Polycystic ovarian syndrome

Zoltán Garamvölgyi M.D.

Polycystic ovarian syndrome (PCOS)

Most common female endocrin disorder, eg. in German 1 million females

1921. C. Achard and J. Thiers: 7 obese women with hirsutism

Hyperandrogenism associated with carbohydret disorder

„Diabetic women with moustaches“

1935. Stein and Leventhal „polycystic ovaries, hirsutism, amenorrhea, obesity”(may occur in women without ovarian cysts)Menstrual cycle disorders and infertility due to hyperandrogenism andchronic anovulation

Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935; 29: 181-910

PCOS: from “the diabetes of

bearded women” to Rotterdam

2003 and beyond

1921 1947 1968 1976 1980 1990 2003

Archad and

Thiers, the

diabetes of

bearded women

Kierland et al,

Acanthosis nigricans

is frequent in women

with

hyperandrogenism and

diabetes

Bron and Winkelmann

suggested a genetic

base for Insulin

resistance diabetes

mellitus

Khan et al.

Focus on the

association between

insulin resistance,

acanthosis

nigricans, and

hyperandrogenism

Burghen et al.

PCOS with

hyperandrogenism

had insulin

resistance

NIH expert conference

1) Hyperandrogenism

2) Oligo-ovulation

3) Exclusion of other

disorders

Rotterdam criteria1) Oligo/anovulation

2) Clinical or biochemical

hyperandrogenism

3) Polycystic ovariesStein and

Leventhal

Amenorrhea with

Polycystic ovaries

1935 2011

NIH (United States National Institutes of Health) 1990.

oligo-ovulation or anovulation (oligomenorrhea, amenorrhea)

hyperandrogenism (clinical or/and biochemical evidence of androgen excess)

exclusion of other disorders (menstrual irreg., hyperandrogenism)

Diagnostic criteria

The Androgen Excess and PCOS Society (AE-PCOS) 2006.

Oligo-ovulation and/or polycystic ovaries

Clinical/biochemical evidence of hyperandrogenism

Exclusion of related disorders PCOS, Rotterdam-criterions 2003 (ESHRE/ASRM)Diagnosed when 2 of the 3 criterions fulfilled:

1. chronic anovulation (oligo- or amenorrhea)2. Clinical and/or biochemical

hyperandrogenism3. polycystic ovaries

United States: 4-12%, European countries: 6,5-8%

Ethnic variability in hirsutismAsian: less hirsutism than white women given the same serum androgen values.

In hirsute women: sign. increase in the incidence of acne/menstrualirregul./polycystic ovaries/acanthosis nigricans

PCOS affects premenopausal women

The age of onset is perimenarchal.

(fast mature of reproductive axis/weight gain, less exercise unmaskes PCOS, early manifestation)

Epidemiology

Hispanian women: insulin resistance worse than in caucasian women

Lean women:unmasked when gain weight

Serena Williams

High serum cc. of androgenic hormones (testosterone, androstendione, DHEAS)Individual variation (might have normal androgen levels)

Peripheral insulin resistance and hyperinsulinemia

Obesity

Etiology

Etiology

direct effect on muscle/fatty tissue/liver/ovaries (theca and granulosacells)

Insulin resistance:Secondary to a postbinding defect in insulin rec. signaling pathways

Supression of hepatic generation of SHBG

Supr. of adiponectin (regulates of lipid metab. and glucose levels)

Increased production of IGF-1

Dyslipidemia

PAI-1 increasing (plasminogen activator inhibitor) (risk for thrombosis)

Insulin

Etiology

Hyperinsulinemia not equal with PCOS.

Not every PCOS women have IR.

(genetic background, gene polymorphism: cysteinprotease Calpain 10, proinsulin, insulinrec. (IRS-1, IRS-2)

PCOS: not a consequence of IR!Theca + granulosacells have inzulinreceptors:

Insulin is in synergism with LH.Rec.: insulin + IGF-1.

The androgen production increases. Effect on the ACTH- cortisol axis,

facilitats the androgen production of the adrenalgls.

Insulin enhances the sensitivity of the gran.cells to the FSH: the number of the follicles increase

Enhanced IR: anovulatorical cycles + hyperandrogenism

Damage of the postreceptor pathway of the insulin!

Normal: IRS1 activates the PI3: the intracellular glucose transport increases.

PCOS:the autophosphorisation of the tyrosin decreases, the serin phosphorilisation increasesActivation of the cytochrom P450c17α (adr.glands + ovaries) – level of the androgens increases.

Insulin blocks the production of the IGFBP-1 of the liver: IGF-1 cc. increasesEffect on the granulosacells + thecacells (LH and androgens cc. increase).

Obesity and PCOS:normal LH cc. can also enhancesthe receptors of the LH and the sensitivity of the ovaries to the LH

25 % of the hyperandrogenism of the PCOS is due to the adr.glands!

Peripherial androstendion transforms to testosteron and DHT (5α-reductase)

Ovarial effect of the insulin

Acts on atypical IGF receptors

Upregulation of the IGF-I receptor

Decreases of the IGF-bp cc.

Synergism with the IGF-I and LH

in the androgen production

Hypophyseal effect of the insulin

Anovulation

Endometrial effect of the insulin

Blocks the implantation

Granulosa cell

Etiology Hypothalamic intrinsic disorder + low progesteron cc.Decreased progesteron-sensitivity? (Flutamid- androgen rec. antagonist-increases prog.sensitivity)

GnRH-puls frequence increasing

Pituitary: LH increasing (LH>FSH)

Ovaries: theca-cells: cytochrom P450 c17 (17α-hydroxylase + 17,20 lyase activity)

Androstendion production

17β-hydroxysteroid-dehydrogenase

Testosteron

Eostrogen cc. increases

Gran.cells: FSH decreases

„Two cells- two gonadotropins „ hypothesis

LH

LH-receptor

FSH

FSH-receptor

ATP cAMP

cholesterin

androstendion

Blood vessels

androstendion estrogen

aromatase enzyme

ATP cAMP

Fluid of the follicles

LH-receptor

thecacells

granulosacells

Genetically heterogeneous syndromeDifficult condition to study genetically, candidategene?Fathers of PCOS women: can be abnormal hairyMothers: oligomenorrhea

Family history of type2 diabetes in a first-degreefamily member

Dutch twin-family study: PCOS heritability of 0,71 in monozygotic twin sisters

Link between PCOS and obesity, associated genes:FTO-geneCYP17 promoter activity 4x in cells of PCOS womenHomozygous for an allele of interest in IGF2 (stimulates androgen secretion in the ovaries and adrenal glands)

Genome-wide association:Chinese population: 2p16 locus: near genes formate testis/encode LH-rec and hCG.Near FSHR gene (encodes FSH-receptor)

Family history:

•Menstrual disorders•Adrenal enzyme deficiences•Hirsutism•Infertility•Obesity and metabolic sy. •Diabetes

Intrauterin environment

Maternal: Diabetes

GDM

PCOS

Obesity

Hypothyreoidism

GnRH/LH ↑

PCO PCOS

Chronical anovulation

Insulinresistance Hyperandrogenism

Serotonin↓GABA↑

Pathomechanism of the PCOS

Dopamin ↓ Opioids ↓

Burghen et al: JCEM 1980, 50, 113

Depressive disorders: 35 % (3X)

Phenotypes of the PCOS

Hyperandrogenism + not obes + non IR Extrem obesity + IR + hyperandrogenism

PCOS Severe(complet)

Fourthphenotype

Ovulation Mild(non hyperandrogenic)

Bleeding irregular irregular reggular irregular

UH PCO normal PCO PCO

Androgen cc. high high high Minimal increased

Insulin cc. low high high Normal

Frequency 61% 7% 16% 16%

Metabolic disorder > Metabolic disorderHyperandr./hirsut. Hyperandr./hirsut.Oligoanovulátion Ovulatory ciclus

PCO-form

Hyperinsulinaemia > HyperinsulinaemiaMetabolic sy.: 42,3 %2TDM : 3-6 %

signs A B C D E F G H I

Hyperandr + + + + - - + - +

Hirsutismus + + - - + + + + -

Oligoanov + + + + + + - - -

PCO. + - + - + - + + +

AES, 2006.

0

10

20

30

40

50

60

70

80

90

100

Norm Non

PCOS

obes

PCOS

thin

PCOS

obes

Insulin sensitivity

Signs Frequency

sterility 74%

hirsutism 68%

Irregular bleeding 52%

obesity 44%

Bilaterally or unilaterally enlarged, polycystic ovariesHyperplasia of the theca stromal cells surrounding arrested follicles

80-100 % of all PCOS women. Enlarged ovaries not always be present. >= 12 follicles (2-8 mm in size)

23 % of women with normal menstrual cycle have polycystic ovaries.

Enlarged, polycystic ovaries

Anovulation, monophasic cycle, disorder of the selection of thefollicules because of the prolonged follicular menstrual phase

Overstimulation, twin pregnancies

75 %

Chronic anovulation (menstrual disturbance in premenarche)

Oligomenorrhea (menstr. bleeding occurs at intervals of 35 daysto 6 months, < 9 menstrual periods per year)

Secondary amenorrhea (an absence of menstruation for 6 months)

Ovulatory and menstrual dysfunction 75%

75 % of PCOS women: primaer or secondary sterilitydue to anovulation

Rate of miscarrieges is high: 25-44%

Infertility

ABORTUS SPONTANEUS Maternal Chr. Subclinicalinflammation

Embryo/fetus?Habitualis ab.: 40-80 % of PCOS!

LH: effect on to the implantation (non PCOS vs PCOS= 12-15% vs 30-50%)

Uterinal factor: perifollicular bloodcirculation worse

Folliculus gene expression (androgén hatás)

IGF-1: Y IGF-1 rec. downregulation

(morula’s gl.uptake decreases before the implantation)

GLUT-4 (cc. decr.)

IGFBP-1(cc.decr.) implantation/adhesion romlik

Diabetes Prevention Program (DPP)Troglitazine in prevention of Diabetes (TRIPOD)

Metformin and PCOS

CC CC + metformin

Ovulation 42 % 76 %

More effective:>28 age + visceral.fatty tissue

(p<0,001) CC CC + metformin metformin

Pregnancy 22,5 % 26,8 % 7,2 %

Metformin és PCOS

Diabetes Prevention Program (DPP)Troglitazine in prevention of Diabetes (TRIPOD)

Ab.spontaneus Metformin vs. placebo Odds r. 0,36, 95% CI, 0,09-1,47

CC vs. CC + metformin Odds r. 1,61, 95% CI, 1,00-2,60

No advantage

Metformin placebo

PE 7,4 % 3,7 % P=0,18

GDM 17,6 % 16,9 % P=0,87

Premature

labour

3,7 % 8,2 % P=0,12

Σ 25 % 24,4 % P=0,78Previous GDM: metformin mitigates 2TDM risk 50 % vs 14 %

excess terminal body hair in a male distribution pattern(upper lip, chin, nipples, linea alba, lower abdomen)

acneandrogenic alopecia

other signs: clitoromegaly+ increased mucle mass + voicedeepening

(extreme forms of PCOS, hyperthecosis or androgen-producingtumors, virilizing congenital adrenal hyperplasia)

Hyperandrogenism 60-80%

Female type of metabolic sy.?Manifestation: later than acne or hirsutism.

50% of PCOS women are obese.28 % of all obese women suffered from PCOS.

American PCOS women have a higher BMI than italian PCOS women.

PCOS: obesity and metabolic syndrome

43% prevalence of metabolic syndrome, characterized by:

→abdominal obesity (waist circumference: >88 cm.)→dyslipidemia (TG level > 150 mg/dL)→ High-density lipoprotein cholesterol (HDL-C) level <50 mg/dL→ elevated blood pressure (> 130/85 mmHg)→ IFG or IGT

(>=3: metabolic sy. )

+: elevated C-reactive protein level, elevated plasminogen

activator inhibitor-1 (PAI-1), fibrinogen levels.

1/3 of PCOS women had IFG or IGT within 13-19 years old

40% of patients with PCOS have insulin resistance that is independent of body weight.(increased risk for type 2 diabetes and cardiovascular complications)

American Association of Clinical Endocrinologists:

screening for diabetes by age 30 years in all patients with PCOS! Should be periodically reassessed throughout their lifetime.

Every 3-5 years screening for diabetes!

PCOS: obesity and metabolic syndrome

PCOS: obesity and metabolic syndrome

Diabetes mellitus:

Insulin resistance compensated long in most PCOS women. (problem in women with positive familiy history.)

2 type diabetes risk: 7x

10% of women with PCOS have type 2 diabetes mellitus

30-40 % of women with PCOS have impaired glucose tolernace (IGT) by 40 yeares of age

Screening with OGTT. Early diagnosis. Latens state of insulin resistance willchanged to manifested IR in GDM/th. with glucocorticoids

HOMA-index:

normal ≤ 1suspicious of IR: > 2 possibility of IR: > 2,5 diabetes mellitus: > 5

Elevated serum lipoprotein levelsLean PCOS women: also endothelian dysfunction (thickened intima media)

CRP and endothelin-1 increase

Coronarian diseases and macroangiopathy: TG/LDL increase, HDL level decreasescoronary artery calcification

Risk for AMI:7X in women at age of 40-60 years

Sleep apnea: obstructive sleep apnea syndrome (OSAS)An independent risk factor for cardiovascular disease. (excessive daytime somnolence)

HypoD-vitamism (73%)Vit.D-gene regulates 3% of the human genom (glucose/lipid/ metabolism/blood pressure)

Decreased D-vit. level associated with•Dylipidemia•Insulin resistance•Obesity

Risk for cardiovascular and cerebrovascular disease

Increased risk for endometrial hyperplasia and carcinoma. (constant endometrial stimulation with estrogen without progesterone).

Recommended induction of withdrawal bleeding with progesterons a minimum of every 3-4 months.

No known association with breast or ovarian cancer has been found.

Carcinoma

common symptom of PCOS.Rare in japanese women with PCOS. (In caucasian PCOS women: 9% hirsutism)

In the skin-cells:

testosteron ---- 5α-reductase ---- dihydrotestosteron (DHT)the enzyme is activated by insulin/IGF-1/androgens

Physical examinationHirsutism and virilizing signs

Hirsutism: 60 %

1961: Ferriman-Gallwey score (9 body areas. 0 (no hair) to 4 (frankly virile))

upper lip, chin, chest, upper and lower abdomenthighs, upper and lower back, arm, forearm, buttocks. >=8: hirsutism

A total score of 8 or more: abnormal for an adult white womenScore of 44: most severe

The modified Ferriman-Gallwey score grades 11 body areas.

Acne:12 % of all adult women23-35 % of all PCOS women.

Androgen alopecia: 5 %not common, responsible is the DHT (+ ovarian and adrenalandrogenes)

Physical examination

Hirsutism and virilizing signs

Diffuse, velvety thickening and hyperpigmentation of the skin

Present at the nape of the neck/axillae/beneath the breasts/intertriginousareas/exposed areas (elbows, knuckles)

Result of insulin resistance.

Can also be a cutaneous marker of malignancy!

Physical examination Acanthosis nigricans

Scoring system: Absent (0)Present (1): on close visual inspection, extent not measurableMild (2): limited to the base of the skull (does not extend tot the lateral margins of the neck)Moderate (3): extends tot he lateral margins of the neckSevere (4): visible anteriorlySevere (5): circumferential

PCOS appearance

forms

Hyperandrogenism, acne, hirsutism

,acanthosis nigricansalopecia

Menstruation disorder,oligo/anovulation and

Sterility

Psychologicalproblems,

Depression

dermatologistendocrinologist

DiabetologistEndocrinologist

Gynecologist

Psychologist

Insulin resistanceHyperinsulinism

2TDM

Worsening folliclesquality

Unsuccessful ART

IVFspecialist

PCOS: else metab./endocrin. disorders

CRH-ACTH-kortizol axis activated

Hyperreninaemia/hyperaldosteronismus

PRL 2-3X

PAI-1/fibrinogen incr.

Hyperuricaemia/homociszteinaemia

Ferritin cc. Incr. (storage of iron incr.)

NAD(P)H-oxidase aktiv.Szuperoxid freeradical incr.

obesity

Musculature: gl.uptake decr.

Liver: inz.metab.decr.IR

GI tr.:Iron uptake incr.

Diagnosis of the PCOS

testosterone (total or free) and SHBG

Free Androgen Index (FAI).

FAI = total testosterone [nmol/l] x 100 / SHBG [nmol/l]

LH, FSH, estradiol, progesteron, prolaktin, TSH

17-OH progesteron, androstendion, DHEAS, basal cortisol

LH>FSH (2x-3x): seeing in follicule phase of the menstrual cycle

OGTT

Liver enzymes, kidney function, serum ions

LHRH-test: 25 ug Buserelin iv. 0-30-60 min. (GnRH-analog: the constans stimulation of the pituitarydecreases LH and FSH secretion)

LH level increasing > FSH level increasing (not diagnostic)

Diagnosis of PCOS

DD.:

Ovarian hyperthecosis (luteinized cells throughout the stroma)

Congenital adrenal hyperplasia (late-onset)

Drugs (Danazol, androgenic progestins)

Hypothyroidism

Idiopathic/familial hirsutism

Masculinizing tumors of the adrenal gland or ovary (rapid onset of signs of

virilisation)

Cushing –sy. (low K+, striae, central obesity, high cortisol, high androgens)

Hyperprolactinemia

Exogenous anabolic steroid use

Stromal hyperthecosis (valproic acid)

Diagnostic considerations

Therapy of the PCOS

Variability of the clinical symptomps!

Fit the therapy to the

• Actuel symptomps (hirsutism, acne etc.)

• Wishes (contraception, pregnancy)

• Different life periods (adolescence, praemenopausa, postmenopausa)

Oral contraceptive pill

estragens: LH level decreases/SHBG level increasesbut: insulin resistance and cardiovascular risk enhanced(recommended progestin only pill)

progestins: II.generations of the progestins- levonogestrel- have androgen effect!cyproteron acetat Le Figaro: „Sept décès en France liés à la pilule Diane 35”

dienogestspironolacton

flutamid (non steroid antiandrogen drug: very effective, but hepatotoxic effect)

Glucocorticoids (Lowers only adrenal glands –DHEA,DHEAS, androstendion-androgens level)

Finasterid (non steroid antiandrogen drug: benign hyperplasia of prostata, against adrogen alopecia)

Therapy of the PCOS

Induce the sensitivity of insulinby more exercise/life style modifications/insulin sensitisers

Insulin sensitisers:

Metformin(contraindicated the use of it in pregnancy in Hungary/German)

Thiazolidtroglitazon: effective, but hepatotoxic (1997.: prohibited in the U.K.)rosiglitazon: not hepatotoxic, but increase the liver enzymes reversible.

Enzyme inhibitors:

Acarbose /Glucobay/Lowers the enteral uptake/absorption of glucose, lowers the postprandialhyperinsulinemiaReversible blocks (competetive antagonism) the α-glucosidase-hydroxylaseenzyme of the bowel-musosa. Flatulation, tenesmus, diarrhea!

Therapy of the PCOS

Inositol:

6-C-atoms, cyclic polyalcohol.

9 stereo-isomer knownmyo-inositol:The most frequent natural form

• Intracellular Ca2++ cc. control– Maintenance of the cellular membranpotential

• Metabolic effects– Insulin signal transduction– Lipolysis , serum cholesterin cc. decreasing

• Other– Serotonin activity modulation– Nervous system regulation

• Gen expression

Function of the inositolSignal transmission and sec. messenger

Inositol-foszfolipid-Ca++ as sec. messenger

OOCYTA evolutionOOCYTAMaturity

FERTILISATION(early stadium)

METFORMIN (biguanid)PRO: Insulinsensitiser

KONTRA: GI side effects

CLOMIPHENE CITRATE

PRO: Anti-oestrogen, stimulation of the FSH, LH secretion

KONTRA endometrium atrophied

EXOGEN GONADOTROPIN

PRO: direct effect on the ovaries, subcutan injection,

monitorisation of its effect by ultrasound

KONTRA Ovarium hyperstimulation syndrome

Combined therapy:Metformin + clomiphen citrate:>28 years, waist-hip ratio is high

(metformin therapy decreases the development of the hyperstimulation)

Ovulation: 60-85 %

Pregnancy: 30-50 %

After 6 ovulatory cycles

Therapy of the PCOS

Clomiphen-resistance: laparoscopic ovarian drilling

ovulation increasing (30% to 90%)

possibility of gravidity increasing (13,5 to 88 %)