PCO-SPCO-SPathophysiology and Pathophysiology and

treatmenttreatment

Michel Abou Abdallah , M.D.Michel Abou Abdallah , M.D.

Regulation of the Menstrual

Cycle

LH Pulse Frequency:LH Pulse Frequency:Early follicular phase – 90 minutes.Early follicular phase – 90 minutes.Late follicular phase – 60-70 minutes.Late follicular phase – 60-70 minutes.Early luteal phase – 100 minutes.Early luteal phase – 100 minutes.Late luteal phase – 200 minutes.Late luteal phase – 200 minutes.

LH Pulse Amplitude:LH Pulse Amplitude:Early follicular phase – 6.5 IU/L.Early follicular phase – 6.5 IU/L.Midfollicular phase – 5.0 IU/L.Midfollicular phase – 5.0 IU/L.Late follicular phase – 7.2 IU/L.Late follicular phase – 7.2 IU/L.Early luteal phase – 15.0 IU/L.Early luteal phase – 15.0 IU/L.Midluteal phase – 12.2 IU/L.Midluteal phase – 12.2 IU/L.Late luteal phase – 8.0 IU/L.Late luteal phase – 8.0 IU/L.

O

VU

LATIO

N

14-24 hours

10-12 hours

Regulation of the Menstrual Cycle

Regulation of the Menstrual Cycle

PCOSPCOS- diagnostic dillema’s -- diagnostic dillema’s -

Clinical featuresClinical features hirsutism/acnehirsutism/acne obesityobesity anovulationanovulation

Endocrine Endocrine featuresfeatures high androgenshigh androgens high LHhigh LH insulin insulin

resistanceresistance

Polycystic ovariesPolycystic ovaries increased follicle #increased follicle # increased stromaincreased stroma increased ovarian increased ovarian

volumevolume

Applied criteria for PCOS Applied criteria for PCOS diagnosis in the literaturediagnosis in the literature

Elevated LH Elevated LH Yen, SchoemakerYen, Schoemaker

Elevated androgens Elevated androgens Lobo, Barbieri, NIHLobo, Barbieri, NIH

UltrasoundUltrasound Jacobs, Franks, Jacobs, Franks, BalenBalen

LH + USLH + US Conway, RismaConway, Risma

Androgens + USAndrogens + US Fauser, NormanFauser, Norman

LH + AndrogensLH + Androgens Shelly, ArdeansShelly, Ardeans

LH + Andr + USLH + Andr + US Eden, PacheEden, Pache

Insulin resistanceInsulin resistance Nestler, DunaifNestler, Dunaif

PCOSPCOS- phenotype expression during adult life -- phenotype expression during adult life -

Oligo- Oligo- amenorrheaamenorrheaInfertilityInfertilityObesityObesityHirsutismHirsutismType 2 diabetesType 2 diabetesOtherOther

GynecologistGynecologist gynecologistgynecologist InternistInternist DermatologistDermatologist InternistInternist

PCOS diagnostic criteriaPCOS diagnostic criteria- 1990 NIH ‘concensus’ -- 1990 NIH ‘concensus’ -

Chronic anovulationChronic anovulationHyperandrogenism Hyperandrogenism (clinical or biochemical)(clinical or biochemical)

exclusion of other exclusion of other etiologiesetiologies

(both criteria)(both criteria)Dunaif. PCOS. 1992. Blackwell Scientific

Normal Normal ProlactinProlactin Increasing hyperprolactinemia Increasing hyperprolactinemia

Normal Normal OvulationOvulation

Inadequate Inadequate luteal phaseluteal phase AnovulationAnovulation AmenorrheaAmenorrhea

Abnormal Feedback SignalsAbnormal Feedback Signals Estradiol levels must rise and fall in Estradiol levels must rise and fall in

synchrony with morphologic events,synchrony with morphologic events,1)1) Estradiol levels may not fall low Estradiol levels may not fall low

enough to allow sufficient FSH enough to allow sufficient FSH response for the initial growth response for the initial growth stimulus stimulus

2)2) Levels of estradiol may be Levels of estradiol may be inadequate to produce the positive inadequate to produce the positive stimulatory effects necessary to stimulatory effects necessary to induce the ovulatory surge of LH. induce the ovulatory surge of LH.

A.A. Loss of FSH StimulationLoss of FSH Stimulation

B.B. Persistent Estrogen SecretionPersistent Estrogen Secretion PregnancyPregnancy

Ovarian or adrenal tumorOvarian or adrenal tumor

C. Abnormal Estrogen clearance & metabolismHepatic Disease

ThyroidHyperthyroidism & Hypothyroidism can cause

persistentanovulation by altering:

1. Metabolic clearance

2. Peripheral conversion rates among the various steroids.

D.D. Extraglandular Estrogen ProductionExtraglandular Estrogen Production

The The Adrenal gland does not secrete Adrenal gland does not secrete E2 but:E2 but:

1.1. Contributes to the total estrogen level by Contributes to the total estrogen level by the extragonadal peripheral conversion of the extragonadal peripheral conversion of C-19 androgenic precursors, C-19 androgenic precursors, androstenedione to estrogenandrostenedione to estrogen

2.2. Psychological or physical stress may Psychological or physical stress may increase the adrenal contribution of increase the adrenal contribution of estrogenic precursor.estrogenic precursor.

E.E. Loss of LH StimulationLoss of LH Stimulation

Gonadal dysgenesis Gonadal dysgenesis

Ovarian FailureOvarian Failure

Regulation of the Menstrual Cycle

Regulation of the Menstrual Cycle

Local OvarianConditionsLocal OvarianConditions

1.1. Selection of the dominant follicle is established during days 5-Selection of the dominant follicle is established during days 5-7, and consequently, peripheral levels of E7, and consequently, peripheral levels of E22 begin to rise begin to rise

significantly by cycle day 7.significantly by cycle day 7.

2.2. Derived from the dominant follicle, EDerived from the dominant follicle, E22 levels increase steadily levels increase steadily and, through negative feedback effects, exert a progressively and, through negative feedback effects, exert a progressively

greater suppressive influence on FSH release.greater suppressive influence on FSH release.

3.3. Insulin- like growth factor-II (IGF-II) is produced in theca cells in Insulin- like growth factor-II (IGF-II) is produced in theca cells in response to gonadotropin stimulation, and this response is response to gonadotropin stimulation, and this response is

enhanced by estradiol and growth hormone. In an autocrine enhanced by estradiol and growth hormone. In an autocrine action, IGF-II increases LH stimulation of androgen production action, IGF-II increases LH stimulation of androgen production

in thecal cells.in thecal cells.

4.4. IGF-II stimulates granulosa cell proliferation, aromatase IGF-II stimulates granulosa cell proliferation, aromatase activity, and progesterone synthesis.activity, and progesterone synthesis.

5.5. FSH inhibits IGF binding protein synthesis and thus maximizes FSH inhibits IGF binding protein synthesis and thus maximizes growth factor availability.growth factor availability.

6.6. FSH stimulates inhibin and activin production by granulosa cells.FSH stimulates inhibin and activin production by granulosa cells.

7.7. Activin augments FSH activities: FS receptor expression, aromatization, Activin augments FSH activities: FS receptor expression, aromatization, inhibin/activin production, and LH receptor expression.inhibin/activin production, and LH receptor expression.

8.8. Inhibin enhances LH stimulation of androgen synthesis in the theca to Inhibin enhances LH stimulation of androgen synthesis in the theca to provide substrate for aromatization to estrogen in the granulosa.provide substrate for aromatization to estrogen in the granulosa.

9.9. While directing a decline in FSH levels, the midfollicular risein estradiol While directing a decline in FSH levels, the midfollicular risein estradiol exerts a positive feedback influence on LH secretion. LH levels rise exerts a positive feedback influence on LH secretion. LH levels rise

steadily during the late follicular phase, stimulating androgen steadily during the late follicular phase, stimulating androgen productionin the theca.productionin the theca.

10.10. The positive action of estrogen also includes modification of the The positive action of estrogen also includes modification of the gonadotropin molecule, increasing the quality (the bioactivity) as well gonadotropin molecule, increasing the quality (the bioactivity) as well

as the quantity of LH at midcycle..as the quantity of LH at midcycle..

11.11. Inhibin and, less importantly, follistatin, secreted by the granulosa cells Inhibin and, less importantly, follistatin, secreted by the granulosa cells in response to FSH, directly suppress pituitary FSH secretion.in response to FSH, directly suppress pituitary FSH secretion.

12.12. FSH induces the appearance of LH receptors on granulosa cells.FSH induces the appearance of LH receptors on granulosa cells.

Aromatization

Inhibitory

Estrogens

5 α - androgens

Androgens

5 α - reduction

N

Critical Role for the Concentration of A in the Ovarian Follicle

Excess Body WeightExcess Body Weight

The frequency of obesity 35% to 60%The frequency of obesity 35% to 60%1.1. Increased peripheral aromatization of Increased peripheral aromatization of

androgens to estrogens.androgens to estrogens.2.2. Decreased levels of sex hormone-Decreased levels of sex hormone-

binding globulin (SHBG), resulting in binding globulin (SHBG), resulting in increased levels of free estradiol and increased levels of free estradiol and testosterone.testosterone.

3.3. Increased insulin levels that can Increased insulin levels that can stimulate ovarian stomal tissue stimulate ovarian stomal tissue production of androgens.production of androgens.

Normal Coordination

Persistent Anovulation

+LH increases Androstenedio

ne increasesTestosterone increases

Estrone increases

SHBG decreases

Free testosterone increases

Free estradiol increases

Endometrial cancer

Hirsutism

Atresia

The Vicious Cycle

The characteristics of the ovary The characteristics of the ovary reflect this dysfunctional state.reflect this dysfunctional state.

1.1. The surface area is doubled, giving an The surface area is doubled, giving an average volume increase of 2.8 timesaverage volume increase of 2.8 times

2.2. The same number of primordial follicles is The same number of primordial follicles is present, but the number of growing and present, but the number of growing and atretic follicles is doubled. Each ovary may atretic follicles is doubled. Each ovary may contain 20-100 cystic follicles.contain 20-100 cystic follicles.

3.3. The thickness of the tunica (outermost The thickness of the tunica (outermost layer) is increased by 50%.layer) is increased by 50%.

4.4. There are 4 times more ovarian hilus cell There are 4 times more ovarian hilus cell nests (hyperplasia).nests (hyperplasia).

HyperthecosisHyperthecosisPatches of luiteinized theca-like Patches of luiteinized theca-like

cells scattered throughout the cells scattered throughout the ovarian stromaovarian stromaSame histologic findingsSame histologic findingsIntense androgenizationIntense androgenizationLower LH levelsLower LH levels

+LH Androstenedione

+

Testosterone

IGF-II

? IGF-I+

How Does Hyperinsulinemia Produce Hyperandrogenism?

Hyperinsulinemia

Ovary

HyperandrogenemiaHyperandrogenemia

LiverLiver Adrenal

IGF-BP

SHBG

LH

Pituitary

IGF-1LH

Weight increases

Inherited defects in insulin action

Insulin receptors disorders

Insulin increases

SHBG decreases

IGFBP-1 decreases

Weight increases

Inherited defects in insulin action

Insulin receptors disorders

Insulin increases

SHBG decreases

IGFBP-1 decreases

+

LHFree Testosterone increases

Free estradiol increasesTheca

(IGF-II, ?IGF-I)

Androstenedione increases

Testosterone increases

The Clinical Consequences of The Clinical Consequences of Persistent AnovulationPersistent Anovulation

1.1. Infertility.Infertility.

2.2. Menstrual bleeding problems, ranging from Menstrual bleeding problems, ranging from amenorrhea to dysfunctional uterine amenorrhea to dysfunctional uterine bleeding.bleeding.

3.3. Hirsutism, alopecia, and acne.Hirsutism, alopecia, and acne.

4.4. An increased risk of endometrial cancer An increased risk of endometrial cancer and, perhaps, breast cancer.and, perhaps, breast cancer.

5.5. An increased risk of cardiovascular diseaseAn increased risk of cardiovascular disease

6.6. An increased risk of diabetes mellitus in An increased risk of diabetes mellitus in patients with insulin resistance.patients with insulin resistance.

Weight increases

Inherited defects in insulin action

Insulin receptors disorders

Insulin increases

SHBG decreases

IGFBP-1 decreases

+

LH increases FSH decreases

Free Testosterone increases

Free estradiol increases

Theca (IGF-II, ?IGF-I)

Androstenedione increases

Testosterone increases

Estrone increases

Endometrial cancer

Hirsutism

Atresia

Overall Goals of TreatmentOverall Goals of Treatment

1.1. Reduce the production and circulating Reduce the production and circulating levels of androgens.levels of androgens.

2.2. Protect the endometrium against the Protect the endometrium against the effects of unopposed estrogen.effects of unopposed estrogen.

3.3. Support lifestyle changes to achieve Support lifestyle changes to achieve normal body weight.normal body weight.

4.4. Lower the risk for cardivascular disease.Lower the risk for cardivascular disease.

5.5. Avoid the effects of hyperinsulinemia on Avoid the effects of hyperinsulinemia on the risks of cardiovascular disease and the risks of cardiovascular disease and diabetes mellitus.diabetes mellitus.

6.6. Induction of ovulation to achieve Induction of ovulation to achieve pregnancy.pregnancy.

Cervical Cervical FactorFactor

ScoreScore

00 11 22 33

Amount of Amount of cervical cervical secretionsecretion

0 = no secretion0 = no secretion 1 = little 1 = little secretion. A secretion. A small amount of small amount of cervical cervical secretion can be secretion can be detected in the detected in the cervical canal cervical canal

2= 1 drop of secretion. 2= 1 drop of secretion. A shiny drop of secretion A shiny drop of secretion projects from the projects from the cervical orifice. The cervical orifice. The secretion can easily be secretion can easily be removed from the removed from the cervical canal.cervical canal.

3= copious 3= copious secretion, which secretion, which flows flows spontaneously spontaneously from the cervical from the cervical canal.canal.

SpinnbarkeSpinnbarkeitit

0=none0=none 1=slight 1=slight Spinnbarkeit”. A Spinnbarkeit”. A mucus thread mucus thread can be drawn can be drawn about ¼ of the about ¼ of the distance from distance from the cervical the cervical orifice to the orifice to the vulva without vulva without breaking.breaking.

2=good “Spinnbarkeit” 2=good “Spinnbarkeit” A mucus thread can be A mucus thread can be drawn about half the drawn about half the distance from the distance from the cervical orifice to the cervical orifice to the vulva without breaking.vulva without breaking.

3= extremely good 3= extremely good “Spinnbarkeit” A “Spinnbarkeit” A mucus thread can mucus thread can be drawn the be drawn the entire distance entire distance from the cervical from the cervical orifice to the vulva orifice to the vulva without breaking.without breaking.

Fern Fern phenomenphenomenonon

0= no secretion 0= no secretion or amorphous or amorphous secretionsecretion

1= linear . Slight 1= linear . Slight linear linear crystallization is crystallization is seen only in seen only in several sites. several sites. Without lateral Without lateral branching.branching.

2= partial Good “fern” 2= partial Good “fern” crystallization with crystallization with lateral branching in lateral branching in some sites but only some sites but only linear crystallization in linear crystallization in other areas, and also the other areas, and also the presence of amorphous presence of amorphous areas.areas.

3= complete the 3= complete the fern phenomenon fern phenomenon is fully expressed is fully expressed throughout the throughout the smear.smear.

CervixCervix O= closed O= closed Pale pink Pale pink mucosa. mucosa. External os External os barely accessible barely accessible with narrow with narrow probe. probe.

2= partially open , Pink 2= partially open , Pink mucosa. Probe readily mucosa. Probe readily enters the cervical enters the cervical canal.canal.

3= wide open 3= wide open Hyperemic Hyperemic mucosa. External mucosa. External os wide open.os wide open.

Cervical score scheme according to INSLER