1 / 49

Treatment strategies for the infertile PCOS patient

Treatment strategies for the infertile PCOS patient. PCOS revised diagnostic criteria ~ 2003 Rotterdam consensus ~ 2 out of 3 criteria required. Oligo - and/or anovulation Hyperandrogenism (clinical and/or biochemical) Polycystic ovaries Exclusion of other etiologies.

lhale
Download Presentation

Treatment strategies for the infertile PCOS patient

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Treatment strategies for the infertile PCOS patient

  2. PCOS revised diagnostic criteria~ 2003 Rotterdam consensus ~2 out of 3 criteria required • Oligo- and/or anovulation • Hyperandrogenism (clinical and/or • biochemical) • Polycystic ovaries • Exclusion of other etiologies

  3. Multiple Choices • Lifestyle modification: Weight loss • Clomiphene citrate (CC) • Aromatase inhibitors (AI’s) • Insulin lowering medications • Low dose FSH • Laparoscopic ovarian drilling • IVF: new options

  4. Lifestyle modification • Obesity associated with: • Anovulation • Pregnancy loss, late pregnancy complications • Failure or delayed response to CC, FSH, LOD. • Weight loss recommended as 1st line therapy in obese PCOS women seeking pregnancy

  5. OBESE PCOS - LOSS OF WEIGHT • Loss of >5% of body weight - • Reduces - insulin levels • - ovarian androgen production • - circulating free testosterone • Induces ovulation • Facilitates ovulation induction • Reduces miscarriage rates • Kiddy et al,1992;Hamilton-Fairley et al,1992

  6. Lifestyle modification • Behavioural counselling • Diet (caloric restriction) & exercise • Bariatric surgery

  7. Lifestyle changes in women with polycystic ovary syndrome 2011 • There was no evidence of effect for lifestyle intervention on improving glucose tolerance or lipid profiles and no literature assessing clinical reproductive outcomes. • Long term complicated studies, dropout rates, fertility seeking patients are impatient…

  8. CC ER ER ER ER E2 FSH Day 5 Clomiphene Citrate Treatment

  9. Clomiphene Citrate • Starting on day 2,3,4 or 5 makes no difference • Dose 50-150 mg/day • 6 Ovulatory cycles recommended • 75% of pregnancies in first 3 cycles

  10. Response to clomiphene No response 27% • Ovulation • No pregnancy • 37% Ovulation&pregnancy 36%

  11. Should we monitor clomiphene cycles with ultrasound? Konig, Homburg et al, ESHRE, 2009

  12. Non-Response to Clomiphene Failure to ovulate • Androgens • BMI • LH • Insulin

  13. Reasons for Clomiphene Failure Ovulation but no conception • Anti-estrogen effects - cervical mucus - endometrium • Fetal toxicity: category X

  14. Anti-estrogen effect on endometrium • Endometrial thinning in 15-50% (Gonen &Casper, 1990;Dickey et al, 1993) • Causes ER downregulation and depletion. • Suppresses pinopode formation (Creus et al, 2003) • No pregnancies when endometrial thickness at midcycle< 7mm • Not dose related and recurs in repeat cycles • E2 supplementation of marginal benefit (Homburg et al, 1999)

  15. AI’s Original ArticleLetrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome 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., Heping Zhang, Ph.D., for the NICHD Reproductive Medicine Network N Engl J Med Volume 371(2):119-129 July 10, 2014

  16. Study Overview • This double-blind, multicenter, randomized trial showed that letrozole, as compared with clomiphene, was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome.

  17. Kaplan–Meier Curves for Live Birth. Legro RS et al. N Engl J Med 2014;371:119-129

  18. Congenital malformations • Letrozole: imperforate anus + spina bifida, Dandy walker, CP, VSD • CC: VSD+pul stenosis

  19. Letrozole and fetal toxicity • In 2005, Biljan et al published an abstract of a study that compared 150 babies born to women who had used letrozole with 36,005 babies born to low-risk pregnant women. • The results of this study suggested that letrozole might increase the risk of cardiac and bone anomalies. • Following this publication, the manufacturer of letrozole (Novartis) issued a statement to physicians not to use letrozolein pre-menopausal women.

  20. COCHRANE May 2018 • Live birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse. • There is low‐quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling. • OHSS rates are similar with letrozole or clomiphene.

  21. GONADOTROPHIN STIMULATIONComplications • Multiple folliculogenesis - OHSS - Multiple pregnancies • High miscarriage rate

  22. CONVENTIONAL REGIMEN (IU) 300 225 150 75 5 5 5 5 Days

  23. Results of conventional therapy14 series, 1966-1984, WHO I & II Hamilton-Fairley & Franks, 1990

  24. Low-Dose rFSH (“low-slow”) 100-150 IU 75-112.5 IU 50-75 IU 14 7 7 Days

  25. Low Dose GonadotropinsSummary of ResultsPatients = 841, Cycles= 1556 Updated from Homburg & Howles, 1999

  26. Summary – low-dose FSH • Only a low-dose protocol should be used for ovulation induction in PCOS. • Step-up more efficient and safer than step-down. • Small starting and incremental dose increases recommended with no dose change for 14 days.

  27. Metformin for ovulation induction?Live birth rates • CCMetforminCC+metformin • 22.5% 7.2% 26.8% • Legro et al, NEJM, 2007 • 15.4% 7.9% 21.1% • Zain et al, FertilSteril, 2009

  28. Metformin alone Obese PCOS N=143 PCOS, BMI>30 Placebo vs metformin (1700 mg) for 6 months All on diet and exercise No difference - Placebo and metformin improved menstrual function and weight loss equally Menstrual regularity correlated with weight loss Tang et al, 2006

  29. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. ASRM Practice Committee September 2017 Should not be used as first-line therapy for anovulation because oral ovulation induction agents such as clomiphene citrate or letrozole alone are much more effective in increasing ovulation, pregnancy, and live-birth rates in women with PCOS. insufficient evidence that metformin in combination with other agents used to induce ovulation increases live-birth rates.

  30. LOD for PCOS

  31. Laparoscopic 'drilling' by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome, 2012. • Ovarian drilling with/out ovulation induction, was as effective as medical ovulation induction alone in inducing ovulation, but the risk of multiple pregnancies was lower in the group of women who had laparoscopic ovarian drilling. • Approximately 37% of women will have a live birth and 7% will have a miscarriage with either procedure.

  32. IVF • Main concern: OHSS • Keep the option of agonist trigger • Individual patient-based decision: Freeze all? Fresh transfer? • If fresh transfer: how to handle luteal phase? 2012

  33. LUTEAL PHASE: INTENSIVE E+P OHSS high-risk patients Engmann et al, 2008

  34. HCG-based luteal support: fixed time points • 1,000 IU with trigger (Griffin) • 1,500 IU with OPU (Humaidan) • 1,500 IU 3 days post OPU (Haas) • Can we be more patient specific??? • Can we tailor hCG support to a specific patient endocrine response???

  35. How to rescue the CL? Humaidan et al, 2013

  36. Mid-luteal P after 1,500 IU hCG on day of OPU: 74 nmol/l - too low

  37. How to rescue the CL? No data on mid-luteal P Papanikolaou et al, 2011

  38. How to rescue the CL? Mid-luteal P in the range of 300 nmol/l: good! Andersen et al, 2015

  39. How to rescue the CL? Mid-luteal P median of 190 nmol/l: good! Bar-Hava et al 2016

  40. Luteolysis kinetics (P) Kol et al, RBMOnline 31:633, 2015

  41. Thomsen et al HR 2018

  42. If we rescue the CL, do we really need to supplement with E+P? Timing is everything…just before luteolysis begins, peak P day 7, right on time!

  43. P-free luteal support? • 44 pregnancies, GnRHa trigger followed by day 2 hCG (1,500 IU) support-only (study group). • Data from these 44 cycles were compared with the latest 44 pregnancies obtained following hCG (6,500 IU) trigger followed by progesterone luteal support (control group).

  44. Robust luteal activity post day 2 hCG 1,500 Vanetik et al GynEndocrinol 21:1, 2017

  45. In summary • Following GnRHa trigger, a bolus of 1,500 IU hCG 48 hours after oocyte retrieval adequately rescues the corpora lutea, without the need of any additional support • If OHSS risk: freeze all JUST SIX CLICKS

  46. Very simple… Nothing…..

  47. Benefits and limitation • Patient friendly: cheap, simple, short. No need for daily vaginal P for a long time…. • Effective: Peak P when needed: implantation window. • No early luteal over-stimulation • Limitation: no RCT

  48. Summary: GnRH a is for trigger, hCG for LPS • Post hCG trigger • Consider hCG-based LPS if no OHSS risk • Post GnRH agonist LPS • If high OHSS risk – freeze all • Fresh transfer: single bolus of 1,500 hCG 48 hours post OPU

  49. Putting it all together for the PCOS IVF patient • Always choose antagonist protocol so agonist trigger can be used. • Mild stimulation is the aim: Up to 15 oocytes. • Assess OHSS risk: age, BMI, previous history, number of follicles>12 mm, estradiol level. • If in doubt – freeze all. • If low risk: agonist trigger followed by hCG 1500 IU given 48 hrs post OPU

More Related