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Polycystic ovarian syndrome
Dr. Nizar Albache
Head of Diabetes Research Unit, Aleppo University
President of Syrian Endocrine SocietyJuly 25 2011
Key Learning Objectives
To be able to recognize and diagnose PCOS
To understand the lifelong manifestations of PCOS
To understand management options for:
longterm health hirsutism infertility
Prevalence & Diagnosis
PCOS - past and present
Menstrual disorder
Hirsutism
Obesity
Infertility
PCO
Stein IF, Leventhal ML. Am J Obstet Gynecol. 1935;29:181-191.
Stein-Leventhal Synd.
The celebrated “La Barduba”
by Ribera, a 52-year-old lady
nursing her child. She became
markedly hirsute at age 37
after having had three
spontaneous abortions.
FREQUENCY OF PCOS
•General population 4% - 8% •Women with secondary amenorrhea 30% • women with oligomenorrhea 75% •Women with hirsutism 90% •Normal women met the sonographic criteria for pcos 23% •Anovulation in women diagnosed with pcos 75% •Anovulation in hirsute women with normal menses 40%
How to make a diagnosis
Clinical suspicion Primary or secondary amenorrhoea Oligomenorrhoea Unexplained infertility Acne/ hirsutism Obesity
HIRSUTISM :excessive growth of body hair in women at androgen-
dependent areas: where normally very few hairs are found
- LIPS - CHIN
- CHET - ABDOMEN
- BACK - FEMORAL REGION
HIRSUTISM CLASSIFICATION From Slight Hirsutism To Virilim
Ferriman-Gallwey score : 9 areas Score = 0 – 4
N = 6 – 8 HIRSUT >8 VIRILISM 36
VERY SUBJECTIVE 18% OVERLAP REPORTERS DIFFERENCES NO FLEXIBILITY
Change in the form and rate of hair growth
* Recently: a technique for assessing Hirsutism : video equipment and computer software. Digital imaging of hair development
Criteria For The Diagnosis Of Polycystic Ovary Syndrome
(Pcos)TO INCLUDE ALL OF THE FOLLOWING: NIH (1990)
1: HYPERANDROGENISM AND/OR HYPERANDROGENAEMIA
2: OLIGO-OVULATION
3: EXCLUSION OF RELATED DISORDERS
TO INCLUDE TWO OF THE FOLLOWING, INCLUDING THE EXCLUSION OF
ESHRE/ARMS (ROTTERDAM
RELATED DISORDERS: 2003)
1: OLIGO- OR ANOVULATION
2: CLINICAL AND/OR BIOCHEMICAL SIGNS OF HYPERANDROGENISM
3: POLYCYSTIC OVARIES
TO INCLUDE ALL OF THE FOLLOWING: ANDROGEN EXCESS SOCIETY (2006)
1: HIRSUTISM AND/OR HYPERANDROGENAEMIA
2: OLIGO-ANOVULATION AND/OR POLYCYSTIC OVARIES
3: EXCLUSION OF ANDROGEN EXCESS OR RELATED DISORDERS
PCOS definition
Chronic Anovulation and Hyperandrogenism 5-10% reproductive age women
Diagnosis: 2/3 criteria *1. Oligo-ovulation &/or anovulation2. Hyperandrogenism (clinical or biochemical)3. Polycystic ovaries on ultrasound (PCO)* other causes for hyperandrogenism excluded
ESHRE/ASRM PCOS Consensus Workshop May 2003
Diagnosis: PCO on ultrasound
At least 1 ovary with 12+ follicles 2-9mm &/or ovarian volume > 10mls
NB: US picture on 1 occasion suffices for diagnosis
ESHRE/ASRM PCOS Consensus Workshop May 2003
25% of women have PCO, but only 5% have PCOS
Differential diagnosis of PCOS:
The differential diagnosis of hirsutism & oligomenorrha includes:
- congenital adrenal hyperplasia
- cushing syndrome - hyperthecosis ovarii - benign & malignant androgen secreting tumors or ovaries.
Causes & Mechanisms
Pathophysiology of PCOS:
PCOS is a condition that originates possibly at the time of puberty due to interplay of:
(1) obesity & excess of ovarian androgen production, due to hyperinsulinemia
(2) intrauterine environment. (3) genetic factors both X-linked, autosomal
dominant modes of inheritance.
(4) disturbance to hypothalamic-pituitary-ovarian axis.
Causes Syndrome = a collection of symptoms and
signs. There is no single cause but multiple predisposing factors.
Genetic Family linkage studies Over 70 candidate genes investigated
Steroidogenic & insulin pathways, ovarian follicle development
Candidate genes may regulate hypothalamic-pituitary-ovarian axis, as well as those resposible for insulin resistance
Environmental Fetal programming/ ‘thrifty gene hypothesis’ Obesity
Insulin Resistance
Insulin resistance (IR):
is a prominent feature in both obese (65-90%) and lean (25-45%) women with PCOS
is unique to PCOS as occurs independently to obesity, but is aggravated by obesity
(Franks S 1989; Dunaif A 1994)
Weight increase
Inherited defects in insulin actions
Insulin receptordisorders
Insulin increase
SHBG decreases
IGFBP-1decrease
By direct inhibition of hepatic synthesis of SHBG & IGFBP -1
Theca (IGF-II,?IGF-I)
Intrauterine Environment & PCOS:
Hague et al 1988 postulated that the intrauterine environment has a role in the pathogenesis of PCOS, & suggested that hyperandrogenism during fetal life may be the determining factor.
The apparent influence of intrauterine milieu in poorly controlled diabetics who end with stillborn fetuses, showed ovarian changes similar to those seen in PCOS.
Ovary
Compensatory Hyperinsulinemia
Insulin resistance
Serum insulin
And
roge
ns
Cause-and-effect relationship
?
Pathophysiology
Insulin acts synergistically with lh to enhance androgen production in the ovarian theca cells
Insulin also decreases hepatic synthesis and secretion of sex hormone-binding globulin
Women with pcos and hyperinsulinemia typically have elevated free testosterone
but the total testosterone concentration may be at the upper range of normal or only modestly elevated
LH and IGF-I effect
on theca cells
Cytochrome p-450c 17-alpha activity
Androgen secretion
Non-obese Obese
IGFBP-I
IGF-I
Insulin resistance Hyperinsulinemia
SHBG
LH GH
PCOD
Different hormone
concentrations in obese and
non-obese PCO patients
Wei
ght/
heig
ht2
20
40
BMI
20
40
Andr EstradSHBGTest
P<0.0001
P<0.017
P=NS
P<0.02
P<0.027
P<0.0001
LH
Insulin resistantNon-insulin resistant
Meirow et al. Hum Reprod 1995
Insulin resistant and non-resistant PCOS37 patients 18
19
Role of leptin in the pathophysiology of PCOS:
Leptin is considered as one of the major peripheral signals that affects food intake & energy balance.
Obesity is a classic condition of circulating leptin excess.
Leptin (OB)
16 KDa protein encoded by ob gene.Expressed & secreted by – adipocytes, placenta, gastric epithelium.Directly proportional to the total amount of fat in the body.
mice are homozygous for single gene mutation.ob/ob –protein hormone leptin db/db –receptor for leptin .
High degree of homology
Role of leptin in the pathophysiology of PCOS:
The discrepancy between increased leptin blood levels & its central effects represents a leptin resistance as shown by study of Moschos et al 2002 in Fertility Sterility Journal.
Mitchell m in 2005, there is evidence that leptin acts directly on the ovaries through functional receptors defect.
Role of leptin in reproduction
Fertility influenced by stored body fat
Leptin signals the onset of puberty .
Regulates hypothalamic- pituitary – ovarian function .
Signalling Pathway of Leptin Action
Potential Role Of The Endocannabinoid System
involved in the dynamic & homeostatic regulation of feeding & energy metabolism.
regulate multiple endocrine functions including H-P-O axis
fluctuates during ovarian cycle in both the hypothalamus & pituitary, thus influencing hormonal secretion & sexual behavior through CB1 receptor activation
Despite JP et al 2005 used rimonabant in patients as a new pharmacological treatment for tackling obesity
Table :Representative Candidate Genes with Evidence of Linkage, Association, or Both, with the
Polycystic Ovary Syndrome (PCOS)Pathway and protein (Gene)Insulin secretion and actionInsulin receptor (INSR) region-D195884Insulin variable-number tandem repeats (VNTR)Insulin receptor substrate 1 (IRS-1)Insulin receptor substrate 2 (IRS-2)Calpaim 10 (CAPN10)Peroxisome-proliferator-activated receptor (g PPAR g)Protein phosphatase 1 regulatory subunit (PPP1R3)
Gonadotropin secretion and actionFollistatin (FST)
Androgen biosynthesis, secretion, transport, and metabolismAndrogen receptor (AR)Sex hormone-binding globulin (SHBG)Cytochrome P450c17 (CYP17)Cytochrome P-45011a (CYP11a)11b-hydroxysteroid dehydrogenase (11b-HSD) and hexose-6-phosphate
dehydrogenase (H6PD)
life-long condition
PCOS is a life-long condition
0 10 20 30 40 50 60 70
? IUGR
? Pronounced adrenarche
Menstrual irregularities
Hirsutism
Infertility, miscarriageGestational hypertensionGestational diabetes
Hypercholesterolaemia
DiabetesHypertension
Coronary heart disease
Age (years)Long-term health
Precocious puberty
Reproductive disorder
Metabolic syndrome
Cancer (uterine; ?breast)
PCOS and glucose intolerance
Increased prevalence of glucose intolerance (35%) and type 2 diabetes (10%) Also increased in non-obese PCOS (10%, 1.5%)
Increased risk (x3-7) of developing type 2 diabetes
PCOS women develop glucose intolerance at an early age (3rd-4th decade)
PCO is risk factor for gestational diabetes
Long-term health risks
Reproductive: Endometrial Cancer
Metabolic: Diabetes, Dyslipidaemias, Hypertension, Obesity
Unproven:
Cardiovascular Disease
Breast cancer
Established:
Acanthosis Nigricans ( An ) Is A Clinical Marker Of
Ir “Velvety, mossy, verrucous, hyperpigmented skin change
often found over the nape of the neck, in the axillae or beneath the breasts
Caused from the binding of insulin to insulin-like growth factor receptors on keratinocytes and fibroblasts which results in hyperplasia of the skin
IR is present in more than 90% of patients with AN
Evaluation
The 3 steps of androgen metabolism in women
Adapted from: Beylot C. et al. Oral Contraceptives and Cyproterone Acetate in Female Acne Treatment.
Dermatology 1998; 196: 148-152.
Investigations
Serum (early follicular phase): LH/FSH Total testosterone, Free androgen index (FAI) Exclude other endocrinopathies
*TSH, Prolactin, DHEAS, 17-OH progesterone Pelvic ultrasound scan for the
ovarian features of PCO
Diabetes screen, lipid profile , BP check
Hormone levels: PCOS vs. Idiopathic hirsutism
Hormone PCOS
n=213
Idiopathic hirsutism n=97
Healthy women n=40
LH )IU/L) 14.3* 3.5 3.7FSH )IU/L) 5.3 5.5 5.8Androstenedione )µg/L) 3.6* 2.0 1.8Testosterone (T) )µg/L) 1.0* 0.5 0.4Free T )ng/L) 3.6* 1.8 1.6DHEAS )mg/L) 2.9* 1.9 1.63a-diolG )µg/L) 6.3** 6.0** 1.5SHBG )nmol/L) 22.1* 49.8 51.1
Falsetti L. et al. Management of Hirsutism. Am J Clin Dermatol 2000 Mar-Apr; 1 )2): 89-99
Baseline plasma hormone levels in patients with PCOS or idiopathic hirsutism and in healthy women (mean values)
*=p<0.001: PCOS vs. idiopathic hirsutism and healthy women**=p<0.001: PCOS and idiopathic hirsutism vs. healthy women
Metabolic problems
Hypertension Dyslipidaemia
TC, LDL-C, TG’s
HDL-C Future diabetes ? Cardiovascular disease (CVD)
coronary disease myocardial infarction
Figure Diagnostic alogorithm for the Polycystic Ovary Syndrome
Any 2 of the following 3 disorders confirmed:Oligomenorrhea or amenorrhea
Hyperandrogenism )e.g., hirsutism,Acne, alopecia) or hyperandrogenemia
)e.g., elevated levels of total or freeTestosterone)
Polycystic ovaries on ultrasonography
All of the following disorders ruled out:Hyperprolactinemia
Nonclassic congenital adrenal hyp[erplasiaCushing’s syndrome
Androgen –secreting neoplasm Acromegaly
Polycystic ovary syndrome
Ancillary studies
Risk assessment forEndometrial carcinoma
Risk assessment forGlucose intolerance
Fasting chol, HDLChol, Tg, LDL-c
Risk assessment for obstructive sleep apnea
Endometrial biopsyIf risk increased
Oral glucose-tolerance testIf risk increased
PolysomnographyIf risk increased
Treatment
Management of PCOs
Primary or secondary amenorrhoea Oligomenorrhoea Acne/ hirsutism Obesity infertility Long-term health risk
Treatment: The first step is to help the patient
understand that this chronic disease process can be controlled by changes in lifestyle.
Lifestyle modification must be emphasized to include appropriate diets & exercise program is essential.
Treatment (cont): Metformin may complement the
effects of lifestyle modification, it causes marked improvement in menstrual pattern & may improve the response to ovulatory agents.
Clomifene-citrate is the standard first line method of medical ovulation induction in anovulatory women.
The second line treatment, laparoscopic ovarian diathermy, gonadotrophin therapy.
Treatment (cont): Adrenal suppression by
dexamethasone 0.5mg at night facilitate ovulation.
Anti-androgens: cyproterone acetate & EE in combination (dianatte)
Spironolactone: alternative anti-androgen.
Low dose of oral contraceptives are effective in treating acne & hirsutism, minimum of 2 years & cosmetic measures are needed to achieve good results.
Lifestyle/Diet Caloric reduction
Estimated caloric deficit of 3500 kcal =0.45 kg of fat
Reducing intake &/or increasing expenditure
Usual target is dietary reduction of 500 kcal/day to achieve a deficit of 3500 kcal/week (15% protein, 30% fat)
What is a healthy diet?
Less 20-30 % of total KCarbohydrate: 55%
Protein: 15% Fat: 30% Variety Moderation
Pharmacologic therapy for pcos
EXAMPLES USES MECHANISM OF ACTION AGENT
SPIRONOLACTONE (ALDACTONE): 50-200 MG/DAY FLUTAMIDE (EULEXIN): 250 MG BID OR TID
ANDROGEN SYMPTOMS (E.G., HIRSUTISM, ACNE, OILY SKIN
INHIBIT ANDROGENS FROM BINDING TO THE RECEPTORS
ANTIANDROGENS
METFORMIN (GLUCOPHAGE): INITIALLY, 500 MG BID OR 850 INCREASE FROM 500 MG TWICE DAILY TO 850 MG TWICE DAILY MAXIMUM DAILY DOSE IS 2.5 G IN TWO OR THREE DIVIDED DOSES
ANDROGEN SYMPTOMS; MENSTRUAL IRREGULARITY; OVULATION INDUCTION; INSULIN RESISTANCE
REDUCES HEPATIC GLUCOSE PRODUCTION, LOWERING INSULIN LEVELS; POSSIBLE IMPROVEMENT IN OVARIAN STEROIDOGENESIS
BIGUANIDES
CLOMID: START WITH LOWEST AVAILABLE DOSE (50 MG), WITH 50 MG INCREMENTS OF INCREASED DOSAGE IF OVULATION IS NOT DETECTED
OVULATION INDUCTION ANTIESTROGEN; ACTS TO INDUCE RISE IN FSH AND LH
CLOMIPHENE CITRATE (CLOMID
ORAL CONTRACEPTIVES; ORTHO EVRA TRANSDERMAL PATCH; NUVARING
ANDROGEN SYMPTOMS; MENSTRUAL IRREGULARITY
INCREASES SHBG; SUPPRESSES LH AND FSH; ANTIANDROGEN
HORMONAL CONTRACEPTION (ESTROGEN-PROGESTIN COMBINATION THERAPY)
PIOGLITAZONE (ACTOS): INITIALLY 15 MG OR 30 MG ONCE DOSAGE 45 MG ONCE DAILY
ANDROGEN SYMPTOMS; MENSTRUAL IRREGULARITY; OVULATION INDUCTION; INSULIN RESISTANCE
ENHANCES INSULIN ACTION AT TARGET TISSUES LEVEL
THIAZOLIDINEDIONE
Metformin Women with PCOS: over 6 years:
9% develop impaired glucose tolerance 8% develop diabetes
Metformin can reduce progression to diabetes by 31% in non-PCOS populations
Metformin
Direct intracellular effects to reduce hepatic gluconeogenesis, improve glucose metabolism
Target dose: 1500 – 2550mg daily with meals
Most common side effects are GI (diarrhea, nausea/vomiting, flatulence, indigestion, abdo discomfort)
Rare problem of lactic acidosis: never been reported in PCOS
Metformin in PCOS
• ‘Lifestyle’ 1st line treatment if overweight
• Some advocate lifelong metformin from puberty
• Currently no long-term data on metformin use
• Uncertain advantage adding metformin to OCP
0Fast.Insulinpmol/L
Free Tpmol/L
SHBGnmol/L
20
40
60
80
100
120
140
Before
After
Effect of Metformin on Lean PCOS
Nestler, JCEM, 1997
Improvement in:• menstrual pattern• fertility +/- clomid
Glitazones: potential Impact on CVD Risk
TZDIR
Hyperglycemia
HDL and sdLDL
BP
PAI-1 Microalbuminuria
Vascular reactivityCRP
Atherosclerosis, CVD?
OCP use in PCOS women
Outcome Improvement No effect Worsening
Glucose tolerance
Pasquali 1999 Korythowski 1995Morin-Papunen 2003a & bCagnacci 2003Guido 2004
Nader 1997Morin-Papunen 2000
Insulin resistance & sensitivity
Pasquali 1999 Morin-Papunen 2003bArmstrong 2001Cibula 2002Guido 2004
Korythowski 1995Dahlgren 1998Vrbikova 2004Mastorakos 2006
Lipid levels Falsetti 1995Mastorakos 2002Guido 2004Pasquali 1999
Prelevic 1990Mastorakos 2002Guido 2004Pasquali 1999
Prelevic 1990Falsetti 1995Mastorakos 2002Guido 2004
Vrbikova 2005The pill is safe in PCOS women
Diane-35 in acne: antiandrogenic effect on the
target tissue
Leyden J. Therapy for acne vulgaris.N Engl J Med 1997; 336: 1156-1162
Acne is the most common skin disease
– affecting 80% of females at some time after the onset of puberty
Most patients seem to have sebaceous glands that are hypersensitive to androgens
Treatment:2-menstrual irregularity
Oral contraceptives have clear benefits :1) Induction of regular withdrawal bleeding2) Protection of the endometrium from
unopposed estrogen3) Reduction in LH secretion and consequent
reduction in ovarian androgen secretion 4) Increased levels of sex hormone-binding
globulin and a consequent reduction in free testosterone
5) Improvement in hirsutism and acne
CPA 2 mg / EE 35 µgin PCOS: Hormone levels after 9 cycles treatment (n
= 46) LH/FSH ratio: p<0.001
Testosterone: p<0.001
Androstenedione: p<0.025
DHEAS: p<0.02
SHBG: p<0.0001
Prelevic et al. Gynecol Endocrinol 1989; 3: 269-280
Reverse-Sequential Treatment
Androcur 10
An analogue of spironolactone it has :
• An antiandrogenic activity
• Less or non antimineralocorticoid
• Approved for use in combination with E.E For
PCOS and hirsutism
Drospirenone
Drospirenone is different
• Drospirenone is a novel class progestogen
• Drospirenone is derived from 17α-spirolactone• Drospirenone’s pharmacological profile is closer to natural progesterone
than any other currently available synthetic progestogene
A normal cycle ( no oral contraceptive)
Estrogen Day1-14
Salt/Water Retention
Na+/water retentionK+ elimination
Angiotensin II
Aldosterone
Progesterone
Angiotensin I
Renin substrate(angiotensinogen)
+Estrogen
Renin-angiotensin-aldosterone system
(RAAS)
Natural Prog will Counter balanceEstrogen mediated fluid/water retention
Na+/water retentionK+ elimination
Angiotensin II
Aldosterone
Less Water retention-related symptoms
) edema, bloating, weight gain(
Progesterone
Angiotensin I
Renin substrate(angiotensinogen)
+Estrogen
DRSP
Renin-angiotensin-aldosterone system (RAAS)
Yasmin )n = 450) EE/DSG )n = 450)
Diff
ere
nce
in k
g
1
0.8
0.6
0.4
0.2
0
–0.2
–0.4
–0.6
–0.8
Cycle
Follow up
p < 0.0001 p < 0.0009
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Mean change in body weight while using Yasmin and EE/DSG
The pill versus metformin
OCP Cycle control Contraceptive Side effects Contraindications Reduce ovarian
cancer
Metformin Induce ovulation
70% No contraception Well tolerated No
contraindications Only use if proven
hyperinsulinaemia ??
Infertility: anovulatory
Weight loss if BMI >25 (diet/ exercise)
Clomid (50 - 150mg) versus metformin
Clomid and metformin combined FSH stimulation Ovarian drilling IVF IVM
Clomiphene citrate Used since 1960s Safe to use for 9-12 months
continuously Oestrogen receptor antagonist:
boost natural FSH release Can have detrimental effect on
endometrium Try tamoxifen alternative
FSH stimulation
Low doses Need cycle monitoring Pregnancy rates 15-20%
Ovarian drilling
As effective as FSH stimulation ‘natural conception’ No multiples Laparoscopy Risk of adhesions (unproven)
Free Androgen Index and the outcome of LOD
0
20
40
60
80
100
<4 4-14.9 >14.9
Ovulation Pregnancy
FAI
%
***
**
* P < 0.05** P < 0.01
*** P < 0.001
BMI and the outcome of
LOD
0
20
40
60
80
100
<29 29-34 >34
Ovulation Pregnancy
%
BMI (kg/m2)
*
**
* P < 0.05** P < 0.01
*** P < 0.001
Randomized controlled trial comparing
laparoscopic ovarian diathermy with
clomiphene citrate as a first-linemethod of ovulation induction in
women with polycystic ovary syndrome
Amer, Li, Metwally, Emarh & LedgerHuman Reproduction 2009
LOD group (n=33)
Clomiphene group (n=32)
Ovulation 64% 76%
Conception after first treatment
27% 44%
Conception after second treatment ( at 12m)
53% 63%
miscarriage 12% 10%
Live Birth 46% 56%
SUMMARY
Laparoscopic ovarian diathermy, a very simple form of surgery, has a high success rate and has a definite, useful role in the management of anovulatory infertility in women with PCOS.
With Proper Patient Selection, The Pregnancy Rate After Laparoscopic
Ovarian Diathermy Is Up To 80 %
IVF Best way to achieve singlet on pregnancy
in PCOS infertility Main risk is OHSS (ovarian
hyperstimulation syndrome) Low doses of stimulation Careful and frequent monitoring Co-treatment with metformin unproven
benefit: ongoing trial at IVFA Blastocyst transfer Sometimes freeze all embryos
IVM (in vitro maturation)
Collect immature eggs Culture in vitro Fertilise and transfer embryos
Few centres worldwide Recently reported 1st success in UK
Twins as 2 embryos transferred 400 babies born (versus >2 million IVF)
Pregnancy Outcomes:
Maternal: Gestational Diabetes (OR 2.94) Pregnancy induced hypertension (OR
3.67) Cesarean sections Acne
Neonatal: Admission to ICU Premature delivery (OR 1.75)
metformin during pregnancy ?
Management of PCOS-longer term
consider OCP, metformin, progestins, antiandrogens, ovulation induction, lipid lowering agents, antihypertensives as necessary
surveillance for diabetes, hypertension and dyslipidemia especially if positive family history and overweight
monitor endometrium
active weight loss and exercise programme
Conclusions
1. PCOS is common.
2. Always focus on presenting problem, but
also educate patients about the long-term
health risk
3. Life-style modification is a very effective
treatment option in PCOS.
4. Do not be scared of using the OCP.
5. Drospirenone has more advantages than
others OCP
The presence of polycystic ovaries and/or PCOS Cannot be elicited by a cursory evaluation alone
Only 50% of women with PCOS are overweight
THANK YOU