Treatment strategies for the infertile PCOS patient PCOS

Treatment strategies for the infertile PCOS patient

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

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

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

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

Lifestyle modification üBehavioural counselling üDiet (caloric restriction) & exercise üBariatric surgery 6

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

Clomiphene Citrate Treatment CC ER ER E 2 FSH Day 5 8

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

Response to clomiphene e s n o p s e r No 27% Ovulation&pregnancy 36% 10 Ovulation -No pregnancy 37%

Should we monitor clomiphene cycles with ultrasound? With U/S + h. CG No U/S or h. CG n 105 150 Cumulative pregnancy rate 48% 34. 7% Deliveries 35. 6% 26. 7% Multiple pregnancies 0 1 11 Konig, Homburg et al, ESHRE, 2009

Non-Response to Clomiphene Failure to ovulate üAndrogens üBMI üLH üInsulin 12

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

Anti-estrogen effect on endometrium ü Endometrial thinning in 15‐ 50% (Gonen &Casper, 1990; Dickey et al, 1993) ü Causes ER downregulation and depletion. ü Suppresses pinopode formation (Creus et al, 2003) ü No pregnancies when endometrial thickness at midcycle < 7 mm ü Not dose related and recurs in repeat cycles üE 2 supplementation of marginal benefit (Homburg et al, 1999) 14

AI’s Original Article Letrozole 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 15

Study Overview ü 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. 16

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

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

Letrozole and fetal toxicity ü 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. üThe results of this study suggested that letrozole might increase the risk of cardiac and bone anomalies. üFollowing this publication, the manufacturer of letrozole (Novartis) issued a statement to physicians not to use letrozole in pre‐menopausal women. 19

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

GONADOTROPHIN STIMULATION Complications üMultiple folliculogenesis ‐ OHSS ‐ Multiple pregnancies üHigh miscarriage rate 21

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

Results of conventional therapy 14 series, 1966 -1984, WHO I & II Hamilton-Fairley & Franks, 1990 23

Low-Dose r. FSH (“low-slow”) 100 -150 IU 75 -112. 5 IU 50 -75 IU 14 7 Days 24 7

Low Dose Gonadotropins Summary of Results Patients = 841, Cycles= 1556 Updated from Homburg & Howles, 1999 25

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

Metformin for ovulation induction? Live birth rates CC 22. 5% Metformin 7. 2% CC+metformin 26. 8% Legro et al, NEJM, 2007 15. 4% 7. 9% 21. 1% Zain et al, Fertil Steril, 2009 27

Metformin alone Obese PCOS üN=143 PCOS, BMI>30 üPlacebo vs metformin (1700 mg) for 6 months üAll on diet and exercise üNo difference ‐ Placebo and metformin improved menstrual function and weight loss equally üMenstrual regularity correlated with weight loss Tang et al, 2006 28

Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. ASRM Practice Committee September 2017 üShould 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. ü insufficient evidence that metformin in combination with other agents used to induce ovulation increases live‐birth rates. 29

LOD for PCOS 30

Laparoscopic 'drilling' by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome, 2012. üOvarian 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. üApproximately 37% of women will have a live birth and 7% will have a miscarriage with either procedure. 31

IVF 2012 üMain concern: OHSS üKeep the option of agonist trigger üIndividual patient‐based decision: Freeze all? Fresh transfer? üIf fresh transfer: how to handle luteal phase? 32

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

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

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

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

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

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

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

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

Thomsen et al HR 2018 41

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! 42

P‐free luteal support? ü 44 pregnancies, Gn. RHa trigger followed by day 2 h. CG (1, 500 IU) support‐only (study group). ü Data from these 44 cycles were compared with the latest 44 pregnancies obtained following h. CG (6, 500 IU) trigger followed by progesterone luteal support (control group). 43

Robust luteal activity post day 2 h. CG 1, 500 Vanetik et al Gyn Endocrinol 21: 1, 2017 44

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

Very simple… Nothing…. . 46

Benefits and limitation üPatient friendly: cheap, simple, short. No need for daily vaginal P for a long time…. üEffective: Peak P when needed: implantation window. üNo early luteal over‐stimulation üLimitation: no RCT 47

Summary: Gn. RH a is for trigger, h. CG for LPS • Post h. CG trigger üConsider h. CG‐based LPS if no OHSS risk • Post Gn. RH agonist LPS üIf high OHSS risk – freeze all üFresh transfer: single bolus of 1, 500 h. CG 48 hours post OPU 48

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