Polycystic Ovary Syndrome

in Adolescence

Lee Ching Yin

CMC
May, 2004
Definition of PCOS

1st described by Stein and

Leventhal 1935
 NIH criteria (National
 ESHRE (European Society
Institute of Health) 1990 for Human Reproduction)
 Hyperandrogenism
& ASRM (American Society
of Reproductive Medicine)
 Chronic Anovulation
2003
with exclusion of other Ax: 2 of the 3 elements:
Cushing,
 Hyperandrogenism
CAH,
hyperprolactinemia (clinical or biochemical)
 Chronic anovulation
 USS – polycystic ovaries
 Polycystic ovaries
Minerva Ginecologica 2004
 LFL CFY WYK AKM

Age of presentation 17 yr 12 ½ yr (on Epilim) 17 yr 18 yr

BMI 32.2 (Obese) 31.7 (Obese) 18.9 18.6
Anovulation
Presentation Oligomenorrhoea/ 20 amenorrhoea 20 amenorrhoea Oligomenorrhoea
20 amenorrhoea
Age of menarche 12 yr 9 ½ yr old 10 yr 12 yr
Onset irregular cycle Since menarche 1½ yr after menarche Since menarche Since menarche
Hyperandrogenism
Hirsutism +ve (F-G score =7) +ve (F-G score =8) Nil Nil
Acne +ve Mild Nil Nil
Testosterone nmol/L 5.9 2.5 1.3 1.6
USS Ovary
Polycystic No No Yes Yes
Volume R-7.8 ml, L-7.3 ml R-10.8 ml, L-7.7 ml R-9.3 ml, L-7.9 ml R-16 ml, L-18.4 ml
LH 9.3 7.6 16 31.7
LH:FSH ratio 1.6 1.4 2.4 5.2
Insulin reistance
Acanthosis Nigricans +ve (OGTT normal) +ve (OGTT normal) Nil Nil
Fasting insulin mIU/L 24 36 9.2 14
HOMA 5.2 4.48 1.96 2.92

Prolactin ng/ml normal normal Transient  to 61.7 normal

(N: 1.4-24.2 ng/ml) MRI brain - normal

Family Hx Normal Normal Mother-Prolactinoma Normal

Prevalence

 Prevalence
 ~ 4-4.7% Screening 277 women 18-45 yr
Knochenhauer et al 98

 10 diagnosis in
 Oligomenorrhoea 87%
 Anovulatory infertility >75%
 Hirsutism 90%
 20 amenorrhoea 32%
Definition of PCOS

 ESHRE (European Society for Human Reproduction)

& ASRM (American Society of Reproductive
Medicine) 2003

2 of the 3 elements:
 Hyperandrogenism

(clinical or biochemical)
 Chronic anovulation

 Polycystic ovaries
Minerva Ginecologica 2004
Hyperandrogenism

 Clinical signs / symptoms

 Hirsutism
assessment– Ferriman-Gallwey score > 5 (ref: 18-38 yr white women)
 8 in Paed studies
(Ibanez et al 2001)
‘male-pattern’ hair – upper lip, chin, lower abdomen, inner thigh
 Acne

 Androgenetic alopecia

 Biochemically
  serum testosterone / androstenedione
 Subclinical hyperandrogenism
Hyperandrogenism

 Source of hyperandrogenemia
Ovary & / or Adrenal Rosenfield et al, J Ped Endo & Meta, 2000

Ovary
In-vivo culture of theca cells from PCOS vs normal ovaries:
 general  steroidogenesis

 Augmented expression of CYP11A, CYP17 mRNA

  CYP17, 3 -hydroxysteroid dehydrogenase enzyme activity
Nelson et al, Mol Endo, 99
Nelson et al, JCEM, 2001
Hyperandrogenism

 Source of hyperandrogenemia

Adrenal
Mechanism:
 Ovarian products promote adrenal androgen production
studies – GnRH analog  DHEAS in PCOS
 generalized hyperresponsiveness of adrenal cortex to ACTH
 Dysregulation (overactivity) of adrenal 17,22 lyase
 Hyperinsulinemia –promote adrenal 17-hydrxylase & 17,22 lyase
Rosenfield, JCEM, 96
Anovulation

 Clinical signs
 Menstrual disturbance:
amenorrhoea (estrogen replete) – oligomenorrhoea – DUB

 6 spontaneous vaginal bleed per year

irregular menses from menarche- consistent feature

may start from menarche with delayed menarche

or 10 amenorrhoea

 Infertility
Polycystic ovary

International consensus definitions

at least 1 of the following in USS:

  12 follicles 2-9 mm diameter

 Ovarian volume > 10 cm3

(ovarian volume= dimension 1x dimension 2 x dimension 3 x 0.5233)
Prolate spheroid volume = /6 x transverse dia x AP dia2
Spherical volume method = /6 x [(transverse dia+AP dia+long dia)/3]3
Nardo et al, Fert & Ster, 2003

 Dx is sufficient that only 1 ovary is affected

Balen et al, Human Reprod Update 2003
Polycystic ovary

 Distribution of follicles
 Subcapsular cysts, produce a ‘string of pearls’ sign
Description of stroma
  stromal echogenicity &/or stromal volume

 Pathogenesis
  circulating insulin level   Ovarian size Markussis et al 94

 Exaggerated LH pulsatile messages

 multifollicularity, stroma,  androgen production
Porcu et al, Curr Op Ped, 94
Other conditions with Polycystic ovaries

 Normal women with normal ovulatory function (16%)

 Hyperprolactinaemia (50%)
 Hypothyroidism (36.4%)
 Hypogonadotrophic hypogonadism (23.7%)
 CAH (100%)
 Androgen-producing adrenal tumours

 Prevalence in PCOS (~ 53%)

Abdel Gadir et al 92
Associated Clinical features in PCOS

 Obesity
 ~50% PCOS women are obese Gambineri et al 2002

 An independent predictor of conversion to IGT or T2 DM

Norman et al 2001

 Acanthosis nigricans
Pathogenesis

 Insulin resistance
  Gn-RH dynamics
 Insufficient FSH
 Genetics
 Premature pubarche
 Low birth weight
Pathogenesis – Insulin resistance

 Insulin resistance

 In both lean & obese PCOS women

more severe in obese PCOS > obese control > lean PCOS
(clamp study) Dunaif et al, Diabetes, 89

 Not universal finding in PCOS Robinson et al 93

Pathogenesis – Insulin resistance

 Mechanisms of Insulin Resistance:

 insulin sensitivity in: Peripheral tissue  Liver

Peripheral tissues – muscle (85%), adipose tissue

cellular mechanisms:
?  binding of insulin to receptor
 insulin-mediated glucose transport
 expression of glucose-transporter protein GLUT-4
Pathogenesis - Insulin resistance

Liver ()
 Obese adult PCOS - hepatic production less suppressed with
insulin Dunaif et al, Diabetes, 92

 obese adolescents PCOS 120.7 yr old – hepatic production not

suppressed with insulin Lewy et al, J Ped 2001

BUT other studies in adult PCOS show:

no  insulin sensitivity in liver Peiris et al JCEM 89
Franks NEJM 95

 Insulin resistance  basal insulin secretion

&  hepatic insulin clearance
 Hyperinsulinemia Dunaif et al, Endocrine Review 97
Pathogenesis - Insulin resistance

 Hyperinsulinemia  Hyperandrogenism
diazozide that  insulin conc
weight loss  androgen conc
insulin sensitizers Nestler, JCEM 89; Dunaif JCEM 96

in-vitro insulin (& IGF-1)

 ovarian growth &
synergizes with LH  promote androgen production by ovary
Nobels et al, Medline review, 92; Bergh et al 93 (but no support from in-vivo models)

Insulin   hepatic production of SHBG Sharp et al 91

Insulin & insulin growth factors signal intracellular pathways in ovary 

promote androgen production Guzick 2004

Insulin may potentiate adrenal 17-hydroxylase & 17,22 lyase activity

Rosenfield, JCEM, 96
 adrenal sensitivity to ACTH Nobel et al, Fert & Ster, 92
Pathogenesis – Insulin resistance

 Insulin resistance + Hyperandrogenism may  Anovulation

Carmina , Minerva Ginecol 2004

 Hyperandrogenism  Anovulation
ovarian wedge resection   androgen producing tissue
 restore follicular maturation & ovulation Jeroma et al, Ann NY Acad Sci, 2003

 Hyperinsulinism  IGF system -  IGFBP-1,  free IGF-I

normal total IGF-I

  adrenal hyperandrogenism & peripheral androgen conversion

in non-obese PCOS
Homburg et al 92, Silfen at al 2003
Pathogenesis – Insulin resistance

 Insulin resistance – underlying Ax

 Genetic
 Obesity
 LBW
 Premture pubarche
Pathogenesis -  Gn-RH dynamics

 gonadotropin-releasing hormone dynamics

  LH pulse frequency & amplitude   24 hr mean conc

Morales et al JCEM 1996
Kalro et al 2001

  LH may  excess androgen production:

androgen production by theca cells is LH dependent
LHRH analog   LH   testosterone & androstenedione

BUT blunting of pulse amplitude in obese (BMI>30) PCOS

 24 hr mean LH conc ~ normal cycling women
Arroyo et al, JCEM 97
Pathogenesis -  Gn-RH dynamics

 Ax of  Gn-RH dynamics ( GnRH pulse frequency):

? Metabolic, central neuromodulators, paracrine factors

: catecholamines, IGF1, opiods, leptin, insulin / insulin resistance
androgens, inhibin (ovary) Kalro et al, Obst & Gyne Clin N Am, 2001

? 10 neuroendocrine abnormality driving excess Gn secretion

? abnormal feedback of another factor

(in adolescents or older women)
Taylor, J Ped Endo & Meta, 2000

? Genetic predisposition to hypersecrete ovarian androgens

  hypothalamic-pituitary function
Jerome et al, Ann NY Acad Sci, 2003
Pathogenesis – Insufficient FSH

Insufficient FSH  Anovulation Guzick, Am Ob & Gyne 2004

 Inappropriate hypothalamic GnRH secretion

 relative low FSH
 not permit effective aromatization
 excess androgen & poor estrogen
  maturation of follicles (direct effect or induce stroma hypertrophy)
 anovulation
Venturolli et al, Clin Endo, 1988

 Adequate conc of FSH essential for

pre-ovulatory follicle development
& selection of a single preovulatory follicle

van Weissenbruch et al 1993

Pathogenesis - Genetics

Genetics

 AD gene effect with variable phenotype of PCOS

study on 92 patients
41% sisters & 19% mothers have PCOS
phenotypic heterogeneity within affected families determined by
other factors ? Diet, ex, peripubertal stress, hormone
genetic defects of insulin secretion
Kahsar-Miller et al, 1998
Pathogenesis - Genetics

 Region 1 MB centromeric to the insulin receptor gene on

chromosome 19
Linkage & association studies of
1st degree relatives (with hyperandrogenism) of PCOS Urbanek et al 2000

 Susceptible gene on chromosome 19p13.3 in insulin receptor

gene region - Insulin receptor gene marker D19S884
- significant association with PCOS
- study of 85 PCOS women (case-control)
- ? INSR gene itself or a closely related gene Tucci et al, JCEM, 2001

 Locus on chromosome 19p13.3

linkage with testosterone level (steroid phenotype) in Caucasians
HERITAGE Family study with genomewide scan Ukkola et al, JCEM, 2002
Pathogenesis - Genetics

 CYP11a gene
in association & linkage studies
a major genetic susceptibility locus for PCOS with hirsutism
Gharani et al,Hum Mol Genet, 97

 VNTR regulatory polymorphism in chromosome 11p15.5

of insulin gene ( insulin production)
study 17 families of PCOS Waterworth et al, Lancet, 97

 Genetic abnormality (kinase)in serine-phosphorylation (hyper-) of

Insulin receptor   signalling  insulin resistance
P450c17   post-translational regulation of 17,20-lyase activity
  androgen
BUT the kinase not identified yet Auchus et al, TEM, 98
(explain association of PCOS & insulin resistance)
Pathogenesis - Genetics

Genetic mechanism
?
   androgen
 programme hypothalamus-pit with excess LH
 preferential abdominal adiposity & IR (also genetics)
Abbott et al, J Endo 2002

  Insulin resistance, Hyperinsuliniemia

Jerome et al, Ann NY Acad Sci, 2003
Pathogenesis - Premature Pubarche

 ~30% have marked adrenal Hyperandrogenism (Pre-pubertal)

- have Insulin resistance (FSIGT)
- continue to have these features & obesity & irregular menses
Nardi, J Ped Endo Meta, 2000

 41% have polycystic ovaries on USS Battaglia et al, JCEM, 2002

 exaggerated ovarian androgen synthesis (FOH) throughout

puberty Ibanez et al, Fert Ster, 97
Ibanez et al, JCEM, 93

 Hyperinsulinemia Ibanez et al, JCEM, 97

Pathogenesis - Premature Pubarche

 ? Pathogenesis (Premature pubarche  PCOS)

 cytochrome P450c17 activity (in adrenal & gonads)
Ibanez et al, JCEM, 93

Hyperinsulinemia as underlying 10 mechanism Rosenfield, JCEM, 96

Premature pubarche
Antecedent of
 FOH
 Hyperinsulinemia
 Dyslipidemia
 PCOS – premature pubarche being the earliest recognized
PCOS phenotype in life
Kent et al, Adolesc Med, 2002
BUT ? How often
Pathogenesis – Low birth weight

 Low Birth Weight

associated with postnatal
 Insulin resistance – T2 DM

 Dyslipidemia

  BP Barker et al, Diabetologia 93

 Exaggerated adrenarche (study in post-menarche girls)

 Hyperinsulinemia Ibanez et al, JCEM 99

 Ovary dysfunction,  ovary development

Study ovary volume & primordial follicles in foetus deBruin et al 98
Pathogenesis – Low birth weight

 Low Birth Weight ?  PCOS in adult

? belong to the ‘classic’ PCOS

Screening PCOS in general population of 2007 women
 26% have symptoms of PCOS

 no association with SFD, LBW, gestation

Laitinen et al 2003
Pathogenesis – LBW + Premature pubarche

 Premature Pubarche + LBW

 risk of PCOS

Premature pubarche (PP) + LBW vs PP + normal birth weight

 Pre-puberty – no difference
 Early puberty -  triglyceride & LDL
 Post-menarche -  insulin sensitivity (HOMA), insulin (OGTT)
ovarian dysfunction ( 17OHP to leuprolide test,
 FSH)

BMI SD score  in both groups in all stages

(catch-up growth may  greater insulinemia) Ibanez et al, Clin Endo 2001
DDx of PCOS

Menstrual irregularities / Hirsutism

 Congenital Adrenal Hyperplasia
 premature pubarche, androgen excess
 21-hydroxylase deficiency
 3 -hydroxysteroid dehydrogenase deficiency
 Hyperprolactinemia
 Acromegaly
 Androgen-secreting tumour of ovary or adrenal gland
 Cushing’s disease
Dx Approach

 Hx
 Clinical exam
 Lab Ix
Dx – Laboratory Ix

  LH , LH:FSH ratio > 2:1, normal FSH

 Lower LH in obese (BMI >30) PCOS Arroyo et al, JCEM, 97

 BUT usually normal (in ~40%)

because of pulsatile nature of Gn
lower lab result with immunofluorometic assay
 an insensitive test but quite specific ( LH with normal FSH)

 FSH
level ~ mid-follicular phase of normal menstrual cycle
essential Ix to exclude 10 ovarian failure in DDx
Dx – Laboratory Ix

 Androgens
 Testosterone > 60 ng/dL (2 nmol/L)
 Cutoff = 2 SD above mean in cycling women
 Free testosterone assay – more expensive, variable reliability

 17 OH-progesterone < 2 ng/ml

 To rule out CAH
 ACTH  test- rule out 21-hydroxylase deficiency
& 3 -hydroxysteroid dehydrogenase deficiency

 DHEAS (> 21.6 µmol/L – suggest adrenal tumour)

Dx – Lab Ix

 Subclinical Hyperandrogenism

 Nafarelin test (Leuprolide acetate 500 µg sc)

study performed in follicular phase (Day 3-8) of menstrual cycle

 17 OHP (peak > 160 ng/dL or 4.57 nmol/L),  androstenedione

 LH, estradiol

at baseline, 6 hr (maxi pit ) & 24 hr (maxi gonadal ) in PCOS

 ACTH stimulation test -  17OH pregnenolone or androstenedione

 adrenal source
Dx - Ix

 USS ovaries
 Follicles
 Ovarian volume

 Hyperprolactinemia
 Prevalence in PCOS 5-30%
 Need exclude other Ax of hyperprolactinemia

 Thyroid function test

 To exclude hypothyroidism
Other Ix

Obesity, acanthosis nigricans, premature pubarche:

 Dyslipidemia

 Screen for Glucose intolerance / DM

 Fasting glucose
 OGTT

2 hr post-challenge plasma glucose more reliable than fasting

glucose in PCOS to screen IGT / DM
 Adolescent PCOS Palmert et al, 2002

 Adult & adolescent (14-44 yr old) PCOS Legro et al, JCEM 99

Legro, Obst Gyn Clin N A, 2001
Other Ix

 Insulin resistance (IR)

 Fasting insulin
correlate with Insulin resistance in obese adolescent PCOS vs clamp study
Lewy et al, J Ped, 2001

 Fasting glucose: insulin (glucose in mg/dL, insulin u/L)

<4.5 indicate IR in adult obese PCOS Legro et al, JCEM 98

<7 useful index of IR in adolescents Kent et al, Adol Med 2002

2.3 for IGT in adolescent PCOS Palmert et al, JCEM 2002
mean ~1.9 in obese adolescents PCOS Lewy et al, J Ped, 2001
( < adult may because of  insulin secretion)

Not appropiate if  fasting glucose Quon, JCEM 2001

Other Ix

 HOMA-IR (G0 x I0) 22.5

sensitivity 78%, specificity 89% Palmert et al, JCEM 2002

 QUICKI (1 (log G0 + logI0)) Quon, JCEM 2001

Good correlation with IS (Euglycemic clamp study)

in non-diabetic PCOS adolescents
 Fasting insulin
 Fasting Glucose / Insulin
 HOMA IS (=1/HOMA-IR)
 QUICKI Gungor et al, J Ped, 2004
PCOS – origin in Adolescence

 Clinical features - acne

hirsutism
anovulatory menstruation
 Biochemical abnormalities

of adult PCOS
are observed in adolescents in normal general population
Adolescence –Anovulatory Cycles

 Development of menstrual cyclicity in Adolescents

(measure serum progesterone)

 1st yr after menarche anovulatory in 85%

 3rd yr 59%
 6th yr 25%
Apter and Vihko, Year Book, 85
Adolescence – Ovarian volume

 Ovarian volume centiles

in normal children
& adolescents
Bridges et al 1993
Adolescence –Polycystic ovaries

 Prevalence of Polycystic
ovaries (PCO) in adolescence
 Prevalence of polycystic
ovaries  throughout puberty
6% at 6 yr old
26% by 15 yr old
Bridges, Brook et al 1993
Adolescence – Insulin resistance

 Insulin resistance & insulin secretion – pubertal changes

OGTT test – significant results
 Mean serum insulin -  at Tanner stage II & then similar in III-V
 SI (insulin sensitivity) - lower at Tanner stage II then higher in stage III-V

 insulin-resistant state coincide with Tanner stage II

Potau et al, Hormone Research 97
FSIGT test
 SI – significant  in Tanner stage II & further insignificant  in stage III-V
Cook et al, JCEM, 93
 Hyperinsulinemia
  ovarian & adrenal steroid / androgen synthesis
Nobel et al, Fert & Ster, 92
Leuteinizing hormone in Normal Puberty

 LH pulse frequency & amplitude

 Early puberty –  nocturnal pulse amplitude
 Advancing puberty - further  pulse frequency & amplitude
 Immediately before menarche - accentuation of circadian profile –
night time LH > adult
 Ovulatory – pulse amplitude ~ adult
Anovulatory – normal mean LH, daytime LH amplitude & freq ~ ovulatory
night time LH ~ premenarche

OR -  mean LH level > adult ,  LH frequency, amplitude,

- higher value during daytime-desynchronization rhythm
~ PCOS
Porcu et al 87; Venturoli et al, Curr Op Ped 94
Physiological changes in Adolescence

 Hyperinsulinemia & Insulin resistance

(exaggerated by genetic & / or obesity)
 Hyperpulsatile gonadotrophin secretion

 Hyperactive ovarian androgen synthesis

 Hyperactive adrenal androgen synthesis

 Menstrual irregularities

  level of IGFBP-1, SHBG

~ PCOS
 insulin levels, IGF-1 activity, androgen, during puberty
probably as inducing factors in development of PCOS
in susceptible subjects Nobel et al, Fert & Ster, 92

(After puberty, insulin & IGF-1 progressively  in most females  normal)

PCOS in Adolescence

 Risk factors
 Premature pubarche (before 8 yr old)
- more common in – African-American
 Obesity
 Family Hx
 Ethnicity
PCOS in Adolescence

Risk for development of adult life PCOS

 Persistent irregular cycles by 6th Gyne yrs
 40% cycles remain anovulatory
 Higher testosterone, androstendione, LH
 Lower premenstrual 17OHP, progesterone, E1, E2
vs ovulatory cycle / adult control Venturoli et al, Ster Fert 87

 Adolescents with anovulatory cycles after menarche x 3-4 yrs

high LH group  57% anovulation (43% ovulation)
normal LH  83% normal ovulation

 PCOS pattern exist > 2 yrs  high risk of life-long abnormality

Venturoli et al 94
PCOS in Adolescence

 Clinical findings  adult PCOS

 cf Adolescents ( 18 yr) & Adults ( 19 yr) with PCOS
 No statistically significant differences in :
prevalence of hirsutism
prevalence of menstrual irregularities
estradiol, LH, FSH, prolactin, testosterone, 17OHP,
androstenedione, DHEAS
ovarian volume
 +ve correlation of ovarian volume with LH, testosterone, DHEAS,
androstenedione
in both adolescents & adult
Gulekli et al, Gyne Endo, 93
PCOS in Adolescence

 Clinical findings  adult PCOS

 LH pattern
Augmented LH pulsatility – LH pulse amplitude & frequency
 mean LH level
 LH/FSH ratio

  production of ovarian androgens

Taylor, J Ped E M, 2000
Apter et al, JCEM, 94 & 95
PCOS in Adolescence

 Clinical findings  adult PCOS

 Higher Insulin resistance vs control
Adolescents 12  0.7 yrs old (clamp study)
obese PCOS (oligomenorrhoea + hyperandrogenism)
vs obese control
Peripheral insulin sensitivity 50% lower
Lewy et al, J Ped, 2001

Adolescents 11-18 yr old (IVGTT)

PCOS (Hyperandrogenism +  ovarian volume)
vs age-matched control
Decreased insulin sensitivity (IVGTT) Apter et al, JCEM, 94 & 95
PCOS in Adolescence

 Clinical findings may  adult PCOS

 Insulin secretion
Obese Adolescents (120.7 yr)- 1st phase & 2nd phase secretion
Lewy et al, J Ped, 2001
Obese Adolescent with IGT - 1st phase insulin secretion
Arslanian et al, JCEM 2001

Obese & non-obese Adult without IGT / T2 DM

-  cell dysfunction with  insulin secretion (+ IR)
( disposition index)
Dunaif et al, JCEM, 96

(different may because of duration of PCOS Lewy et al, 2001)

PCOS in Adolescence

 Study on 12.9 -18 yr old , obese vs non-obese PCOS

(hyperandrogenism + oligo- / amenorrhoea) vs Obese control
 USS – ovaries–polycystic 100% (non-obese) 75% (obese) >control
- ovary volume : no difference & ~ adult PCOS
 Mean LH non-obese > obese PCOS > obese control
 DHEAS/4-A non-obese > obese > obese control
 Testosterone non-obese ~ obese > obese control
  SHBG non-obese < obese < obese control
  Lipid non-obese < obese ~ obese control
 Insulin sensitivity (Fasting insulin, I0/G0, QUICKI, ISI comp in OGTT)
non-obese > obese ~ obese control
  IGFBP-1 non-obese < obese PCOS
  Free IGF-1 level non-obese > obese PCOS
 more pronounced  H-P-A axis in non-obese PCOS
more marked  insulin sensitivity in obese PCOS
IGF system different in non-obese & obese PCOS Silfen et al JCEM 2003
Long-term Sequaelae of PCOS

 Irregular menstruation
 Infertility -73% of anovulatory infertility Hull et al 87

  risk of IGT / Type 2 diabetes

 Prevalence IGT x3 control
T2 DM x7 control Dahlgren et al 92

 IGT 35%, T2 DM 10% Ehrmann et al 99

IGT or DM at 40 yr old - 40% Legro 2001
 non-obese (14-44 yr old)
IGT 10.3% , DM 1.5% Legro et al 99

 Lean & *obese adolescent PCOS (13.9-19 yr old, 27 subjects)

IGT 30%, T2 DM 3.7% Palmert et al, JCEM, 2002
Long-term Sequaelae of PCOS

 Lipid abnormalities
 Sign lower HDL, higher total chol, LDL, TG Talbott et al 95

  risk of CVS disease

  risk factors for CVS disease
 subclinical athersclerotic disease
(greater carotid intimamedia wall thickness & coronary Ca++) Talbott et al 2001

 BUT no data on  prevalence of cardiovascular events

vs general population

  risk of endometrial carcinoma

 Unopposed estrogen on endometrium
PCOS in Epilepsy

  prevalence in patients on antiepileptic drugs

study 69 patients with epilepsy
: 42 off Px
27 taking antiepileptic drugs
51 control

27 still taking antiepileptic drugs:

 Significant higher testosterone, androstenedione

 PCOS 38% (off Px: 6%, control 11%, p=0.005)

on Na valproate (Epilim) 63%

other antiepileptic 25%
Mikkonen et al, Neurology 2004
Treatment

 Early recognition & Mx

 Screening parameters
 BMI
 BP
 Fasting lipid profile
 Fasting glucose / OGTT
(obese, acanthosis nigricans, premature pubarche)
Treatment

 Obese
 Weight reduction – Diet + Exercise / Lifestyle modification

wt loss 2-5%   testosterone by 21%

resume regular ovulation in 50% women
JCEM 99
most important long-term Px in obese females

 Other general lifestyle factors

 Avoid alcohol, smoking, psychosocial stressors
TEM 2002
Treatment

 Anovulation
 Oral contraceptives
advantages: regular withdrawal bleeding
 risk of endometrial hyperplasia or cancer
 LH secretion  ovarian androgen
 SHBG production   free testosterone
improvement of hirsutism & acne

use non-androgenic progestogen, norethindrone-only (not  IR)

? Long-term benefit on reproduction
stop Px  androgen return to pre-Px level Siegberg et al 87
choice for sexually active women / adolescents
 Cyclical progestins
-avoid with androgenic activity : norgestrel, norethindrone
-medroxyprogesterone 5 mg daily x 13 days Q 1-2 month
 Infertility – ovulation induction
Treatment

 Hirsutism
 Cosmetic Px – waxing, laser, eflornithine cream
 Anti-androgen
Spironolactone 200 mg/day
- may associated with erratic vaginal bleeding
usually + low dose OC

Cyproterone acetate – also progestogenic

2 mg + ethinyl estradiol 35 mcg daily x 21 days (Diane-35)
( SHBG, prevent pregnancy)

Flutamide
Treatment

 Metformin
 Meta-analysis of RCT

achieve ovulation OR= 3.88 (95%CI 2.25-6.69)

(rate  wt loss with lifestyle intervention Clark et al 98)
 fasting insulin mean difference 5.37 IU/L
BP mean difference 9 (systolic), 5.69 (diastolic)
LDL mean difference 0.44

BUT no data on safety of long term use in young women

Lord et al, BMJ, 2003
Treatment

 Adolescent PCOS with oligo- or amenorrhoea

Metformin 1.5-2.55 gm/day x 10  6.4 months + low CHO diet

91% resume regular normal menses

 testosterone
 cholesterol Glueck et al, J Adolesc Health 2001

 Adolescents (mean age 16.8 yr) non-obese, premature pubarche

with hirsutism, ovarian hyperandrogen, oligomenorrhoea, lipid,  insulin
Metformin 1.275 gm /day x 6-10 months

100% had regular menses by 4/12

significant  hirsutism score, androgen (testosterone, DHEAS…)
improve lipid profile
BUT stop Px  reversal to pre-Px conditions in 3/12
Ibanez et al, JCEM 2000
Treatment

 Early post-menarche 24 girls (12.40.2 yr old), non-obese, LBW

& Precocious pubarchy
Ovarian Hyperandrogenemia (leuprolide test 17OHP >160 ng/ml) +
Hyperinsulinemic (OGTT insulin peak >150 or mean > 84 mU/L)

Dyslipidemia
Excess truncal fat (W-H ratio) &  lean body mass (DEXA)
Higher androgen, IGF-1, GH cf. weight & height matched normal

Metformin 850 mg / day for 12 months in 12 girls (RCT)

Px group – abnormalities significantly improved at 6 month

body composition further improve 6/12-1 yr
Control group – significantly deterioate further

 Metformin prevent progression to PCOS in this high risk group

Role of hyperinsulinemic IR in ontogeny of PCOS
Ibanez et al, J Ped, 2004
Treatment

 BUT

- ? This group  classic PCOS patient in adulthood

- no effect on reducing obesity
- no documented adverse outcome in this group
- no data on long-term risk-benefit ratio

- ? Should start long-term Px in adolescence

Cedars, Editorial, J Ped, 2004
 LFL CFY WYK AKM

Age of presentation 17 yr 12 ½ yr (on Epilim) 17 yr 18 yr

BMI 32.2 (Obese) 31.7 (Obese) 18.9 18.6
Anovulation
Presentation Oligomenorrhoea/ 20 amenorrhoea 20 amenorrhoea Oligomenorrhoea
20 amenorrhoea
Age of menarche 12 yr 9 ½ yr old 10 yr 12 yr
Onset irregular cycle Since menarche 1½ yr after menarche Since menarche Since menarche
Hyperandrogenism
Hirsutism +ve (F-G score =7) +ve (F-G score =8) Nil Nil
Acne +ve Mild Nil Nil
Testosterone nmol/L 5.9 2.5 1.3 1.6
USS Ovary
Polycystic No No Yes Yes
Volume R-7.8 ml, L-7.3 ml R-10.8 ml, L-7.7 ml R-9.3 ml, L-7.9 ml R-16 ml, L-18.4 ml
LH 9.3 7.6 16 31.7
LH:FSH ratio 1.6 1.4 2.4 5.2
Insulin reistance
Acanthosis Nigricans +ve (OGTT normal) +ve (OGTT normal) Nil Nil
Fasting insulin mIU/L Pending result 36 9.2 14
HOMA Pending result 4.48 1.96 2.92

Prolactin ng/ml normal normal Transient  to 61.7 normal

(N: 1.4-24.2 ng/ml) MRI brain - normal

Family Hx Normal Normal Mother-Prolactinoma Normal