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Optimal protocols for Ovulation induction (Assisted Reproductive technologies)
The document discusses ovulation induction (OI) protocols, highlighting the prevalence of anovulation as a significant cause of infertility among reproductive age couples, and outlines various treatment options tailored to specific etiologies of infertility. It emphasizes the necessity of precise diagnostic evaluations and the role of hormonal treatments, including the use of exogenous FSH and aromatase inhibitors like letrozole, in improving ovulation rates and overall fertility outcomes. The guidelines also recommend lifestyle modifications as a first-line approach and suggest that letrozole should be considered as a preferred treatment for patients with PCOS and obesity.
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Optimal protocols for Ovulation induction (Assisted Reproductive technologies)
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- 2. Ovulation Induction Causes ofanovulation Treatment Choices To arrive at algorithms Goals & Objectives
- 3. Infertility Highly prevalent, 15% of reproductive age couples. World: 60-80 million couples
- 4. After 12 monthsof regular inter course After 6 months over 35 yrs. age. What Is The Right Time
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- 7. ‘ Anovulation contributes infertilityin one-quarter of couples ’
- 8. Ovulation Induction • etiologicaldiagnosis – Right patient – Right treatment – Whether or not IUI is needed • Most anovulatory patients – Ideal candidates for OI
- 9. Treatment Options Certaintypes of Infertility – Severe male factor ART – Complete tubal obstruction – Hypergonadotropic anovulation Most types (initially) – Ov. Disorders – 27 % OI – Mild male factor– 25 % OI + IUI – Unexplained infertility – 17 %
- 10. Folliculogenesis Unknown factor ± 3 months14 days Recruitement Selection Dominance Menses OVULATION Hypophysal gonadotrophins 2-4 days Ovulation Induction Resting phase
- 11. Folliculogenesis D-3 D5 D6D8 D9 D14 Recruitement Selection Dominance FSH - FSH + FSH - Ovulation Induction ‘Gate Mehanism’ ‘Mature by chance’
- 12. Process Of Ovulation ‘LHsurge’ maturation Luteinisation Ovulation
- 13. Indications:- • To stimulateovulation in anovulatory infertility • To augment ovulation in ovulatory infertility • To stimulate production of several mature follicles (cos) in conjunction with ART Ovarian Stimulation
- 14. Duration of FSHsecretion limited by negative feedback from estrogen produced by larger follicles Smaller follicles with fewer FSH receptors no longer stimulated to grow by decreasing FSH levels undergo atresia Therefore a single follicle reaches maturation stage FSH estrogen atresia mature follicle Mono follicular ovulation negative feedback reduced stimulation Single follicle development in natural cycles Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
- 15. Duration of FSH secretionincreased by exogenous FSH injections Smaller follicles stimulated to grow by continued FSH support Multiple follicles develop to mature state Increased risk of hyperstimulation & multiple pregnancies Exogenous FSH Estrogen feedback does not work with exogenous FSH More smaller follicles are rescued Multiple follicle develop stimulation continues Risk of hyperstimulation & multiple pregnancies Multiple follicle development in ART cycles Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
- 16. Strategies to improveoutcome (sequential steps) I II III IV Select & prepare Optimize Ov. Stim. protocols Adjuvant medical therapies Management Of luteal phase Age & duration Cause - endometriosis - tubal dysfunction Life style factors - concurrent medical conditions
- 18. PAO Normal Decline 25000 Accelerated Decline Early Menopause •37 – 38 yrs – 25,000 follicles • 51 yrs – menopause, 1000 follicles Accelerated decline in fertility at age • Approx 13.5yrs Time period between accelerated decline in fertility is fixed at Normal Decline 25000 Accelerated Decline Early Menopause
- 19. Ovarian Reserve Markers •AMH 3 – 5 ng/ml (normal) More reliable No cyclical variation • AFC > 5 – 2-6 mm follicles Good predictor, cost effective • FSH > 10 m IU / ml - low reserve Less reliable Rise when Function deeply compromised
- 20. ART requiredin tubal problems and poor semen quality Best results obtained by timely release of mature ovum Extensive Counselling Side effects, risks Expenses Logistics of Treatment and Prognosis Points To Remember
- 21. Anovulatory Infertility • MH •Age of menarche • Frequency of I.C. • Medical, surgical, drug history • BMI – (kg / m²) HISTORY & EXAMINATION INVESTIGATIONS • FSH, LH (N – 5-10 mIu/ml) • Estradiol (20-400 pg/ml) • Prolactin (1-20 ng/ml) • TSH • Testosterone / SHBG • Midluteal progesterone • Rubella immunity • Pelvic ultrasound • Tubal patency test • Semen Analysis
- 22. WHO Classification Group I (5– 10%) Hypogonado- trophic Hypogonadism (Hypothalamic pit. Failure) Group II (75 – 85%) Hypothalamic- Pituitary dysfunction Group III (10 – 20%) Hypergonado- trophic anovulation Group IV (5 – 10 %) Hyper- prolactinaemic anovulation Usually caused by microadenoma FSH/LH production FSH / LH / E2 FSH - N LH / E2 FSH / LH E2 PRL
- 23. Group – I(5 – 10 %) Hypogonadotrophic Hypogonadism (Hypothalamic pit. Failure) Selective failure of pit. – to produce FSH & LH • prim. or sec. amenorrhoea • neg. prog. Challenge • FSH / E2 Causes Absent / abnormal Hypothalamic GnRH sec. Pit. Insensitive to GnRH Physical, Nutritional or Emotional stress Wt. loss Kallman syndrome Sheehan’s syndrome Isolated Gonado- trophin deficiency • excessive exercise • anorexia nervosa May need Hypothalamic-pit. Imaging-to exclude Mass lesion
- 24. Management – hypothalamic-pit.failure Correction of • underwt. • malnutrition & • exercise Pulsatile GnRH (pit. Failure sec. to hypothalamic dysfunction) Gonadotrophins (primary pit. Failure) • pure FSH – not indicated • antiestrogens not effective Group I
- 25. WHO group -III Hypergonadotrophic hypogonadism • Indicates POF < 40 yrs • End-organ deficiency • Neg. prog. challenge • FSH / AMH & E2 • ov. Induction- not indicated • long term HRT Genetic abnormalities • turner’s syndrome (45 XO) commonest • translocations & deletions of X chromosome • Androgen insensitivity syndrome-46XY with intrabdominal gonads - surgical removal Oocyte donation - realistic treat.
- 26. WHO group -IV Hyperprolactinaemic anovulation (5-10 %) Inhibits Gonadotrophin Secretion • low / low normal FSH & E2 • Commonest presentation sec.amenorrhoea • may have oligomenorrhoea, Galactorrhoea, • headaches, disturbed vision- may indicate macroadenoma Etiology • pit.prolactin secreting adenoma • primary hypothyroidism • drugs 30% of women with irregular cycles Prolactin Levels • euestrogenic women – 30 – 40 ng/ml • hypoestrogenic - 20 – 25 ng/ml
- 27. Hyperprolactinaemia - management Etiology Hypothalamic pituitaryimaging – to exclude mass lesion Dopamine agonists • Bromocriptine – 2.5 mg/d • other drugs - Lisuride - Pergolide • cabergoline (long acting) Results • normalizes prl levels - 60 – 85 % • Cyclic menses - 70 – 90 % • ovulatory cycles - 50 – 75 % These drugs are given in combination with Anti-estrogens, Gonadotrophins or pulsatile GnRH.
- 28. WHO gp.II -Hypothalamic pit.dysfunction (Eugonadotrophic Euestrogenic anovulation) • Largest gp – 75 – 85% • Prog. Challenge test +ve • S. FSH/E2 – normal • LH – normal or elevated • 90% women – PCO • Most common endocrinopathy • 5 – 10% of fertile age women • Irregular cycles • clinical / biochemical hyperandrogenism U/S – PCO • 12 ≥ follicles (2-9 mm. diam.) • Ov. Volume > 10 cm³
- 29. PCOS-spectrum of clinical manifestations SYMPTOMS •Hyperandrogenism (hirsutism, acne, alopecia) • Infertility • Obesity POSSIBLE LATE SEQUELAE • Type II diabetes mellitus • Dyslipidaemia • Hypertension • Cardiovascular disease • Endometrial carcinoma
- 31. Definition Of Pcos •Much debated • Refined definition of PCOS by ‘The Rotterdam, ESHRE / ASRM PCOS consensus work shop group, 2004’ Presence of 2 out of 3 criteria : i. Oligo and or anovulation ii. Hyperandrogenism (clinical, Biochemical) iii. Polycystic ovaries Ovary with 12 or more follicles Measuring 2-9 mm. diam. & / or increased ovarian volume > 10 cm³
- 34. PCOS - SerumEndocrinology • LH / Testosterone / Androstenedione • or normal FSH • Normal or high E2 • or normal fasting insulin
- 36. PCOS – Mainfeatures • Hyperandrogenism • Hyperinsulinism • Driven by LH Slim PCO • By insulin, which acts as ‘co- Gonadotrophin’ & • Amplifies effect of LH Obese PCO
- 37. Insulin resistance -PCO • common feature in – Obese & to a lesser extent in lean PCO • Overall prevalence 50 – 75 % • PCOS – 35 % exhibit impaired glucose tolerance (140-199 mg/d1) – 7-10 % meet criteria for type II diabetes mellitus (≥ 200 mg/d1)
- 39. PCOS – menstrualproblems • Likely to benefit from cyclical hormone therapy – In unpredictable, irregular and heavy bleeding • ed risk of endometrial hyperplasia and adeno ca.- – Risk factors – obesity, long term unopposed est., nulliparity and infertility • Important to shed endometrium at least every 3 months.
- 40. Supra-physiologic synthesis of estrogen Strongnegative feedback signals to hypothalamus & pituitary Low GnRH production, with +ve feedback on LH Low FSH & high LH No ovulation Hypothalamus/Pituita ry Strong estrogen -ve feedback Low FSH Follicle does not develop Low GnRH Anovulation Very high levels of estrogen High LH 1 2 3 4 5 6 Anovulation in PCOS patients Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
- 41. WHO group II– management Life style changes • 50% PCOS - ≥ 30 BMI • Loss of 5% body wt. - 30% reduction in visceral fat. oral anti- estrogens injectable gonadotrophins laparoscopic ov. drilling
- 42. Principles of O.I LifeStyle Changes • Fertility adversely affected by an individual being overweight, hyperandrogenism and elevated serum LH • Optimize health before OI induce regular unifollicular ovulation, minimize risk of OHSS and multiple pregnancy
- 43. Life Style Management •Weight reduction ‘first-best’ treatment • Weight loss or prevention of weight gain recommended (diet, exercise and behavioral interventions) • Should be the ‘first–line therapy’ for 3–6 m., arbitrarily aiming for a 5-7 % weight reduction
- 44. Bariatric Surgery • Inwomen with BMI > 35 kg/m² after failed attempts at weight loss for >than 1 yr. • Risks of surgery and p-o nutritional deficiencies to be informed • Pregnancy to be avoided for at least 6-12 m. after surgery
- 45. Normogonadotropic normogonadism – medicaltreatment oral anti- estrogens • CC • Tamoxifen insulin sensitizing agents • metformin Aromatase inhibitors • letrozole • anastrazole injectable gonadotrophins alone With GnRH-a, GnRH-ant.
- 46. Aromatase Inhibitors • Letrozole– (2.5 – 7.5 mg/d) • Anastrazole – (1mg/bd) • 3rd generation AI • Non-steroidal, potent and selective
- 47. Ovaries Brain Adipose tissue Muscle Liver Breast tissue Malignant breast cancers Androstenedione Testosterone Estrogen Estradiol Aromatase Role of aromatase enzyme Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771
- 48. Inhibits aromatase inovaries & peripheral tissues reducing estrogen levels Negative feed back being active stimulates hypothalamus- pituitary axis GnRH release produces FSH FSH-mediated stimulation of follicle Rising estrogen level from follicle suppresses FSH leaving a single dominant-follicle Hypothalamus Pituitary -ve feedback stimulation Smaller follicles undergo atresia Single follicle develop estrogen –ve feedback FSH stimulation 1 2 3 4 6 androstenedione estrogen aromatase inhibition GnRH released Falling FSH 5 Letrozole: Mechanism of action Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
- 49. Rapid clearanceof drug from body Reversible aromatase inhibition Elevated FSH supports more aromatase synthesis androstenedion e estrogen aromatas e Will it affect oocyte and pregnancy results? androstenedione Will limit androgen accumulation in ovaries Estrogen production should be relatively normal at time of ovulation increased follicular sensitivity to FSH Testosterone augments FSH receptors in follicle Testosterone augments IGF in follicle folliculogenesis Would low estrogen/high androgen levels be harmful? Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
- 50. Prescribing information; CasperRF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771; Harriet et al. Drugs 1998; 56(6):1125-1140; Bhatnagar AS. Breast Cancer Res Treat 2007;105:7–17 Letrozole: Pharmacokinetics Parameter Data Absorption Rapid & complete (Cmax within 1 h) Bioavailability 99.9% Food Absorption not affected by food Metabolism Inactive metabolite, by CYP 2A6 & 3A4 Elimination T1/2 ~2 days (45 h) Excretion Renal (90%), rapid clearance, no accumulation Safety Well tolerated Letrozole: Pharmacokinetics
- 51. Advantages of AIover CC –Does not deplete ERS throughout the body –Keeps H-P axis intact –Short acting • Improved endometrial thickness and cervical mucus • Monofollicular and better folliculogenesis
- 52. Current evidence supporting‘Letrozole’ for ovulation induction The need for an alternative to CC for ovulation induction was realised since 1990. Robert casper and mohamed F-M mitally proposed concept of aromatase inhibitors as an alternative to O.I. A pilot study was initiated to test Letrozole for O.I in women with CC failure, 2001. An oral abstract in 2005, reported congenital anomalies in 150 babies born from infertile women with Letrozole since then large studies with better design have been published comparing safety of Letrozole & CC in infertile group Available medical data shows that Letrozole is at least as effective as CC
- 53. Legro RS, etal. N Engl J Med. 2014 Jul 10;371(2):119-29. Richard S. Legro, M.D., Robert G. Brzyski, M.D., Ph.D., Michael P. Diamond, M.D., Christos Coutifaris, M.D., Ph.D., William D. Schlaff, M.D., Peter Casson, M.D., Gregory M. Christman, M.D., Hao Huang, M.D., M.P.H., Qingshang Yan, Ph.D., Ruben Alvero, M.D., Daniel J. Haisenleder, Ph.D., Kurt T. Barnhart, M.D., G. Wright Bates, M.D., Rebecca Usadi, M.D., Scott Lucidi, M.D., Valerie Baker, M.D., J.C. Trussell, M.D., Stephen A. Krawetz, Ph.D., Peter Snyder, M.D., Dana Ohl, M.D., Nanette Santoro, M.D., Esther Eisenberg, M.D., M.P.H., and Heping Zhang, Ph.D., for the NICHD Reproductive Medicine Network* 2012-2017 Recent Clinical Evidence Conclusions LTZ was associated with higher live-birth & ovulation rates LTZ was superior to CC as a treatment for anovulatory infertility in women with PCOS
- 54. Latest evidence...2017! Tatsumi T,et al. Hum Reprod. 2017 Jan;32(1):125-132.
- 55. LTZ stimulation Reduces risk of miscarriage Noincrease in risk of Major congenital anomalies Adverse pregnancy outcomes Adverse neonatal outcomes Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132. Conclusions Safer option for mild ovarian stimulation
- 56. Society Year Recommendation AmericanCollege of Obstetricians and Gynaecologists 2016 LTZ should be considered as 1st-line therapy for OI in patients with PCOS & BMI > 30 because of increased LBR compared to CC WHO guideline 2016 CC or LTZ (when available & permissible) should be 1st line pharmacological therapy to improve fertility outcomes in women with PCOS & anovulatory infertility, with no other infertility factors Australian National Health and Medical Research Council (NHMRC) guideline 2015 LTZ, under caution, could be offered as pharmacological treatment for OI indicated for infertile anovulatory women with PCOS with no other infertility factors -Considered as 1st line pharmacological treatment for OI in therapy naive, infertile anovulatory women with PCOS with no other infertility factors AACE/ACE/Androg en Excess and PCOS Society Disease State Clinical Review 2015 Treatment for women with PCOS & anovulatory infertility should begin with oral agent such as CC or LTZ Guidelines
- 57. Advantages of letrozoleover CC Parameters Clomiphene citrate Letrozole MOA SERM Aromatase inhibitor Half-life Long, 5-7 days Short, 45 h Anti-estrogenic effects Thin endometrium & altered cervical mucus Thick endometrium & favourable cervical mucus Uterine blood flow Decreased Increased Miscarriages Possibly high Less incidence OHSS risk High Low Multiple pregnancy High Low Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
- 58. Aromatase inhibitors - Endometriosis& adenomyosis - Uterine fibroids - Endometrial stromal sarcoma ‘most benefit’ E2 dependent disorders - Endometriosis - Breast ca. - Inherent clotting abnormality Luteal phase aromatase inhibitors - drastically reduces E2 levels - potential use in egg donors and in high risk of OHSS
- 59. Oral antiestrogens CC Selective estrogen receptormodulator (SERM) Tamoxifen Mild antiestrogenic Estrogen Agonist Reduced negative est. feed back Alters GnRH sec. pattern Antagonist less desirable peripheral action thinnning of endomet. & cx mucus Ov. Women - pulse frequently PCO – pulse amptitude pituitary gonadotrophins ovulation 20 – 40 mg/d • CC resistants • side effects to CC
- 60. CC – Non– steroidal triphenyl ethylene derivative (2-isomers) En –CC (62%) • more potent • relatively short ½ life Zu – clomiphene (38%) • clears slowly • may accumulate gradually over a series of cycles
- 61. CC Dosage • orally –25 -100 mg/d 3rd – 7th day if responds - ov. occurs with in 5-7 d of last CC tab. • extended CC regimen 7 – 10 days • ‘stair-step protocol’ side effects • vasomotor disturbances • visual – 1-2% reversible • Alopecia • Ov. enlargement • U/s before each new CC cycle
- 62. CC Risks • multiple pregnancy •approx – 7-10% • treat with lowest effective dose • OHSS – small risk • Ov. Ca • ed risk with > 12 cycles • to recommend for – no more than 6 cycles Results • induces ovulation - 70 – 85% • cumulative preg. Rate (6 m) - 40 – 60%
- 63. CC resistant: Ifpatient fails to ovulate despite 6 CC cycles CC failure: CC-resistant plus women who ovulate, but do not get pregnant or get pregnant but end in miscarriage About 20-25% of anovulatory women are CC- resistant* Clomiphene resistant / failure Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9. *Azargoon A, et al. Iran J Reprod Med. 2012 Jan; 10(1): 33–40.
- 64. Management of CC-resistantPCOS Obese women Lifestyle modifications =weight loss (Diet + Exercise): If BMI> 29 kg/m2 Non-obese women Metformin + CC (3-6 cycles) Letrozole (3-6 cycles) LOD Gonadotropins In vitro fertilization Failure Hashim HA (2012). Management of Women with Clomifene Citrate Resistant Polycystic Ovary Syndrome – An Evidence Based Approach, Polycystic Ovary Syndrome, Dr. Mukherjee S. (Ed.), InTech. LOD: Laparoscopic ovarian drilling.
- 65. Insulin Sensitizing Agents PCOS Increasedinsulin resistance Hyperinsulineamia - 80% obese - 20% normal wt. PCOS LH / Ov. Androgens Hyperandrogeneamia Follicular atresia
- 66. • 500 –2,500 mg/d - side effects - G1 symptoms • ‘caution’ - renal & Hepatic function - undergoing surgery - with IV contrast administration • Metformin + CC combination better than metformin alone Indications • PCOS – resistant to CC • BMI > 25 • Associated glucose intolerance Metformin – widely used Insulin - Sensitizers
- 67. Metformin - recommendations i.‘Could’ be used alone to improve ovulation rate and PR in PCOS who are anovulatory with no other infertility factors, or if facilities are not available for monitoring of CC or Let, which are more effective. ii. Can be combined with CC to improve fertility outcomes
- 68. Adjuvant & CombinationTreatments – Glucocorticoids Follicular phase (D 5-14) » Predn. 5mg/d or » Dexamethasone 0.5-2mg/d – Exogenous HCG – Metformin – Deserve consideration who prove CC resistant – Before proceeding to ov. Drilling or treatment with gonadotrophin – Preliminary suppression; contraceptives
- 69. Laparoscopic ov. drilling alternatefor CC resistant PCOS success rates comparable with FSH • risks of surgery / anaesthesia • adhesion formation • potential risk of POF in the future Favourable responders • slim women • LH > 10 IU/L
- 71. Contra indications • Ovarianfailure • untreated Hyperprolactinaemia • uncontrolled thyroid, adrenal function • Pituitary tumours • Ov. Cysts • Lack of appropriate monitoring, patient cooperation or trained personnel 2nd line treatment for O.I Gonadotrophin therapy Indications • Hypothalamic pituitary dysfunction • Hypogonadtropic hypogonadism • CC failures • ART
- 72. Gonadotrophins Increase the no.of follicles recruited into the growing pool + Maintaines their growth until the stage of ovulation One or more oocytes are available for fertilisation
- 73. Mechanism Of IncreasedOvulation Rate Rescuing of follicles undergoing early atresia Recruitment of smaller healthy follicles Reduced follicular atresia
- 74. Different Gonadotropin prep. FSHLH activity content activity content hMG 75 IU 75 IU pFSH 75 IU 1 IU HP FSH 75 IU < 0.1 IU Recombinant r-hFSH follitropin-a 75 IU 0 r-hFSH follitropin-b 50-100 IU 0 r-hLH 0 75 Corifollitropin α r-hCG
- 75. ‘Which preparation touse’ Recombinant drugs • allergic reactions • potential risk of infection • High specific activity: less acid isoforms • Sub-cutaneous administration • HMG, purified urinary FSH & recombinant FSH - equally effective • choice depends on • availability • user’s convenience • cost
- 76. Dilemmas Are : Consider– • Wt. • AFC / PCO • Previous responses What dosage 5th, 6th & 7th day 7th & 8th day 3rd & 8th day 5th & 7th day (alt.days)! When to start No set protocols
- 77. Pool of recruitablefollicles Follicular response to FSH Genetic polymorphisms FSH bioavailability BMI DOSE DECISION
- 78. ‘Which Gonadotrophin ToUse’ • FSH – represents ‘primum movens’ of follicle growth • LH – autonomously & in synergy with FSH to Stimulate support foll. development & function • HMG – Hypogonadotropic hypogonadism • FSH – for PCOS • CC + FSH / HMG – preferably Regimens step step combined up down • Ovulation trigger • Luteal support HCG GnRH-a
- 79. Low dose Step-upregimen • allow the FSH threshold to be reached gradually,minimizing excessive stimulation and hence decreasing the risk of multifollicularresponse • monofollicularg rowth reported in 69% of cycles(Hombury& Howles, 1995) • recommend in PCOS patients who have tendency for over-response during ovarian stimulation
- 81. Low dose Step-downregimen • Induction ovulation protocol which mimic more closely the FSH threshold and window of the natural cycle • Another approach for PCOS patients with monofollicular growth reported in 56 % of cycles (van sant brink et al, 1995) • So far, results compared with step-up approach are conflicting but some suggestions of shorter duration of treatment and smaller conception of gonadotrophin, but lower monofollicular growth and higher hyperstimulation rate
- 83. ‘Low-Slow treatment regimens’ •Expense and frustration associated with canceled cycles usually can be avoided by; (involving low doses 37.5 – 75 IU/d) –Small increments & a longer duration of treatment • Most gonadotrophin stimulations span an interval of 7 – 12 days
- 84. Cycle Cancellation OVARIAN OVER-RESPONSE • Cycle abandoned because of the risk of high multiple pregnancy • HCG should be withdrawn and patient should be advised not to have intercourse POOR OVARIAN RESPONSE • Low responders usually encountered in patients with high basal FSH or patients with characteristics of more severe PCOS (eg : obesity, hyperandrogenism) PREMATURE LH SURGE • Adjuvant use of OC pretreatment or down regulation by regulation by GnRH before ovarian stimulation may be considered in subsequent cycle
- 85. Ovulation Induction –GnRH analogues + HMG (agonists / antagonists) As a routine in most IVF centres Severe PCOS Poor responders to HMG Premature LH surges
- 86. GnRH-agonist & Antagonist Regimen Ago n i s t A n t a go n i s t
- 88. GnRH – analogues& Gonadotrophins in Hyperstimulation rate Risk of multiple pregnancy Higher cost Routine use not justified
- 89. COMPLICATIONS Multiple Pregnancy Increased incidence of heterotopic pregnancies OHSS Gonadotrophin Therapy
- 90. Ectopic & HeterotopicPregnancies • Incidence of ectopic – 1.5 - 2 % With Ovulation Induction - 3 % With ART - 5 % • Incidence of Heterotopic Pregnancies – 1 in 30,000 With Ovulation Induction & ART – 1 % • Surgical treatment – viable option 1/3rd spontaneous miscarriages • A high index of suspicion required
- 91. Ovarian Hyperstimulation Iatrogeniccondition ‘epidemic’ caused by doctors Incidence of mod. & severe OHSS ranges from 0.1 – 4% Condition can not be completely avoided
- 92. Mild OHSSis seen 3 - 20% and severe form in 0.4 - 4% Increased risk in younger women and PCO PCO highly sensitive to Gonadotrophins OHSS
- 93. OHSS ‘ Loss ofcontrol over COH ’ Only after overstimulated ovaries ‘ exposed to hCG inj ’ C U L P R I T HMG HCG
- 94. AN OHSS –FREE CLINIC Segmentation – of – IVF treatment
- 95. Segmentation of IVF OHSScan be ‘erased’ by applying ovarian stimulation using a combination of GnRH-antagonist with GnRH-agonist trigger - freeze all
- 96. Gonadotrophin - Risks OHSS Mildsevere 3-2% 0.4-4% • strictly speaking – OHSS can not be prevented • Adopt low dose regimens • cycle cancellation • GnRH–ant. protocols • cabergoline 0.5 mg/d - 8 d. from HCG • GnRH-a triggering • Luteal support – prog. High order Multiple preg. Ways to aggressive reduce cancellation policy • monovulatory cycles • normogonadotrophic • diet & exercise • insulin sensitizing agents • LOD Heterotopic preg. • ectopic preg – 1.5 – 2% - with O.I – 3% • Heterotopic preg. - with O.I & ART– 1%
- 97. Gonadotrophins – strongrecommendations ‘could’ be second-line pharmacological therapy in PCOS with CC resistance and / or failure Where appropriate to use gonadotrophins – provide low dose protocol and appropriate monitoring – to minimize risk of multiple pregnancy
- 98. Gonadotrophins – pointsto be considered i. Cost of intervention ii. Expertise required for use of intervention iii. Degree of intensive monitoring required iv. Implications of multiple preg & risk of OHSS v. The most ‘cost-effective’ gonadotrophin should be used – no significant difference in effectiveness between preparations
- 99. Ovulation Induction -IUI Associated male factor Failure to conceive despite successful O.I
- 100. ART / IVF- When Anovulation – not an indication Failed 1st & 2nd line treatment With associated pathology – Tubal damage Severe endometriosis PGD Male factor Low ovarian reserve
- 101. PCOS / IVF– Strong recommendations i. Increased risk of OHSS; needs careful monitoring ii. GnRH-ant. protocol safer to reduce risk of OHSS iii. If a long GnRH-a protocol used; addition of metformin reduces risk of OHSS iv. Insufficient data to recommend IVM for anovulatory PCOS
- 102. Ovulation Induction –Effective Approaches 1. Antiestrogens (with clomiphene) ovulation – 77 % Pregnancy – 47 % Singleton birth rate – 47 % Multiple live births – 2 % 2. FSH / HMG Induction Ovulation – 82 % Pregnancy rate – 56 % Single birth rate – 43 % Multiple birth rate – 5 % 3. Remaining group IVF – 40 % Live birth rate after max. 3 cycles
- 103. Fertility Treatment –“Futile” • ASRM defines – “Futile” when prognosis for desired end ≤ 1 % • Women at all Ages with FSH 10 – 15 mIU/ml & E2 ≥ 40 pg/ml - unlikely to achieve live birth after COH - IUI • Forty & Over - immediate IVF
- 104. Questions & Concerns Factors determining recruitment & Selection not defined Recruited follicles are also Susceptible to atresia Follicle selection does not gaurantee ovulation
- 105. Congenital anomalies I. CC •NTD • Hypospadias II. OI / IUI Higher risk with i. Increasing intensity of treatment ii. Severity of parental reproductive morbidity III. ART crude total malformation rate – 8.3 % vs 5.8 in background population
- 106. Ovarian Cancer PersistentStimulation may increase mitotic activity of granulosa cells might have carcinogenic effect Increased risk of Border line and invasive tumours (Mosagard et al,1997) Prolonged use of CC may increase risk However evidence is unclear and requires prospective studies
- 107. Difficult Situations In OvarianStimulation Ovarian deficiency Obesity Polycystic ovaries Endometriosis
- 108. Patients At RiskOf Ov. Deficiency Age History of ov. Surgery Short cycles High FSH Prior insufficient response Severe endometriosis Smoking Pelvic Infection Strong F/H of early menopause
- 109. Whist women withPCOS may take longer to become pregnant their life time fertility is not impaired (koivunen et al’, 2008) May display sustained fertility with advancing age as compared with infertile ovulatory women (Mellembakken et al, 2011)
- 110. Diagnosis Of CauseOf Anovulation Amenorrhoea Progestogen challenge test ( MPA 20mg x 5days ) Bleeding +ve -ve Chronic anovulation E-P challenge test eg. PCOS +ve -ve Gonadotropin assay End organ fault Pregnancy >40 mIU / ml < 5 mIU / ml Ovarian failure Hypogonadotropism
- 111. Flowchart of diagnosisand treatment History and examination FSH and prolactin prolactin Pituitary imaging TSH Dopamine agonists Rarely surgery FSH Karyotype Autoantibody Donor eggs Normal FSH Body weight Pelvic scan Weight reduction Anti-oestrogen / letrozole Insulin sensitizing agents Gonadotrophins Ovarian drilling FSH Body Weight Pituitary imaging Weight gain Pulsatile GnRH Gonadotrohpin Hyperprolactinaemia Hypergonadotrophic Hypogonadism Hypogonadotrophic Hypogonadism Normogonadotrophic anovulation
- 115. Conclusion Prescribe onlyif necessary Imitate Physiology as much as possible Analyse results carefully To consider multiple pregnancies as failure Consider newer techniques to increase success rates and reduce risks
- 116.