Table 1.
Prenatal Manipulations Generating PCOS-like First-Generation Offspring
| Species | NHP | Sheep | Rat | Mouse | |||||
|---|---|---|---|---|---|---|---|---|---|
| Treatment | Testosterone propionate | Testosterone propionate | DHT propionate | T | DHT | T | DHT | DHT | AMHc or proAMH |
| Age of treatment | GD 40-80 | GD 110-140 | GD 40-95/100 | GD 30-90 GD 60-90 | GD 30-90 | E15-19 | E16-19 | E16.5-18.5 / E0-delivery | E16.5-E18.5 |
| Dose of treatment | 10-15mg (=1.4-2.1 mg/kg) daily s.c. | 10mg (=1.4 mg/kg) daily s.c. | 10-15mg (=1.4-2.1 mg/kg) daily s.c. | 100mg (=1.2 mg/kg) twice weekly i.m. | 100mg (=1.2 mg/kg) twice weekly i.m. | 0.5 mg/kg/day s.c | 3 mg/day s.c. | 250ug | 0.12 mg/kg daily (i.p.) |
| Duration of treatment | 15-40 days | 25-30 days | 55-60 days | 30, 60 days | 60 days | 5 days | 4 days | 3 days | 3 days |
| Traits approximating or biomarkers for criteria used for PCOS diagnosis in women (at least 2 out of 3 required) | |||||||||
| Intermittent or absent ovulatory cycles | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
| Elevated endogenous androgen levels or biomarkers of elevated androgens | ✔ | ✔ | ✔ | ✖ | ✔/✖ | ✔/✖ | ✔/ ✖ | ✔ | |
| Polyfollicular ovaries | ✔ | ✔ | ✖ | ✖ | ✖ | ||||
| Traits accompanying PCOS | |||||||||
| 1. Ovary | |||||||||
| ↑ Ovary weight or size | ✔ | ✖ | ✖ | ✖ | ✖ | ✖ | |||
| ↑ Preantral /antral follicles | ✔ | ✔ | ✖ | ✔ | ✔ | ✖ | ✖ | ||
| Antral follicle arrest | ✔ | ✖ | ✔ | ✖ | |||||
| ↑ Follicle atresia | ✔ | ✔ | ✔ | ✔ | |||||
| ↓ Granulosa and ↑ theca cell layer thickness | ✔ | ||||||||
| Altered follicular steroid hormone receptor expression | ✔ | ✔ | |||||||
| Altered AMH or AMHR2 expression | ✖ | ✔ | ✖ | ✖ | |||||
| ↓ Oocyte maturation or developmental competence | ✔ | ✖ | ✔ | ||||||
| ↓ Fertility or fecundity | ✔ | ✖ | ✔ (GD 60-90) | ✔ | ✔ | ||||
| 2. Placenta and pregnancy | |||||||||
| Pregnancy complications | ✔ | ✔ | ✔ | ||||||
| Placental defects | ✔ | ✔ | ✔ | ✔ | |||||
| Fetal growth abnormalities, ↑AGD | ✔ | ✖ | ✔ | ✔ | ✔ | ✔ | ✔ | ||
| ↓ Placental capacity to metabolize androgens | ✔ | ✔ | ✔ | ||||||
| 3. Neuroendocrine regulation | |||||||||
| ↑ LH or ↑ LH:FSH ratio | ✔ | ✖ | ✔ | ✔ | ✔/✖ | ✔ | |||
| ↑ GnRH/LH pulse frequency | ✔ | ✔ | ✔ | ✔ | ✔ | ||||
| Altered hypothalamic GABA or KnDY neuronal morphology or function | ✔ | ✔ | ✔ | ✔ | |||||
| ↑ Pituitary LH responsiveness to GnRH | ✔ | ✔ | ✔ | ||||||
| ↓ E2 negative feedback | ✔ | ✖ | ✔ | ✔ | |||||
| ↓ P4 negative feedback | ✔ | ✔ | ✔ | ✔ | |||||
| Compromised E2 positive feedback | ✖ | ✖ | ✔ | ✖ | |||||
| 4. Metabolic traits | |||||||||
| ↑ Body weight | ✖ | ✖ | ✖ | ✔ | ✖ | ✖ | ✖ | ||
| ↑ Body fat or BMI | ✔ | ✔ | ✖ | ✔/✖ | |||||
| Adipocyte hypertrophy | ✖ | ✖ | ✔ | ||||||
| Adipogenic constraint | ✔ | ✔ | ✔ | ||||||
| Dyslipidemia | ✔ | ✔ | ✖ | ||||||
| Insulin resistance | ✔ | ✖ | ✔ | ✔ | ✔ | ✖ | |||
| Presence of liver steatosis | ✔ | ✔/✖ | |||||||
| Pancreatic β-cell defects | ✔ | ✖ | ✔ | ✔ | |||||
| Hypertension/Echo-cardiographic alterations | ✔ | ✔ | ✔ | ||||||
| 5. Behavioral traits | |||||||||
| Behavioral deficits/abnormalities | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | |||
| 6. References | (41-44) | (42-44) | (42-45) | (46-85) | (47, 57-59, 61, 62, 64) | (86-90) | (91, 92) | (93-105) | (106, 107) |
Abbreviations: AMH; anti-Müllerian hormone; DHT, dihydrotestosterone; T, testosterone.
✔, PCOS-like trait present; ✖, PCOS-like trait not present; “blank,” not reported by investigators in publication.