Transcript Polycystic Ovary Syndrome

Polycystic Ovary Syndrome
in Adolescence
Lee Ching Yin
CMC
May, 2004
Definition of PCOS
1st described by Stein and
Leventhal 1935
 NIH criteria (National
Institute of Health) 1990
Hyperandrogenism
 Chronic Anovulation
with exclusion of other Ax:
Cushing,
CAH,
hyperprolactinemia
 USS – polycystic ovaries


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
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
20 amenorrhoea
20 amenorrhoea
Oligomenorrhoea
Age of menarche
Onset irregular cycle
Oligomenorrhoea/
20 amenorrhoea
12 yr
Since menarche
9 ½ yr old
1½ yr after menarche
10 yr
Since menarche
12 yr
Since menarche
Hyperandrogenism
Hirsutism
Acne
Testosterone nmol/L
+ve (F-G score =7)
+ve
5.9
+ve (F-G score =8)
Mild
2.5
Nil
Nil
1.3
Nil
Nil
1.6
USS Ovary
Polycystic
Volume
No
R-7.8 ml, L-7.3 ml
No
R-10.8 ml, L-7.7 ml
Yes
R-9.3 ml, L-7.9 ml
Yes
R-16 ml, L-18.4 ml
LH
LH:FSH ratio
9.3
1.6
7.6
1.4
16
2.4
31.7
5.2
Insulin reistance
Acanthosis Nigricans
Fasting insulin mIU/L
HOMA
+ve (OGTT normal)
24
5.2
+ve (OGTT normal)
36
4.48
Nil
9.2
1.96
Nil
14
2.92
Prolactin ng/ml
(N: 1.4-24.2 ng/ml)
normal
normal
Transient  to 61.7
MRI brain - normal
normal
Family Hx
Normal
Normal
Mother-Prolactinoma
Normal
Anovulation
Presentation
Prevalence

Prevalence

~ 4-4.7% Screening 277 women 18-45 yr
Knochenhauer et al 98

10 diagnosis in




Oligomenorrhoea
Anovulatory infertility
Hirsutism
20 amenorrhoea
87%
>75%
90%
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

Exaggerated LH pulsatile messages
Markussis et al 94
 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
insulin sensitizers
 androgen conc
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
 adrenal sensitivity to ACTH
Rosenfield, JCEM, 96
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

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

Urbanek et al 2000
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
(explain association of PCOS & insulin resistance)
Auchus et al, TEM, 98
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

exaggerated ovarian androgen synthesis (FOH) throughout
puberty
Ibanez et al, Fert Ster, 97
Battaglia et al, JCEM, 2002
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
BUT usually normal (in ~40%)
Arroyo et al, JCEM, 97
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)



17 OH-progesterone < 2 ng/ml



Cutoff = 2 SD above mean in cycling women
Free testosterone assay – more expensive, variable reliability
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



Hyperprolactinemia



Follicles
Ovarian volume
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
<7 useful index of IR in adolescents
2.3 for IGT in adolescent PCOS
mean ~1.9 in obese adolescents PCOS
( < adult may because of  insulin secretion)
Not appropiate if  fasting glucose
Legro et al, JCEM 98
Kent et al, Adol Med 2002
Palmert et al, JCEM 2002
Lewy et al, J Ped, 2001
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
3rd yr
6th yr
anovulatory in 85%
59%
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
normal LH
 57% anovulation (43% ovulation)
 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

 risk of IGT / Type 2 diabetes




Prevalence IGT
x3 control
T2 DM x7 control
IGT 35%, T2 DM 10%
IGT or DM at 40 yr old - 40%
Dahlgren et al 92
Ehrmann et al 99
Legro 2001
non-obese (14-44 yr old)
IGT 10.3% , DM 1.5%

Hull et al 87
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
 risk of CVS disease


 risk factors for CVS disease
subclinical athersclerotic disease
(greater carotid intimamedia wall thickness & coronary Ca++)


Talbott et al 95
BUT no data on  prevalence of cardiovascular events
vs general population
 risk of endometrial carcinoma

Talbott et al 2001
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
Control group
body composition further improve 6/12-1 yr
– 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
20 amenorrhoea
20 amenorrhoea
Oligomenorrhoea
Age of menarche
Onset irregular cycle
Oligomenorrhoea/
20 amenorrhoea
12 yr
Since menarche
9 ½ yr old
1½ yr after menarche
10 yr
Since menarche
12 yr
Since menarche
Hyperandrogenism
Hirsutism
Acne
Testosterone nmol/L
+ve (F-G score =7)
+ve
5.9
+ve (F-G score =8)
Mild
2.5
Nil
Nil
1.3
Nil
Nil
1.6
USS Ovary
Polycystic
Volume
No
R-7.8 ml, L-7.3 ml
No
R-10.8 ml, L-7.7 ml
Yes
R-9.3 ml, L-7.9 ml
Yes
R-16 ml, L-18.4 ml
LH
LH:FSH ratio
9.3
1.6
7.6
1.4
16
2.4
31.7
5.2
Insulin reistance
Acanthosis Nigricans
Fasting insulin mIU/L
HOMA
+ve (OGTT normal)
Pending result
Pending result
+ve (OGTT normal)
36
4.48
Nil
9.2
1.96
Nil
14
2.92
Prolactin ng/ml
(N: 1.4-24.2 ng/ml)
normal
normal
Transient  to 61.7
MRI brain - normal
normal
Family Hx
Normal
Normal
Mother-Prolactinoma
Normal
Anovulation
Presentation