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Developmental programming: impact of prenatal testosterone treatment and postnatal obesity on ovarian follicular dynamics

Published online by Cambridge University Press:  07 March 2012

V. Padmanabhan ,
P. Smith  and
A. Veiga-Lopez
V. Padmanabhan*
Affiliation:
Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA Reproductive Sciences Program, University of Michigan, Ann Arbor, MI, USA
P. Smith
Affiliation:
AgResearch Invermay, Mosgiel, New Zealand
A. Veiga-Lopez
Affiliation:
Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
*
*Address for correspondence: Dr V. Padmanabhan, Department of Pediatrics and Reproductive Sciences Program, University of Michigan, Room 1138, 300 North Ingalls Building, Ann Arbor, MI 48109-5404, USA. (Email [email protected])
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Abstract

Prenatal testosterone (T) excess leads to reproductive dysfunctions in sheep with obesity exaggerating such defects. Developmental studies found ovarian reserve is similar in control and prenatal T sheep at fetal day 140, with prenatal T females showing increased follicular recruitment and persistence at 10 months of age (postpubertal). This study tested whether prenatal T sheep show accelerated depletion prepubertally and whether depletion of ovarian reserve would explain loss of cyclicity in prenatal T females and its amplification by postnatal obesity. Stereological examinations were performed at 5 (prepubertal, control and prenatal T) and 21 months of age (control, prenatal T and prenatal T obese, following estrus synchronization). Obesity was induced by overfeeding from weaning. At 5 months, prenatal T females had 46% less primordial follicles than controls (P < 0.01), supportive of increased follicular depletion. Depletion rate was slower and a higher percentage of growing follicles was present in 21-month compared with 5-month-old prenatal T females (P < 0.01). Postnatal obesity did not exaggerate the impact of prenatal T on follicular recruitment indicating that compounding effects of obesity on loss of cyclicity females is not due to depletion of ovarian reserve. Assessment of follicular dynamics across several time points during the reproductive lifespan (this and earlier study combined) provides evidence supportive of a shift in follicular dynamics in prenatal T females from one of accelerated follicular depletion initiated before puberty to stockpiling of growing follicles after puberty, a time point critical in the development of the polycystic ovary syndrome phenotype.

Keywords

fetal origin of adult diseasefollicular persistencefollicular recruitmentovarian reservepolycystic ovary syndrome
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 3 , Issue 4 , August 2012 , pp. 276 - 286
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012

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References

1.Meisel, RL, Ward, IL. Fetal female rats are masculanized by male littermates located caudally in the uterus. Science. 1981; 213, 239–242.CrossRefGoogle ScholarPubMed
2.Foster, DL, Jackson, LM, Padmanabhan, V. Novel concepts about normal sexual differentiation of reproductive neuroendocrine function and the developmental origins of female reproductive dysfunction: the sheep model. Soc Reprod Fertil Suppl. 2007; 64, 83–107.Google ScholarPubMed
3.Padmanabhan, V, Manikkam, M, Recabarren, S, Foster, DL. Prenatal testosterone programs reproductive and metabolic dysfunction in the female. Mol Cell Endocrinol. 2006; 246, 165–174.CrossRefGoogle ScholarPubMed
4.Padmanabhan, V, Sarma, HN, Savabieasfahani, M, Steckler, TL, Veiga-Lopez, A. Developmental reprogramming of reproductive and metabolic dysfunction in sheep: native steroids vs. environmental steroid receptor modulators. Int J Androl. 2009; 33, 394–404.CrossRefGoogle Scholar
5.Padmanabhan, V, Veiga-Lopez, A. Developmental origin of reproductive and metabolic dysfunctions: androgenic vs. estrogenic reprogramming. Sem Reprod Med. 2011; 29, 173–186.CrossRefGoogle Scholar
6.Birch, RA, Padmanabhan, V, Foster, DL, Robinson, JE. Prenatal programming of reproductive neuroendocrine function: fetal androgen exposure produces progressive disruption of reproductive cycles in sheep. Endocrinology. 2003; 144, 1426–1434.CrossRefGoogle ScholarPubMed
7.Manikkam, M, Steckler, TS, Welch, KB, Inskeep, EK, Padmanabhan, V. Fetal programming: prenatal testosterone treatment leads to follicular persistence/luteal defects. Partial restoration of ovarian function by cyclic progesterone treatment. Endocrinology. 2006; 147, 1997–2007.CrossRefGoogle ScholarPubMed
8.Steckler, TL, Herkimer, C, Dumesic, DA, Padmanabhan, V. Developmental Programming: excess weight gain amplifies the effects of prenatal testosterone excess on reproductive cyclicity – implication to PCOS. Endocrinology. 2009; 150, 1456–1465.CrossRefGoogle Scholar
9.Smith, P, Steckler, TL, Veiga-Lopez, A, Padmanabhan, V. Developmental programming: differential effects of prenatal testosterone and dihydrotestosterone on follicular recruitment and depletion of follicular reserve. Biol Reprod. 2009; 80, 726–736.Google Scholar
10.Manikkam, M, Crespi, EJ, Doop, DD, et al. . Fetal Programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep. Endocrinology. 2004; 145, 790–798.CrossRefGoogle ScholarPubMed
11.Veiga-Lopez, A, Steckler, TL, Abbott, DH, et al. . Developmental programming: impact of excess prenatal testosterone on intra-uterine fetal endocrine milieu and growth. Biol Reprod. 2011; 84, 87–96.CrossRefGoogle Scholar
12.Gundersen, HJ, Jensen, EB. The efficiency of systematic sampling in stereology and its prediction. J Microsc. 1987; 147(Pt 3), 229–263.CrossRefGoogle ScholarPubMed
13.Lundy, T, Smith, P, O'Connell, A, Hudson, NL, McNatty, KP. Populations of granulosa cells in small follicles of the sheep ovary. J Reprod Fertil. 1999; 115, 251–262.CrossRefGoogle ScholarPubMed
14.Smith, P, O, WS, Hudson, NL, et al. . Effects of the Booroola gene (FecB) on body weight, ovarian development and hormone concentrations during fetal life. J Reprod Fertil. 1993; 98, 41–54.CrossRefGoogle ScholarPubMed
15.Hay, MR, Cran, DG, Moor, RM. Structural changes occurring during atresia in sheep ovarian follicles. Cell Tissue Res. 1976; 169, 515–529.CrossRefGoogle ScholarPubMed
16.Steckler, T, Wang, J, Bartol, F, Roy, SK, Padmanabhan, V. Fetal programming: prenatal testosterone treatment causes intrauterine growth retardation, reduces ovarian reserve and increases ovarian follicular recruitment. Endocrinology. 2005; 146, 3185–3193.CrossRefGoogle ScholarPubMed
17.McNatty, KP, Reader, K, Smith, P, Heath, DA, Juengel, JL. Control of ovarian follicular development to the gonadotrophin-dependent phase: a 2006 perspective. Soc Reprod Fertil Suppl. 2007; 64, 55–68.Google Scholar
18.Vendola, K, Zhou, J, Wang, J, et al. . Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol Reprod. 1999; 61, 353–357.Google Scholar
19.Qureshi, AI, Nussey, SS, Bano, G, et al. . Testosterone selectively increases primary follicles in ovarian cortex grafted onto embryonic chick membranes: relevance to polycystic ovaries. Reproduction. 2008; 136, 187–194.CrossRefGoogle ScholarPubMed
20.Ortega, HH, Salvetti, NR, Padmanabhan, V. Developmental programming: prenatal androgen excess disrupts ovarian steroid receptor balance. Reproduction. 2009; 137, 865–877.CrossRefGoogle ScholarPubMed
21.Juengel, JL, Sawyer, HR, Smith, PR, et al. . Origins of follicular cells and ontogeny of steroidogenesis in ovine fetal ovaries. Mol Cell Endocrinol. 2002; 191, 1–10.CrossRefGoogle ScholarPubMed
22.Quirke, LD, Juengel, JL, Tisdall, DJ, et al. . Ontogeny of steroidogenesis in the fetal sheep gonad. Biol Reprod. 2001; 65, 216–228.CrossRefGoogle ScholarPubMed
23.Veiga-Lopez, A, Ye, W, Phillips, DJ, et al. . Developmental programming: deficits in reproductive hormone dynamics and ovulatory outcomes in prenatal, testosterone-treated sheep. Biol Reprod. 2008; 78, 636–647.CrossRefGoogle ScholarPubMed
24.Padmanabhan, V, Veiga-Lopez, A, Abbott, DH, Recabarren, SE, Herkimer, C. Developmental programming: impact of prenatal testosterone excess and postnatal weight gain on insulin sensitivity index and transfer of traits to offspring of overweight females. Endocrinology. 2010; 151, 595–605.CrossRefGoogle ScholarPubMed
25.Recabarren, SE, Padmanabhan, V, Codner, E, et al. . Postnatal developmental consequences of altered insulin sensitivity in female sheep treated prenatally with testosterone. Am J Physiol (Endocrinol Metab). 2005; 289, 801–806.CrossRefGoogle ScholarPubMed
26.Steckler, T, Manikkam, M, Inskeep, EK, Padmanabhan, V. Developmental programming: follicular persistence in prenatal testosterone-treated sheep is not programmed by androgenic actions of testosterone. Endocrinology. 2007; 148, 3532–3540.CrossRefGoogle Scholar
27.Robinson, JE, Forsdike, RA, Taylor, JA. In utero exposure of female lambs to testosterone reduces the sensitivity of the gonadotropin-releasing hormone neuronal network to inhibition by progesterone. Endocrinology. 1999; 140, 5797–5805.Google Scholar
28.Willis, D, Mason, H, Gilling-Smith, C, Franks, S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab. 1996; 81, 302–309.Google ScholarPubMed
29.Poretsky, L, Cataldo, NA, Rosenwaks, Z, Giudice, LC. The insulin-related ovarian regulatory system in health and disease. Endocr Rev. 1999; 20, 535–582.CrossRefGoogle ScholarPubMed
30.Logan, K, Juengel, JL, McNatty, KP. Onset of steroidogenic enzyme gene expression during ovarian follicular development in sheep. Biol Reprod. 2002; 66, 906–916.CrossRefGoogle ScholarPubMed
31.Padmanabhan, V, Salvetti, NR, Veiga-Lopez, A, Ortega, HH. Developmental programming: impact of prenatal testosterone excess on ovarian cell proliferation and survival factors. 44th Annual Meeting of the Society for the Study of Reproduction, Portland, Oregon, USA, 2011; Abstract No. 641, p. 150.CrossRefGoogle Scholar
32.Webber, LJ, Stubbs, SA, Stark, J, et al. . Prolonged survival in culture of preantral follicles from polycystic ovaries. J Clin Endocrinol Metab. 2007; 92, 1975–1978.CrossRefGoogle ScholarPubMed
33.Das, M, Djahanbakhch, O, Hacihanefioglu, B, et al. . Granulosa cell survival and proliferation are altered in polycystic ovary syndrome. J Clin Endocrinol Metab. 2008; 93, 881–887.Google Scholar
34.Maciel, GAR, Baracat, EC, Benda, JA, et al. . Stockpiling of transitional and classic primary follicles in ovaries of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004; 89, 5321–5327.Google Scholar
35.Teixeira Filho, FL, Baracat, EC, Lee, TH, et al. . Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002; 87, 1337–1344.Google Scholar
36.Sarma, HN, Manikkam, M, Herkimer, C, et al. . Fetal programming: excess prenatal testosterone reduces postnatal LH, but not FSH responsiveness to estradiol negative feedback in the female. Endocrinology. 2002; 146, 4281–4291.CrossRefGoogle Scholar
37.Manikkam, M, Thompson, RC, Herkimer, C, et al. . Developmental programming: impact of prenatal testosterone excess on pre- and postnatal gonadotropin regulation in sheep. Biol Reprod. 2008; 78, 648–660.CrossRefGoogle ScholarPubMed
38.Braw-Tal, R, McNatty, KP, Smith, P, et al. . Ovaries of ewes homozygous for the X-linked Inverdale gene (FecXI) are devoid of secondary and tertiary follicles but contain many abnormal structures. Biol Reprod. 1993; 49, 895–907.CrossRefGoogle ScholarPubMed
39.Nicol, L, Bishop, SC, Pong-Wong, R, et al. . Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep. Reproduction. 2009; 138, 921–933.CrossRefGoogle ScholarPubMed
40.Korach, KS, Emmen, JM, Walker, VR, et al. . Update on animal models developed for analyses of estrogen receptor biological activity. J Steroid Biochem Mol Biol. 2003; 86, 387–391.CrossRefGoogle ScholarPubMed
41.Nilson, JH, Abbud, RA, Keri, RA, Quirk, CC. Chronic hypersecretion of luteinizing hormone in transgenic mice disrupts both ovarian and pituitary function, with some effects modified by the genetic background. Recent Prog Horm Res. 2000; 55, 69–91.Google ScholarPubMed
42.Wartenburg, H. Development of the early human ovary and role of the mesonephros in the differentiation of the cortex. Anat Embryol. 1982; 165, 253–280.Google Scholar
43.Sawyer, HR, Smith, P, Heath, DA, et al. . Formation of ovarian follicles during fetal development in sheep. Biol Reprod. 2002; 66, 1134–1150.CrossRefGoogle ScholarPubMed
44.Hirshfield, AN. Theca cells may be present at the outset of follicular growth. Biol Reprod. 1991; 44, 1157–1162.CrossRefGoogle ScholarPubMed
45.Forsdike, RA, Hardy, K, Bull, L, et al. . Disordered follicle development in ovaries of prenatally androgenized ewes. J Endocrinol. 2007; 192, 421–428.CrossRefGoogle ScholarPubMed
46.Gilling-Smith, C, Willis, DS, Beard, RW, Franks, S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab. 1994; 79, 1158–1165.Google ScholarPubMed
47.The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2002; 19, 41–47.Google Scholar
48.Webber, LJ, Stubbs, S, Stark, J, et al. . Formation and early development of follicles in the polycystic ovary. Lancet. 2003; 362, 1017–1021.CrossRefGoogle ScholarPubMed
49.Homburg, R, Amsterdam, A. Polysystic ovary syndrome – loss of the apoptotic mechanism in the ovarian follicles? J Endocrinol Invest. 1998; 21, 552–557.CrossRefGoogle ScholarPubMed
50.Hughesdon, PE. Morphology and morphogenesis of the Stein-Leventhal ovary and of so-called “hyperthecosis”. Obstet Gynecol Surv. 1982; 37, 59–77.Google Scholar