A survey on luteal phase support:

A survey on luteal phase support: An IVF Worldwide Survey results I have no conflict of interest!

The reason why luteal phase support is needed: The normal physiological support of the corpus luteum the pulsatile secretion of LH by the anterior pituitary is disrupted during controlled ovarian stimulation Mid luteal LH levels ~ 6.0 IU/l in natural cycle (Tavaniotou and Devroey 2003) ~ 1.5 IU/l GnRHa trigger (Humaidan et al. 2005) ~ 0.2 IU/l HCG trigger (Humaidan et al. 2005)

The luteal phase after COS Supraphysiological steroid level of E2 and P in early mid luteal phase exerts a negative feed back on the hypothalamic pituitary axis reducing LH secretion in early luteal phase. (Tavaniotou and Devroey, 2006; Tavaniotou et al., 2001) COS per se constitutes an indication for luteal phase support Adapted from Jones 1996 by Fauser and Devroey 2003

Pharmacokinetics of hcg administration Weissman et al., Gynecol Endocrinol 10; 273 6: 1996.

Figure 1 Chronologic characteristics of the effects of exogenous hcg and hcg produced by the conceptus De Ziegler et al., Fertility and Sterility 2018 109, 749-755

Luteal phase support in ART Formulation and route of administration When to start? When to stop? What should be included? Should LPS in ART be individualized?

Evidence Based Medicine

Type of reporting bias Publication bias Time lag bias Multiple (duplicate) publication bias Location bias Citation bias Language bias Outcome reporting bias Definition The publication or non publication of research findings, depending on the nature and direction of the results The rapid or delayed publication of research findings, depending on the nature and direction of the results The multiple or singular publication of research findings, depending on the nature and direction of the results The publication of research findings in journals with different ease of access or levels of indexing in standard databases, depending on the nature and direction of results. The citation or non citation of research findings, depending on the nature and direction of the results The publication of research findings in a particular language, depending on the nature and direction of the results The selective reporting of some outcomes but not others, depending on the nature and direction of the results Jonathan AC Sterne, Matthias Egger and David Moher on behalf of the Cochrane Bias Methods Group, 2011.

Ties with the industry: 87% of authors have ties to industry 58% receive financial support for research 38% serves as employs or consultants Roger Collier, CMAJ, 2011:183;3

Focus on professional education Surveys Blogs / Forums Genetics Virtual Academy Physicians consulting physicians Newsletters Online Journal Education Center Clinic Locator IVF Worldwide Online Informed Consent Virtual university

IVF Worldwide surveys Large number of units (over 3,800) All 6 continents Data from academic and non academic practices A global scale

The Wisdom of the Crowds James Surowiecki 2004 Why the many are smarter than the few and how collective wisdom shapes business, economies, societies and nations

Anti Mullerian hormone (AMH) and antral follicular count (AFC) The Surveys Minimising the risk of infection and bleeding at trans vaginal ultrasound guided ovum pick up Vitrification, GnRH trigger and differed ET Mechanical Infertility Oocyte Donation Reproductive Immunology Practice in IVF Embryo Culture and Catheter Loading Egg Collection and Embryo Transfer Techniques PCOS Definition, Diagnosis and Treatment Poor Responders The use of GnRH agonist in IVF protocols Metformin Use In IVF Patients Frozen Thawed Embryo Transfer Updated survey on the use of progesterone for luteal phase support in stimulated IVF cycles Progesterone Support In IVF

1 st 2009 2 nd 2012

Geographic distribution of IVF units participating in the survey Continent IVF Cycles % of cycles IVF units % of IVF units USA & Canada 44900 13.9 52 11.9 South America 31100 9.6 59 13.5 Australia & New Zealand 15400 4.8 12 2.7 Asia 64900 20.2 90 20.6 Europe 153400 47.6 200 45.8 Africa 12700 3.9 24 5.5 Total 322400 100 437 100

% Which factor is most important to you when deciding which luteal support regimen to use?

% In most cases, how do you determine which luteal support regimen to use for your patients?

If you support the luteal phase, when do you start the regimen you use? At the time of hcg admin. At the time OPU One day post OPU At the time of ET 6 days post OPU

Figure 1 Chronologic characteristics of the effects of exogenous hcg and hcg produced by the conceptus De Ziegler et al., Fertility and Sterility 2018 109, 749-755

LBR (%) 21.1 20.0 20.5 400 mg micronized progesterone Vaginally b.i.d

RCT

RCT LPS: Uterogestan 400 mg/d Group A: from the evening of the day of oocyte retrieval Group B: from the evening of embryo transfer (2nd day).

RCT LPS: Micronized progesterone (3 200 mg); 2 mg of estradiol valerate p.o. ; 20 mg of dydrogesterone Group A: from the first day after oocyte retrieval (n = 526) Group B: From day 4 after oocyte retrieval (n = 527).

RCT LPS: Prometrium, 200 mg intravaginally t.i.d. Group A: from the morning of the 3rd day after oocyte retrieval Group B: from the morning of the 6th day after oocyte retrieval

When to start LPS? Day of OPU Day after OPU Day of ET All equally effective Initiating LPS on the day of or day after oocyte retrieval, has now become a routine practice in ART

% If you support the luteal phase, when do you start the regimen you use?

How long do you continue progesterone supplementation if the patient conceives? At the time of pregnancy test At the time of 1 st US (6W) At 8 W At 10 12 W

Ongoing pregnancy rate

Ongoing pregnancy rate

Live birth rate

Miscarriage rate

When to stop LPS? Day of positive hcg Day fetal heartbeat Week 8 10 12 All have similar ongoing pregnancy rates On the day of the positive hcg the CL is supported by hcg of embryonic origin Clinical data now confirm this view This should encourage treatment teams to discontinue LPS on the day of positive hcg

% How long do you continue progesterone supplementation if the patient conceives?

How long do you continue progesterone supplementation if the patient conceives? 80 70 60 50 40 30 20 10 0 Positive bhcg Clinical preg Week 8 12 2009 2012 2018

% In the majority of the cases, which agent/route is your treatment of choice for LPS?

Vaginal P for luteal support: Targeted drug delivery One hour after application Four hours after application Progressive diffusion of progesterone from the cervix to the fundus of the uterus Bulletti et al. Hum Reprod. 1997;12:1073-9

Steady State Serum vs Tissue Levels of Progesterone Serum P ng/ml Tissue ng/mg protein 30 25 29.42 1.2 1 20 0.8 1.05 15 0.6 10 5 0 4.82 0.4 0.2 0 0.43 Crinone 8% IMP Cicinelli et al. Obstet Gynecol 2000;95:403-6

% If you use vaginal progesterone, which formulation do you prefer to use in the majority of cases?

Child et al., RBM Online, in press

% If you use oral progesterone, which drug do you prefer?

Oral Micronized Progesterone

Progesterone for luteal support: the oral route Micronization: improved absorption of oral P Poor bioavailability Circulating levels are too low for adequate support Liver first pass leads to massive metabolism At best 10% circulates as active P Inadequate secretory transformation Dose increase: unacceptable somnolence Nahoul and de Ziegler D. Fertil Steril 1994;61:790 2. Bourgain et al., Hum Reprod 1990;5:537 43.

Serum levels of P after oral vs. vaginal administration (RIA and liqiud chromatography mass spectrometry) Levine et al., Fertil Steril 2000 16 14 12 10 8 6 4 2 0 0 12 24 36 48 60 Vag - true Vag - RIA Oral - true Oral - RIA Crinone 90mg vaginally vs Prometrium 100mg orally

Outcome with oral P administration 70 Licciardi et al. 1999 50 Friedler et al. 1999 60 45 40 50 35 40 30 30 25 20 20 10 * 15 10 5 * 0 CPR IR IM P PO P * P<0.05 0 CPR IR Miscarriage Vag P PO P

Oral dydrogesterone

Oral dydrogesterone for luteal phase support in IVF An oral retroprogesterone progesterone agonist Approved for: Threatened and recurrent miscarriage (associated with proven progesterone deficiency) Infertility due to luteal phase insufficiency It has been extensively used for a variety of indications since 1960 Compared with progesterone: Greater affinity for the progesterone receptors Can be used at lower oral doses to promote endometrial proliferation owing to its better bioavailability and to the progestogenic activity of its metabolites Schindler AE et al., Maturitas 2008;61:171 180.

Barbosa Et al., Ultrasound Obstet Gynecol 2016; 48: 161 170

RCT LPS: From the day of oocyte retrieval Group A: MVP 200 mg capsules TID with oral placebo tablets TID Group B: Oral dydrogesterone 10 mg tablets TID with placebo intravaginal capsules TID

Ongoing pregnancy rates and live birth rates in the (total n = 974) LOTUS I trial. Fertility and Sterility 2018 109, 756-762DOI: (10.1016/j.fertnstert.2018.03.034)

Proportion of female subjects reporting treatment emerging adverse events according to organ system in the two groups of the LOTUS I trial. Fertility and Sterility 2018 109, 756-762DOI: (10.1016/j.fertnstert.2018.03.034)

Noninferiority of daily 30 mg oral dydrogesterone for luteal phase support Well tolerated as vaginal progesterone in safety analyses No new fetal safety concerns Widespread preference of women for an oral compound Dydrogesterone may well become the new standard for LPS in fresh IVF ET cycles

IM Progesterone

Progesterone for luteal support: The intramuscular route P is highly water insoluble P in oil Standard route of P delivery High efficiency: avoids hepatic first pass Several drawbacks: *Painful and uncomfortable * Preservatives (benzyl alcohol) *Sterile abscess formation *Allergic response *Time and cost

Progesterone for luteal support: The intramuscular route IM dosing: 25 100 mg daily Long acting formulations Mean production rate of progesterone of 25 mg/24 h Gold standard of LPS in phase endometrial architecture Satisfactory pregnancy/miscarriage rates Able to delay menses in most women

Progesterone regimens: IM versus vaginal/rectal: Live birth and ongoing pregnancy rates OR 1.37, 95% CI 0.94 to 1.99 seven RCTs, 2309 women, I2 = 71%, random effects, very low quality evidence Live birth rate, no evidence suggested differences between groups OR 1.31, 95%CI 0.84 to 2.05 four RCTs, 1222 women, I2 = 59%, random effects model Van der Linden et al., Cochrane Database of Systematic Reviews 7 JUL 2015

% If you use IM progesterone, which interval/formulation do you prefer?

SC Progesterone

Aqueous subcutaneous progesterone Water insolubility of P: an aqueous preparation of P was seemingly impossible Enhancing polarity by encapsulation of P molecules in a starch residue, cyclodextrine On reaching bodily fluids, cyclodextrine is readily digested This liberates native P, which reaches the general circulation Prolutex is available in single use preparations Contains no preservatives de Ziegler et al., Fertil Steril 2013

Non inferiority of SC P versus vaginal P Ongoing PR (10 wks) (%) Live birth rate (%) Prolutex 27.4 26.8 Crinone 95% CI 30.5 9.91 3.373 29.9 9.87 3 3.58 Lockwood et al. Fertil Steril 2013 Prolutex Endometrin 95% CI Ongoing PR (10 wks) (%) 41.6 44.4 9.7 4.2 Live birth rate (%) 41.1 43.1 8.9 4.9 Baker VL et al. Hum Reprod 2014 Prolutex vs. Vag P (n=1435) Ongoing PR (10 wks) (%) Live birth rate (%) OR 0.865 0.889 95% CI 0.694 1.077 0.714 1.106 Doblinger et al. Plos One 2016

% If you use a combination of progesterone treatments, which do you prefer?

Do you include estradiol in your luteal support regimen?

Normal menstrual cycle

Figure 1 Chronologic characteristics of the effects of exogenous hcg and hcg produced by the conceptus De Ziegler et al., Fertility and Sterility 2018 109, 749-755

RCT Patients with E2 >2500 pg/ml on hcg day LPS: IM + Vag P Group A: 2 mg of E2 (Estrofem) p.o. b.i.d. starting on day 7 after ET (n=136) Group B: P only (n=149)

Luteal phase estradiol supplementation 45 40 * 35 30 25 20 15 10 5 0 CPR IR Miscarriage * P<0.05 P only P+E Farhi et al. Fertil Steril 2000

RCT Patients <40 years on long GnRH a protocol LPS: Uterogestan 200 mg t.i.d from opu day Group A: Uterogestan only Group B: Uterogestan + 2 mg E2 Group B: Uterogestan + 6 mg E2

4 Progesterone vs progesterone + oestrogen, outcome: 4.1 Live birth/ongoing pregnancy rate. Van der Linden et al., Cochrane Database of Systematic Reviews 7 JUL 2015

% Do you include estradiol in your luteal support regimen?

When triggering ovulation with a GnRH agonist, which luteal support do you use?

GnRH agonist trigger Individualized luteal support regimen Intensive luteal support Adjuvant low dose hcg o o o Dual trigger with hcg (range 1,000 2500IU) Adjuvant hcg at time of oocyte retrieval Micro hcg doses Recombinant LH GnRH agonists Freeze all

Mid luteal LH levels ~ 6.0 IU/l in natural cycle ~ 1.5 IU/l GnRHa trigger ~ 0.2 IU/l HCG trigger

F.C.H. personal DATA (7/2015 12/2017) n=647 Age Group: <= 30 31 35 36 39 >= 40 Age 28,38 ±1,77 (48) 33,37 ±1,37 (178) 37,80 ±1,09 (220) 41,88 ±1,93 (201) Mean Nr. Cycles 1,60 ±1,18 (48) 2,22 ±1,81 (178) 2,71 ±2,62 (220) 3,46 ±2,73 (201) BMI 24,54 ±4,01 (46) 23,74 ±4,43 (178) 23,17 ±3,63 (220) 22,60 ±3,24 (201) Cycles 48 178 220 201 Freeze All (FA) 10 (20,8%) 38 (21,6%) 20 (9,2%) 12 (6,0%) PBGT 10 (20,8%) (3) 50 (28,4%) (18) 129 (59,4%) (47) 169 (84,5%) (33) (nr.pregnant) ETs (%/without FA) 33 (86,8%) 128 (92,8%) 173 (87,8%) 108 (57,4%) CPR (%/ET) 19 (59%) 82 (64,1%) 87 (50,3%) 40 (37%) Twin(%/Pregnancy ) 5 (26,3%) 28+1 (35,4%) 25 (28,7%) 4 (10,0%) Clinical Misscar. 1 (5,3%) 13 (14,6%) 14 (14,9%) 12 (30,0%) Ongoing/LBR 18 (48,7%) 69 (50,0%) 73 (37,1%) 28 (14,9%) OHSS (E+L) 0 0 0 0 Total pos hcg/et 22 (66,7%) 90 (70,3%) 96 (55,5%) 48 (44,4%) Bioch.Preg. 3 8 9 8 I.R. 43,6% 51,6% 40,1% 29,7%

46 patients at risk for OHSS GnRH a trigger Nafarein (Synarel) 200 g*2 daily from the evening of OPU No other form of luteal support Fertil Steril, 2016

% When triggering ovulation with a GnRH agonist, which luteal support do you use?

% If all progesterone formulations were found to yield the same live birth rates, which route would?

Evolution of luteal support policies across the years First study (September 2009) Second study (June 2012) Current study (2018) Use of vaginal progesterone only (%) 64 71.8 76.7 Use of IM progesterone only (%) 13 5 7.1 Use of Oral progesterone only 2 0.5 1.3 Use of combined drugs 16 17.3 12.6 Use of hcg only 5 0 1.5 https://ivf worldwide.com/survey/a survey on luteal phase progesterone support.html

% Are more studies needed to reach a decision on the efficacy of the various luteal phase support?

% I would like to see more research data about the following routes/formulations:

Team

Amount of information generated by meta analyses. PubMed search of the words meta analysis in the published literature. Greco et al., Heart Lung Vessel. 2013; 5): 219 225.

Van der Linden et al., Cochrane Database of Systematic Reviews 7 JUL 2015