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