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OVULATION INDUCTIONDr Anitha MAssociate ProfessorS A T HospitalTrivandrum. Ovarian stimulation aims at the developmentof one or more ovarian follicles to reach thestage of maturity culminating in the release ofone or more mature oocytes ready forfertilization . Ovulation Induction mono ovulation Controlled Ovarian Hyperstimulation multifollicular development What are the objectives ofovulation induction .To induce monofolliculardevelopment and ovulation inanovulatory infertile womenTo augment ovulation inunexplained infertility.For controlled ovarianhyperstimulation COH in IUI and Duration of FSHsecretion limited byreduced stimulation negative feedback from.negative feedback estrogen produced bylarger follicles Smaller follicles withfewer FSH receptors nolonger stimulated to grow.by decreasing FSH levelsundergo atresia Thereforea single folliclereaches maturation stage.Mono follicular FSH stimulatesgranulosa cellproliferation andaromatase production.granulosa cells LH stimulatesandrostenedioneproduction by thecacells that diffuses into.granulosa cellsandrostenedione Aromataseconvertsandrostenedione intotheca cells. Prevalence ofPolycystic ovaries arepresent in5 7 of womenworldwide .PCOS with anovulationconstitute 60 85 ofWHO group II womenwho would benefitfrom OI therapy. Life style interventions Important in WHO 2 group anovulatory Insulinresistance Hyperandrogenism. Clinical Biochemical Obesity 50 of PCOS have BMI 25 kg m2 miscarriage Congenital abnormalities. Gestational diabetes PIH Still birth Maternal mortality Long term effects DM CVD Benefits of weight reduction. Normalises endocrine mileu Improvement of insulin sensitivity hyperandrogenism Return of regular spontaneous ovulation All obese women with a BMI 35 kg m2 .seeking pregnancy should be denied any formof fertility treatment until limited at least 5 10 weight reduction has been achieved Stop smoking depletes follicles Diet restriction reduction of glycaemic load. Exercise Mechanism of Ovarian Stimulation Pharmacological agents Moderate and manipulate endogenousgonadotropins . Oral agents Selective Oestrogen receptor modulators Clomiphene citrate Tamoxifen Modulate oestrogen production Aromataseinhibitors .Letrozole Anastrazole Clomiphene citrateFirst line drug for most anovulatory oroligo ovulatory infertile women withadequate estrogen WHO type II esp.and a positive progesterone challengeNot for women with low E levels WHOtype I and III women Clomiphene Citrate Greenblatt in 1962 . Long half life 5 21 days Stored in body fats Estrogen agonist and antagonist SERM Agonist properties manifest only whenendogenous oestrogen levels are very low . Racemic mix of enclomiphene andZuclomiphene Enclomiphene more potent antioestrogenic Responsible for the ovulation stimulation Half life of few days . Zuclomiphene cleared more slowly Responsible for the peripheral action CC binds to ER anddepletes receptorconcentrations.Hypothalamusestrogen ve feedbackinterruptedFSH stimulation3 continues.More smaller follicles areMultiple follicles Mechanism of action Binds to estrogen receptors Bindings lasts upto weeks . Depletes estrogen receptors Main site is hypothalamus also the pituitary ER depletion interpreted as low levels Reduced negative feed back GnRH FSH LH . So intact HT Pituitary axis endogenous E Why the peripheralantiestrogenic effects CC has a long half life of days upto 7Prolonged ER depletion.This results in prolonged increase of FSHSupraphysiological levels of EAll this causes the antiestrogenic effects inthe endometriumExtension of the FSH window leads to.multiple ovulation and increased multiple 50 mg daily D 2 D 5 Increments of 50 mg Dose ranging from 50 250 mg day No indication to further dose once ovulation. Higher doses do not improve pregnancy rates Failure to respond to 150 mg will requirealternative treatments Pregnancy rates increased in the first 3 cycles Beyond 6 cycles not recommended BFS .12 m RCOG Results of accelerated dose and extendeddose has not been found to be effective Follicular monitoringBaseline scan on day 2.Start monitoring on day 7 10Pre ovulatory follicle 17 to 25 mmEndometrial thickness at least 7 mmtriple line appearance Efficacy of.ClomipheneClomipheneinduces ovulation in 60 80 of well selected casesMore than 70 will ovulate at the 50 100 mg doses.However pregnancy rate is only 20 Pregnancy rate cycle is a mere 10 Failure to conceive within 6 monthsof ovulatory cycles should warrantother investigations. Drawbacks ofclomiphenepituitary Induces ovulationhypothalamusAnti Estrogenic effects contributing to reduced pregnancy.clomiphene Endometrial thickness 5 6 mm Reduction in glandular densityisomers endometrium Increase in number of vacuolated cells Decreased uterine blood flow during earlyluteal phase.cervical mucus Change in quantity or quality of mucusMiscarriage rate of Clomiphene side effectsMultiple pregnancy 3 13 Hyperstimulation 6 .Vasomotor flushesVisual symptoms like blurring of visionBreast tendernessPersistence of follicular cystsAbdominal discomfort. Question of whether treatment with ovulationinduction drugs increases risk of ovariantumours or cancer remains unsettled butcannot be summarily dismissed Women who are offered ovulation induction.should be informed that a possible associationbetween ovulation induction therapy andovarian cancer remains uncertain Practitioners should confine the use ofovulation induction agents to the.lowest effective dose and duration of use Nice Fertility Guidelines 2004 Adjuvants to clomipheneBromocriptine or cabergoline inassoc hyperprolactinaemia.Thyroxine in assochypothyroidismDexona in the rare case ofincreased DHEAS levelsHCG for the LH surge. Clomiphene resistance CC resistance CRA Failure to ovulate Insulin resistance Inappropriate indication.About 20 25 of anovulatory women arCC resistantCC failures CCF Ovulate but fail to get pregnant Underlying other factors. Antioestrogenic effects Clomiphene resistance how to manage CC gonadotrophinsGonadotrophins.Lap ovarian puncture Aromatase Inhibitors Aromatase enzyme catalyses the rate limitingstep the conversion of androgens tooestrogens . Role of aromatase Ovariesandrostenedione Adipose tissuearomatas Muscle.testosterone e estradiol Breast tissue Malignant breastCasper RF and Mitwally M et al Review Aromatase inhibitors for ovulation induction J Clin Endocrinol Metab 2006 91 Pharmacokinetics.Rapidly absorbed bioavailabilityWidely dist in all tissues esp brainMetabolised and eliminated in liverHalf life is very short about 50 Comp and reversibly binds to haem.subunit of aromatase3 ve feedback stimulation Inhibitsaromatase in ovaries and4 GnRH released Hypothalamus peripheral tissues reducing.Pituitary estrogen levels Negativefeed back being activestimulates hypothalamus pituitaryFSH stimulation axis5 GnRH release produces FSH. FSH mediated stimulation ofFalling estrogen ve feedback2 follicle Risingestrogen level from follicle.suppresses FSH leaving a singledominant follicleSmaller follicles Normal FSH windowundergo atresia. Physiological levels of Eandrostenedion estrogen6 Single follicle develop earomatase inhibition Peripheral.Androgen accumulate in folliclestimulates FSH receptors and IGF 1which promote folliculogenesis Low E levels results in up regulation ofER in the endometrium and increasing.sensitivity to subsequent E andthereby normal endometrialdevelopment Dose of letrozoleDosage is 2 5 5 mg daily from day.3 for 5 daysSide effects very mild GIT related and seldom necessitatediscontinuation Clomiphene Letrozole.Long half life Short half life only 2Mechanism is receptor Mechanism isblockade aromatase inhibitionAntiestrogenic effects No such effectsSupraphysiological Physiological levels of.levels of E detrimental Eto embryosReceptors are depleted No effect on receptorsin the endometrium and ER are upregulated andso poor endometrial endo response is good.response may impairimplantationLess chanceMore chance ofmiscarriage. Letrozole along withgonadotrophins in COH Letrozole plusgonadotrophinsSignificant reduction in FSH dose.Less antiestrogenic effectscompared with clomiphenePregnancy rates equivalent toFSH alone and twice that withFSH and clomiphene.Marked reduction in costMay improve response to FSH inpoor responders What is the place ofaromatase inhibitors .1 Ovulation induction inclomiphene resistance andfailures in PCOS andunexplained infertility2 As an alternative to clomiphene.3 Along with FSH for COH for IUI4 In poor responders of FSH Ovarian stimulation by aromatase inhibitors isassociated with significantly lower oestrogenproduction per follicle hence overall lower E. Certain groups are definitely benefitted by Women with oestrogen dependent disorderslike endometriosis or breast cancer or thosewith inherent clotting abnormality Gonadotropins. CRA CCF HMG HP HMG Recombinant FSH Direct stimulation of the follicular growth Step up Step down protocol Strict cancellation criteria 3 follicles 12 mm. Ovulation 82 Pregnancy 58 Multiple pregnancy 11 44 GonadotrophinsClose monitoring.Usually step up protocolsStart with lowest dose in PCOSTVS from day 7 and increased doseMultiple pregnancy 20 Insulin sensitizers. Metformin Biguanide Restores endocrine mileu Lowers insulin resistance Lowers hyperandrogenism Normalises ovarian response to FSH. Dose 500 mg 2 3 times daily Not a first line drug combination with CC not superior Second line in patients with CRA and BMI 35 and IGT ESHRE ASRM Not licensed for OI. GI side effects nausea vomiting diarrhea Drilling small holes in the ovarian cortex drains androgen rich fluid Cumulative pregnancy rate live birth rate abortion rate comparable with gonadotropins. Multiple pregnancy rates lowered significantly Risk of surgery accelerated decline of ovarian To take home In chronic anovulation life style modificationmay be the first step . Important to distinguish between WHO Type 1and 2 anovulation Follow the traditional sequence for OI CCfollowed by exogenous FSH Frequent monitoring and strict cancellation.criteria will prevent serious complications likehigh order pregnancy and OHSS Enhancement of local circumstances aiming toreduce hyperinsulinaemia andhyperandrogenism. CC for not more than 6 cycles Start with lowest dose accelerate only when Gonadotropins in CRA CCF COH Ovulation induction to be restricted topatients presenting with infertility and chronic.anovulation and it should primarily aim atrestoring physiology A baby is God s opinion that theshould go on Carl Sandburg.Ovulation Induction â€“ mono ovulation. Controlled Ovarian Hyperstimulation â€“ multifollicular development. ... PCOS with . anovulation. constitute 60-85% of WHO group II women who would benefit from OI therapy. Prevalence of PCOS. Life style interventions. Important in WHO 2 group â€“anovulatory. Insulin resistance . Hyperandrogenism.