Table 1.

Prenatal Manipulations Generating PCOS-like First-Generation Offspring

SpeciesNHPSheepRatMouse
TreatmentTestosterone propionateTestosterone propionateDHT propionateTDHTTDHTDHTAMHc or proAMH
Age of treatmentGD 40-80GD 110-140GD 40-95/100GD 30-90 GD 60-90 GD 30-90E15-19E16-19E16.5-18.5 / E0-deliveryE16.5-E18.5
Dose of treatment10-15mg (=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 treatment15-40 days25-30 days55-60 days30, 60 days60 days5 days4 days3 days3 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)
SpeciesNHPSheepRatMouse
TreatmentTestosterone propionateTestosterone propionateDHT propionateTDHTTDHTDHTAMHc or proAMH
Age of treatmentGD 40-80GD 110-140GD 40-95/100GD 30-90 GD 60-90 GD 30-90E15-19E16-19E16.5-18.5 / E0-deliveryE16.5-E18.5
Dose of treatment10-15mg (=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 treatment15-40 days25-30 days55-60 days30, 60 days60 days5 days4 days3 days3 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.

Table 1.

Prenatal Manipulations Generating PCOS-like First-Generation Offspring

SpeciesNHPSheepRatMouse
TreatmentTestosterone propionateTestosterone propionateDHT propionateTDHTTDHTDHTAMHc or proAMH
Age of treatmentGD 40-80GD 110-140GD 40-95/100GD 30-90 GD 60-90 GD 30-90E15-19E16-19E16.5-18.5 / E0-deliveryE16.5-E18.5
Dose of treatment10-15mg (=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 treatment15-40 days25-30 days55-60 days30, 60 days60 days5 days4 days3 days3 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)
SpeciesNHPSheepRatMouse
TreatmentTestosterone propionateTestosterone propionateDHT propionateTDHTTDHTDHTAMHc or proAMH
Age of treatmentGD 40-80GD 110-140GD 40-95/100GD 30-90 GD 60-90 GD 30-90E15-19E16-19E16.5-18.5 / E0-deliveryE16.5-E18.5
Dose of treatment10-15mg (=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 treatment15-40 days25-30 days55-60 days30, 60 days60 days5 days4 days3 days3 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.

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