Roy Homburg

2 Polycystic ovary syndrome (PCOS) Criteria*: oligo- or anovulation clinical and/or biochemical signs of hyperandrogenism polycystic ovaries on ultrasound *2003 Rotterdam PCOS consensus

Barker hypothesis ‘developmental origin of adult disease’ ‘The womb may be more important than the home’

PCOS - Candidate Genes PCOS is strongly familial Genetically defined basis not found – almost all initial candidates failed to maintain linkage with PCOS phenotype ? inheritance is modified by environmental factors ? Re-programming of genes in utero.

Excess androgens in utero - defeminization of sexual function Prenatal maternal testosterone levels – dose- related link with gender role behaviour in pre- school girls (Hines et al, 2002) Girls exposed to high levels of T pre-natally (CAH) show distinct masculine-type behavioral traits (Berenbaum & Hines, 1992) Traits also correlate with T levels in amniotic fluid (Grimshaw et al, 1995)

Discrete Prenatal Androgen Excess During Gestation (10-15 mg testosterone propionate injected s.c. daily into pregnant mothers)

Serum testosterone levels TP injected females (n=9) Oil injected controls (n=5) * P < vs controls TP injected Oil injected Backtransformed means  95% CI (a) Mothers (b) Fetuses(c) Infants TP injected mothers Oil injected mothers * * *

Ovulatory menstrual cycles in control and prenatally androgenized females over a 6-month period 7 * † p < 0.02 vs. controls p < 0.03 vs. controls Control females ( n = 6) Early PA females females ( n = 6 ) ( n = 6 ) Late PA females ( n = 5 ) * † Number of cycles per six month period

Serum Levels of (a) immuno-LH in year old Females during the Follicular Phase and (b) bioactive LH in year old Females *** *** p < vs controls * * p < 0.03 vs controls (a) (b)(b)(b)(b)

In the beginning…. A excess in utero Programming of PCOS Insulin + LH Pre/small antral Thecal follicle number enzymes serine phosphorylation Androgen excess

Hypothesis for Prenatal Androgen Programming of Females for PCOS

Abbott et al (2002) J Endocr. 174:1-5

16 Androgens in girls with PCOS mothers Does prenatal exposure to androgens cause PCOS? Origin of androgens in PCOS women: Maternal origin  placental passage during gestation Fetal origin  is the fetus making the androgens?

The androgen circle of PCOS XS androgens Exposure In utero Multiple small follicles InsulinLH AMH Anovulation HirsutismAcne PCOSphenotype Homburg R, Hum Reprod, 2009

One in every five women has polycystic ovaries.

Polycystic Ovary Syndrome (PCOS) About 20% of the female population have polycystic ovaries. 5-10% of the female population suffer from symptoms.

Manifestations of PCOS Menstrual disturbance Menstrual disturbance Hirsutism Hirsutism Acne Acne Infertility Infertility Obesity Obesity High LH High LH High Testosterone High Testosterone Hyperinsulinemia Hyperinsulinemia Ultrasound appearance Ultrasound appearance

Manifestations of PCOS Menstrual disturbance (66%) Menstrual disturbance (66%) Hirsutism (66%) Hirsutism (66%) Acne (35%) Acne (35%) Infertility (75%) Infertility (75%) Obesity (38%) Obesity (38%) LH up (40%) LH up (40%) T up (30%) T up (30%) Insulin up Insulin up - in obese 80% - in obese 80% - in slim 30-40% - in slim 30-40%

RANGE OF PCOS I_______________________________I NORMAL OVULATORY CYCLES, MILD HIRSUTISM AMENORRHEAHIRSUTISM/ACNEINFERTILITYOBESITY

* The fundamental disturbance of PCOS involves a primary lesion in the ovary. * The expression of the lesion is determined in part by extra-ovarian factors.

ultra- sound hormones symptoms OBESITY INSULIN after Dewailly, 2003

ultra- sound hormones symptoms OBESITY INSULIN WEIGHT LOSS after Dewailly, 2003

Main disturbances in PCOS Abnormal steroidogenesis Increased ovarian production of: Androgens Androgens Progesterone Progesterone Estradiol Estradiol

Androstendione 17,20 lyase 17OHase P450c17 INSULIN rLH + LH free IGF-1 serine phosphorylation E2 TGFa / EGF / / __+ _ Follistatin Follistatin cholesterol P450scc pregnenelone FSH +

PCOS morphology x6 the density of pre-antral follicles compared with normal ovary. (Webber et al, 2003) Large cohort of small follicles arrest in development but capable of responding to exogenous FSH.

Human Follicle Growth ( Gougeon, Endocr Rev 1996 ) Primary follicle 1 layer cuboidal GCs (46 µm,  570) Secondary follicle 2 layers of GCs (77 µm,  480) 2 layers of GCs (77 µm,  480) Pre-antral follicle class 1 (theca cells & arterioles) (120 µm,  350) Early antral follicle class 2 ( µm,  170) Small antral follicle class 4 (2 mm,  25) Primordial follicle 1 layer flat granulosa cells (36µm,  570)

ANDROGENS ++ ANDROGENS ++ Accelerated follicular development 2-5mm PrimordialPre-antral Early antral Arrest of development XS early antral follicles (PCO) (PCO) Insulin + LH +

Anovulation Anovulation A excess LH +insulin Multiple small follicles AMH E2 AMH E2 FSH action FSH action Anovulation progesterone Anovulation progesterone

Insulin LH P450c17 Androgen excess Free Testosterone + Free Testosterone + Dihydrotestosterone Dihydrotestosterone 5alpha- reductase Hirsutism,Acne SHBG Dermatological symptoms

PCOS - Late sequelae Hyperinsulinemia / hyperandrogenism / obesity Diabetes mellitus x7Diabetes mellitus x7 Hypertension x4Hypertension x4 Low HDL/high LDLLow HDL/high LDL All are risk factors for cardiovascular disease and CVA *All are risk factors for cardiovascular disease and CVA

Main disturbances in PCOS Insulin resistance 80% of obese PCOS 30-40% of lean PCO 30-40% of lean PCO Genetic post-receptor defect unique to PCO Exaggerated by obesity Exaggerated by obesity

Metabolic syndrome Abdominal obesity (waist >88 cm) Triglycerides (>150 mg/dl) HDL cholesterol (<50 mg/dl) BP >130/>85 Glucose (fasting >110, 2hr >140 mg/dl) Any 3 out of 5 Any 3 out of 5

Sleep Disorders in PCOS PCOS n=53, controls n=452 Risk of Sleep Apnea in PCOS Odds Ratio 29 (95% CI 5-294) Adjusted for differences in BMI Vgontzas et al, JCEM, 2001

Copyright ©2001 The Endocrine Society Fogel, R. B. et al. J Clin Endocrinol Metab 2001;86: Elevated Testosterone in PCO Associated with Sleep Apnea

The androgen circle of PCOS XS androgens Exposure In utero Multiple small follicles InsulinLH AMH Anovulation HirsutismAcne PCOSphenotype Homburg R, Hum Reprod, 2009