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  • Online publication date: March 2021

Chapter 4 - Physiology of the Female Reproductive System

from Section 1 - Physiology of Reproduction


The physiological importance of the female reproductive system is the production of offspring. The female produces gametes that can be fertilized by the male gamete to form the first cell of the offspring. The sequence of events is tightly dependent on the proper functionality of the endocrine system.

Much of the endocrine system is governed by rhythms, some of which are intrinsic, while others are influenced by the environment. Rhythms that are longer than 24 hours, the infradian rhythms, include the seasonal breeding patterns in some animals and the female menstrual cycle. Circadian or 24-hour rhythms include the sleep–wake cycle and the increase in gonadotropin secretion seen at night in adolescents. Finally, cycles of less than 24 hour, the ultradian cycles, include the pulsatile release of luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone, and prolactin.

1.Gottsch, ML, Cunningham, MJ, Smith, JT, et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 2004; 145:40734077.
2.Moreno, I, Codoñer, FM, Vilella, F, et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am. J. Obstet. Gynecol. 2016; 215:684703.
3.Ravel, J, Gajer, P, Abdo, Z, et al. Vaginal microbiome of reproductive-age women. Proc. Natl. Acad. Sci. U. S. A. 2011; 108(Suppl. 1):46804687.
4.Gougeon, A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr. Rev. 1996; 17:121155.
5.Ng, EH, Yeung, WS, Fong, DY, Ho, PC. Effects of age on hormonal and ultrasound markers of ovarian reserve in Chinese women with proven fertility. Hum. Reprod. 2003; 18:21692174.
6.Dierich, A, Sairam, MR, Monaco, L, et al. Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc. Natl. Acad. Sci. U. S. A. 1998; 95:1361213617.
7.Jayaprakasan, K, Hilwah, N, Kendall, NR, et al. Does 3D ultrasound offer any advantage in the pretreatment assessment of ovarian reserve and prediction of outcome after assisted reproduction treatment? Hum. Reprod. 2007; 22:19321941.
8.Kumar, TR, Wang, Y, Lu, N, Matzuk, MM. Follicle stimulating hormone is required for ovarian follicle maturation but not for male fertility. Nat. Genet. 1997; 15:201204.
9.Matthews, CH, Borgato, S, Beck-Peccoz, P, et al. Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat. Genet. 1993; 5:8386.
10.Eppig, J. Oocyte control of ovarian follicular development and function in mammals. Reproduction 2001; 122:829838.
11.Kidder, GM, Mhawi, AA. Gap junctions and ovarian folliculogenesis. Reproduction 2002; 123:613620.
12.Eppig, JJ, Wigglesworth, K, Pendola, FL. The mammalian oocyte orchestrates the rate of ovarian follicular development. Proc. Natl. Acad. Sci. U. S. A. 2002; 99:28902894.
13.Vitt, UA, Hayashi, M, Klein, C, Hsueh, AJW. Growth differentiation factor-9 stimulates proliferation but suppresses the follicle stimulating hormone-induced differentiation of cultured granulosa cells from small antral and preovulatory rat follicles. Biol. Reprod. 2000; 62:370377.
14.Parrott, JA, Skinner, MK. Kit-ligand/stem cell factor induces primordial follicle development and initiates folliculogenesis. Endocrinology 1999; 140:42624271.
15.Nilsson, E, Parrott, JA, Skinner, MK. Basic fibroblast growth factor induces primordial follicle development and initiates folliculogenesis. Mol. Cell. Endocrinol. 2001; 25:123130.
16.Dissen, GA, Garcia-Rudaz, C, Ojeda, SR. Role of neurotrophic factors in early ovarian development. Semin. Reprod. Med. 2009; 27:2431.
17.Nilsson, E, Dole, G, Skinner, MK. Neurotrophin NT3 promotes ovarian primordial to primary follicle transition. Reproduction 2009; 138:697707.
18.Abir, R, Fisch, B, Jin, S, et al. Presence of NGF and its receptors in ovaries from human fetuses and adults. Mol. Hum. Reprod. 2005; 11:229236.
19.El-Fouly, MA, Cook, B, Nekola, M, Nalbandov, AV. Role of the ovum in follicular luteinization. Endocrinology 1970; 87:286293.
20.Nekola, MV, Nalbandov, AV. Morphological changes of rat follicular cells as influenced by oocytes. Biol. Reprod. 1971; 4:154160.
21.Weenen, C, Laven, JSE, von Bergh, ARM, et al. Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol. Hum. Reprod. 2004; 10:7783.
22.Jeppesen, JV, Anderson, RA, Kelsey, TW, et al. Which follicles make the most anti-Müllerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection. Mol. Hum. Reprod. 2013; 19:519527.
23.Amsterdam, A, Koch, Y, Lieberman, ME, Lindner, HR. Distribution of binding sites for human chorionic gonadotropin in the preovulatory follicle of the rat. J. Cell. Biol. 1975; 67:894900.
24.Lawrence, TS, Dekel, N, Beers, WH. Binding of human chorionic gonadotropin by rat cumuli oophori and granulosa cells: a comparative study. Endocrinology 1980; 106:11141118.
25.Chen, L, Russell, PT, Larsen, WJ. Functional significance of cumulus expansion in the mouse: roles for the preovulatory synthesis of hyaluronic acid within the cumulus mass. Mol. Reprod. Dev. 1993; 34:8793.
26.Peng, XR, Hsueh, AJ, LaPolt, PS, Bjersing, L, Ny, T. Localization of luteinizing hormone receptor messenger ribonucleic acid expression in ovarian cell types during follicle development and ovulation. Endocrinology 1991; 129:32003207.
27.Gougeon, A. Rate of follicular growth in the human ovary. In: Rolland, R, Van Hall, EV, Hillier, SG, McNatty, KP, Schoemaker, JS, eds., Follicular Maturation and Ovulation. Amsterdam: Excerpta Medica. 1982; 155163.
28.McNatty, KP, Hillier, SG, van den Boogaard, AMJ, et al. Follicular development during the luteal phase of the human menstrual cycle. J. Clin. Endocrinol. Metab. 1983; 56:10221031.
29.Pache, TD, Wladimiroff, JW, de Jong, FH, Hop, WC, Fauser, BCJM. Growth patterns of non dominant ovarian follicles during the normal menstrual cycle. Fertil. Steril. 1990; 54:638642.
30.Gougeon, A, Lefèvre, B. Evolution of the diameters of the largest healthy and atretic follicles during the human menstrual cycle. J. Reprod. Fert. 1983; 69:497502.
31.Kobayashi, M, Nakano, R, Ooshima, A. Immunocytochemical localization of pituitary gonadotrophins and gonadal steroids confirms the ‘two-cell, two-gonadotrophin’ hypothesis of steroidogenesis in the human ovary. J. Endocrinol. 1990; 126:483488.
32.Soules, MR, Steiner, RA, Clifton, DK, et al. Progesterone modulation of pulsatile luteinizing hormone secretion in normal women. J. Clin. Endocrinol. Metab. 1984; 58:378383.
33.Crowley, WF, McArthur, JW. Simulations of the normal menstrual cycle in Kallmann’s syndrome by pulsatile administration of luteinizing hormone-releasing hormone (LHRH). J. Clin. Endocrinol. Metab. 1980; 51:173175.
34.Solovyeva, EV, Hayashi, M, Margi, K, et al. Growth differentiation factor-9 stimulates rat theca-interstitial cell androgen biosynthesis. Biol. Reprod. 2000; 63:12141218.
35.Dunlop, CE, Anderson, RA. The regulation and assessment of follicular growth. Scand. J. Clin. Lab. Invest. Suppl. 2014; 244:1317.
36.Donez, J, Squifflet, J, Jadoul, P, et al. Pregnancy and live birth after autotransplantation of frozen-thawed ovarian tissue in a patient with metastatic disease undergoing chemotherapy and hematopoietic stem cell transplantation. Fertil. Steril. 1987; 2011:e1-e4.
37.Choi, J. Smitz, J. Luteinizing hormone and human chorionic gonadotropin: origins of difference. Mol. Cell. Endocrinol. 2014; 383:203213.
38.Casarini, L, Lispi, M, Longobardi, S, et al. LH and hCG action on the same receptor results in quantitatively and qualitatively different intracellular signaling. PLoS One 2012; 7, e46682.
39.Wide, L, Bakos, O. More basic forms of both human follicle-stimulating hormone and luteinizing hormone in serum at midcycle compared with the follicular or luteal phase. J. Clin. Endocrinol. Metab. 1993; 76:885889.
40.McNatty, KP. Ovarian follicular development from the onset of luteal regression in humans and sheep. In: Rolland, R, Van Hall, EV, Hillier, SG, McNatty, KP, Schoemaker, JS, eds., Follicular Maturation and Ovulation. Amsterdam: Excerpta Medica. 1982; 118.
41.Liu, L, Kong, N, Xia, G, Zhang, M. Molecular control of oocyte meiotic arrest and resumption. Reprod. Fertil. Dev. 2013; 25:463471.
42.Reddy, P, Adhikari, D, Zheng, W, et al. PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles. Hum. Mol. Genet. 2009; 18:28132824.
43.Meduri, G, Charnaux, N, Driancourt, MA, et al. Follicle-stimulating hormone receptors in oocytes? J. Clin. Endocrinol. Metab. 2002; 87:22662276.
44.Patsoula, E, Loutradis, D, Drakakis, P, et al. Messenger RNA expression for the follicle-stimulating hormone receptor and luteinizing hormone receptor in human oocytes and pre-implantation-stage embryos. Fertil. Steril. 2003; 79:11871193.
45.Otsuka, F, Shimasaki, S. A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: its role in regulating granulosa cell mitosis. Proc. Natl. Acad. Sci. U. S. A. 2002; 99:80608065.
46.Lefievre, L, Conner, SJ, Salpekar, A, et al. Four zona pellucida glycoproteins are expressed in the human. Hum. Reprod. 2004; 19:15801586.
47.Motta, PM, Makabe, S, Naguro, T, Correr, S. Oocyte follicle cells association during development of human ovarian follicle. A study by high resolution scanning and transmission electron microscopy. Arch. Histol. Cytol. 1994; 57:369394.
48.Bergh, C, Olsson, JH, Selleskog, U, Hillensjo, T. Steroid production in cultured thecal cell obtained from human ovarian follicles. Hum. Reprod. 1993; 8:519524.
49.Gilling-Smith, C, Franks, S. Ovarian function in assisted reproduction. In: Leung, PC, Adashi, EY, eds., The Ovary, 2nd ed. San Diego: Elsevier Academic Press. 2004; 473488.
50.Gougeon, A. Steroid 3β-ol-dehydrogenase activity in the largest healthy and atretic follicles in the human ovary during the menstrual cycle. Ann. Biol. Anim. Biochim. Biophys. 1977; 17:10871094.
51.Curtis, EM. Normal ovarian histology in infancy and childhood. Obstet. Gynecol. 1962; 19:444454.
52.Dekel, N, David, MP, Yedwab, GA, Kraicer, PF. Follicular development during late pregnancy. Int. J. Fertil. 1977; 22:2429.
53.Bloom, W, Fawcett, DW. A Textbook of Histology, 10th ed. Philadelphia: Saunders. 1975.
54.Amsterdam, A, Rotmensch, S. Structure-function relationships during granulosa cell differentiation. Endocr. Rev. 1987; 8:309337.
55.Hillier, SG, Yong, EL, Illingworth, PJ, et al. Effect of recombinant inhibin on androgen synthesis in cultured human thecal cells. Mol. Cell. Endocrinol. 1991; 75:R1R6.
56.Roberts, VJ, Barth, S, El-Roeiy, A, Yen, SSC. 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. Endocrinol. Metab. 1993; 77:14021410.
57.Sasano, H, Okamoto, M, Mason, JI, et al. Immunolocalization of aromatase, 17ɑ-hydroxylase and side-chain cleavage cytochrome P-450 in the human ovary. J. Reprod. Fertil. 1989; 85:163169.
58.Hernandez, ER, Hurwitz, A, Vera, A, et al. Expression of the genes encoding the insulin-like growth factors and their receptors in the human ovary. J. Clin. Endocrinol. Metab. 1992; 74:419425.
59.Salas, C, Julio-Pieper, M, Valladares, M, et al. Nerve growth factor-dependent activation of trkA receptors in the human ovary results in synthesis of follicle-stimulating hormone receptors and estrogen secretion. J. Clin. Endocrinol. Metab. 2006; 91:23962403.
60.Shima, K, Kitayama, S, Nakano, R. Gonadotropin binding sites in human ovarian follicles and corpora lutea during the menstrual cycle. Obstet. Gynecol. 1987; 69:800806.
61.McNatty, KP, Makris, A, DeGrazia, C, Osathanondh, R, Rayan, KJ. The production of progesterone, androgens, and estrogens by granulosa cells, thecal tissue, and stromal tissue from human ovaries in vitro. J. Clin. Endocrinol. Metab. 1979; 49:687699.
62.McNatty, KP, Smith, DM, Makris, A, Osathanondh, R, Ryan, KJ. The microenvironment of the human antral follicle: interrelationship among the steroid levels in antral fluid, the population of granulosa cells and the status of the oocyte in vivo and in vitro. J. Clin. Endocrinol. Metab. 1979; 49:851860.
63.Hillier, SG. Intrafollicular paracrine function of ovarian androgen. J. Steroid. Biochem. 1987; 27:351357.
64.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; 109:356362.
65.Wulff, C, Wiegand, SJ, Saunders, PT, Scobie, GA, Fraser, HM. Angiogenesis during follicular development in the primate and its inhibition by treatment with truncated Flt-1-Fc (vascular endothelial growth factor Trap[A40]). Endocrinology 2001; 142:32443254.
66.Pauerstein, CJ, Eddy, CA, Croxatto, HD, et al. Temporal relationships of estrogen, progesterone, and luteinizing hormone levels to ovulation in women and infra-human primates. Am. J. Obstet. Gynecol. 1978; 130:876886.
67.Park, SJ, Goldsmith, LT, Skurnick, JH, Wojtczuk, A, Weiss, G. Characteristics of the urinary luteinizing hormone surge in young ovulatory women. Fertil. Steril. 2007; 88:684690.
68.Direito, A, Bailly, S, Mariani, A, Ecochard, R. Relationships between the luteinizing hormone surge and other characteristics of the menstrual cycle in normally ovulating women. Fertil. Steril. 2012; 99:279285.
69.Alliende, ME. Luteinizing hormone surge in normally ovulating women. Fertil. Steril. 2013; 99:e14e15.
70.Yussman, MA, Taymor, MI, Miyata, J, Pheteplace, C. Serum levels of follicle-stimulating hormone, luteinizing hormone, and plasma progestins correlated with human ovulation. Fertil. Steril. 1970; 21:119125.
71.Kerin, J. Ovulation detection in the human. Clin. Reprod. Fertil. 1982; 1:2754.
72.Richards, JS, Russell, DL, Ochsner, S, Espey, LL. Ovulation: new dimensions and new regulators of the inflammatory-like response. Ann. Rev. Physiol. 2002; 64:6992.
73.Okamura, H, Okazaki, T, Nakajima, A. Effects of electrical stimulation on human ovarian contractility. Obstet. Gynecol. 1975; 45:557561.
74.Okamura, H, Takenaka, A, Yajima, Y, Nishimura, T. Ovulatory changes in the wall at the apex of the human Graafian follicle. J. Reprod. Fertil. 1980; 58:153155.
75.Duffy, DM. Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway. Hum. Reprod. Update 2015; 21:652670.
76.Priddy, AR, Killick, SR, Elstein, M, et al. Ovarian follicular fluid eicosanoid concentrations during the pre-ovulatory period in humans. Prostaglandins 1989; 38:197202.
77.Duffy, DM, Stouffer, RL. The ovulatory gonadotrophin surge stimulates cyclooxygenase expression and prostaglandin production by the monkey follicle. Mol. Hum. Reprod. 2001; 7:731739.
78.Tjugum, J, Norström, A, Dennefors, B, Lundin, S. Oxytocin in human follicular fluid and its possible role in the ovulatory process as studied in vitro. Hum. Reprod. 1986; 1:283286.
79.Meidan, R, Altstein, M, Girsh, E. Biosynthesis and release of oxytocin by granulosa cells derived from preovulatory bovine follicles: effects of forskolin and insulin-like growth factor-I. Biol. Reprod. 1992; 46:715720.
80.Horka, P, Malickova, K, Jarosova, R, et al. Matrix metalloproteinases in serum and the follicular fluid of women treated by in vitro fertilization. J. Assist. Reprod. Genet. 2012; 29:12071212.
81.Hernandez-Gonzalez, I, Gonzalez-Robayna, I, Shimada, M, et al. Gene expression profiles of cumulus cell oocyte complexes during ovulation reveal cumulus cells express neuronal and immune-related genes: does this expand their role in the ovulation process? Mol. Endocrinol. 2006; 20:13001321.
82.Edson, MA, Nagaraja, AK, Matzuk, MM. The mammalian ovary from genesis to revelation. Endocr. Rev. 2009; 30:624712.
83.Gershon, E, Plaks, V, Dekel, N. Gap junctions in the ovary: expression, localization and function. Mol. Cell. Endocrinol. 2008; 282:1825.
84.Freimann, S, Ben-Ami, I, Dantes, A, Ron-El, R, Amsterdam, A. EGF-like factor epiregulin and amphiregulin expression is regulated by gonadotropins/cAMP in human ovarian follicular cells. Biochem. Biophys. Res. Commun. 2004; 324:829834.
85.Park, JY, Su, YQ, Ariga, M, et al. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 2004; 303:682684.
86.Hizaki, H, Segi, E, Sugimoto, Y, et al. Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP(2). Proc. Natl. Acad. Sci. U. S. A. 1999; 96:1050110506.
87.Gueripel, X, Brun, V, Gougeon, A. Oocyte bone morphogenetic protein 15, but not growth differentiation factor 9, is increased during gonadotropin-induced follicular development in the immature mouse and is associated with cumulus oophorus expansion. Biol. Reprod. 2006; 75:836843.
88.Elvin, JA, Yan, C, Matzuk, MM. Oocyte-expressed TGF-beta superfamily members in female fertility. Mol. Cell. Endocrinol. 2000; 159:15.
89.Maruo, T, Katayama, K, Barnea, ER, Mochizuki, M. A role for thyroid hormone in the induction of ovulation and corpus luteum function. Horm. Res. 1992; 37 (Suppl. 1):1218.
90.Chaffkin, LM, Luciano, AA, Peluso, JJ. Progesterone as an autocrine/paracrine regulator of human granulosa cell proliferation. J. Clin. Endocrinol. Metab. 1992; 75:14041408.
91.Sasano, H, Mori, T, Sasano, N, Nagura, H, Mason, JI. Immunolocalization of 3beta-hydroxysteroid dehydrogenase in human ovary. J. Reprod. Fertil. 1990; 89:743751.
92.Brezinka, C. 3D ultrasound imaging of the human corpus luteum. Reprod. Biol. 2014; 14:110114.
93.Jokubkiene, L, Sladkevičius, P, Rovas, L, Valentin, L. Assessment of changes in volume and vascularity of the ovaries during the normal menstrual cycle using three dimentional power Doppler ultrasound. Hum. Reprod. 2006; 21:26612668.
94.Stouffer, RL, Bishop, CV, Bogan, RL, Xu, F, Hennebold, JD. Endocrine and local control of the primate corpus luteum. Reprod. Biol. 2013; 13:259271.
95.Nishimori, K, Dunkel, L, Hsueh, A, Yamoto, M, Nakano, R. Expression of luteinizing hormone and chorionic gonadotropin receptor messenger ribonucleic acid in human corpora lutea during menstrual cycle and pregnancy. J. Clin. Endocrinol. Metab. 1995; 80:14441448.
96.Crisp, TM, Dessouky, DA, Denys, FR. The fine structure of the human corpus luteum of early pregnancy and during the progestational phase of menstrual cycle. Am. J. Anat. 1970; 127:3769.
97.Meidan, R, Girsh, E, Blum, O, Aberdam, E. In vitro differentiation of bovine theca and granulosa cells into small and large luteal-like cells: morphological and functional characteristics. Biol. Reprod. 1990; 43:913921.
98.Sanders, SL, Stouffer, RL. Localization of steroidogenic enzymes in macaque luteal tissue during the menstrual cycle and simulated early pregnancy: immunohistochemical evidence supporting the two-cell model for estrogen production in the primate corpus luteum. Biol. Reprod. 1997; 56:10771087.
99.Reynolds, L, Redmer, D. Growth and development of the corpus luteum. J. Reprod. Fertil. Suppl. 1999; 54:181191.
100.Robinson, RS, Woad, KJ, Hammond, AJ, et al. Angiogenesis and vascular function in the ovary. Reproduction 2009; 138:869881.
101.Ferrara, N, Chen, H, Davis-Smyth, T, et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat. Med. 1998; 4:336340.
102.Wulff, C, Dickson, SE, Duncan, WC, Fraser, HM. Angiogenesis in the human corpus luteum: simulated early pregnancy by hCG treatment is associated with both angiogenesis and vessel stabilization. Hum. Reprod. 2001; 16:25152524.
103.Forsythe, JA, Jiang, BH, Iyer, NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 1996; 16:46044613.
104.Fraser, HM, Duncan, WC. Regulation and manipulation of angiogenesis in the ovary and endometrium. Reprod. Fertil. Dev. 2009; 21:277392.
105.Spencer, TE, Bazer, FW. Conceptus signals for establishment and maintenance of pregnancy. Reprod. Biol. Endocrinol. 2004; 2:49.
106.Horton, EW, Poyser, NL. Uterine luteolytic hormone: a physiological role of prostaglandin F2α. Physiol. Rev. 1976; 56:595651.
107.Miyamoto, A, Shirasuna, K, Shimizu, T, Bollwein, H, Schams, D. Regulation of corpus luteum development and maintenance: specific roles of angiogenesis and action of prostaglandin F2α. Soc. Reprod. Fertil. Suppl. 2010; 67:289304.
108.Best, CL, Pudney, J, Welch, WR, Burger, N, Hill, JA. Localization and characterization of white blood cell populations within the human ovary throughout the menstrual cycle and menopause. Hum. Reprod. 1996; 11:790797.
109.Townson, DH, Liptak, AR. Chemokines in the corpus luteum: implications of leukocyte chemotaxis. Reprod. Biol. Endocrinol. 2003; 1:94.
110.Girsh, E, Milvae, RA, Wang, W, Meidan, R. Effect of endothelin-1 on bovine luteal cell function: role in prostaglandin F2a-induced antisteroidogenic action. Endocrinology 1996; 137:13061312.
111.Wulff, C, Wilson, H, Largue, P, et al. Angiogenesis in the human corpus luteum: localization and changes in angiopoietins, tie-2, and vascular endothelial growth factor messenger ribonucleic acid. J. Clin. Endocrinol. Metab. 2000; 85:43024309.
112.Zalman, Y, Klipper, E, Farberov, S, et al. Regulation of angiogenesis-related prostaglandin F2α-induced genes in the bovine corpus luteum. Biol. Reprod. 2012; 86:92.
113.Farberov, S, Meidan, R. Thrombospondin-1 affects bovine luteal function via transforming growth factor β1-dependent and independent actions. Biol. Reprod. 2016; 94:25.
114.Yadav, VK, Lakshmi, G, Medhamurthy, R. Prostaglandin F2α-mediated activation of apoptotic signaling cascades in the corpus luteum during apoptosis: involvement of caspase-activated DNase. J. Biol. Chem. 2005; 280:1035710367.
115.Duncan, WC, McNeilly, AS, Fraser, HM, Illingworth, PJ. Luteinizing hormone receptor in the human corpus luteum: lack of down regulation during maternal recognition of pregnancy. Hum. Reprod. 1996; 11:22912297.
116.Jabbour, HN, Kelly, RW, Fraser, HM, Critchley, HO. Endocrine regulation of menstruation. Endocr. Rev. 2006; 27:1746.
117.Nagaoka, SI, Hassold, TJ, Hunt, PA. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat. Rev. Genet. 2012; 13:493504.
118.Huang, L, Tong, X, Luo, L, et al. Mutation analysis of the TUBB8 gene in nine infertile women with oocyte maturation arrest. RBM Online 2017; 35:305310.
119.American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Age-related fertility decline. Obstet. Gynecol. 2008; 112:409411.
120.Ziebe, S, Devroey, P. Assisted reproductive technologies are an integrated part of national strategies addressing demographic and reproductive challenges. Hum. Reprod. Update. 2008; 14:583592.
121.Menken, J, Trussell, J, Larsen, U. Age and infertility. Science 1986; 233:13891394.
122.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; 7:13421346.
123.Rosen, MP, Johnstone, E, McCulloch, CE, et al. A characterization of the relationship of ovarian reserve markers with age. Fertil. Steril. 2012; 97:238243.
124.Hansen, KR, Knowlton, NS, Thyer, AC, et al. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum. Reprod. 2008; 23:699708.
125.Wang, YA, Dean, J, Badgery-Parker, T, Sullivan, EA. Assisted Reproduction Technology in Australia and New Zealand 2006. Sydney: AIHW National Peritnatal Statistics Unit. 2008.
126.Fitzgerald, O, Paul, RC, Harris, K, Chambers, GM. Assisted Reproductive Technology in Australia and New Zealand 2016. Sydney: National Perinatal Epidemiology and Statistics Unit, the Univeristy of New South Wales Sydney. 2018.
127.Gilbert, WM, Nesbitt, TS, Danielsen, B. Childbearing beyond age 40: pregnancy outcome in 24,032 cases. Obstet. Gynecol. 1999; 93:914.
128.Meng, L, Jan, SZ, Hamer, G, et al. Preantral follicular atresia occurs mainly through autophagy, while antral follicles degenerate mostly through apoptosis. Biol. Reprod. 2018; 99:853863.
129.Baker, TG. A quantitative and cytological study of germ cells in human ovaries. Proc. R. Soc. Lond. B. Biol. Sci. 1963;158:417433.
130.Richardson, SJ, Senikas, V, Nelson, JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J. Clin. Endocrinol. Metab. 1987; 65:12311237.
131.Murray, A, Schoemaker, MJ, Bennett, CE, et al. Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency. Genet. Med. 2014; 16:1924.
132.Broekmans, FJ, Soules, MR, Fauser, BC. Ovarian aging: mechanisms and clinical consequences. Endocr. Rev. 2009; 30:465493.
133.Johnson, NP, Bagrie, EM, Coomarasamy, A, et al. Ovarian reserve tests for predicting fertility outcomes for assisted reproductive technology: the International Systematic Collaboration of Ovarian Reserve Evaluation protocol for a systematic review of ovarian reserve test accuracy. BJOG 2006; 113:14721480.
134.te Velde, ER, Pearson, PL. The variability of female reproductive ageing. Hum. Reprod. Update 2002; 8:141154.
135.Klein, NA, Battaglia, DE, Miller, PB, et al. Ovarian follicular development and the follicular fluid hormones and growth factors in normal women of advanced reproductive age. J. Clin. Endocrinol. Metab. 1996; 81:19461951.
136.Burger, HG, Hale, GE, Dennerstein, L, Robertson, DM. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause 2008; 15:603612.
137.Klein, NA, Battaglia, DE, Fujimoto, VY, et al. Reproductive aging: accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women. J. Clin. Endocrinol. Metab. 1996; 81:10381045.
138.Rossmanith, WG. Gonadotropin secretion during aging in women. Exp. Gerontology 1995; 30:369381. Bruin, JP, Bovenhuis, H, van Noord, PA, et al. The role of genetic factors in age at natural menopause. Hum. Reprod. 2001; 16:20142018.
140.van Asselt, KM, Kok, HS, Pearson, PL, et al. Heritability of menopausal age in mothers and daughters. Fertil. Steril. 2004; 82:13481351.
141.Kalmbach, KH, Antunes, DM, Kohlrausch, F, Keefe, DL. Telomeres and female reproductive aging. Semin. Reprod. Med. 2015; 33:389395.
142.Keefe, DL, Marquard, K, Liu, L. The telomere theory of reproductive senescence in women. Curr. Opin. Obstet. Gynecol. 2006; 18:280285.
143.Keefe, DL. Telomeres, reproductive aging, and genomic instability during early development. Reprod. Sci. 2016; 23:16121615.
144.Westhoff, C, Murphy, P, Heller, D. Predictors of ovarian follicle number. Fertil. Steril. 2000; 74:624628.
145.Stock, D, Knight, JA, Raboud, J, et al. Rotating night shift work and menopausal age. Hum. Reprod. 2019; 34:539548.
146.Pellestor, F, Andreo, B, Arnal, F, Humeau, C, Demaille, J. Maternal aging and chromosomal abnormalities: new data drawn from in vitro unfertilized human oocytes. Hum. Genet. 2003; 112:195203.
147.Alberman, E, Creasy, M, Elleott, M, Spicier, C. Maternal factors associated with fetal chromosomal anomalies in spontaneous abortions. Br. J. Obstet. Gynecol. 1976; 83:621627.
148.Volarcik, K, Sheean, L, Goldfarb, J, et al. The meiotic competence of in-vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum. Reprod. 1998; 13:154160.
149.Yun, Y, Holt, JE, Lane, SI, et al. Reduced ability to recover from spindle disruption and loss of kinetochore spindle assembly checkpoint proteins in oocytes from aged mice. Cell Cycle 2014; 13:19381947.
150.Hassold, T, Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2001; 2:280291.
151.Chiang, T, Duncan, FE, Schindler, K, Schultz, RM, Lampson, MA. Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes. Curr. Biol. 2010; 20:15221528.
152.Cheng, JM, Liu, YX. Age-related loss of cohesion: causes and effects. Int. J. Mol. Sci. 2017; 18. doi:10.3390/ijms18071578.
153.Kuliev, A, Verlinsky, Y. Meiotic and mitotic nondisjunction: lessons from preimplantation genetic diagnosis. Hum. Reprod. Update 2004; 10:401407.
154.Nagaoka, SI, Hassold, TJ, Hunt, PA. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat. Rev. Genet. 2012; 13:493504.
155.May-Panloup, P, Boucret, L, Chao de la Barca, JM, et al. Ovarian ageing: the role of mitochondria in oocytes and follicles. Hum. Reprod. Update 2016; 22:725743.
156.Broekmans, FJ, Faddy, MJ, Scheffer, G, te Velde, ER. Antral follicle counts are related to age at natural fertility loss and age at menopause. Menopause 2004; 11:607614.
157.Tietze, C. Fertility after discontinuation of intrauterine and oral contraception. Int. J. Fertil. 1968; 13:385389.
158.Gunby, J, Bissonnette F, , Librach, C, Cowan, L; IVF Directors Group of the Canadian Fertility and Andrology Society. Assisted reproductive technologies (ART) in Canada: 2006 results from the Canadian ART Register. Fertil. Steril. 2010; 93:21892201.
159.Noci, I, Borri, P, Chieffi, O, et al. Aging of the human endometrium: a basic morphological and immunohistochemical study. Eur. J. Obstet. Gynecol. Reprod. Biol. 1995; 63:181185.
160.Wang, YA, Farquhar, C, Sullivan, EA. Donor age is a major determinant of success of oocyte donation/recipient programme. Hum. Reprod. 2012; 27:118-125.
161.Sherman, BM, West, JH, Korenman, SG. The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J. Clin. Endocrinol. Metab. 1976; 42:629636.
162.Sabatini, L, Zosmer, A, Hennessy, EM, Tozer, A, Al-Shawaf, T. Relevance of basal serum FSH to IVF outcome varies with patient age. RBM Online 2008; 17:1019.
163.Broekmans, FJ, de Ziegler, D, Howles, CM, et al. The antral follicle count: practical recommendations for better standardization. Fertil. Steril. 2010; 94:10441051.
164.Broekmans, FJ, Kwee, J, Hendriks, DJ, Mol, BW, Lambalk, CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum. Reprod. Update 2006; 12:685718.
165.La Marca, A, Volpe, A. Anti-Mullerian hormone (AMH) in female reproduction: is measurement of circulating AMH a useful tool? Clin. Endocrinol. 2006; 64:603610.
166.Li, HWR, Yeung, WSB, Lau, EYL, Ho, PC, Ng, EHY. Evaluating the performance of serum antimullerian hormone concentration in predicting the live birth rate of controlled ovarian stimulation and intrauterine insemination. Fertil. Steril. 2010; 94:21772181.
167.Hehenkamp, WJ, Looman, CW, Themmen, AP, et al. Anti-Mullerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation. J. Clin. Endocrinol. Metab. 2006; 91:40574063.
168.Sowers, MR, Eyvazzadeh, AD, 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; 93:34783483.
169.Broekmans, FJ. Testing for ovarian reserve in assisted reproduction programs: the current point of view. Fact Views Vis. Obgin. 2009; 1:7981.