POLYCYSTIC OVARY SYNDROME (PCOS)

POLYCYSTIC OVARY SYNDROME (PCOS)

Yasser Orief M.D.

Fellow , Lübeck University, Germany.

DAOG, Auvergné University, France.

AgendaAgenda

DefinitionDefinition EpidemiologyEpidemiology PathophysiologyPathophysiology Diagnostic approachDiagnostic approach Long term ConsequencesLong term Consequences TreatmentTreatment Follow upFollow up

PCOS: HistoryPCOS: History 17211721

Antonio VallisneriAntonio Vallisneri “…“…Young peasant woman, married, moderately plump, Young peasant woman, married, moderately plump,

infertile, with ovaries larger than normal, like doves’ infertile, with ovaries larger than normal, like doves’ eggs, lumpy, shiny and whitish”eggs, lumpy, shiny and whitish”

19351935 Dr. Irving Stein and Dr. Michael LeventhalDr. Irving Stein and Dr. Michael Leventhal Coined Stein-Leventhal disorderCoined Stein-Leventhal disorder

19801980 Linked to hyperinsulinemia and impaired glucose Linked to hyperinsulinemia and impaired glucose

tolerancetolerance

20062006 What causes PCOS?What causes PCOS?

Lanham 2006

IntroductionIntroductionStein and Leventhal Stein and Leventhal They were the first to recognize an association between the presence of They were the first to recognize an association between the presence of

polycystic ovaries and signs of hirsutism amenorrhea (oligomenorrhea, obesity)polycystic ovaries and signs of hirsutism amenorrhea (oligomenorrhea, obesity)

Polycystic Ovarian DiseasePolycystic Ovarian Disease After successful wedge resection of the ovaries in women diagnosed with Stein-After successful wedge resection of the ovaries in women diagnosed with Stein-

Leventhal syndrome, menstrual cycles become regular and the patients were able Leventhal syndrome, menstrual cycles become regular and the patients were able to conceive. Primary ovarian disorder come to be known as polycystic ovarian to conceive. Primary ovarian disorder come to be known as polycystic ovarian diseasedisease

Polycystic ovarian syndromePolycystic ovarian syndrome Biochemical, clinical and endocrinological abnormalities have shown an array of Biochemical, clinical and endocrinological abnormalities have shown an array of

underlying abnormalities; hence condition known as polycystic ovarian syndrome( underlying abnormalities; hence condition known as polycystic ovarian syndrome( PCOS)PCOS)

Syndrome O Syndrome O gets to the real heart of the problem and indicates: Ovarian confusion and gets to the real heart of the problem and indicates: Ovarian confusion and

Ovulation disruption caused primarily by Over nourishment and Overproduction of Ovulation disruption caused primarily by Over nourishment and Overproduction of insulin insulin

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

Introduction Introduction Most attention has been paid to the management Most attention has been paid to the management

of the presenting complaint (infertility, hirsutism..of the presenting complaint (infertility, hirsutism.. etc.)etc.)

It has become clear that the polycystic ovary It has become clear that the polycystic ovary phenotype is linked to a number of metabolic phenotype is linked to a number of metabolic disturbances, including type II diabetes and disturbances, including type II diabetes and possibly atherosclerosispossibly 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 the gynecologists have a good understanding of the long-term implications of the diagnosislong-term implications of the diagnosis

DefinitionDefinition

Common names and confused Common names and confused with… with…

Stein-Leventhal SyndromeStein-Leventhal Syndrome Polycystic ovary diseasePolycystic ovary disease Functional ovarian Functional ovarian

hyperandrogenismhyperandrogenism Hyperandrogenic chronic Hyperandrogenic chronic

anovulationanovulation Ovarian dysmetabolic syndromeOvarian dysmetabolic syndrome Polycystic ovarian syndromePolycystic ovarian syndrome

DefinitionDefinition

Stein and Levanthal (1935): Stein and Levanthal (1935): association of association of amenorrhea with polycystic ovaries and variably: amenorrhea with polycystic ovaries and variably: hirsutism and/or obesityhirsutism and/or obesity

ACOG and NIH (1990): ACOG and NIH (1990): hyperandrogenism and hyperandrogenism and chronic anovulation excluding other causeschronic anovulation excluding other causes

Criteria of the PCOCriteria of the PCO

National Institutes of National Institutes of HealthHealth

Presence of Presence of menstrual abnormalitiesmenstrual abnormalities and and anovulationanovulation Presence of clinical and/or biochemical Presence of clinical and/or biochemical

hyperandrogenaemiahyperandrogenaemia

Ultrasound examination ?Ultrasound examination ? peripheral cystsperipheral cysts (10 or more) (10 or more) less than 10mmless than 10mm in size in an in size in an

enlarged ovaryenlarged ovary with significant increase with significant increase in the central in the central stromastroma

Absence of Absence of hyperprolactinaemiahyperprolactinaemia or or thyroid diseasethyroid disease Absence of Absence of late-onset congenital adrenal hyperplasialate-onset congenital adrenal hyperplasia Absence of Absence of Cushing’s syndromeCushing’s syndrome

2003 ESHRE/ASRM-sponsored 2003 ESHRE/ASRM-sponsored

PCOS Consensus workshopPCOS Consensus workshop

1990 Criteria (both 1 and 2)1990 Criteria (both 1 and 2) 1. Chronic anovulation and1. Chronic anovulation and 2. Clinical and/or biochemical signs of hyperandrogenism2. Clinical and/or biochemical signs of hyperandrogenism and exclusion of other etiologies.and exclusion of other etiologies.

Revised 2003 criteria (2 out of 3)Revised 2003 criteria (2 out of 3) 1. Oligo- or anovulation1. Oligo- or anovulation 2. Clinical and/or biochemical signs of hyperandrogenism,2. Clinical and/or biochemical signs of hyperandrogenism, 3. Polycystic ovaries3. Polycystic ovaries and exclusion of other causes of hyperandrogenism and exclusion of other causes of hyperandrogenism

(congenital adrenal hyperplasia, androgen-secreting tumors, (congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome)Cushing's syndrome)

PCOS: Diagnostic CriteriaPCOS: Diagnostic Criteria

Other concurrent manifestationsOther concurrent manifestations Insulin resistanceInsulin resistance Features of metabolic syndromeFeatures of metabolic syndrome Increased risk for diabetes mellitus II, Increased risk for diabetes mellitus II,

cardiovascular disease, endometrial cardiovascular disease, endometrial bleeding or cancerbleeding or cancer

Milnar et al. 2006

Carmina 2006

PathologyPathology

Appearance of ovariesAppearance 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 follicles surrounding arrested follicles

Microscopically luteinizing theca cells are Microscopically luteinizing theca cells are seenseen

increased sizeincreased size and a and a smooth white smooth white surfacesurface reflecting reflecting thickening of thickening of

the capsulethe capsule

Showing Showing multiple cystsmultiple cysts with with diameter <10mmdiameter <10mm arranged around the periphery of the ovary. arranged around the periphery of the ovary. The The stroma is increasedstroma is increased, and the , and the ovary ovary enlargedenlarged

PrevelancePrevelance

EpidemiologyEpidemiology

Prevalence: Prevalence: 4-6%4-6% females females Probably same world wideProbably same world wide

No difference between blacks and whitesNo difference between blacks and whites

75%75% of women w/ irregularity or infertility of women w/ irregularity or infertility

PathophysiologyPathophysiology

PCOS: PathopysiologyPCOS: PathopysiologyWhat we think we know.What we think we know.

““Vicious cycle”Vicious cycle” Abnormal gonadotropin secretionAbnormal gonadotropin secretion

Excess LH and low, tonic FSHExcess LH and low, tonic FSH Hypersecretion of androgensHypersecretion of androgens

Disrupts follicle maturationDisrupts follicle maturation Substrate for peripheral aromatizationSubstrate for peripheral aromatization

Negative feedback on pituitaryNegative feedback on pituitary Decreased FSH secreationDecreased FSH secreation

Insulin resistance, Elevated insulin levelsInsulin resistance, Elevated insulin levels

PCOS: Current theories of PCOS: Current theories of pathopysiologypathopysiology

AutosomalAutosomalDominant GeneDominant Gene

Insulin Insulin ResistanceResistance PCOSPCOS

GnRH

LH

A

E2DownstreamSignal Defect

A=androgens, E2=estradiol

functional hyperandrogenismfunctional hyperandrogenism

Salehi M. et al., Metabolism 2004; 53: 358-376

Theories of the Pathogenesis of PCOS

Tscichorozidou T et al.., Clin Endocrinol 60: 1-17, 2004

PATHWAYS LEADING TO ANDROGEN EXCESS IN PCOS

Diagnostic ApproachDiagnostic Approach

Manifestations of PCOS Manifestations of PCOS at different agesat different ages

Manifestations of PCOS Manifestations of PCOS at different agesat different ages

PCOS: Signs and SymptomsPCOS: Signs and Symptoms

SYMPTOMSSYMPTOMS Menstrual Menstrual

irregularityirregularity InfertilityInfertility Hirsutism, acne, Hirsutism, acne,

etcetc ObesityObesity

SIGNSSIGNS Hirsutism, acneHirsutism, acne ObesityObesity Ovarian Ovarian

enlargementenlargement Acanthosis Acanthosis

nigricansnigricans

PCOS: Signs and Symptoms PCOS: Signs and Symptoms

Polycystic Ovarian SyndromePolycystic Ovarian Syndrome

HistoryHistory

Complete a good menstrual historyComplete a good menstrual history menarchemenarche duration, frequency, intensity of bleedingduration, frequency, intensity of bleeding periods always irregular or new onsetperiods always irregular or new onset Menorrhagia / metrorrhagiaMenorrhagia / metrorrhagia Attempt to determine if irregular bleeding ovulatory Attempt to determine if irregular bleeding ovulatory

or anovulatoryor anovulatory


HistoryHistory OvulatoryOvulatory bleeding suggested by presence of bleeding suggested by presence of

premenstrual symptoms: premenstrual symptoms: breast engorgementbreast engorgement pelvic crampingpelvic cramping fluid retentionfluid retention mood swingsmood swings

Menstrual regularity more suggestive of Menstrual regularity more suggestive of ovulatoryovulatory

AnovulatoryAnovulatory absence of premenstrual symptomsabsence of premenstrual symptoms frequently long periods of amenorrhea followed frequently long periods of amenorrhea followed

by irregular bleedingby irregular bleeding


Life long history of irregular menses, hirsutism, Life long history of irregular menses, hirsutism, infertility, and obesity is suggestive of PCOinfertility, and obesity is suggestive of PCO

Family Hx of PCOFamily Hx of PCO


PelvicPelvic ovarian enlargement-irregularity suggestive of ovarian enlargement-irregularity suggestive of

cystscysts clitoral hypertrophyclitoral hypertrophy

BreastsBreasts GalactorrheaGalactorrhea

Suggestive of hyperprolactinemiaSuggestive of hyperprolactinemia

InvestigationsInvestigations

Transvaginal ultrasoundTransvaginal ultrasound is the best imaging mode is the best imaging mode

Endometrial thicknessEndometrial thickness should always be assessed to should always be assessed to exclude significant endometrial pathologyexclude significant endometrial pathology

(A) Pelvic ultrasound examination(A) Pelvic ultrasound examination

Ultrasound assessment of the Polycystic ovaries International consensus definitions

Although the 1990 National Institute of Health Conference on PCOS

recommended that diagnostic criteria should include evidence of

hyperandrogenism and ovulatory dysfunction, in the absence of non-

classic adrenal hyperplasia, and that evidence of polycystic ovarian

morphology was not essential, the Rotterdam ESHRE/ASRM-sponsored

PCOS consensus considered that PCO should be considered as one of the

possible criteria for PCOS.

Ultrasound assessment of the Polycystic ovaries International consensus definitions

1. The PCO should have at least one of the following: either 12 or more follicles measuring

2-9 mm in diameter or increased ovarian volume (>10 cm3). If there is evidence of a dominant

follicle (>10 mm) or a corpus luteum, the scan should be repeated during the next cycle.

2. The subjective appearance of PCOs should not be substituted for this definition. The follicle distribution should be omitted as well as the

increase in stromal echogenicity and/or volume. Although the latter is specific to polycystic ovary,

it has been shown that measurement of the ovarian volume is a good surrogate for the

quantification of the stroma in clinical practice.

Ultrasound assessment of the Polycystic ovariesInternational consensus definitions (continued)

3. Only one ovary fitting this definition or a single occurrence of one of the above criteria is sufficient to define the PCO. The presence of an abnormal cyst or

ovarian asymmetry, which may suggest a homogeneous cyst, necessitates further

investigation.

4. This definition does not apply to women taking the oral contraceptive pill, as

ovarian size is reduced, even though the `polycystic' appearance may persist.


5. A woman having PCO in the absence of an ovulation disorder or hyperandrogenism

(`asymptomatic PCO') should not be considered as having PCOS, until more is

known about this situation.

6. In addition to its role in the definition of PCO, ultrasound is helpful to predict fertility outcome

in patients with PCOS (response to clomiphene citrate, risk for ovarian hyperstimulation syndrome (OHSS), decision for in-vitro

maturation of oocytes). It is recognized that the appearance of PCOs may be seen in women undergoing ovarian stimulation for IVF in the absence of overt signs of PCOS. Ultrasound

also provides the opportunity to screen for endometrial hyperplasia.


7. The following technical recommendations should be respected:

State-of-the-art equipment is required and should be operated by appropriately trained personnel.

The transvaginal approach should be preferred, particularly in obese patients.

Regularly menstruating women should be scanned in the early follicular phase (days 3±5). Oligo-/amenorrhoeic

women should be scanned either at random or between days 3±5 after a progestogen-induced bleed.

If there is evidence of a dominant follicle (>10mm) or a corpus luteum, the scan should be repeated the next

cycle. Calculation of ovarian volume is performed using the

simplified formula for a prolate ellipsoid (0.5 3 length 3 width 3 thickness).

Follicle number should be estimated both in longitudinal, transverse and antero-posterior cross-sections of the

ovaries. Follicle size should be expressed as the mean of the diameters measured in the three sections.

The usefulness of 3-D ultrasound, Doppler or MRI for the definition of PCO has not been sufficiently ascertained to date, and should be confined to research studies.

Hormone assaysHormone assays

Blood tests needed to exclude ?Blood tests needed to exclude ? Late-onset congenital adrenal hyperplasia Late-onset congenital adrenal hyperplasia

((17-hydroxyprogesterone17-hydroxyprogesterone)) Thyroid abnormalityThyroid abnormality ( (TSHTSH)) HyperprolactinaemiaHyperprolactinaemia ( (prolactinprolactin) ) Cushing’s syndrome Cushing’s syndrome These tests can be omitted if other features are These tests can be omitted if other features are

not suggestive.not suggestive.

AndrogensAndrogens

testosterone testosterone (total or adjusted for SHBG) is (total or adjusted for SHBG) is helpful to showhelpful to show hyperandrogenaemiahyperandrogenaemia and to rule and to rule out an out an androgen-secreting tumourandrogen-secreting tumour

Total testosterone concentration Total testosterone concentration greater than 60 greater than 60 ng/dLng/dL ; consistent with PCOS ; consistent with PCOS

dehydroepiandrosterone sulfatedehydroepiandrosterone sulfate and and androstenedioneandrostenedione is not particularly useful. is not particularly useful.

Insulin Insulin resistanceresistance

It is essential to exclude glucose intolerance with It is essential to exclude glucose intolerance with glucose tolerance testingglucose tolerance testing

It is doubtful whether It is doubtful whether insulin measurementinsulin measurement is is indicated, as indicated, as interpretation is clouded by obesityinterpretation is clouded by obesity

calculating an calculating an index of insulin resistanceindex of insulin resistance from from glucose and insulin levelsglucose and insulin levels

(eg, the homeostasis model assessment [HOMA] or quantitative insulin sensitivity check index [QUICKI])

random and fasting glucose levelsrandom and fasting glucose levels are usually are usually normalnormal in women with PCOS, the standard in women with PCOS, the standard Australian recommendations for diagnosing Australian recommendations for diagnosing diabetes by measuring these levels are not diabetes by measuring these levels are not applicable, and applicable, and glucose tolerance testingglucose tolerance testing is is recommendedrecommended

Lipid statusLipid status

Assessment of Assessment of lipid status lipid status is justifiedis justified

- total and HDL cholesterol - total and HDL cholesterol

- triglyceride levels- triglyceride levels

Criteria for the metabolic syndrome in women with Criteria for the metabolic syndrome in women with PCOS*PCOS*

Risk factor Cut-off

1. Abdominal obesity(waist circumference) >88 cm (>35 in)

2. Triglycerides >150 mg/dl

3. HDL-C <50 mg/dl

4. Blood pressure >130/>85 mmHg

5. Fasting and 2 h glucose from OGTT110±126 mg/dl and/or2 h glucose 140±199 mg/dl

*Three out of five qualify for the syndrome

Other investigationsOther investigations

Laparoscopy of the pelvis, computed Laparoscopy of the pelvis, computed tomography and magnetic resonance imaging tomography and magnetic resonance imaging are are never justifiable never justifiable for suspected PCOS alone. for suspected PCOS alone.

Endometrial biopsyEndometrial biopsy and and hysteroscopyhysteroscopy may be may be used to investigate used to investigate unexplained vaginal unexplained vaginal bleedingbleeding..

Long-term health Long-term health consequences consequences

of PCOSof PCOS

Long-term health consequences of PCOS

There is no doubt that women with PCOS cluster risk factors for diabetes,

cardiovascular disease and endometrial cancer.

Women with PCOS are also thought to be at increased risk for endometrial

cancer through chronic anovulation with unopposed estrogen exposure of the

endometrium. However, epidemiological evidence to support this hypothesis is

limited.

Long-term health consequences of PCOS (continued)

PCOS is associated with an increased risk of type 2 diabetes. The risk is greater in

anovulatory women with PCO, in obese subjects and those with a family history of type 2

diabetes.

The risk of cardiovascular disease is uncertain at present. Limited epidemiological data have

shown no increase in cardiovascular events, but two factors need to be borne in mind: The young age of the cohorts studied so far (~55 years) and

the possibility that unknown factor(s) may be present in PCOS which protect the heart in the

face of other risk factors.

TreatmentTreatment

Treatment PlansTreatment Plans What are your goals? What are your goals?

Treat short-term problems?Treat short-term problems?

Prevent long-term risks?Prevent long-term risks?

Pregnancy?Pregnancy?

Have other options failed?Have other options failed?

Short-term managementShort-term management

InfertilityInfertility HirsutismHirsutism AcneAcne ObesityObesity MiscarriageMiscarriage

TreatmentTreatment

TreatmentTreatment

Patient's height and weight to calculate her Patient's height and weight to calculate her body body mass index mass index

BPBP at the first visit at the first visit Fasting lipid panel Fasting lipid panel to evaluate cardiovascular riskto evaluate cardiovascular risk Fasting glucose concentration Fasting glucose concentration to evlauate the to evlauate the

possibility of possibility of IGTIGT or non-insulin-dependent or non-insulin-dependent diabetes mellitus diabetes mellitus 2-hour oral glucose tolerance test 2-hour oral glucose tolerance test is preferable is preferable

TreatmentTreatment

In In overweight patient overweight patient (body mass index 26 or (body mass index 26 or higher), higher),

major component of any treatment should be major component of any treatment should be directed at weight reduction directed at weight reduction Best weight loss strategy - integrated behavioral Best weight loss strategy - integrated behavioral

program program Include exercise, moderate caloric restriction Include exercise, moderate caloric restriction Result in significant favorable impact on insulin, Result in significant favorable impact on insulin,

androgens, and ovulationandrogens, and ovulation

No data on long-term outcomes of such lifestyle No data on long-term outcomes of such lifestyle modification programsmodification programs

Metformin - not sliver bullet for all aspects of PCOS Metformin - not sliver bullet for all aspects of PCOS treatment treatment

TreatmentTreatment

Irregular menstruation Irregular menstruation

Without the additional concerns of hirsutism or Without the additional concerns of hirsutism or infertility infertility

OCsOCs remain an excellent choice remain an excellent choice Progestins Progestins (eg, medroxyprogesterone acetate or (eg, medroxyprogesterone acetate or

norethisterone) norethisterone)

Present hirsutism Present hirsutism OCs plus spironolactoneOCs plus spironolactone, at a dose of 200 mg/d is , at a dose of 200 mg/d is

standard choice standard choice

TreatmentTreatment

Several clear Several clear benefitsbenefits in the in the treatment of irregular treatment of irregular menstrual cyclesmenstrual cycles in women in women with PCOSwith PCOS

1.Regular withdrawal bleeding 1.Regular withdrawal bleeding 2. Reduction in the risk of endometrial hyperplasia or cancer 2. Reduction in the risk of endometrial hyperplasia or cancer

because ofbecause of progestin opposition of estrogen progestin opposition of estrogen 3. Reduction in LH secretion and consequent reduction of 3. Reduction in LH secretion and consequent reduction of

ovarian androgens ovarian androgens 4. Increased sex hormone binding globulin production and 4. Increased sex hormone binding globulin production and

consequent reduction in free testosterone consequent reduction in free testosterone 5. Improvement in hirsutism and acne 5. Improvement in hirsutism and acne

Measruable decline in hirsutism after 6 months of Measruable decline in hirsutism after 6 months of treatment, while notreatment, while no effect on hirsutismeffect on hirsutism was seen with was seen with metformin metformin

TreatmentTreatment

Common reason for a physician consultation ;Common reason for a physician consultation ; infertilityinfertility

Assuming a normal semen analysis, ovulation Assuming a normal semen analysis, ovulation induction induction

Hysterosalpingography to confirm a normal Hysterosalpingography to confirm a normal genital tract if history of PID, endometriosis, or genital tract if history of PID, endometriosis, or previous abdominal surgery previous abdominal surgery

TreatmentTreatment

TreatmentTreatment

Most physiologic approach to ovulation induction ; Most physiologic approach to ovulation induction ; weight loss weight loss

Failing that -> Failing that -> clomiphene citrate clomiphene citrate

Excellent initial pharmacologic strategy Excellent initial pharmacologic strategy Use the lowest clomiphene citrate dose that Use the lowest clomiphene citrate dose that

will initiate the smallest numberwill initiate the smallest number of ovulatory of ovulatory follicles(hopefully, only one!) follicles(hopefully, only one!)

Starting dose ; 50 mg/d for 5 days(usually days 5-9) Starting dose ; 50 mg/d for 5 days(usually days 5-9) approximately 50% ovulation on 50 mg approximately 50% ovulation on 50 mg

TreatmentTreatment

Ultrasound on day 13 to assess follicle Ultrasound on day 13 to assess follicle development development More than 2 preovulatory follicles on day 13 ; More than 2 preovulatory follicles on day 13 ;

reduced to 25 mg/d inreduced to 25 mg/d in subsequent cycles subsequent cycles No follicle development ; dose and duration of No follicle development ; dose and duration of

treatment increased treatment increased Never exceed 150 mg/d for 5 days Never exceed 150 mg/d for 5 days Once regimen that induces ovulation if there is no Once regimen that induces ovulation if there is no

pregnancypregnancy Should repeat that regimen and not increase Should repeat that regimen and not increase

the dose in subsequent cycles the dose in subsequent cycles -> Goal is ovulation, not superovulation -> Goal is ovulation, not superovulation Overall, approximately Overall, approximately 80% of women with PCOS 80% of women with PCOS

- ovulate on clomiphene- ovulate on clomiphene citrate citrate

TreatmentTreatment

How should ovulation be induced in the 20% of How should ovulation be induced in the 20% of women who are refractory to clomiphene citrate?women who are refractory to clomiphene citrate?

Use of Use of metformin hydrochloride metformin hydrochloride

Common and effective strategy Common and effective strategy Used extensively in the treatment of non-insulin-dependent Used extensively in the treatment of non-insulin-dependent

diabetes mellitus diabetes mellitus Helps with glycemic control by reducing hepatic glucose Helps with glycemic control by reducing hepatic glucose

output and by increasing peripheral uptake of glucose output and by increasing peripheral uptake of glucose Kidney or liver ds., alcoholism, heart failure treated with Kidney or liver ds., alcoholism, heart failure treated with

furosemide should not take metformin furosemide should not take metformin

∵ ∵ lactic acidosis risk ↑lactic acidosis risk ↑ Begun at a dose of 500 mg/d to minimize Begun at a dose of 500 mg/d to minimize

gastrointestinal side effects and increased gastrointestinal side effects and increased gradually as tolerated gradually as tolerated

Postulated role for insulin-sensitising agents

Harborne L et al.,Lancet2003; 361:894-1901

TreatmentTreatment

Small percentage of women with PCOS (about 5-Small percentage of women with PCOS (about 5-10%) who are refractory to clomiphene citrate 10%) who are refractory to clomiphene citrate alone and to metformin plus clomiphene citrate alone and to metformin plus clomiphene citrate or who cannot tolerate these medications or who cannot tolerate these medications

Laparoscopic ovarian drillingLaparoscopic ovarian drilling

Gonadotropins Gonadotropins Hypersensitive to exogenous FSH Hypersensitive to exogenous FSH

Risk of multiple pregnancy and hyperstimulation Risk of multiple pregnancy and hyperstimulation Should be used in conjunction with in vitro Should be used in conjunction with in vitro

fertilizationfertilization

; Number of embryos that are transferred to the ; Number of embryos that are transferred to the uterine cavity controlled uterine cavity controlled

Follow-UpFollow-Up

Women with PCOS who are being seen for Women with PCOS who are being seen for infertility infertility Followed closely with regards to ovulation induction Followed closely with regards to ovulation induction

If no pregnancy after 6 months of documented If no pregnancy after 6 months of documented ovulationovulation

Additional infertility evaluation Additional infertility evaluation

If no pregnancy after 9-12 months of documented If no pregnancy after 9-12 months of documented ovulation, and if no otherovulation, and if no other infertility factors infertility factors

Blend with unexplained infertility Blend with unexplained infertility Intrauterine insemination is addedIntrauterine insemination is added

If lack of pregnancy despite multiple cycles of If lack of pregnancy despite multiple cycles of ovulation induction andovulation induction and intrauterine insemination intrauterine insemination

Lead to consideration of the use of gonadotropins Lead to consideration of the use of gonadotropins

Follow-UpFollow-Up

For women with PCOS who are not interested in For women with PCOS who are not interested in pregnancypregnancy

Follow-up at 6 month intervals Follow-up at 6 month intervals

HirsutismHirsutism

oral contraceptive pilloral contraceptive pill (eg, (eg, ethinyloestradiol 35 μg + cyproterone acetate ethinyloestradiol 35 μg + cyproterone acetate

2mg daily for 21 of 28 days)2mg daily for 21 of 28 days)

cosmetic measurescosmetic measures (eg, (eg, laser electrolysis, bleaching, waxing or shavinglaser electrolysis, bleaching, waxing or shaving))

oral oestrogenoral oestrogen and and cyproterone acetatecyproterone acetate ((oestradiol valerate 2mg daily oestradiol valerate 2mg daily and and cyproterone acetate 50 mg for 14 days a monthcyproterone acetate 50 mg for 14 days a month))

spironolactonespironolactone ( (75–200mg daily75–200mg daily))

other drugsother drugs

reduce androgen production / inhibit androgen-binding to reduce androgen production / inhibit androgen-binding to the receptorthe receptor

- antiandrogen - antiandrogen flutamideflutamide

- antifungal agent - antifungal agent ketoconazoleketoconazole

Response times Response times for drugs can be up to for drugs can be up to 3 months3 months

TABLE 2 -- THERAPEUTIC OPTIONS FOR HIRSUTISM

Hormonal Suppression Antiandrogens Physical Methods

Oral contraceptives Spironolactone Temporary depilation

Dexamethasone Cyproterone acetate (not available in US)

Shaving

GnRH agonists Chemical depilatories

Bromocriptine Flutamide Temporary epilation

Ketoconazole Finasteride Plucking

Weight reduction Waxing

Insulin-sensitizing agents Permanent hair removal

Metformin Electrolysis

Troglitazone

Surgery

GnRH = gonadotropin-releasing hormone.

Endometrial hyperplasiaEndometrial hyperplasia

Ultrasound examinationUltrasound examination

Endometrial biopsy Endometrial biopsy

HysteroscopyHysteroscopy

Hormonal therapy Hormonal therapy (oral contraceptive pill or progestins)(oral contraceptive pill or progestins)

RCOG GuidelinesRCOG Guidelines (May 2003) (May 2003)

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

Guidelines (RCOG, May 2003)Guidelines (RCOG, May 2003) 1- Patients presenting with PCOS particularly if they are 1- Patients presenting with PCOS particularly if they are

obeseobese, should be offered measurement of fasting blood , should be offered measurement of fasting blood glucose and urine analysis for glycosuria. Abnormal glucose and urine analysis for glycosuria. Abnormal results should be investigated by a glucose tolerance results should be investigated by a glucose tolerance

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

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

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

3- Measurement 3- Measurement of fasting cholesterol, lipids and of fasting cholesterol, lipids and triglyceridestriglycerides should be offered to patients with should be offered to patients with PCOS, since early detection of abnormal levels PCOS, since early detection of abnormal levels might encourage improvement in diet and might encourage improvement in diet and exercise (Evidence level III[C])exercise (Evidence level III[C])

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

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

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

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

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

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

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POLYCYSTIC OVARY SYNDROME (PCOS)