Semin Reprod Med 2010; 28(5): 370-379
DOI: 10.1055/s-0030-1262896
© Thieme Medical Publishers

Determinants of Female Reproductive Senescence: Differential Roles for the Ovary and the Neuroendocrine Axis

Erkan Buyuk1 , Edward Nejat1 , Genevieve Neal-Perry1 , 2
  • 1Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Montefiore Medical Center and Albert Einstein College of Medicine and Yeshiva University, Bronx, New York
  • 2Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York
Further Information

Publication History

Publication Date:
15 September 2010 (online)

ABSTRACT

Aging in women is a complex process that begins with the transition into reproductive senescence and evolves to impact not just women's procreative potential but also multiple health-related parameters including longevity. Although somatic aging is an equal opportunity nemesis, certain disease states correlate highly with ovarian failure and the menopause, such as osteoporosis, diabetes, cardiovascular disease, and compromised cognitive function. Epidemiological studies suggest that a delayed natural menopause confers longevity and decelerates the appearance of many of the debilitating morbidities associated with the menopause. However, recent randomized clinical trials assessing the benefits of menopausal hormone therapy during the postmenopause clearly suggest that attenuation of the negative consequences of reproductive aging involves much more than a simple add back of ovarian steroids in the postmenopause. Conflicts between observations in epidemiological studies and in randomized clinical trials give good reason for continued innovative research focused on identifying the mechanisms that bring about the transition from peak reproductive potential to female reproductive quiescence. This article provides a brief update on our current understanding of the physiological and cellular mechanisms that precipitate and/or commit women to transit into reproductive senescence.

REFERENCES

  • 1 Hall J E. Neuroendocrine changes with reproductive aging in women.  Semin Reprod Med. 2007;  25(5) 344-351
  • 2 Johnson J, Bagley J, Skaznik-Wikiel M et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood.  Cell. 2005;  122(2) 303-315
  • 3 Johnson J, Canning J, Kaneko T, Pru J K, Tilly J L. Germline stem cells and follicular renewal in the postnatal mammalian ovary.  Nature. 2004;  428(6979) 145-150
  • 4 Virant-Klun I, Rozman P, Cvjeticanin B et al. Parthenogenetic embryo-like structures in the human ovarian surface epithelium cell culture in postmenopausal women with no naturally present follicles and oocytes.  Stem Cells Dev. 2009;  18(1) 137-150
  • 5 Zhang D, Fouad H, Zoma W D, Salama S A, Wentz M J, Al-Hendy A. Expression of stem and germ cell markers within nonfollicle structures in adult mouse ovary.  Reprod Sci. 2008;  15(2) 139-146
  • 6 Santoro N. The menopausal transition.  Am J Med. 2005;  118(Suppl 12B) 8-13
  • 7 Faddy M J, Gosden R G, Gougeon A, Richardson S J, Nelson J F. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause.  Hum Reprod. 1992;  7(10) 1342-1346
  • 8 Wu J M, Zelinski M B, Ingram D K, Ottinger M A. Ovarian aging and menopause: current theories, hypotheses, and research models.  Exp Biol Med (Maywood). 2005;  230(11) 818-828
  • 9 Burger H G, Hale G E, Dennerstein L, Robertson D M. Cycle and hormone changes during perimenopause: the key role of ovarian function.  Menopause. 2008;  15(4 Pt 1) 603-612
  • 10 Soules M R, Sherman S, Parrott E et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW).  Fertil Steril. 2001;  76(5) 874-878
  • 11 Lenton E A, Landgren B M, Sexton L, Harper R. Normal variation in the length of the follicular phase of the menstrual cycle: effect of chronological age.  Br J Obstet Gynaecol. 1984;  91(7) 681-684
  • 12 van Montfrans J M, Hoek A, van Hooff M H, de Koning C H, Tonch N, Lambalk C B. Predictive value of basal follicle-stimulating hormone concentrations in a general subfertility population.  Fertil Steril. 2000;  74(1) 97-103
  • 13 van Rooij I A, Broekmans F J, Scheffer G J et al. Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study.  Fertil Steril. 2005;  83(4) 979-987
  • 14 Jayaprakasan K, Campbell B, Hopkisson J, Johnson I, Raine-Fenning N. A prospective, comparative analysis of anti-Müllerian hormone, inhibin-B, and three-dimensional ultrasound determinants of ovarian reserve in the prediction of poor response to controlled ovarian stimulation.  Fertil Steril. 2010;  93(3) 855-864
  • 15 Seifer D B, Lambert-Messerlian G, Hogan J W, Gardiner A C, Blazar A S, Berk C A. Day 3 serum inhibin-B is predictive of assisted reproductive technologies outcome.  Fertil Steril. 1997;  67(1) 110-114
  • 16 Sowers M R, Eyvazzadeh A D, McConnell D et al. Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition.  J Clin Endocrinol Metab. 2008;  93(9) 3478-3483
  • 17 van Rooij I A, Tonkelaar I, Broekmans F J et al. Anti-müllerian hormone is a promising predictor for the occurrence of the menopausal transition.  Menopause. 2004;  11(6 Pt 1) 601-606
  • 18 van Disseldorp J, Lambalk C B, Kwee J et al. Comparison of inter- and intra-cycle variability of anti-Mullerian hormone and antral follicle counts.  Hum Reprod. 2010;  25(1) 221-227
  • 19 Gougeon A, Chainy G B. Morphometric studies of small follicles in ovaries of women at different ages.  J Reprod Fertil. 1987;  81(2) 433-442
  • 20 Jiang J Y, Cheung C K, Wang Y, Tsang B K. Regulation of cell death and cell survival gene expression during ovarian follicular development and atresia.  Front Biosci. 2003;  8 d222-d237
  • 21 Tilly J L, Kowalski K I, Johnson A L, Hsueh A J. Involvement of apoptosis in ovarian follicular atresia and postovulatory regression.  Endocrinology. 1991;  129(5) 2799-2801
  • 22 Morita Y, Perez G I, Paris F et al. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy.  Nat Med. 2000;  6(10) 1109-1114
  • 23 Kugu K, Ratts V S, Piquette G N et al. Analysis of apoptosis and expression of bcl-2 gene family members in the human and baboon ovary.  Cell Death Differ. 1998;  5(1) 67-76
  • 24 Ratts V S, Flaws J A, Kolp R, Sorenson C M, Tilly J L. Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad.  Endocrinology. 1995;  136(8) 3665-3668
  • 25 Kim M R, Tilly J L. Current concepts in Bcl-2 family member regulation of female germ cell development and survival.  Biochim Biophys Acta. 2004;  1644(2–3) 205-210
  • 26 Perez G I, Robles R, Knudson C M, Flaws J A, Korsmeyer S J, Tilly J L. Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency.  Nat Genet. 1999;  21(2) 200-203
  • 27 Hsu S Y, Lai R J, Finegold M, Hsueh A J. Targeted overexpression of Bcl-2 in ovaries of transgenic mice leads to decreased follicle apoptosis, enhanced folliculogenesis, and increased germ cell tumorigenesis.  Endocrinology. 1996;  137(11) 4837-4843
  • 28 Perez G I, Jurisicova A, Wise L et al. Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice.  Proc Natl Acad Sci U S A. 2007;  104(12) 5229-5234
  • 29 Matsuda-Minehata F, Inoue N, Goto Y, Manabe N. The regulation of ovarian granulosa cell death by pro- and anti-apoptotic molecules.  J Reprod Dev. 2006;  52(6) 695-705
  • 30 Kondo H, Maruo T, Peng X, Mochizuki M. Immunological evidence for the expression of the Fas antigen in the infant and adult human ovary during follicular regression and atresia.  J Clin Endocrinol Metab. 1996;  81(7) 2702-2710
  • 31 Matsuda-Minehata F, Goto Y, Inoue N, Manabe N. Changes in expression of anti-apoptotic protein, cFLIP, in granulosa cells during follicular atresia in porcine ovaries.  Mol Reprod Dev. 2005;  72(2) 145-151
  • 32 Matsuda-Minehata F, Goto Y, Inoue N, Sakamaki K, Chedrese P J, Manabe N. Anti-apoptotic activity of porcine cFLIP in ovarian granulosa cell lines.  Mol Reprod Dev. 2007;  74(9) 1165-1170
  • 33 Agarwal A, Gupta S, Sharma R K. Role of oxidative stress in female reproduction.  Reprod Biol Endocrinol. 2005;  3 28
  • 34 Carbone M C, Tatone C, Delle Monache S et al. Antioxidant enzymatic defences in human follicular fluid: characterization and age-dependent changes.  Mol Hum Reprod. 2003;  9(11) 639-643
  • 35 Seino T, Saito H, Kaneko T, Takahashi T, Kawachiya S, Kurachi H. Eight-hydroxy-2′-deoxyguanosine in granulosa cells is correlated with the quality of oocytes and embryos in an in vitro fertilization-embryo transfer program.  Fertil Steril. 2002;  77(6) 1184-1190
  • 36 Dennehy C E. The use of herbs and dietary supplements in gynecology: an evidence-based review.  J Midwifery Womens Health. 2006;  51(6) 402-409
  • 37 Ruder E H, Hartman T J, Goldman M B. Impact of oxidative stress on female fertility.  Curr Opin Obstet Gynecol. 2009;  21(3) 219-222
  • 38 Sharara F I, Beatse S N, Leonardi M R, Navot D, Scott Jr R T. Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test.  Fertil Steril. 1994;  62(2) 257-262
  • 39 De Bruin M L, Van Dulmen-den Broeder E, Van den Berg M H, Lambalk C B. Fertility in female childhood cancer survivors.  Endocr Dev. 2009;  15 135-158
  • 40 Vermeulen A. Environment, human reproduction, menopause, and andropause.  Environ Health Perspect. 1993;  101(Suppl 2) 91-100
  • 41 Hoyer P B, Cannady E A, Kroeger N A, Sipes I G. Mechanisms of ovotoxicity induced by environmental chemicals: 4-vinylcyclohexene diepoxide as a model chemical.  Adv Exp Med Biol. 2001;  500 73-81
  • 42 Holehan A M, Merry B J. Lifetime breeding studies in fully fed and dietary restricted female CFY Sprague-Dawley rats. 1. Effect of age, housing conditions and diet on fecundity.  Mech Ageing Dev. 1985;  33(1) 19-28
  • 43 Chun S Y, Billig H, Tilly J L, Furuta I, Tsafriri A, Hsueh A J. Gonadotropin suppression of apoptosis in cultured preovulatory follicles: mediatory role of endogenous insulin-like growth factor I.  Endocrinology. 1994;  135(5) 1845-1853
  • 44 Bartke A, Chandrashekar V, Dominici F et al. Insulin-like growth factor 1 (IGF-1) and aging: controversies and new insights.  Biogerontology. 2003;  4(1) 1-8
  • 45 Wilshire G B, Loughlin J S, Brown J R, Adel T E, Santoro N. Diminished function of the somatotropic axis in older reproductive-aged women.  J Clin Endocrinol Metab. 1995;  80(2) 608-613
  • 46 Todd B J, Merhi Z O, Shu J, Etgen A M, Neal-Perry G S. Hypothalamic insulin-like growth factor-I receptors are necessary for hormone-dependent luteinizing hormone surges: implications for female reproductive aging.  Endocrinology. 2010;  151(3) 1356-1366
  • 47 Baker J, Hardy M P, Zhou J et al. Effects of an Igf1 gene null mutation on mouse reproduction.  Mol Endocrinol. 1996;  10(7) 903-918
  • 48 Billig H, Furuta I, Hsueh A J. Gonadotropin-releasing hormone directly induces apoptotic cell death in the rat ovary: biochemical and in situ detection of deoxyribonucleic acid fragmentation in granulosa cells.  Endocrinology. 1994;  134(1) 245-252
  • 49 Yang Y, Balla A, Danilovich N, Sairam M R. Developmental and molecular aberrations associated with deterioration of oogenesis during complete or partial follicle-stimulating hormone receptor deficiency in mice.  Biol Reprod. 2003;  69(4) 1294-1302
  • 50 Danilovich N, Sairam M R. Haploinsufficiency of the follicle-stimulating hormone receptor accelerates oocyte loss inducing early reproductive senescence and biological aging in mice.  Biol Reprod. 2002;  67(2) 361-369
  • 51 Hosaka T, Biggs III W H, Tieu D et al. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification.  Proc Natl Acad Sci U S A. 2004;  101(9) 2975-2980
  • 52 Brenkman A B, Burgering B M. FoxO3a eggs on fertility and aging.  Trends Mol Med. 2003;  9(11) 464-467
  • 53 Castrillon D H, Miao L, Kollipara R, Horner J W, DePinho R A. Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a.  Science. 2003;  301(5630) 215-218
  • 54 Rebar R W. Premature ovarian failure.  Obstet Gynecol. 2009;  113(6) 1355-1363
  • 55 van Dooren M F, Bertoli-Avellab A M, Oldenburg R A. Premature ovarian failure and gene polymorphisms.  Curr Opin Obstet Gynecol. 2009;  21(4) 313-317
  • 56 Weiss G, Goldsmith L T, Taylor R N, Bellet D, Taylor H S. Inflammation in reproductive disorders.  Reprod Sci. 2009;  16(2) 216-229
  • 57 Brann D W, Mahesh V B. The aging reproductive neuroendocrine axis.  Steroids. 2005;  70(4) 273-283
  • 58 Wise P M, Smith M J, Dubal D B et al. Neuroendocrine modulation and repercussions of female reproductive aging.  Recent Prog Horm Res. 2002;  57 235-256
  • 59 Anzalone C R, Hong L S, Lu J K, LaPolt P S. Influences of age and ovarian follicular reserve on estrous cycle patterns, ovulation, and hormone secretion in the Long-Evans rat.  Biol Reprod. 2001;  64(4) 1056-1062
  • 60 Burger H G, Robertson D M, Cahir N et al. Characterization of inhibin immunoreactivity in post-menopausal women with ovarian tumours.  Clin Endocrinol (Oxf). 1996;  44(4) 413-418
  • 61 Cooper R L, Conn P M, Walker R F. Characterization of the LH surge in middle-aged female rats.  Biol Reprod. 1980;  23(3) 611-615
  • 62 Guthrie J R, Dennerstein L, Hopper J L, Burger H G. Hot flushes, menstrual status, and hormone levels in a population-based sample of midlife women.  Obstet Gynecol. 1996;  88(3) 437-442
  • 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(4) 732-741
  • 64 Weiss G, Skurnick J H, Goldsmith L T, Santoro N F, Park S J. Menopause and hypothalamic-pituitary sensitivity to estrogen.  JAMA. 2004;  292(24) 2991-2996
  • 65 Veldhuis J D. Aging and hormones of the hypothalamo-pituitary axis: gonadotropic axis in men and somatotropic axes in men and women.  Ageing Res Rev. 2008;  7(3) 189-208
  • 66 Downs J L, Wise P M. The role of the brain in female reproductive aging.  Mol Cell Endocrinol. 2009;  299(1) 32-38
  • 67 Aschheim P. Results provided by heterochronic grafts of the ovaries in the study of the hypothalamo-hypophyso-ovarian regulation of senile rats [in French].  Gerontologia. 1964–1965;  10 65-75
  • 68 Peng M T, Huang H H. Aging of hypothalamic-pituitary-ovarian function in the rat.  Fertil Steril. 1972;  23(8) 535-542
  • 69 Wise P M. Alterations in proestrous LH, FSH, and prolactin surges in middle-aged rats.  Proc Soc Exp Biol Med. 1982;  169(3) 348-354
  • 70 Neal-Perry G, Lebesgue D, Lederman M, Shu J, Zeevalk G D, Etgen A M. The excitatory peptide kisspeptin restores the luteinizing hormone surge and modulates amino acid neurotransmission in the medial preoptic area of middle-aged rats.  Endocrinology. 2009;  150(8) 3699-3708
  • 71 Neal-Perry G S, Zeevalk G D, Santoro N F, Etgen A M. Attenuation of preoptic area glutamate release correlates with reduced luteinizing hormone secretion in middle-aged female rats.  Endocrinology. 2005;  146(10) 4331-4339
  • 72 Hoffman G E, Finch C E. LHRH neurons in the female C57BL/6J mouse brain during reproductive aging: no loss up to middle age.  Neurobiol Aging. 1986;  7(1) 45-48
  • 73 Krajnak K, Rosewell K L, Wise P M. Fos-induction in gonadotropin-releasing hormone neurons receiving vasoactive intestinal polypeptide innervation is reduced in middle-aged female rats.  Biol Reprod. 2001;  64(4) 1160-1164
  • 74 Rubin B S, Bridges R S. Alterations in luteinizing hormone-releasing hormone release from the mediobasal hypothalamus of ovariectomized, steroid-primed middle-aged rats as measured by push-pull perfusion.  Neuroendocrinology. 1989;  49(3) 225-232
  • 75 Le W-W, Wise P M, Murphy A Z, Coolen L M, Hoffman G E. Parallel declines in Fos activation of the medial anteroventral periventricular nucleus and LHRH neurons in middle-aged rats.  Endocrinology. 2001;  142(11) 4976-4982
  • 76 Rubin B S, Lee C E, King J C. A reduced proportion of luteinizing hormone (LH)-releasing hormone neurons express Fos protein during the preovulatory or steroid-induced LH surge in middle-aged rats.  Biol Reprod. 1994;  51(6) 1264-1272
  • 77 Herbison A E, Augood S J, Simonian S X, Chapman C. Regulation of GABA transporter activity and mRNA expression by estrogen in rat preoptic area.  J Neurosci. 1995;  15(12) 8302-8309
  • 78 Mitsushima D, Shwe T T, Funabashi T, Shinohara K, Kimura F. GABA release in the medial preoptic area of cyclic female rats.  Neuroscience. 2002;  113(1) 109-114
  • 79 Mohankumar P S, Thyagarajan S, Quadri S K. Correlations of catecholamine release in the medial preoptic area with proestrous surges of luteinizing hormone and prolactin: effects of aging.  Endocrinology. 1994;  135(1) 119-126
  • 80 Ping L, Mahesh V B, Wiedmeier V T, Brann D W. Release of glutamate and aspartate from the preoptic area during the progesterone-induced LH surge: in vivo microdialysis studies.  Neuroendocrinology. 1994;  59(4) 318-324
  • 81 Ottem E N, Godwin J G, Krishnan S, Petersen S L. Dual-phenotype GABA/glutamate neurons in adult preoptic area: sexual dimorphism and function.  J Neurosci. 2004;  24(37) 8097-8105
  • 82 Jarry H, Wise P M, Leonhardt S, Wuttke W. Effects of age on GABA turnover rates in specific hypothalamic areas in female rats.  Exp Clin Endocrinol Diabetes. 1999;  107(1) 59-62
  • 83 Neal-Perry G S, Zeevalk G D, Shu J, Etgen A M. Restoration of the luteinizing hormone surge in middle-aged female rats by altering the balance of GABA and glutamate transmission in the medial preoptic area.  Biol Reprod. 2008;  79(5) 878-888
  • 84 Krajnak K, Kashon M L, Rosewell K L, Wise P M. Aging alters the rhythmic expression of vasoactive intestinal polypeptide mRNA but not arginine vasopressin mRNA in the suprachiasmatic nuclei of female rats.  J Neurosci. 1998;  18(12) 4767-4774
  • 85 Brann D W, Mahesh V B. Endogenous excitatory amino acid involvement in the preovulatory and steroid-induced surge of gonadotropins in the female rat.  Endocrinology. 1991;  128(3) 1541-1547
  • 86 Jennes L, Jennes M E, Purvis C, Nees M. c-fos expression in noradrenergic A2 neurons of the rat during the estrous cycle and after steroid hormone treatments.  Brain Res. 1992;  586(1) 171-175
  • 87 Lederman M A, Lebesgue D, Gonzalez V V et al. Age-related LH surge dysfunction correlates with reduced responsiveness of hypothalamic anteroventral periventricular nucleus kisspeptin neurons to estradiol positive feedback in middle-aged rats.  Neuropharmacology. 2010;  58(1) 314-320
  • 88 Arias P, Carbone S, Szwarcfarb B et al. Effects of aging on N-methyl-D-aspartate (NMDA)-induced GnRH and LH release in female rats.  Brain Res. 1996;  740(1-2) 234-238
  • 89 Miller B H, Gore A C. N-Methyl-D-aspartate receptor subunit expression in GnRH neurons changes during reproductive senescence in the female rat.  Endocrinology. 2002;  143(9) 3568-3574
  • 90 MohanKumar S M, MohanKumar P S. Aging alters norepinephrine release in the medial preoptic area in response to steroid priming in ovariectomized rats.  Brain Res. 2004;  1023(1) 24-30
  • 91 Wise P M. Norepinephrine and dopamine activity in microdissected brain areas of the middle-aged and young rat on proestrus.  Biol Reprod. 1982;  27(3) 562-574
  • 92 Miller B H, Gore A C. Alterations in hypothalamic insulin-like growth factor-I and its associations with gonadotropin releasing hormone neurones during reproductive development and ageing.  J Neuroendocrinol. 2001;  13(8) 728-736
  • 93 Sahu A, Kalra S P. Absence of increased neuropeptide Y neuronal activity before and during the luteinizing hormone (LH) surge may underlie the attenuated preovulatory LH surge in middle-aged rats.  Endocrinology. 1998;  139(2) 696-702
  • 94 van der Beek E M, van Oudheusden H J, Buijs R M, van der Donk H A, van den Hurk R, Wiegant V M. Preferential induction of c-fos immunoreactivity in vasoactive intestinal polypeptide-innervated gonadotropin-releasing hormone neurons during a steroid-induced luteinizing hormone surge in the female rat.  Endocrinology. 1994;  134(6) 2636-2644
  • 95 Hiney J K, Srivastava V K, Pine M D, Les Dees W. Insulin-like growth factor-I activates KiSS-1 gene expression in the brain of the prepubertal female rat.  Endocrinology. 2009;  150(1) 376-384
  • 96 Lara J I, Lorenzo M J, Cacicedo L et al. Induction of vasoactive intestinal peptide gene expression and prolactin secretion by insulin-like growth factor I in rat pituitary cells: evidence for an autoparacrine regulatory system.  Endocrinology. 1994;  135(6) 2526-2532
  • 97 Servoss S J, Lee S J, Gibney G, Gozes I, Brenneman D E, Hill J M. IGF-I as a mediator of VIP/activity-dependent neurotrophic factor-stimulated embryonic growth.  Endocrinology. 2001;  142(8) 3348-3353
  • 98 Rance N E, McMullen N T, Smialek J E, Price D L, Young III W S. Postmenopausal hypertrophy of neurons expressing the estrogen receptor gene in the human hypothalamus.  J Clin Endocrinol Metab. 1990;  71(1) 79-85
  • 99 Park S J, Goldsmith L T, Weiss G. Age-related changes in the regulation of luteinizing hormone secretion by estrogen in women.  Exp Biol Med (Maywood). 2002;  227(7) 455-464
  • 100 Shaw N D, Srouji S S, Histed S N, McCurnin K E, Hall J E. Aging attenuates the pituitary response to gonadotropin-releasing hormone.  J Clin Endocrinol Metab. 2009;  94(9) 3259-3264
  • 101 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(5) 2290-2296
  • 102 Chang C C, Sung L Y, Amano T, Tian X C, Yang X, Nagy Z P. Nuclear transfer and oocyte cryopreservation.  Reprod Fertil Dev. 2009;  21(1) 37-44

Genevieve Neal-PerryM.D. Ph.D. 

1300 Morris Park Avenue, Ullmann 1211

Albert Einstein College of Medicine and Yeshiva University, Resnick Campus, Bronx, NY 10641

    >