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 Clomiphene citrate (CC) Aromatase inhibitors (AI’s)
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. Clomiphene Citrate TreatmentER E2
FSH
Day 5 CC
Figure 2. Administration of clomiphene citrate (CC) from days 3 to 7 results in estrogen receptor (ER) depletion at the level of the pituitary and mediobasal hypothalamus. As a result, estrogen negative feedback centrally is interrupted and FSH secretion increases from the anterior pituitary leading to multiple follicular growth. By the late follicular phase, because of the long tissue retention of CC, there continues to be ER depletion centrally and increased estradiol secretion from the ovary is not capable of normal negative feedback on FSH. The result is multiple dominant follicle growth and multiple ovulation.

9. Clomiphene Citrate Starting on day 2,3,4 or 5 makes no difference
Dose 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?
No U/S or hCG
With U/S + hCG
150
105 n
34.7%
48%
Cumulative pregnancy rate
26.7%
35.6%
Deliveries 1
Multiple pregnancies
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 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):
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.
Figure 1 Kaplan–Meier Curves for Live Birth. Live-birth rates are shown according to treatment group in Panel A and according to treatment group and maternal body-mass index (BMI, the weight in kilograms divided by the square of the height in meters), in thirds, in Panels B, C, and D.
Legro RS et al. N Engl J Med 2014;371:

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 letrozole in 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 STIMULATION Complications
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 therapy 14 series, 1966-1984, WHO I & II
Hamilton-Fairley & Franks, 1990

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

25. Low Dose Gonadotropins Summary of Results Patients = 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
CC Metformin CC+metformin
22.5% % %
Legro et al, NEJM, 2007
15.4% % %
Zain et al, Fertil Steril, 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
2012
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?

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 Gyn Endocrinol 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