbach,et al.  Neuroendocrine control mechanisms and the onset of puberty. , 1982, Annual review of physiology.

[68]  Gary Jeng,et al.  Trends in multiple births conceived using assisted reproductive technology, United States, 1997-2000. , 2003, Pediatrics.

[69]  J. Deutschberger,et al.  Relation of the Mother's Age to Obstetric Performance , 1964, Obstetrics and gynecology.

[70]  J. Visser,et al.  Anti-Müllerian hormone and its role in ovarian function , 2003, Molecular and Cellular Endocrinology.

[71]  Shuang Lu,et al.  Deficit of mitochondria-derived ATP during oxidative stress impairs mouse MII oocyte spindles , 2006, Cell Research.

[72]  R. Gosden,et al.  Demonstration of a mechanism of aneuploidy in human oocytes using Multifluor fluorescence in situ hybridization. , 2001, Fertility and sterility.

[73]  Edmonson Mb,et al.  Maternal Age at First Childbirth and Risk of Low Birth Weight and Preterm Delivery in Washington State , 1993 .

[74]  S. Korenman,et al.  The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. , 1976, The Journal of clinical endocrinology and metabolism.

[75]  V. Padmanabhan,et al.  GnRH agonist stimulation of the pituitary-gonadal axis in children: age and sex differences in circulating inhibin-B and activin-A. , 2004, Human reproduction.

[76]  A. Gougeon Dynamics of follicular growth in the human: a model from preliminary results. , 1986, Human reproduction.

[77]  K. Mogi,et al.  A Role of gAmino Butyric Acid ( GABA ) and Glutamate in Control of Puberty in Female Rhesus Monkeys : Effect of an Antisense Oligodeoxynucleotide for GAD 67 Messenger Ribonucleic Acid and MK 801 on Luteinizing Hormone-Releasing Hormone Release * , 1999 .

[78]  D. Harman Free‐Radical Theory of Aging , 1992, Mutation research.

[79]  J. Bidart,et al.  Anti-Müllerian hormone is a specific marker of sertoli- and granulosa-cell origin in gonadal tumors. , 2000, Human pathology.

[80]  B. Dale,et al.  Association between nondisjunction and maternal age in meiosis-II human oocytes. , 1996, American journal of human genetics.

[81]  K. Clément,et al.  A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction , 1998, Nature.

[82]  M. Grumbach,et al.  The ontogenesis of human foetal hormones. II. Luteinizing hormone (LH) and follicle stimulating hormone (FSH). , 1976, Acta endocrinologica.

[83]  J. Hopper,et al.  A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. , 2000, The Journal of clinical endocrinology and metabolism.

[84]  S. Kapen,et al.  HUMAN PUBERTY: 24-HOUR ESTRADIOL PATTERNS IN PUBERTAL GIRLS , 1976 .

[85]  E. Terasawa,et al.  Effects of pulsatile infusion of the GABA(A) receptor blocker bicuculline on the onset of puberty in female rhesus monkeys. , 1999, Endocrinology.

[86]  Joan Vaughan,et al.  Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid , 1986, Nature.

[87]  B. Dale,et al.  The maternal age effect: a hypothesis based on oxidative phosphorylation , 2005, Zygote.

[88]  M. Grumbach,et al.  N-methyl-D-aspartate (NMDA) receptors mediate the release of gonadotropin-releasing hormone (GnRH) by NMDA in a hypothalamic GnRH neuronal cell line (GT1-1). , 1994, Endocrinology.

[89]  K. Collins,et al.  Structure and function of telomerase. , 1996, Current opinion in cell biology.

[90]  J. Studd,et al.  Pregnancy: Age, pregnancy and miscarriage: uterine versus ovarian factors , 1993 .

[91]  V. Padmanabhan,et al.  Diurnal changes in FSH-regulatory peptides and their relationship to gonadotrophins in pubertal girls. , 2005, Human reproduction.

[92]  D. Chan Mitochondria: Dynamic Organelles in Disease, Aging, and Development , 2006, Cell.

[93]  S. Hamamah,et al.  Effect of maternal age on the frequency of cytogenetic abnormalities in human oocytes , 2005, Cytogenetic and Genome Research.

[94]  S. Davis,et al.  Androgen levels in adult females: changes with age, menopause, and oophorectomy. , 2005, The Journal of clinical endocrinology and metabolism.

[95]  S. Freeman,et al.  Risk factors for nondisjunction of trisomy 21 , 2005, Cytogenetic and Genome Research.

[96]  T. G. Baker Radiosensitivity of mammalian oocytes with particular reference to the human female. , 1971, American journal of obstetrics and gynecology.

[97]  G. Schatten,et al.  On Regenerating the Ovary and Generating Controversy , 2005, Cell.

[98]  H. Burger,et al.  Hormonal changes in the menopause transition. , 2002, Recent progress in hormone research.

[99]  M. Gaulden Maternal age effect: the enigma of Down syndrome and other trisomic conditions. , 1992, Mutation research.

[100]  Naoto Ueno,et al.  Pituitary FSH is released by a heterodimer of the β-subunits from the two forms of inhibin , 1986, Nature.

[101]  M. Forest,et al.  Hypophyso-gonadal function in humans during the first year of life. 1. Evidence for testicular activity in early infancy. , 1974, The Journal of clinical investigation.

[102]  E. Blackburn,et al.  Developmentally programmed healing of chromosomes by telomerase in tetrahymena , 1991, Cell.

[103]  S. Lanzendorf,et al.  Characterization of telomerase activity in the human oocyte and preimplantation embryo. , 2000, Molecular human reproduction.

[104]  K. Joseph,et al.  The Perinatal Effects of Delayed Childbearing , 2005, Obstetrics and gynecology.

[105]  H. Peters Migration of gonocytes into the mammalian gonad and their differentiation. , 1970, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[106]  E. Blackburn,et al.  Recognition and elongation of telomeres by telomerase. , 1989, Genome.

[107]  E. Schon,et al.  Chromosomal non-disjunction in human oocytes: is there a mitochondrial connection? , 2000, Human reproduction.

[108]  R. Angell Predivision in human oocytes at meiosis I: a mechanism for trisomy formation in man , 1991, Human Genetics.

[109]  R. Gallo Pulsatile LH release during the ovulatory LH surge on proestrus in the rat. , 1981, Biology of reproduction.

[110]  M. Petersen,et al.  Origin and mechanisms of non-disjunction in human autosomal trisomies. , 1998, Human reproduction.

[111]  R. van den Hurk,et al.  Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. , 2005, Theriogenology.

[112]  P. Nagley,et al.  Mitochondrial DNA mutation and the ageing process: bioenergy and pharmacological intervention. , 1992, Mutation research.

[113]  E. Norwitz,et al.  Maternal physiology and complications of multiple pregnancy. , 2005, Seminars in perinatology.

[114]  J. Luciani,et al.  The microtubular cytoskeleton and chromosomes of unfertilized human oocytes aged in vitro , 1988, Human Genetics.

[115]  J Licinio,et al.  Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defe , 1999, The Journal of clinical endocrinology and metabolism.

[116]  J. Hopper,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. , 1999, The Journal of clinical endocrinology and metabolism.

[117]  E. Terasawa,et al.  gamma-Aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[118]  C. Sorenson,et al.  Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad. , 1995, Endocrinology.

[119]  M. Edmonson,et al.  Maternal age at first childbirth and risk of low birth weight and preterm delivery in Washington State. , 1994, JAMA.

[120]  K. Borum Oogenesis in the mouse. A study of the meiotic prophase. , 1961, Experimental cell research.

[121]  A. Hirshfield,et al.  An overview of follicular development in the ovary: from embryo to the fertilized ovum in vitro. , 1992, Maryland medical journal.

[122]  M. Forman,et al.  Delayed childbearing in Sweden. , 1984, JAMA.

[123]  K. Leveno,et al.  Childbearing among older women--the message is cautiously optimistic. , 1995, The New England journal of medicine.

[124]  P. Motta,et al.  Germ cells in the ovarian surface during fetal development in humans. A three-dimensional microanatomical study by scanning and transmission electron microscopy. , 1986, Journal of submicroscopic cytology.

[125]  Santiago Munné,et al.  Spectral karyotyping of fresh, non-inseminated oocytes. , 2002, Molecular human reproduction.

[126]  G. Dildy,et al.  Very advanced maternal age: pregnancy after age 45. , 1996, American journal of obstetrics and gynecology.

[127]  D. Keefe,et al.  Mitochondrial deoxyribonucleic acid deletions in oocytes and reproductive aging in women. , 1995, Fertility and sterility.

[128]  Mary-Anne Williams,et al.  Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility , 1991, The Lancet.

[129]  M. Grumbach,et al.  The Neuroendocrinology of Human Puberty Revisited , 2004, Hormone Research in Paediatrics.

[130]  T. Plant,et al.  Neuropeptide Y: A hypothalamic brake restraining the onset of puberty in primates. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[131]  N. Skakkebæk,et al.  Inhibin A and B as markers of menopause: a five‐year prospective longitudinal study of hormonal changes during the menopausal transition , 2005, Acta obstetricia et gynecologica Scandinavica.

[132]  T. Hassold,et al.  Etiology of nondisjunction in humans , 1995, Environmental and molecular mutagenesis.

[133]  M. R. Curtis STUDIES ON THE PHYSIOLOGY OF REPRODUCTION IN THE DOMESTIC FOWL VI. DOUBLE- AND TRIPLE-YOLKED EGGS , 1914 .

[134]  M. Forman,et al.  Delayed Childbearing and Risk of Adverse Perinatal Outcome: A Population-Based Study , 1992 .

[135]  J. Habbema,et al.  Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. , 2005, Fertility and sterility.

[136]  R. Ferriani,et al.  Why Do Older Women Have Poor Implantation Rates? A Possible Role of the Mitochondria , 2004, Journal of Assisted Reproduction and Genetics.

[137]  L. Giudice,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. , 2000, The Journal of clinical endocrinology and metabolism.

[138]  R. Angell,et al.  First-meiotic-division nondisjunction in human oocytes. , 1997, American journal of human genetics.

[139]  J. Skurnick,et al.  Decreased inhibin tone and increased activin A secretion characterize reproductive aging in women. , 1999, Fertility and sterility.

[140]  B. Jacobsson,et al.  Advanced Maternal Age and Adverse Perinatal Outcome , 2004, Obstetrics and gynecology.

[141]  A. Mcneilly,et al.  Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. , 1996, The Journal of clinical endocrinology and metabolism.

[142]  T. Nesbitt,et al.  Childbearing beyond age 40: pregnancy outcome in 24,032 cases. , 1999, Obstetrics and gynecology.

[143]  A. Mcneilly,et al.  Is there an FSH-releasing factor? , 2001, Reproduction.

[144]  J. Visser,et al.  Regulation of ovarian function: the role of anti-Müllerian hormone. , 2002, Reproduction.

[145]  C. Greider Telomeres, telomerase and senescence , 1990, BioEssays : news and reviews in molecular, cellular and developmental biology.

[146]  P. Thonneau,et al.  Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study. , 2002, Human reproduction.

[147]  J. Tarín Potential effects of age-associated oxidative stress on mammalian oocytes/embryos. , 1996, Molecular human reproduction.

[148]  Ho-Joon Lee,et al.  Oocyte Generation in Adult Mammalian Ovaries by Putative Germ Cells in Bone Marrow and Peripheral Blood , 2005, Cell.

[149]  V. Padmanabhan,et al.  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. , 1998, The Journal of clinical endocrinology and metabolism.

[150]  D. Warburton The effect of maternal age on the frequency of trisomy: change in meiosis or in utero selection? , 1989, Progress in clinical and biological research.

[151]  T. Hassold,et al.  Human aneuploidy: Incidence, origin, and etiology , 1996, Environmental and molecular mutagenesis.

[152]  M. Sauer,et al.  A preliminary report on oocyte donation extending reproductive potential to women over 40 , 1990, The New England journal of medicine.

[153]  J. Deutschberger,et al.  RELATION OF THE MOTHER'S AGE TO OBSTETRIC PERFORMANCE. , 1964 .

[154]  A. Gougeon Regulation of ovarian follicular development in primates: facts and hypotheses. , 1996, Endocrine reviews.

[155]  A. Gore,et al.  A possible role of neuropeptide Y in the control of the onset of puberty in female rhesus monkeys. , 1993, Neuroendocrinology.

[156]  A. Bukovsky,et al.  Oogenesis in cultures derived from adult human ovaries , 2005, Reproductive biology and endocrinology : RB&E.

[157]  H. Burger,et al.  Inhibins and activins: clinical advances in reproductive medicine , 2003, Clinical endocrinology.

[158]  R. Stanhope,et al.  An evaluation of hormonal changes at puberty in man. , 1988, The Journal of endocrinology.

[159]  A. Veiga,et al.  Chromosome studies in oocytes and zygotes from an IVF programme. , 1987, Human reproduction.

[160]  C. Simón,et al.  Effect of aging on the female reproductive system: evidence for a role of uterine senescence in the decline in female fecundity. , 1995, Fertility and sterility.

[161]  I. Cooke,et al.  The effect of age on the cyclical patterns of plasma LH, FSH, oestradiol and progesterone in women with regular menstrual cycles. , 1988, Human reproduction.

[162]  D. Baird,et al.  CHANGES IN PLASMA LEVELS OF PROLACTIN, IN RELATION TO THOSE OF FSH, OESTRADIOL, ANDROSTENEDIONE AND PROGESTERONE AROUND THE PREOVULATORY SURGE OF LH IN WOMEN , 1984, Clinical endocrinology.

[163]  P. Sluss,et al.  Reproductive ageing and ovarian function: is the early follicular phase FSH rise necessary to maintain adequate secretory function in older ovulatory women? , 2005, Human reproduction.

[164]  J. Peipert,et al.  Maternal Age: An Independent Risk Factor for Cesarean Delivery , 1993, Obstetrics and gynecology.

[165]  Y. Kamiguchi,et al.  Chromosomal analysis of unfertilized human oocytes prepared by a gradual fixation-air drying method , 2004, Human Genetics.

[166]  A. Ld,et al.  An overview of follicular development in the ovary: from embryo to the fertilized ovum in vitro. , 1992 .

[167]  R. Fanchin,et al.  Serum anti-Müllerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. , 2003, Human reproduction.

[168]  F. Malone,et al.  Impact of Maternal Age on Obstetric Outcome , 2005, Obstetrics and gynecology.

[169]  M. L. Genova,et al.  Role of Mitochondria in Oxidative Stress and Aging , 2002, Annals of the New York Academy of Sciences.

[170]  A. Mclaren,et al.  Meiosis and differentiation of mouse germ cells. , 1984, Symposia of the Society for Experimental Biology.

[171]  D. Keefe,et al.  The telomere theory of reproductive senescence in women , 2006, Current opinion in obstetrics & gynecology.

[172]  D. McFadden,et al.  Chromosome abnormalities in human beings. , 1997, Mutation research.

[173]  O. Djahanbakhch,et al.  Elevated nocturnal melatonin is a consequence of gonadotropin-releasing hormone deficiency in women with hypothalamic amenorrhea. , 1998, The Journal of clinical endocrinology and metabolism.

[174]  R. Naeye Maternal Age, Obstetric Complications, and the Outcome of Pregnancy , 1983, Obstetrics and gynecology.

[175]  P. Nurse,et al.  Cohesin Rec8 is required for reductional chromosome segregation at meiosis , 1999, Nature.

[176]  A. Terman Catabolic Insufficiency and Aging , 2006, Annals of the New York Academy of Sciences.

[177]  J. Hansen Older maternal age and pregnancy outcome: a review of the literature. , 1986, Obstetrical & gynecological survey.

[178]  F. Ebling The neuroendocrine timing of puberty. , 2005, Reproduction.

[179]  G. Saretzki,et al.  Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? , 1995, Experimental cell research.

[180]  T. G. Baker,et al.  Development of the ovary and oogenesis. , 1976, Clinics in obstetrics and gynaecology.

[181]  H. Roffwarg,et al.  Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep. , 1974, The Journal of clinical investigation.

[182]  R. Angell,et al.  Maternal age and trisomy – a unifying mechanism of formation , 2000, Chromosoma.

[183]  R Guillemin,et al.  Isolation and partial characterization of a Mr 32,000 protein with inhibin activity from porcine follicular fluid. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[184]  R. Steiner,et al.  A Reassessment of Leptin’s Role in Triggering the Onset of Puberty in the Rat and Mouse , 2001, Neuroendocrinology.

[185]  J. Winter,et al.  Pituitary-gonadal relations in infancy. I. Patterns of serum gonadotropin concentrations from birth to four years of age in man and chimpanzee. , 1975, The Journal of clinical endocrinology and metabolism.

[186]  R. Kirby,et al.  Childbearing Beyond Maternal Age 50 and Fetal Outcomes in the United States , 2003, Obstetrics and gynecology.

[187]  J. Studd,et al.  Obstetric outcome in 232 ovum donation pregnancies , 1998, British journal of obstetrics and gynaecology.

[188]  S. Kapen,et al.  Synchronization of augmented luteinizing hormone secretion with sleep during puberty. , 1972, The New England journal of medicine.

[189]  L. Speroff,et al.  The effect of aging on fertility. , 1994, Current opinion in obstetrics & gynecology.

[190]  Kane Sh Advancing age and the primigravida. , 1967 .

[191]  E. Blackburn,et al.  Telomeres and telomerase. , 2002, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[192]  E. Terasawa,et al.  Role of glutamic acid decarboxylase in the prepubertal inhibition of the luteinizing hormone releasing hormone release in female rhesus monkeys , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[193]  R. Nakano,et al.  Immunohistochemical localization of inhibin/activin subunits in human ovarian follicles during the menstrual cycle. , 1992, The Journal of clinical endocrinology and metabolism.

[194]  S. Bernasconi,et al.  Serum activin A levels in males and females during pubertal development , 2001, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[195]  E. Lieberman,et al.  Increased risk of cesarean delivery with advancing maternal age: indications and associated factors in nulliparous women. , 2001, American journal of obstetrics and gynecology.

[196]  D. Warburton Human female meiosis: new insights into an error-prone process. , 1997, American journal of human genetics.

[197]  D. Seifer,et al.  Dimeric inhibin: a direct marker of ovarian aging. , 1998, Fertility and sterility.

[198]  R. Goodman,et al.  Neuroendocrine basis of seasonal reproduction. , 1984, Recent progress in hormone research.

[199]  H. Shehata,et al.  Obstetric complications of twin pregnancies. , 2004, Best practice & research. Clinical obstetrics & gynaecology.

[200]  M. Raftopoulou Mitochondrial wrinkles: the first signs of ageing? , 2005, Nature Cell Biology.

[201]  N. Santoro,et al.  Inhibins, activins, and follistatin in the aging female and male. , 2004, Seminars in reproductive medicine.

[202]  D. Seidman,et al.  Factors influencing the obstetric and perinatal outcome after oocyte donation. , 2002, Human reproduction.

[203]  L. Harrington Telomerase primer specificity and chromosome healing , 1991, Nature.

[204]  U. Eichenlaub-Ritter,et al.  Nocodazole sensitivity, age-related aneuploidy, and alterations in the cell cycle during maturation of mouse oocytes. , 1989, Cytogenetics and cell genetics.

[205]  N. Ling,et al.  Isolation and partial characterization of follistatin: a single-chain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[206]  R. Stanhope,et al.  Paediatric and Adolescent Gynaecology: Normal childhood, puberty and adolescence , 2004 .

[207]  W. N.,et al.  THE PATHOLOGICAL SOCIETY OF GREAT BRITAIN AND IRELAND , 1906 .