pcos

PCOS

Dr.Veerendrakumar C.M MD.,DNBProfessorDept of OBG,VIMS,Bellary

[email protected]

Polycystic Ovarian Syndrome1st described by Irving Stein and Michael Leventhal as a triad of amenorrhea, obesity and hirsutism (1935)

The most common endocrine disorder in women of reproductive age ~ 2%-8% of women

November 24, 20132Prof.Veerendrakumar CM, VIMS,Bellary.

PCOSIntergenerational problem


PCOSEVOLVED.

From gynecological curiosity to a multi system endocrinopathy Hamburg 1996

Most common but most poorly understood condition with complex pathophysiology with considerable scientific debate.November 24, 20134Prof.Veerendrakumar CM, VIMS,Bellary.

Rotterdam 2003,ESHRE/ASRMOligo-ovulation or anovulation

Clinical or laboratory evidence of hyperandrogenism

and

Polycystic ovaries as defined by ultrasonography

In addition, the definition requires the exclusion of other medical conditions that cause irregular menses and androgen excess


Ultrasound criteria: --- increased ovarian area/volume --- 10-15 microcyst(10 cm

prolate ellipsoid formula for volume

L x B x T x 0.513November 24, 20138Prof.Veerendrakumar CM, VIMS,Bellary.

PCOS US Scan of ovariesUse high resolution equipmentDo on day 3 -5If dominant follicle or corpus luteum found, repeat in next cycle.Whenever possible, use TVSFollicle number estimated in longitudinal and cross sectional views.Remember, all women with polycystic appearance need not have PCOS.November 24, 20139Prof.Veerendrakumar CM, VIMS,Bellary.

PCOS

should remember that 20 to 30 % of women in general population have polycystic ( multi follicular) ovariesNovember 24, 201310Prof.Veerendrakumar CM, VIMS,Bellary.

PCO and PCOS17-23% of population can have polycystic ovaries

76%-80% of these women had clinical manifestations

Polson 1988,Botsis 1995November 24, 201311Prof.Veerendrakumar CM, VIMS,Bellary.

PCO PCOS

increasing BMI

Concept of a spectrumNovember 24, 201312Prof.Veerendrakumar CM, VIMS,Bellary.

PCO V/S MFOPCOMFOSmall folliclesDense stromaIncreased ovarian volumeNo dominant follicleLarger folliclesLesser stroma densityNormal volumeDominant follicle seenNovember 24, 201313Prof.Veerendrakumar CM, VIMS,Bellary.

Multifollicular ovariesDelayed normal pubertyCentral precocious pubertyHypothalamic anovulationHyperprolactinemiaEarly normal follicular dominant phase

Carefully consider clinical/biological components of consensual definition.


Follicular problems..Early follicular growth is excessive

Recruitment of dominant follicle do not occur

Excessive AMH is involved in follicular arrest.

Jonard 2004November 24, 201315Prof.Veerendrakumar CM, VIMS,Bellary.

Other imaging techniques3D USG not superior to 2D USGMRI-main role is to exclude virilizing ovarian tumor.


Aberrant Gonadotropin Secretion

increased LH pulse frequency and amplitude.

secondary to increased pulse frequency of gonadotropin-releasing hormone, which selectively increases LH release,

resultant elevation of the absolute level of circulating LHNovember 24, 201317Prof.Veerendrakumar CM, VIMS,Bellary.

Androgen production by ovarian thecal cells is LH-dependent, and the elevated LH likely contributes to the excess androgens.


In contrast to LH,FSH levels chronically remain in the midfollicular range,which is an insufficient level

Follicle growth and development is arrested and anovulation resultsNovember 24, 201319Prof.Veerendrakumar CM, VIMS,Bellary.

Adrenal androgen production is also increased in many PCOS patients

There may be a common defect in ovarian and adrenal biosynthesisNovember 24, 201320Prof.Veerendrakumar CM, VIMS,Bellary.

Pathogenesis of the Metabolic Syndrome in PCOSPossible theories

(1) insulin resistance

(2) ObesityNovember 24, 201321Prof.Veerendrakumar CM, VIMS,Bellary.

Insulin Resistance

Many PCOS women, both obese and nonobese, are insulin resistant and

insulin resistance is believed to play a prominent role in the pathophysiology of the syndromeNovember 24, 201322Prof.Veerendrakumar CM, VIMS,Bellary.

Hyperinsulinemia causes hyperandrogenism November 24, 201323Prof.Veerendrakumar CM, VIMS,Bellary.

Insulin resistancePost binding defect in signallingInsulin receptor alterationPancreatic beta cell dysfunction November 24, 201324Prof.Veerendrakumar CM, VIMS,Bellary.


Genetic LinkFamilial clustering of PCOS commonFranks S et al, International Journal of Andrology, 2006.Yildiz BO et al, Journal of Clinical Endocrinology & Metabolism, 2003.PCOS is a genetically determined ovarian disorderNovember 24, 201326Prof.Veerendrakumar CM, VIMS,Bellary.

26Heritability. Due to the observable trends within families concerning insulin resistance, the question remains whether PCOS has a genetic connection. For instance, first degree relatives inherit B-cell dysfunction (secretory deficits). Franks and colleagues offered the following hypothesis: Linage analysis-syndrome inherited in autosomal recessive fashion; heterogeneous disorder-need to focus on hyperandrogenism to assign phenotype.

PCOS - GeneticsBelieved to be ? autosomal dominant,? ?X-linked inheritance

Dysregulation of the P450c17 gene controlling steroidogenesis,CYP11a is suspectedInsulin receptor gene defectFollistatin gene defectNovember 24, 201327Prof.Veerendrakumar CM, VIMS,Bellary.

Neo-hormones in PCOSAdiponectin produced in adipose tissue and has anti atherogenic effect. - Lower levels in PCOSResistin- antagonizes insulin action-Higher levels in PCOS

Proportion of adiponectin and resistin influence cardio-metabolic risk in PCOS

Seow 2004 Hum Reprod


Neo-HormonesGhrelin controls food intake and energy balance

Lower levels found in PCOS

Gambineri 2002 Int j obesNovember 24, 201329Prof.Veerendrakumar CM, VIMS,Bellary.

Early Signs: Adolescence

emerging as a common cause of

menstrual disturbances in the adolescent population

Guttmann-Bauman I, Journal of Pediatric Endocrinology & Metabolism, 2005.November 24, 201330Prof.Veerendrakumar CM, VIMS,Bellary.

30Early Signs. In the 1986 WHO-initiated work-up 2 years after menarche, many adolescents present with transitory functional hyperandrogenism. Hyperandrogenism increased T due to increased insulin and LH in obese peripubertal girls (decreased SHBG). With the increase of childhood and teenage obesity in America, recent pediatric literature has asked if PCOS is being misdiagnosed as part of puberty. Earlier work-up, initiated more rapidly by the presentation of obesity, now examines girls 12-18 months after menarche-especially if LBW, family HX of PCOS, abdominal obesity.

Infertility >75% of women with anovulation infertility

Follicular arrest

Impaired selection of dominant follicle

Risk of multiple pregnancy with treatment

Franks et al, International Journal of Andrology, 2006.Jonard S, Dewailly D, Human Reproduction Update, 2004.31Prof.Veerendrakumar CM, VIMS,Bellary.

31Infertility. Franks and colleagues suggested that over 75% of the patients with anovulation were PCOS patients. PCOS involves primary ovarian dysfunction. This intrinsic ovarian abnormality caused an increased density of small preantral follicles, primordial not different, same for ovulatory and anovulatory. Early follicular growth is excessive since the selection of 1 single follicle from the follicular pool to mature to the dominant one not occur.

PCOS obesity40 to 50 % of PCOS women are obese.


Pregnancy ComplicationsSpontaneous AbortionsIncreased in high BMI/PCOS patients

Impaired Glucose Tolerance

Gestational Diabetes

Hypertension

Small for Gestational Age

Wang JX et al, Human Reproduction, 2001.Turhan NO et al, International Journal of Gynecology & Obstetrics, 2003.Bjercke S et al, Gynecologic and Obstetric Investigation, 2002.Weerakiet S et al, Gynecological Endocrinology, 2004.Sir-Petermann T et al, Human Reproduction, 2005.November 24, 201333Prof.Veerendrakumar CM, VIMS,Bellary.

33Reproductive Complications. PCOS not only affects women pre-pregnancy but also post-pregnancy. Several studies have suggested various complications as listed here. Gestational Diabetes(GDM): Lo et al. examined 90,000 births with >5000 cases GDM. PCOS women had a 2.4 fold increased odds of GDM independent of age, race/ethnicity or multiple gestation (Diabetes Care, 2006). Small for Gestational Age (SGA): Polygenic genetically determined factors increase IR-impaired insulin-mediated growth. Environmental-metabolic programming-fetal exposure to sex steroids-maternal intrauterine environment. Although there is some literature that contradicts a few of these claims such as Haakova et al. Hum Reprod. 18:1438; 2003. May ask for audience feedback.

Hirsutism

Racial difference existsMore in South AsiansLess in Eastern Asians


PCOSPCOS is also associated with a characteristic metabolic syndrome that includes:

insulin resistance dyslipidemiahypertension

These features are linked with increased risks of type 2 diabetes and possibility of premature cardiovascular diseaseNovember 24, 201335Prof.Veerendrakumar CM, VIMS,Bellary.

35

PCOS: Metabolic DisorderEndometrial CancerLong-term follow-up of 786 PCOS women found an increased risk of endometrial cancer

Cardiovascular DiseasePCOS is characterized by endothelial dysfunction and resistance to vasodilating action of insulinWild S et al, Human Fertility, 2000.Pillay OC et al, Human Reproduction, 2006.Paradisi G et al, Circulation, 2001.Dahlgren E et al, Acta Obstetricia et Gynecologica Scandinavica, 1992. November 24, 201336Prof.Veerendrakumar CM, VIMS,Bellary.

36Other Complications. Endometrial cancer (EC): Due to the high estrogen levels and lack of normal ovulation cycles, there is a risk for endometrial cancer in PCOS women. Endometrial cancer-described as early as 1949 by Speer-cystic ovaries and EC-persistent estrogen stimulation; hyperplasia-lack of differentiation to secretory endometrium. Prolonged stimulatory effect of estrogen with unopposed inhibition by progesterone. Cardiovascular disease (CVD): Putting into consideration the rates of insulin resistance and obesity together plus the complications of high blood pressure and increased lipids values, PCOS patients are also at risk for CVD. CVD-associated with both increase in androgen and IR-increase in levels of inflammatory cytokines-IL6, TNF alpha-increased lipids, BP, obesity, IR-associate with CVD. Higher BMI-greater risk for both conditions.

PCOS: Metabolic DisorderSleep ApneaIncreased Sleep Disordered Breathing (SDB) and daytime sleepiness in PCOS vs. controls

DepressionHigher prevalence in PCOS patients, associated with higher body mass index (BMI, P=0.05) and greater insulin resistance (P=0.02)

Vgontzas AN et al, Sleep Medicine Reviews, 2005.Rasgon NL et al, Journal of Affective Disorders, 2003.


37Other Complications. Two other areas that have been associated to PCOS patients includes sleep apnea and depression effecting a womans productivity and quality of life. Apnea: Sleep apnea-greater in PCOS greater than obesity alone, not correlate with BMI. Gender difference of sleep-disordered breathing (SDB). Found more common in middle age obese men and infrequently in premenopausal, yet prevalent in PCOS even non-obese-related to IR measures-30-40X age & weight-matched controls. PCOS women-glucose tolerance is directly related to severity of SDB. SDB shown to exacerbate metabolic consequence of IR-accelerate conversion to IGT (Ehrmann 2006). Insulin levels and measures of glucose tolerance are correlated with risk and severity of obstructive sleep apnea which confirms a direct relationship between insulin levels and sleep apnea. Androgen not related. Emotional stress: PCOS can influence feminine identity-less satisfied with sex life despite same frequency of intercourse-50 PCOS, 50 control women-loss self worth-feel less feminine, different than other women even when control for BMI.

PCOS women with the metabolic syndrome had more hyperandrogenemia than PCOS women without the metabolic syndrome

Apridonidze et alNovember 24, 201338Prof.Veerendrakumar CM, VIMS,Bellary.

PCOSHAIRAN SyndromeMay be a severe form of PCOSHA - HyperandrogenismIR - Insulin ResistanceAN - Acanthosis Nigricans

May have clitoromegaly, temporal balding, deepening of voice.November 24, 201339Prof.Veerendrakumar CM, VIMS,Bellary.

DIFFERENTIAL DIAGNOSISHyperprolactinemiaProminent menstrual dysfunctionLittle hyperandrogenism2. Congenital Adrenal Hyperplasiamorning serum 17-hydroxyprogesterone concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosisconfirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL November 24, 201340Prof.Veerendrakumar CM, VIMS,Bellary.

3. Ovarian and adrenal tumorsserum testosterone concentrations are always higher than 150 ng/dLadrenal tumors: serum DHEA-S concentrations higher than 800 mcg/dLLOW serum LH concentrations 4. Cushings syndrome5. Drugs: danazol; OCPs with high androgenicity


28YR OLD Lady presented withIRREGULAR MENSES 10 YRSSCALP HAIR LOSS 6 YRSEXCESSIVE HAIR GROWTH 6 YRSAMENORRHEA 1 YRNovember 24, 201342Prof.Veerendrakumar CM, VIMS,Bellary.

Case scenario to differentiate severe form of PCOS from that of androgen secreting ovarian tumorNovember 24, 201343Prof.Veerendrakumar CM, VIMS,Bellary.

FRONTAL BALDNESS +, HIRSUTISM + SYSTEMIC EXAMINATION NORMALUSG (11/12/2001) POLYCYSTIC OVARIESDOPPLER STUDY OF OVARIAN VESSELS NORMALSUPRARENAL AREA NORMALON EXAMINATION November 24, 201344Prof.Veerendrakumar CM, VIMS,Bellary.

TESTOSTERONE 358 ng/dL (20-80)17-OH PROGESTERONE 0.66 ng/ml (0.1-1.36)DHEA-SULPHATE 224mcg/dL (35-430)THYROID FUNCTION TESTS-NORMALFSH- 3.8miu/ml LH - 3.6miu/mlPRL - 24ng/mlINVESTIGATIONSNovember 24, 201345Prof.Veerendrakumar CM, VIMS,Bellary.

FINASTERIDE 5mg OD FEMILON X 21DAYSMINOXIDIL LOTION FOR TOPICAL APPLICATIONPATIENT GOT HER MENSES BACK & SYMPTOMATICALLY IMPROVED

PATIENT WAS PUT ONNovember 24, 201346Prof.Veerendrakumar CM, VIMS,Bellary.

LOW DOSE OC PILL STOPPED OI WITH CLOMIPHENE TRIED WITHOUT ANY SUCCESSUSG REPEATED ON 12/5/2003 PCOD WITH A WELL DEFINED ROUND HYPER ECHOIC MASS OF 3.5 X 3.4 X 3 cm IN RIGHT OVARYTESTOSTERONE 570 ng/dL

PATIENT GOT MARRIED IN NOV 2002November 24, 201347Prof.Veerendrakumar CM, VIMS,Bellary.

UTERUS & TUBES NORMAL POD CLEAR RT OVARY ENLARGED, EXT SURFACE NORMAL LT OVARY NORMAL

LAPROSCOPY ON 3/6/2003November 24, 201348Prof.Veerendrakumar CM, VIMS,Bellary.

RT SIDED SALPINGO OVARIOTOMY DONESPECIMEN SUBJECTED FOR HPEREPORT WAS STEROID CELL TUMOR



PATIENT UNDERWENT LSCS ON MAY 2004 &DELIVERED MONOZYGOTIC TWINS.November 24, 201351Prof.Veerendrakumar CM, VIMS,Bellary.

TESTINGFasting glucose: elevated 2 hour OGTT: elevated Fasting insulin: elevated Free testosterone: elevatedDHEA-S: normal17-hydroxyprogesterone: normalPelvic USLipids


TESTINGSerum HCGSerum prolactinThyroid panelFSH: r/o ovarian failure Serum luteinizing hormone (LH)elevatedSerum estradiolnormal Serum estroneelevated


PCOS Dietary GoalsConsume more foods rich in complex carbohydrates monounsaturated fat fiber with a decreased ratio of omega-6 to omega-3 fatty acids

Reduce Total caloric intake Saturated fatCholesterol


PCOS: Weight LossFrequency of obesity in women with anovulation and PCO: 30%-75%

Six month weight-loss program for overweight anovulatory womenLost an average of 6.3 kg (13.9 lbs)Decreased fasting insulin and testosterone levels92% resumed ovulation (12/13)85% became pregnant (11/13)

Ehrmann DA, New England Journal of Medicine, 2005.Clark AM et al, Human Reproduction, 1995.November 24, 201355Prof.Veerendrakumar CM, VIMS,Bellary.

55Weight Loss. Tie in similarity of first line of treatment from previous slide. The most effective benefits are from the calorie-restricted diets which limiting carbohydrates rather than fats-reduction of insulin levels. In the Clark study, BMI was still >30, so still obese with weight loss, yet a 5% reduction in body mass was still able to restore ovulation. It is important to offer a program of exercise and sensible eating, plus educate women about long term adverse effects. Infertile women are usually highly motivated since they are also seeking a pregnancy.

PCOS Dietary Recommendations

Focus on lowering dietary fat as a means for promotingnegative energy balance has led to an underestimation ofthe potential role of dietary composition in promotingreductions in energy intake and weight loss

Roberts SB, et al:J Am Coll Nutr 21:140S, 2002

Diets based on low-GI foods produced greater weight loss than did equivalent diets based on high-GI foods.

Low GI diet more effect than low fat in obese children

Spieth LE, et al: Arch Ped Adol, 154:947, 2000November 24, 201356Prof.Veerendrakumar CM, VIMS,Bellary.

PCOS Diet & Weight Loss

Hypocaloric diets reduce insulin resistance 10-20% protein, ~50% carbohydrates < 30% total fat, < 10% saturated fat

ADA nutritional recommendations: Diabetes Care 20S:14, 1997 Further improvement with 5-10kg weight reduction Two fold increase glucose disposal rate with 16% decrease weight

Niskanen L, et al: J Obes Relat Metab Disord 20:154, 1996November 24, 201357Prof.Veerendrakumar CM, VIMS,Bellary.

PCOS Dietary Recommendations

Substitute nonhydrogenated unsaturated fats for saturated and trans-fats

increase omega-3 fatty acids from fish, fish oil supplements, or plant sources

increase fruits, vegetables, nuts, and whole grainsavoid refined grain products.

Simply lowering the percentage of energy from total fat in the diet is unlikely to improve lipid profile or reduce CHD incidence.

Willet WC, et al: JAMA 288:2569, 2002November 24, 201358Prof.Veerendrakumar CM, VIMS,Bellary.

PCOS ExercisePeripheral muscle cells metabolize 80% of glucose Aerobic exercise 3-4x/wk 20-30 min/session Burns 100-200 kcal40% improvement in insulin sensitivity within 48 hrs. J Appl Physiol 71:2502, 1991November 24, 201359Prof.Veerendrakumar CM, VIMS,Bellary.

Insulin sensitizersMetforminPioglitazone,rosiglitazoneNovember 24, 201360Prof.Veerendrakumar CM, VIMS,Bellary.

METFORMINDecreases hepatic glucose productionImproves insulin sensitivityAntilipolytic effect Increases SHBGReduces leptin productionEndometrial action-IGFBP-1 increasedLH mediated action on theca cells reducedNovember 24, 201361Prof.Veerendrakumar CM, VIMS,Bellary.

INFERTILITY TREATMENTMetformin500 mg daily Increase by 500 mg each week until:Normal mensesReached max dose Side-effectsClomid50 mg days 3-7 for 3 months100 mg days 3-7 for 3 months


Pregnancies Following Metformin inPCOSAnovulatory patients (N=48) with PCOS

Metformin 500 mg b.i.d. 6 weeks, t.i.d. thereafterClomiphene added if anovulatory at 12 weeks 31/48 (64.5%) resumed spontaneous menses16/31 (52%) conceived within the first six months 3/16 (19%) had spontaneous abortions Heard MJ, et al: Abstract 140, Society of Gynecologic Investigation, 2001November 24, 201363Prof.Veerendrakumar CM, VIMS,Bellary.

PCOS Metformin & Ovulation(61 PCOS women with BMI >28)

26 women received Placebo- 1 ovulated35 women received Metformin- 14 ovulated1500 mg/day

Nestler et al. N Engl J Med 1998November 24, 201364Prof.Veerendrakumar CM, VIMS,Bellary.

METFORMIN DOSINGTarget1500-2500 mg per day

Clinically significant responses not regularly observed at doses less than 1000 mg per day

Extended release formulationsfewer side-effects. Entire dose should be given with dinnerNovember 24, 201365Prof.Veerendrakumar CM, VIMS,Bellary.

SIDE EFFECTSDiarrhea, nausea, vomiting, flatulence, indigestion, abdominal discomfortCaused by lactic acid in the bowel wallMinimized by slow increase in dosageLactic acidosisrareAvoid in CHF, renal insufficiency, sepsisDiscontinue for procedures using contrast (withhold X 48 hours)Temporarily suspend for all surgical procedures that involve fluid restrictionCimetidine causes increased metformin levelsNovember 24, 201366Prof.Veerendrakumar CM, VIMS,Bellary.

PCOS - TreatmentOvulation inductionClomiphene citrateAromatase inhibitors e.g. LetrazolGonadotrophinsRisk of hyperstimulation is highNovember 24, 201367Prof.Veerendrakumar CM, VIMS,Bellary.

Surgical treatment for ovulation inductionWedge resection obsolete

Laparoscopic ovarian drillingNovember 24, 201368Prof.Veerendrakumar CM, VIMS,Bellary.

Laparoscopic ovarian drilling4 to 5 holes on anterior surface of ovaries.40 watts current, cutting modeDepth of 4mmCurrent passed for 4 secondsSurface intermittent irrigation & suction with salineNovember 24, 201369Prof.Veerendrakumar CM, VIMS,Bellary.

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InfertilityWeight lossreduction in serum testosterone concentration and resumption of ovulationClomid: 80% will ovulate, 50% will conceiveMetformin: when added to clomid, improves ovulatory rates FSH injectionsLaparoscopic surgery: wedge resections, laparoscopic ovarian laser electrocauteryIVF


PCOS Ovarian DrillingAdvantages

Disadvantages

High success rateProlonged response Multiple birthsOHSS Dose, duration ovulationInductionAdhesion formation Interceed not beneficialRequires surgery 1/3 require ovulation medicationsPOF riskLess successful in smokers25% vs 95%November 24, 201371Prof.Veerendrakumar CM, VIMS,Bellary.

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