Long-term consequences Long-term consequences of Polycystic Ovarian of Polycystic Ovarian

syndromesyndrome

Samir F Abdel Aziz MDSamir F Abdel Aziz MD

Obstetrics and GynecologyObstetrics and Gynecology

Al-Azhar universityAl-Azhar university

IntroductionIntroduction

Stein and LeventhalStein and Leventhal They were the first to recognize They were the first to recognize

an association between the an association between the presence of polycystic ovaries presence of polycystic ovaries and signs of hirsutism and signs of hirsutism amenorrhea amenorrhea (oligomenorrhea,obesity)(oligomenorrhea,obesity)

Polycystic Ovarian DiseasePolycystic Ovarian DiseaseAfter successful wedge resection After successful wedge resection

of the ovaries in women of the ovaries in women diagnosed with Stein-Leventhal diagnosed with Stein-Leventhal syndrome, menstrual cycles syndrome, menstrual cycles become regular and the become regular and the patients were able to conceive. patients were able to conceive. Primary ovarian disorder come Primary ovarian disorder come to be known as polycystic to be known as polycystic ovarian diseaseovarian disease

• Polycystic ovarian syndromePolycystic ovarian syndrome• Biochemical, clinical and Biochemical, clinical and

endocrinological abnormalities endocrinological abnormalities have shown an array of underlying have shown an array of underlying abnormalities; hence condition abnormalities; hence condition known as polycystic ovarian known as polycystic ovarian syndrome( PCOS)syndrome( PCOS)

• Syndrome OSyndrome O • gets to the real heart of the gets to the real heart of the

problem and indicates: Ovarian problem and indicates: Ovarian confusion and Ovulation disruption confusion and Ovulation disruption caused primarily by Over caused primarily by Over nourishment and Overproduction nourishment and Overproduction of insulinof insulin

• In reality PCOS, infertility, and In reality PCOS, infertility, and other health problems may be all other health problems may be all consequences of syndrome Oconsequences of syndrome O

Introduction (cont.)Introduction (cont.)

• Most attention has been paid to the Most attention has been paid to the management of the presenting complaint management of the presenting complaint (infertility, hirsutism..etc.)(infertility, hirsutism..etc.)

• It has become clear that the polycystic It has become clear that the polycystic ovary phenotype is linked to a number of ovary phenotype is linked to a number of metabolic disturbances, including type II metabolic disturbances, including type II diabetes and possibly atherosclerosisdiabetes and possibly atherosclerosis

• Since PCOS frequently diagnosed by Since PCOS frequently diagnosed by gynecologists, it is therefore, important that gynecologists, it is therefore, important that gynecologists have a good understanding of gynecologists have a good understanding of the long-term implications of the diagnosisthe long-term implications of the diagnosis

Prevalence of PCOSPrevalence of PCOS

• Estimates of the prevalence of the disorder Estimates of the prevalence of the disorder must be made with caution, since there is no must be made with caution, since there is no overall consensus concerning the diagnostic overall consensus concerning the diagnostic criteria that must be satisfied in order to make criteria that must be satisfied in order to make the diagnosisthe diagnosis

• It was suggested that approximately 20% of It was suggested that approximately 20% of women of reproductive age demonstrate the women of reproductive age demonstrate the ultrasound picture of polycystic ovaries, with ultrasound picture of polycystic ovaries, with half that number having clinical or biochemical half that number having clinical or biochemical signs of anovulation and androgen excesssigns of anovulation and androgen excess

PathophysiologyPathophysiology

• Abnormalities in the metabolism of androgens Abnormalities in the metabolism of androgens and estrogen and in the control of androgen and estrogen and in the control of androgen productionproduction

• High serum androgen may be found High serum androgen may be found (testosterone, anderostendione)(testosterone, anderostendione)

• Peripheral insulin resistance and Peripheral insulin resistance and hyperinsulinemia… elevated insulin levels may hyperinsulinemia… elevated insulin levels may have gonadotropin-augmenting effects on the have gonadotropin-augmenting effects on the ovarian function and is responsible for the ovarian function and is responsible for the dyslipidemia and elevated levels of plasminogen dyslipidemia and elevated levels of plasminogen activator inhibitors which constitute a risk factor activator inhibitors which constitute a risk factor for intravascular thrombosisfor intravascular thrombosis

Pathophysiology (cont.)Pathophysiology (cont.)

• Proposed mechanism for anovulation Proposed mechanism for anovulation and increased androgen:and increased androgen:

• 1-* increased LH stimulates the 1-* increased LH stimulates the ovarian theca cells with increase ovarian theca cells with increase production of androgensproduction of androgens

• 2-*Decreased FSH leads to decrease 2-*Decreased FSH leads to decrease ability of Granulosa cells to ability of Granulosa cells to aromatize androgens aromatize androgens

Gross appearance of ovariesGross appearance of ovaries

• Polycystic ovaries are enlarged bilaterally Polycystic ovaries are enlarged bilaterally and have a smooth thickened capsule that and have a smooth thickened capsule that is avascular is avascular

• On cut section, subcapsular follicles in On cut section, subcapsular follicles in various stages of atresia are seen in the various stages of atresia are seen in the peripheral part of the ovaryperipheral part of the ovary

• The most striking ovarian features of PCOS The most striking ovarian features of PCOS is hyperplasia of the theca stromal cells is hyperplasia of the theca stromal cells surrounding arrested folliclessurrounding arrested follicles

• Microscopically luteinizing theca cells are Microscopically luteinizing theca cells are seenseen

PresentationPresentation

• Patients with PCOS present with various Patients with PCOS present with various symptoms including the following:symptoms including the following:

• *Amenorrhea*Amenorrhea• *Oligomenorrhea*Oligomenorrhea• *Infertility*Infertility• *Hirsutism*Hirsutism• *Obesity*Obesity• *Acne Vulgaris*Acne Vulgaris• *Asymptomatic*Asymptomatic

Physical SignsPhysical Signs

• *Hirsutism*Hirsutism• Patients may have excess Patients may have excess

body hair in male body hair in male distribution pattern and distribution pattern and acne. In some patients acne. In some patients virilizing signs such as virilizing signs such as male pattern balding or male pattern balding or alopecia, increased muscle alopecia, increased muscle mass, deepening of voice mass, deepening of voice or clitoromegally may be or clitoromegally may be encountered and should encountered and should prompt the search for prompt the search for other causes of other causes of hyperandrogenismhyperandrogenism

• *Obesity*Obesity: approximately : approximately 50% of patients are obese50% of patients are obese

• *Acanthosis Nigricans*Acanthosis Nigricans• This is diffuse velvety-This is diffuse velvety-

thickening thickening hyperpigmentation of the hyperpigmentation of the skin. It may present at the skin. It may present at the nape of the neck, axillae, nape of the neck, axillae, area beneath the breasts area beneath the breasts and exposed areas and exposed areas (elbows, knuckles)(elbows, knuckles)

• This is thought to be the This is thought to be the result of insulin resistance result of insulin resistance in these patientsin these patients

Laboratory studiesLaboratory studies

• *Increased androgen levels in blood *Increased androgen levels in blood (testosterone and androstendione)(testosterone and androstendione)

• *Increased LH, exaggerated surge*Increased LH, exaggerated surge

• *Increased fasting insulin*Increased fasting insulin

• *Increased prolactin*Increased prolactin

• *Increased estradiol and estrone levels*Increased estradiol and estrone levels

• *Decreased SHBG levels*Decreased SHBG levels

Imaging studiesImaging studies

• Using ultrasonographgy the number of Using ultrasonographgy the number of cysts in subcapsular region varies cysts in subcapsular region varies between 8-10 cysts with diameter of 2-8 between 8-10 cysts with diameter of 2-8 mm.mm.

• However, there is significant intra-However, there is significant intra-observer and inter-observer variability observer and inter-observer variability and ultrasonography alone may not be a and ultrasonography alone may not be a reliable method of diagnosis or reliable method of diagnosis or excluding PCOSexcluding PCOS

PCOS and risk of type II PCOS and risk of type II diabetesdiabetes

• Evidence from small long-term cohort Evidence from small long-term cohort studies, case-control studies and case series, studies, case-control studies and case series, points to a risk of type II diabetes in middle points to a risk of type II diabetes in middle age of 10-20% with higher rate of impaired age of 10-20% with higher rate of impaired glucose tolerance suggesting that further glucose tolerance suggesting that further cases of diabetes will develop latercases of diabetes will develop later

• Increased body mass particularly obesity and Increased body mass particularly obesity and strong family history of diabetes both strong family history of diabetes both increase the risk of developing type II increase the risk of developing type II diabetes in the presence of polycystic diabetes in the presence of polycystic ovaries phenotypeovaries phenotype

PCOS and risk of PCOS and risk of cardiovascular diseasecardiovascular disease

• Women with PCOS frequently have Women with PCOS frequently have abnormal lipid profiles with raised abnormal lipid profiles with raised triglycerides and total and low-density triglycerides and total and low-density lipoprotein cholesterollipoprotein cholesterol

• There is evidence that risk factors in PCOS There is evidence that risk factors in PCOS women are elevated at an earlier age than women are elevated at an earlier age than among women without PCOS and therefore among women without PCOS and therefore the risks of developing atherosclerotic the risks of developing atherosclerotic conditions, hypertension and myocardial conditions, hypertension and myocardial infarction are greaterinfarction are greater

PCOS and PregnancyPCOS and Pregnancy

• Women with PCOS have greater risk of Women with PCOS have greater risk of developing gestational diabetes: the risk is developing gestational diabetes: the risk is believed to be greater in obese women believed to be greater in obese women with PCOS who required ovulation with PCOS who required ovulation induction in order to conceiveinduction in order to conceive

• Women who have been diagnosed in Women who have been diagnosed in pregnancy with gestational diabetes have pregnancy with gestational diabetes have been found to have a higher prevalence of been found to have a higher prevalence of PCOS on subsequent screeningPCOS on subsequent screening

• This association is more common in This association is more common in women with raised body mass indexwomen with raised body mass index

PCOS and pregnancyPCOS and pregnancy

• The risk of pregnancy induced hypertension The risk of pregnancy induced hypertension among patients with PCOS was shown to be among patients with PCOS was shown to be increased in some studies, however, other increased in some studies, however, other studies showed no relation between PCOS studies showed no relation between PCOS and development of hypertension during and development of hypertension during pregnancypregnancy

• Studies on association between PCOS and Studies on association between PCOS and increased rate of abortion and recurrent increased rate of abortion and recurrent abortion could not demonstrate any abortion could not demonstrate any significant relationship with PCOSsignificant relationship with PCOS

PCOS and CancerPCOS and Cancer

• Oligo- and amenorrheic women with PCOS are Oligo- and amenorrheic women with PCOS are shown to be at increased risk for endometrial shown to be at increased risk for endometrial hyperplasia and endometrial carcinoma due hyperplasia and endometrial carcinoma due to the prolonged continuous estrogenic effect to the prolonged continuous estrogenic effect on the endometriumon the endometrium

• Regular induction of withdrawal bleed with Regular induction of withdrawal bleed with cyclical gestogens is advisable, however, cyclical gestogens is advisable, however, there is no consensus on the optimal there is no consensus on the optimal progestin duration and frequency of progestin duration and frequency of treatment to prevent endometrial carcinoma treatment to prevent endometrial carcinoma in women with PCOSin women with PCOS

PCOS and CancerPCOS and Cancer

• Epithelial ovarian cancer was shown to Epithelial ovarian cancer was shown to increase 2.5 folds among patients with increase 2.5 folds among patients with PCOS than controls. The association was PCOS than controls. The association was shown to be stronger among women who shown to be stronger among women who never used oral contraceptivenever used oral contraceptive

• Further investigations with regard to the Further investigations with regard to the association between PCOS and ovarian association between PCOS and ovarian cancer are awaitedcancer are awaited

• Studies examining the relationship between Studies examining the relationship between PCOS and breast carcinoma have not PCOS and breast carcinoma have not always identified a significant increased riskalways identified a significant increased risk

Identification of patients at risk Identification of patients at risk for long-term consequences of for long-term consequences of PCOSPCOSThe association of clinical The association of clinical

features of truncal obesity, features of truncal obesity, oligo- or amenorrhea and oligo- or amenorrhea and hirsutism with biochemical hirsutism with biochemical evidence of evidence of hyperandrogenemia, elevated hyperandrogenemia, elevated luteinizing hormone and luteinizing hormone and suppressed SHBG and suppressed SHBG and characteristic ovarian characteristic ovarian morphology on ultrasound has morphology on ultrasound has formed the basis of the formed the basis of the diagnosis of PCOSdiagnosis of PCOS

However, the key underlying However, the key underlying abnormalities that lead to abnormalities that lead to long-term health risk appears long-term health risk appears to be insulin resistance-to be insulin resistance-hyperinsulinemia in the hyperinsulinemia in the presence of normoglycemiapresence of normoglycemia

• Identification of Identification of patients with patients with metabolic metabolic complications of PCOS complications of PCOS should focus on should focus on biochemical criteria to biochemical criteria to diagnose the diagnose the syndrome particularly syndrome particularly hyperandrogenemia hyperandrogenemia together with an together with an assessment of fasting assessment of fasting glucose and insulin, glucose and insulin, lipids and triglycerideslipids and triglycerides

Strategies for reduction of riskStrategies for reduction of riskExercise & Weight controlExercise & Weight control

**Improvement in diet Improvement in diet and exercise in obese and exercise in obese young women with young women with PCOS is accompanied PCOS is accompanied by normalization in by normalization in glucose metabolism, glucose metabolism, therefore, life style therefore, life style alteration will reduce alteration will reduce the likelihood of the likelihood of developing type II developing type II diabetes later in lifediabetes later in life

*No clear evidence of an *No clear evidence of an effect of diet or effect of diet or exercise on the long-exercise on the long-term health of women term health of women with PCOS who have with PCOS who have normal body habitués. normal body habitués. However, it seems However, it seems prudent to advise such prudent to advise such patients to maintain patients to maintain their body weight their body weight within normal rangewithin normal range

Reduction of riskReduction of riskDrug therapyDrug therapy

• There is interest in using insulin-sensitizing There is interest in using insulin-sensitizing agents like metformin to reduce insulin-agents like metformin to reduce insulin-resistance and thereby reduce the risk of resistance and thereby reduce the risk of developing diabetes and other metabolic developing diabetes and other metabolic sequel.sequel.

• Studies to date have only assessed the impact Studies to date have only assessed the impact of insulin-sensitizing agents in the short-term of insulin-sensitizing agents in the short-term and well-designed long-term randomized and well-designed long-term randomized control trials with regard to long-term safety control trials with regard to long-term safety and efficacy in non-diabetic women are neededand efficacy in non-diabetic women are needed

Reduction of riskReduction of riskSurgerySurgery• Laparoscopic ovarian electrocautery has shown Laparoscopic ovarian electrocautery has shown

persistence of ovulation and normalization of persistence of ovulation and normalization of serum androgens and SHBG over many years in serum androgens and SHBG over many years in over 60% of patients and the long-term benefits over 60% of patients and the long-term benefits of ovarian drilling, including alterations in of ovarian drilling, including alterations in endocrine profile have been confirmedendocrine profile have been confirmed

• However, the effect on insulin resistance and However, the effect on insulin resistance and serum lipids is not assessed and at present the serum lipids is not assessed and at present the risk of surgery do not justify recommendation of risk of surgery do not justify recommendation of this treatment purely in attempt to ameliorate the this treatment purely in attempt to ameliorate the chances of developing diabetes or coronary chances of developing diabetes or coronary artery disease in later lifeartery disease in later life

RCOG GuidelinesRCOG Guidelines (May 2003) (May 2003)

Evidence based guidelines for Evidence based guidelines for reduction of long-term PCOS reduction of long-term PCOS

consequencesconsequences

Classifications of evidence Classifications of evidence levelslevels• Ia: Evidence obtained from Ia: Evidence obtained from

meta-analysis of meta-analysis of randomized controlled randomized controlled trialstrials

• Ib: Evidence obtained from Ib: Evidence obtained from at least one randomized at least one randomized controlled trialcontrolled trial

• IIa: Evidence obtained from IIa: Evidence obtained from at least one well-designed at least one well-designed controlled study without controlled study without randomizationrandomization

• IIb: Evidence obtained IIb: Evidence obtained from at least one other from at least one other type of well-designed type of well-designed quasi-experimental studyquasi-experimental study

• III: Evidence obtained from III: Evidence obtained from well-designed non-well-designed non-experimental descriptive experimental descriptive studies, such as studies, such as comparative studies, comparative studies, correlation studies and correlation studies and case studiescase studies

• IV: Evidence obtained from IV: Evidence obtained from expert committee reports expert committee reports or opinions and/or clinical or opinions and/or clinical experience of respected experience of respected authoritiesauthorities

Grades of Grades of RecommendationsRecommendations• AA- Requires at least one randomized controlled - Requires at least one randomized controlled

trial as part of a body of literature of overall good trial as part of a body of literature of overall good quality and consistency addressing the specific quality and consistency addressing the specific recommendation. (Evidence levels Ia, Ib)recommendation. (Evidence levels Ia, Ib)

• BB- Requires the availability of well controlled - Requires the availability of well controlled clinical studies but no randomized clinical trials on clinical studies but no randomized clinical trials on the topic of recommendations (Evidence levels IIa, the topic of recommendations (Evidence levels IIa, IIb, III)IIb, III)

• CC- Requires evidence obtained from expert - Requires evidence obtained from expert committee reports or opinions and/ or clinical committee reports or opinions and/ or clinical experiences of respected authorities. Indicates an experiences of respected authorities. Indicates an absence of directly applicable clinical studies of absence of directly applicable clinical studies of good quality. (Evidence level IV)good quality. (Evidence level IV)

Guidelines (RCOG, May Guidelines (RCOG, May 2003)2003)• 1-Patients presenting with 1-Patients presenting with

PCOS particularly if they PCOS particularly if they are obese, should be are obese, should be offered measurement of offered measurement of fasting blood glucose and fasting blood glucose and urine analysis for urine analysis for glycosuria. Abnormal glycosuria. Abnormal results should be results should be investigated by a glucose investigated by a glucose tolerance test.tolerance test.

• Such patients are at Such patients are at increased risk of increased risk of developing type II diabetes developing type II diabetes (Evidence level IIb[C])(Evidence level IIb[C])

• 2- Women who have been 2- Women who have been diagnosed as having PCOS diagnosed as having PCOS before pregnancy (eg before pregnancy (eg those requiring ovulation those requiring ovulation induction for conception) induction for conception) should be screened for should be screened for gestational diabetes in gestational diabetes in early pregnancy, with early pregnancy, with referral to a specialized referral to a specialized obstetric diabetic service if obstetric diabetic service if abnormalities are detected abnormalities are detected (evidence level IIb[B])(evidence level IIb[B])

Guidelines (RCOG, May Guidelines (RCOG, May 2003)2003)• 3-Measurement of 3-Measurement of

fasting cholesterol, fasting cholesterol, lipids and triglycerides lipids and triglycerides should be offered to should be offered to patients with PCOS, patients with PCOS, since early detection since early detection of abnormal levels of abnormal levels might encourage might encourage improvement in diet improvement in diet and exercise and exercise (Evidence level III[C])(Evidence level III[C])

• 4- Olig- and 4- Olig- and amenorrhoeic women amenorrhoeic women with PCOS may develop with PCOS may develop endometrial hyperplasia endometrial hyperplasia and later carcinoma. It is and later carcinoma. It is good practice to good practice to recommend treatment recommend treatment with progestogens to with progestogens to induce withdrawal bleed induce withdrawal bleed at least every 3-4 at least every 3-4 months (Evidence level months (Evidence level IIa[B])IIa[B])

Guidelines (RCOG, May Guidelines (RCOG, May 2003)2003)• 5-A body of evidence has 5-A body of evidence has

accumulated accumulated demonstrating safety and demonstrating safety and in some studies efficacy of in some studies efficacy of insulin-sensitizing agents insulin-sensitizing agents in the management of in the management of short-term complications short-term complications of PCOS, particularly of PCOS, particularly anovulation. Long-term use anovulation. Long-term use of these agents for of these agents for avoidance of metabolic avoidance of metabolic complications of PCOS can complications of PCOS can not as yet be not as yet be recommended (Evidence recommended (Evidence level IV[B])level IV[B])

• 6- No clear consensus has 6- No clear consensus has yet emerged concerned yet emerged concerned regular screening of women regular screening of women with PCOS for later with PCOS for later development of diabetes development of diabetes and dyslipidemia but obese and dyslipidemia but obese women with a strong family women with a strong family history of cardiac disease or history of cardiac disease or diabetes should be assessed diabetes should be assessed regularly in a general regularly in a general practice or hospital practice or hospital outpatient setting. Local outpatient setting. Local protocols should be protocols should be developed and adapted as developed and adapted as new evidence emerges new evidence emerges (Evidence level IV[C])(Evidence level IV[C])

Guidelines (RCOG, May Guidelines (RCOG, May 2003)2003)

• Young women diagnosed with PCOS Young women diagnosed with PCOS should be informed of the possible should be informed of the possible long-term risks to health that are long-term risks to health that are associated with their condition. They associated with their condition. They should be advised regarding weight should be advised regarding weight and exercise (Evidence level III[C])and exercise (Evidence level III[C])