1.5.7.1 Rodent models
Patient material for research is scarce in PCOS, and in vivo research faces ethical limitations. Hence, the use of animal models reproducing some of the reproductive and metabolic features of PCOS is of invaluable aid in the study of the pathogenesis and management of PCOS. Currently, rodent, sheep and non-human primate models of PCOS have been extensively studied (Caldwell et al., 2014). Rodent models have the advantage to be affordable, require easy logistical care, have a short reproductive cycle, brief gestational periods, and can be genetically manipulated (Caldwell et al., 2014).
Numerous rodent models have been generated over the last 50 years, to mimic one or more of the PCOS traits in women, employing a variety of treatments and manipulations, and are reviewed in (Walters et al., 2012a). Hyperandrogenism is the most consistent PCOS feature, and Table 1-4 summarizes the phenotypes of the recent rodent models employing prenatally or postnatally administered testosterone or DHT.
Table 1-4 Ovarian and extra-ovarian phenotype in rodent PCOS models, generated by administration of pre-natal or postnatal testosterone (T) or dihydrotestosterone (DHT). Abreviations: estradiol (E2), progesterone (P4), luteinizing hormone (LH).
Reference Type of rodent and treatment
Intra-ovarian effects Extra-ovarian effects
(Sullivan and Moenter, 2004) Mouse, prenatal DHT Irregular oestrous cycles T and LH (Beloosesky et al., 2004)
Rat, postnatal T Cysts, pre-antral follicles
Delayed puberty, ¯P4,oocyte
degeneration, insulin resistance
(Wu et al., 2010b) Rat, prenatal T and DHT
Irregular oestrous cycles, pre-antral and antral, ¯pre- ovulatory follicles, ¯corpus luteum
T, P4, E2, LH
(Roland et al., 2010) Mouse, prenatal DHT Irregular oestrous cycles T LH fasting glucose, impaired glucose tolerance, size of visceral adipocytes
(van Houten et al., 2012)
Mouse, postnatal DHT
Anoestrous, atretic follicles, cysts
body weight, size of adipocytes, leptin,
¯adiponectin, glucose intolerance (Moore et al., 2013) Mouse, prenatal
DHT Irregular oestrous cycles, antral follicles,¯ovulation T, LH (Caldwell et al., 2014) Mouse, prenatal DHT Irregular cycles,¯ovulation, Adipose hypertrophy
Mouse, postnatal long-term DHT
¯preantral follicle health
Plus ¯antral follicle health and acyclicity
Plus body fat, dyslipidemia
It is important to keep in mind that no single model entirely replicates the full-blown spectrum of PCOS in women. The phenotype heterogeneity of the rodent models is dependent on the time, duration and dose of androgen exposure and the use of aromatisable testosterone likely to induce oestrogen-dependent events. The use of long-term (>3 weeks) DHT in the postnatal pre-pubertal mouse induces most of the PCOS traits found in women (van Houten et al., 2012, Caldwell et al., 2014).
1.5.7.2 Non-human primate models
In utero exposure of non-human primates to androgens has generated model animals that exhibit striking similarities to PCOS women, with regard to anovulation, polycystic ovarian morphology, hyperandrogenism, LH hypersecretion and insulin resistance. These primate studies are highly informative, but come with an elevated cost, and require long developmental periods, and are, in contrast to rodents, not amendable to genetic engineering (Caldwell et al., 2014).
Table 1-5 highlights the ovarian and systemic characteristics of the reported primate PCOS models, generated by gestational or postnatal androgen exposure.
Table 1-5 Ovarian and systemic characteristics on primate models of PCOS, generated by prenatal or postnatal administration of testosterone (T) or dihydrotestosterone (DHT). Abbreviations: progesterone (P4), luteinizing hormone (LH) and Western Style Diet (WSD).
Reference Treatment Intra-ovarian features Extra-ovarian features (Dumesic
et al., 1997)
Prenatal T none LH and LH/FSH
(Vendola et al., 1998)
Postnatal T and DHT
number of antral follicles, enlarged ovaries N/A (Abbott and Bacha, 2013) Prenatal T in early gestation Oligomenorrhea, enlarged polyfollicular ovaries LH, insulin resistance, abdominal obesity, hyperlipidaemia (McGee et al., 2012) Postnatal pre- pubertal T No effect on ovarian morphology, menstrual cyclicity or ovulation rates
LH pulse frequency, no clear metabolic features (McGee et al., 2014) Postnatal pre- pubertal T, and Western Style Diet (WSD) to induce obesity WSD ± T result in number of small antral follicles and
¯ maximum follicle size. T + WSD: number of small antral follicles in the luteal phase and ¯P4
WSD increased body fat from <2 to 15-19% LH pulse frequency in control to similar levels as T-treated animals, LH pulse amplitude ¯ WSD ± T ¯insulin sensitivity after 1 year (Bishop et
al., 2015)
Western-Style Diet (WSD),
WSD ± T result in numbers of small antral follicles, number
differential gene expression for steroid,
with and without pre-pubertal T treatment
of atretic follicles, CYP17A1 staining, differential gene expression for ovarian pathways
carbohydrate, lipid metabolism pathways
Adult primates, exposed during gestation with testosterone, exhibit a variety of ovarian, hormonal and neuro-endocrine PCOS traits (Dumesic et al., 1997, Abbott et al., 2013). These studies raise the question of a fetal origin in PCOS, and to whether in utero exposure to androgen excess, coupled with hyperinsulinaemia and/or hyperglycemia, might predispose or aggravate PCOS in the offspring (Abbott and Bacha, 2013). This interesting hypothesis is challenged by a large prospective human cohort study, failing to observe a relationship between maternal or umbilical cord androgen concentrations and incidence of adolescence PCOS in the child (Hickey et al., 2009). However, the animal studies teach us that the time of androgen exposure during gestation is critical for the outcome of the offspring. Early-mid gestational androgen exposure resulted in LH hypersecretion and adverse metabolic outcomes (such as increased abdominal adiposity and insulin resistance), while androgen excess during late gestation provoked no LH-hypersecretion and induced a milder metabolic risk profile (Walters, 2015).
Feeding Rhesus monkeys with Western-style diet, rich in lipids and carbohydrates, generated obesity, which in turn, independent of androgen levels, provoked some PCOS features, such as LH hypersecretion and exaggerated small antral follicle development. However, obesity combined with androgen excess, clearly exacerbated the PCOS phenotype, inducing increased ovarian androgen secretion, luteal insufficiency, insulin-resistance, and altering the metabolic gene expression (Xu et al., 2015, Bishop et al., 2015, McGee et al., 2014).
In vitro alginate-encapsulated culture revealed that pre-antral follicles from Western-diet fed androgen-excess monkeys had impaired survival, decreased oestrogen and AMH production and produced meiotically-incompetent oocytes (Xu et al., 2015).