The DOI matches its Crossref record; 226 of the 231 references it cites were found in a registry or an index.
Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome
Abstract
The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.
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“Fetal, neonatal, prepubertal, and/or pubertal ovaries may be genetically predisposed to increased androgen secretion [100, 101].”
From Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls (2019) · cites this paper as [101]
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Rodent Models for Human Polycystic Ovary Syndrome1
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“Female rhesus monkeys exposed to androgens early in gestation exhibited hyperandrogenism, oligomenorrhea, large polyfollicular ovaries and other features consistent with the polycystic ovarian disease (PCOS) phenotype seen in humans (Abbott et al., 2005).”
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“Prenatally androgenized female monkeys, sheep and rats exhibit abnormal neuroendocrine function, such as increased LH concentrations and LH (GnRH) pulse frequency during subsequent pubertal maturation (Dumesic et al., 1997; Robinson et al., 1999; Abbott et al., 2005; Foecking et al., 2005).”
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“This finding is particularly exciting, as it suggests that FBN3 may exert its effect during fetal development, and influence a person’s predisposition to PCOS later in life, supporting previously proposed hypotheses on fetal origins for PCOS (Abbott et al., 2005; Ibanez et al., 2001).”
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“Although the etiology of PCOS remains unknown and widely debated (15, 16), abnormally high prenatal androgen (PNA) exposure, as seen in congenital adrenal hyperplasia and Cushing’s disease, has been shown to lead to the cardinal reproductive and endocrine features of PCOS in adult life (17, 18).”
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Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome
Kokosar, M., Benrick, A., Perfilyev, A., Fornes, R., Nilsson, E., Maliqueo, M., Behre, C. J., Sazonova, A., Ohlsson, C., Ling, C., et al. (2016) · Scientific Reports · doi:10.1038/srep22883 · Cited by 137
Diamanti‐Kandarakis, E. (2006) · Endocrine · doi:10.1385/endo:30:1:13 · Cited by 137
“Androgen excess during fetal life and infancy may precipitate the development of abdominal adiposity later in life [50].”
BackgroundHomburg, R. (2007) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1016/j.bpobgyn.2007.07.009 · Cited by 141
Is foetal hyperexposure to androgens a cause of PCOS?
Filippou, P., & Homburg, R. (2017) · Human Reproduction Update · doi:10.1093/humupd/dmx013 · Cited by 152
Effects of lifestyle modification in polycystic ovarian syndrome
Moran, L., Brinkworth, G. D., Noakes, M., & Norman, R. J. (2006) · Reproductive BioMedicine Online · doi:10.1016/s1472-6483(10)61182-0 · Cited by 136
“has also suggested that intrauterine hyperandrogenaemia may interact with genetic and environmental factors to produce the phenotype of PCOS (Abbott et al., 2005).”
BackgroundShi, D., & Vine, D. F. (2012) · Fertility and Sterility · doi:10.1016/j.fertnstert.2012.04.006 · Cited by 137
Androgen circle of polycystic ovary syndrome
Homburg, R. (2009) · Human Reproduction · doi:10.1093/humrep/dep049 · Cited by 134
Physiological and Pathological Androgen Actions in the Ovary
Astapova, O., Minor, B. M. N., & Hammes, S. R. (2019) · Endocrinology · doi:10.1210/en.2019-00101 · Cited by 133
Animal models of the polycystic ovary syndrome phenotype
Padmanabhan, V., & Veiga‐Lopez, A. (2013) · Steroids · doi:10.1016/j.steroids.2013.05.004 · Cited by 131
“Hypergonadotropism (LH excess) seen in women with PCOS [27] is also a feature of prenatal T-treated rhesus monkeys [28,37], sheep [38–40], and rats [33,41] (see Table 1).”
Hyperandrogenic origins of polycystic ovary syndrome-Implications for Pathophysiology and Therapy
Abbott, D. H., Dumesic, D. A., & Levine, J. E. (2019) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2019.1576522 · Cited by 131
“Increased monkey visceral fat accumulation [137], or ‘metabolic obesity’ [138],”
BackgroundThe Role of TGF-β in Polycystic Ovary Syndrome
Raja-Khan, N. T., Urbanek, M., Rodgers, R. J., & Legro, R. S. (2013) · Reproductive Sciences · doi:10.1177/1933719113485294 · Cited by 132
Polycystic ovary syndrome and impact on health
Allahbadia, G. N., & Merchant, R. (2010) · Middle East Fertility Society Journal · doi:10.1016/j.mefs.2010.10.002 · Cited by 127
Exposure to phthalates and female reproductive health: A literature review
Basso, C. G., de Araújo-Ramos, A. T., & Martino‐Andrade, A. J. (2022) · Reproductive Toxicology · doi:10.1016/j.reprotox.2022.02.006 · Cited by 129
Manikkam, M., Steckler, T. L., Welch, K. B., Inskeep, E. K., & Padmanabhan, V. (2005) · Endocrinology · doi:10.1210/en.2005-1338 · Cited by 121
“etiology of PCOS (19), although the prohibitive cost of sub-”
BackgroundResultEpigenetics in polycystic ovary syndrome: a pilot study of global DNA methylation
Xu, N., Azziz, R., & Goodarzi, M. O. (2009) · Fertility and Sterility · doi:10.1016/j.fertnstert.2009.10.020 · Cited by 123
“Female mammals (such as rhesus monkeys, sheep, mice, or rats) that are exposed to androgen excess in utero develop masculinized phenotypes similar to PCOS as an adult (3, 4).”
BackgroundEarly-Life Exposure to Testosterone Programs the Hypothalamic Melanocortin System
Nohara, K., Zhang, Y., Waraich, R. S., Laque, A., Tiano, J. P., Tong, J., Münzberg, H., & Mauvais-Jarvis, F. (2011) · Endocrinology · doi:10.1210/en.2010-1288 · Cited by 120
Ontogeny of the ovary in polycystic ovary syndrome
Dumesic, D. A., & Richards, J. S. (2013) · Fertility and Sterility · doi:10.1016/j.fertnstert.2013.02.011 · Cited by 118
Barry, J. A., Kay, A., Navaratnarajah, R., Iqbal, S., Bamfo, J. E. A. K., David, A. L., Hines, M., & Hardiman, P. J. (2010) · Journal of Obstetrics and Gynaecology · doi:10.3109/01443615.2010.485254 · Cited by 120
“Animal studies have shown that prenatal exposure to excess androgen results in the biochemical and morphological features of PCOS (Abbott et al. 2005).”
BackgroundSun, M., Maliqueo, M. A., Benrick, A., Johansson, J., Shao, R., Hou, L., Jansson, T., Wu, X., & Stener‐Victorin, E. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00421.2012 · Cited by 123
Anderson, H., Fogel, N. R., Grebe, S. K. G., Singh, R. J., Taylor, R. L., & Dunaif, A. E. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2651 · Cited by 118
High prevalence of polycystic ovary syndrome in women born small for gestational age
de Melo, A. S., Vieira, C. S., Barbieri, M. A., Rosa-e-Silva, A. C. J. S., da Sílva, A. A. M., Cardoso, V. C., dos Reis, R. M., Ferriani, R. A., Silva-de-Sa, M. F., & Bettiol, H. (2010) · Human Reproduction · doi:10.1093/humrep/deq162 · Cited by 114
“Over the last few years, experimental studies have indicated fetal reprogramming by prenatal androgen excess as a possible aetiology of PCOS (Abbott et al., 2005), but the relevance of these studies to the developmental origin of human PCOS remains questionable (Hickey et al., 2009).”
BackgroundRice, S., Ojha, K., Whitehead, S. A., & Mason, H. D. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1697 · Cited by 114
Contributions of androgen and estrogen to fetal programming of ovarian dysfunction
Abbott, D. H., Padmanabhan, V., & Dumesic, D. A. (2006) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-4-17 · Cited by 114
Mendiola, J., Roca, M., Mínguez-Alarcón, L., Mira-Escolano, M.-P., López-Espín, J. J., Barrett, E. S., Swan, S. H., & Torres-Cantero, A. M. (2012) · Environmental Health · doi:10.1186/1476-069x-11-90 · Cited by 114
“This prenatal hyperandrogenism results in enlarged cystic ovaries, anovulation or increases ovarian follicular recruitment in female offspring [3,4,7,35].”
BackgroundThe Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS)
Coutinho, E. A., & Kauffman, A. S. (2019) · Medical Sciences · doi:10.3390/medsci7080084 · Cited by 115
“Likewise, PNA monkeys prenatally exposed to testosterone propionate display polycystic ovaries and increased adiposity [32], and also have high LH levels and impaired negative feedback [31].”
BackgroundIbáñez, L., & de Zegher, F. (2006) · Human Reproduction Update · doi:10.1093/humupd/dmi054 · Cited by 109
“Given the rising evidence that such PCOS-prone settings may partly be programmed in early life (reviewed in Abbott et al., 2005), possibly through epigenetic mechanisms, it becomes plausible that the next generation of PCOS-prevention studies will aim at developing a re-programming intervention…”
BackgroundMolecular Mechanisms of Sex Determination in Reptiles
Rhen, T., & Schroeder, A. (2010) · Sexual Development · doi:10.1159/000282495 · Cited by 107
“Female rodents, sheep, and primates treated prenatally or postnatally with dihydrotestosterone develop a phenotype that mimics polycystic ovary syndrome [Abbott et al., 2005; Xita and Tsatsoulis, 2006].”
BackgroundDNA methylation in the pathogenesis of polycystic ovary syndrome
Vázquez-Martínez, E. R., Gómez-Viais, Y. I., García-Gómez, E., Reyes-Mayoral, C., Reyes-Muñoz, E., Camacho‐Arroyo, I., & Cerbón, M. A. (2019) · Reproduction · doi:10.1530/rep-18-0449 · Cited by 111
Nonhuman primate models of polycystic ovary syndrome
Abbott, D. H., Nicol, L. E., Levine, J. E., Xu, N., Goodarzi, M. O., & Dumesic, D. A. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.01.013 · Cited by 111
“Administration of a GnRH antagonist to remove endogenous gonadotropic stimulation of ovary-intact adult female rhesus monkeys was employed to examine the effects of chronic treatment with T, DHT or IGF-1 on ovarian responses to exogenous FSH and LH (Zeleznik et al., 2002, 2004).”
BackgroundInfluentialRosenfield, R. L., & Bordini, B. (2010) · Brain Research · doi:10.1016/j.brainres.2010.08.088 · Cited by 101
“Studies in a variety of animal models support the concept that prenatal androgenization programs development of a masculine pattern of LH secretion at puberty by reducing expression of hypothalamic progesterone receptors (Abbott et al., 2005; Foecking et al., 2005; Sarma et al., 2005).”
BackgroundChaudhary, H., Patel, J. K., Jain, N. K., & Joshi, R. G. (2021) · Journal of Ovarian Research · doi:10.1186/s13048-021-00879-w · Cited by 108
Abbott, D. H., Barnett, D. K., Levine, J. E., Padmanabhan, V., Dumesic, D. A., Jacoris, S., & Tarantal, A. F. (2008) · Biology of Reproduction · doi:10.1095/biolreprod.108.067702 · Cited by 102
“Prenatally androgenized monkeys exposed during early gestation were chosen for the present study because adult female monkeys exposed to such fetal manipulation express LH dysfunction (increased basal levels, increased LH response to GnRH, and decreased sensitivity to sex-steroid negative feedback [1, 15, 16]) more cl…”
InfluentialMechanisms of intergenerational transmission of polycystic ovary syndrome
Dumesic, D. A., Hoyos, L. R., Chazenbalk, G. D., Naik, R., Padmanabhan, V., & Abbott, D. H. (2020) · Reproduction · doi:10.1530/rep-19-0197 · Cited by 101
Self-citationNonClassic Congenital Adrenal Hyperplasia
Witchel, S. F., & Azziz, R. (2010) · International Journal of Pediatric Endocrinology · doi:10.1155/2010/625105 · Cited by 134
Environmental epigenetics in zebrafish
Cavalieri, V., & Spinelli, G. (2017) · Epigenetics & Chromatin · doi:10.1186/s13072-017-0154-0 · Cited by 105
“In a more recent study, the established relationship between fetal androgen exposure and reproductive defects in animal models [75, 76] inspired exploration of global DNA methylation in ovaries of adult zebrafish antecedently exposed to testosterone or dihydrotestosterone during embryogenesis [77].”
Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS
Silva, M. S. B., Prescott, M., & Campbell, R. E. (2018) · JCI Insight · doi:10.1172/jci.insight.99405 · Cited by 102
“In addition, exogenous administration of testosterone or dihydrotestosterone (DHT) to pregnant animal models can drive the development of PCOS-like ovarian and endocrine traits; this is well defined in sheep (43), monkeys (44), rats (45, 46), and mice (25, 26).”
BackgroundAcupuncture in Polycystic Ovary Syndrome: Current Experimental and Clinical Evidence
Stener‐Victorin, E., Jedel, E., & Mannerås, L. (2007) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2007.01634.x · Cited by 100
“Observations in prenatally androgenised rhesus monkeys and sheep ( 38 , 39) suggest that androgen hypersecretion from the ovaries or adrenals, most likely before puberty, can cause clinical and biochemical features of human PCOS.”
Backgroundde Melo, A. S., Dias, S. V., Cavalli, R. D. C., Cardoso, V. C., Bettiol, H., Barbieri, M. A., Ferriani, R. A., & Vieira, C. S. (2015) · Reproduction · doi:10.1530/rep-14-0499 · Cited by 99
“…related to glucose metabolism and visceral obesity predominated in animals that had been treated with androgens during the first half of pregnancy (Abbott et al. 2005; Table 2). www.reproduction-online.org Developmental programming related to PCOS manifestations: aspects relevant to childhood and…”
Metadata
- Authors
- Abbott, D. H., Barnett, D. K., Bruns, C. M., & Dumesic, D. A.
- Corresponding author
- Abbott, D.H.
- Venue
- Human Reproduction Update
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-07-01
- Volume
- 11
- Issue
- 4
- Pages
- 357-374
- ISSN
- 1355-4786 (ISSN-L)
- 1460-2369
- OpenAlex
- W2123009569
- Cited by
- 555
- References
- 231
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 24 · 2023: 27 · 2022: 27 · 2021: 21 · 2020: 27 · 2019: 37 · 2018: 23 · 2017: 30 · 2016: 34 · 2015: 28 · 2014: 32 · 2013: 31 · 2012: 23
- FWCI
- 4.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Reproduction Update (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5u01hd044650-05)
- National Institute on Aging (T32AG000268)
- National Center for Research Resources (R01RR013635, R21RR014093, P51RR000167)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD044405, U01-HD044650)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
- Keywords
- polycystic ovary syndrome, hyperandrogenism, fetal programming, developmental origins of health and disease, rhesus monkeys, prenatal androgen exposure, ovulatory dysfunction, insulin resistance, hyperlipidemia
- MeSH terms
- Androgens, Animals, Female, Genitalia, Female, Humans, Polycystic Ovary Syndrome, Hyperandrogenism
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