Polycystic Ovary Syndrome François Pralong Division of Endocrinology
Polycystic Ovary Syndrome
François PralongDivision of Endocrinology
Association of clinical and/or biochemical evidence of androgen excess with chronic anovulation
Heterogeneous condition with a spectrum of clinical/biochemical features
Estimated prevalence : 25% of all women, full blown syndrome in ~5% of women of reproductive age
Definition
· Hirsutism (95%), acne, alopecia· Enlarged ovaries (95%)· Sterility (75%)· Amenorrhea (55%)· Obesity (40%)· Dysmenorrhea (28%)· Chronic anovulation (20%)
Clinical presentation
PCOS: THE TEXTBOOK VIEW I
Pathogenic hypothesisAbnormal hormonal feedback mechanisms
PCOS: THE TEXTBOOK VIEW I
Hypothalamus
Ovaire
Surrénale
Tissuadipeux
PCOS: THE TEXTBOOK VIEW IIPathogenic hypothesisObesity and insulin resistance
PCOS: A DEVELOPMENTAL VIEW
Adapted from S Franks, 2002
InsulinLH
ANDROGENS
Puberty
•Hirsutism•Acne•Alopecia
Gonadotropin Secretion in PCOS
Increased LH secretion:•Ratio of LH/FSH: 2-3/1•Prevalence: 30 to 90% !
Importance of assessing LH secretion in relation to recent menses
Pituitary
GnRH
LH, FSH
E2,T
GnRH
LH
FSH
GnRHneurons
InhibitionFacilitation
Gonadotrophs
Childhood years
LH
GnRHneurons
InhibitionFacilitation
Gonadotrophs
Post-pubertal Period
LH
Metabolic signals
Adapted from S Franks, 2002
InsulinLH
ANDROGENS
Puberty
?
•Hirsutism•Acne•Alopecia
Possible Mechanisms of Abnormal LH Secretion in PCOS
Altered sex steroid feedback:
•Increased spontaneous LH pulse amplitude
•Increased LH response to GnRH
•Normal FSH response to GnRH
Inherent neuroendocrine abnormality
Study of 5 teenage, post-pubertal girls with PCOS, compared to age-matched controls
Diagnostic criteria:•Chronic anovulatory syndrome•Exclusion of other virilizing syndromes (Cushing, CAH…)•Normal TFTs and PRL
NEJM 309, 1983
Abnormality present in 4 of 5 patients
NEJM 309, 1983
Study of 12 women with PCOS, compared to 21 normal controls
Diagnostic criteria:•Perimenarchal onset of oligo/amenorrhea•Hirsutism and/or acne•Raised LH/FSH ratio•Raised T/androstenedione levels
•E2 lower than controls in MFP and LFP•Estrone higher than controls in EFP and MFP, lower in LFP
J Clin Endocrinol Metab 66, 1988
Normal PCOS
J Clin Endocrinol Metab 66, 1988
J Clin Endocrinol Metab 66, 1988
Study of 13 women (aged 11-18) with hyperandrogenism, compared to 28 aged-matched normal controls
Patients from Adolescent Medicine/Repro Endo clinics, UCSDDiagnostic criteria:
•Chief complaint: hirsutism•No hormonal medication for 3 months
J Clin Endocrinol Metab 79, 1994
J Clin Endocrinol Metab 79, 1994
J Clin Endocrinol Metab 79, 1994
Study of 61 women with PCOS, compared to 24 normal controls (EFP)
Diagnostic criteria:•Chronic oligoamenorrhea (<9 cycles/yr) or amenorrhea•Hyperandrogenism (clinical or biochemical)•Exclusion of late-onset CAH•Normal TFT and PRL•Off all medication for at least 2 months
J Clin Endocrinol Metab 82, 1997
J Clin Endocrinol Metab 82, 1997
J Clin Endocrinol Metab 82, 1997
J Clin Endocrinol Metab 82, 1997
J Clin Endocrinol Metab 82, 1997
High prevalence of gonadotropin secretion abnormalities in PCOS patients
Important associations between the elevated LHsecretion and recent ovulation or LH pulse frequency,
but NOT sex steroids
Strong association between LH pulse frequency and pool LH levels or LH/FSH ratio may suggest an etiologic relationship
J Clin Endocrinol Metab 82, 1997
CONCLUSIONS
Rapid GnRH pulse frequency probably has a role in the abnormal LH secretion pattern in PCOS
Marshall and Eagleson, 1999
CONCLUSIONS
Rapid GnRH pulse frequency probably has a role in the abnormal LH secretion pattern in PCOS
The defect in hypothalamic GnRH secretion seems to be intrinsic to PCOS patients
Could there be a role of elevated insulin levels/insulin resistance in this abnormal GnRH
secretion pattern?
Role of Brain Insulin Receptor in Control of BodyWeight and Reproduction
15
20
25
30
35
40 Body weightG
ram
ms
6 10 14 18 23Age (weeks)
0
20
40
60
80 Leptin
ng/m
L
* **
15
20
25
30
35
40 Body weight
Gra
mm
sWT KO WT KO
Male Female
**
120100806040200
WAT
mg/
g B
W
*
**
150
100
50
0
Food uptake
mg/
g B
W
WT KO WT KO
Male Female
**
Brüning et al., Science 289, 2000
Role of Brain Insulin Receptor in Control of BodyWeight and Reproduction
Spermcount
0
0.1
0.2
0.3
0.4
0.5
Plasma LH
* **
ng/m
L
0
10
20
30
40
Plasma LH one hr afteri.p GnRH agonist
*
ng/m
L
WT KO WT KO
Male Female
WT KO WT KO
Male Female
46
8101214
*
WT KO
Brüning et al., Science 289, 2000
Euglycemic hyperinsulinemic clamp studies in mice
Insulin infusion Glucose 15 % infusion
Glycemia
Insulin Stimulates GnRH Secretion In Vivo
2.5 5.5 20
LH (n
g/m
L)
0,0
0,2
0,4
0,6
0,8
1,0P<0.01
Glucose (mM) 5.5Insulin - + + +
Burcelin et al, Endocrinology 2003
Insulin Stimulates GnRH Secretion In Vitro
0 5 10 15 20 25 30 35 40 45 50
GnR
H (p
g/m
L)
10
20
30
40
Glucose 0.5 mM Glucose 20 mM
Fractions
Insulin 2.5 mg/mL Insulin 2.5 mg/mL
Basal 0.5 1 2.5 50
50
100
150
200
250
300
350
A
B
C*
**
GnR
H (%
of B
L)
Insulin (mg/mL) Burcelin et al, Endocrinology 2003
Insulin stimulates the expression of the GnRH gene
GnR
H m
RN
A(%
of c
ontr
ols)
0
100
200
300
6 hours24 hours
Ct Ins
* *
Burcelin et al, Endocrinology 2003
Hypothalamic GnRH neurons express a functional insulin receptor
A
B
M B HT Gnv-3A
B M B HT Gnv-3
Vollenweider et al, Bern 2003
Insulin signaling and GnRH transcriptionInsulin
IRS P85
P110
Insulin receptor
Grb2Sos
Ras
Raf
Shc
ERK 1/2
PI3 Kinase
GnRH
Hypothalamic neurons
?
Akt
ERK1/2 activation (Phospho ERK) in primary hypothalamic cells
0
100
200
300
2 min 5 min 10 min 30 min
p-ER
K/to
tal E
RK(%
ove
r ba
sal)
n = 5-6
*
*
Time
PI-3 kinase activation
0
450
900
Basal 5 min 15 min 30 min 60 min 120 min
*
*
*
**
PI3
kina
se a
ctiv
ity
(% o
ver
basa
l)IP IRS-1
PI3-kinase
0
125
250
Basal 5 min 15 min 30 min 60 min 120 min
**
**
PI3
kina
se a
ctiv
ity
(% o
ver
basa
l)
IP IRS-2PI3-kinase
Time (min)
ERK1/2 (Phospho ERK) and Akt (Phospho-Akt) activation in GnV-3 cells
0
500
1000
1500
2000
1 min 5 min 10 min 30 min
p-ER
K1/2
/ERK
(% o
ver
basa
l )
n = 5-6*
* *
ERK 1/2
0
350
700
Basal 5 min 15 min 60 min
Akt
p-A
kt/A
kt(%
ove
r ba
sal)
*
**
**
Time Time
The insulin effect on GnRH gene expression is dependent upon Erk1/2 activation in primary hypothalamic neurons
GnRH mRNA levels
Ct Ins Ins + PD PD DMSO
% o
f CT
0
100
200
300
400
500 ** *
The insulin effect on GnRH gene expression is independent of PI3-kinase activation in primary hypothalamic neurons
CT Ins Ins + Wort Wort DMSO
% o
f CT
0
50
100
150
200
250
300
GnRH mRNA
Treatment options
•Oral contraception: retablish menstrual cycles, decrease hyperandrogenism
•Association with an anti-androgen
•Insulin sensitizers: metformin, thiazolidinediones
Usually good clinical response to clomiphene citrate when seeking fertility
Division of EndocrinologyLausanneMicheline GlauserMarie-Jeanne VoirolMarco GiacominiEinar CastilloRoberto SalviRolf Gaillard
Department of Medicine andBotnar Center of ClinicalInvestigationPeter VollenweiderPascal Nicod
Institute of Pharmacology andToxicology, LausanneBernard Thorens
University of ToulouseRémy Burcelin