Treatment of Poor Responders

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1 Treatment of Poor Responders Pathophysiology of Poor Responders Deficiency in systemic IGF 1 levels (Bahceci, 2007) Lower intra ovarian T levels Reduced FSH receptor expression (Cai, 2007) Bahceci, 2007, Eur J Obstet Gynecol Reprod Biol. 130:93 98 Cai, 2007,Fertil Steril;87:

2 Definition of Poor Responder There is no consistent definition of poor responder in the literature, although ESHRE established the Bologna criteria Lack of Uniform Criteria in publications makes comparison of outcomes from various trials difficult 9 26% of ART cycles ESHRE consensus on the definition of poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria At least two of the following three features must be present: Advanced maternal age ( 40 years) or any other risk factor for POR; A previous POR ( 3 oocytes with a conventional stimulation protocol); An abnormal ovarian reserve test (i.e. AFC <5 7 follicles or AMH < ng/ml).

embryo, two embryo, and three or more embryos transferred Gleicher,

3 Live birth rates in very poor prognosis patients, who are defined as poor responders under the Bologna criteria, with non elective single embryo, two embryo, and three or more embryos transferred Gleicher, F&S, September, 2015 Patient/cycle characteristics Gleicher, F&S, September, 2015

Live birth rates Adjusted for cancellation Patients with 1 embryo had 8/129 divided by 2= <4% live birth rate With 2 embryos 8/111 divided by 2= 4% live birth rate With 3 embryos 14/141 divided by

4 Live birth rates Adjusted for cancellation Patients with 1 embryo had 8/129 divided by 2= <4% live birth rate With 2 embryos 8/111 divided by 2= 4% live birth rate With 3 embryos 14/141 divided by 2= 5% live birth rate Gleicher, F&S, September, 2015 Comparison of pregnancy rate in poor responders to normal responders. Text Text Oudendijk, Hum. Reprod. Update (January/February 2012) 18 (1): 1-11.

Female age category and pregnancy rate per cycle started Oudendijk, Hum. Reprod. Update (January/February 2012) 18 (1): 1-11.

5 Female age category and pregnancy rate per cycle started Oudendijk, Hum. Reprod. Update (January/February 2012) 18 (1): Potential Treatments for the Poor Responder Increase Gonadotropin dose Low dose luteal GnRHa or GnRHa stop Microdose Agonist Flare GnRH antagonists Luteal estrogen priming Luteal antagonist Addition of LH Aromatase inhibitors Clomiphene Adjunctive treatment with Testosterone or Growth hormone Minimal stimulation/natural cycle

6 450 IU versus 600 IU gonadotropin for controlled ovarian stimulation in poor responders: a randomized controlled trial Stimulation and cycle outcome Lefebvre, F&S, December 2015:104; 6, 1419 Antagonist/Letrozole vs Microdose lupron Flare (CCRM)

7 Comparison of microdose flare up and antagonist multipledose protocols for poor responder patients: a randomized study Demirol, Fertility and sterility 2009;92: Summary of Micro flare Literature Microdose flair protocols result in improved ovarian response in poor responders compared to mid luteal GnRH a and standard flair protocols OCP pre treatment avoids follicular increase in LH, P, A, and T and there effects on oocyte and embryo quality as well as the endometrium Microdoses of GnRH a result in sustained pituitary release of FSH>LH yet prevent premature LH surges

8 Antagonists for Poor Responders Avoid desensitization and thereby the eliminate the suppression of endogenous gonadotropins during the start of stimulation Evolution of luteal Estrogen and Antagonist Protocols Fanchin, F&S, 2003 Luteal E-2 administration reduces the size and improves the homogeneity of early antral follicles on day 3

9 Luteal GnRH antagonist administration reduces size disparities of early antral follicles on day 2, likely through the prevention of luteal FSH elevation and early follicular development anchin, F&S, 2004: Weitzman, F&S, 2008

10 Comparison of luteal estradiol patch and gonadotropin releasing hormone antagonist suppression protocol before gonadotropin stimulation versus microdose gonadotropin releasing hormone agonist protocol for patients with a history of poor in vitro fertilization outcomes Weitzman, F&S, 2008 LPG group Microdose group P No. of cycles Peak E <.05 Oocytes NS Embryos Transferred NS Cancellation Rate 29% 30% NS Implantation Rate 15% 12.5% NS Ongoinng Pregnancy 30% 26% NS Retrospective analysis of E alone vs E/Ant for luteal priming Retrospective: 313 pts < 43 yrs 5 oocytes with prior cycle Prior cancellation(<4 follicles or peak E 2 <500pg Elassar, F&S, 2011

11 Luteal phase estradiol (LP) versus luteal phase estradiol and antagonist (LPG)protocol for controlled ovarian stimulation prior to IVF in poor responders Elassar, F&S, 2009, Volume 92, Issue 3, Supplement, Page S55 Clomid and Antagonist RCT of Luteal agonist(unspecified doses) vs FSH(600IU) and CC 100(2 6), Antagonist Down reg CC/Antagonist #Ampules No. follicles Peak E Oocytes PR IR 8 14 More oocytes but no SD in PR or IR, but trend favoring CC D Amato, F&S, 2004

12 Aromatase Inhibitors Increased gonadotropin secretion Increase in intraovarian androgens increase FSH receptors Weil, 1998 Aromatase Inhibitors and Antagonist MDL vs Ant + 2.5mg d2 6 More oocytes with MDL, but higher IR with Letrozole MF AL P No. of metaphase II oocytes 5.3 ± ± 2.7 <.01 Implantation rate, % Yarali, F&S, 2009:92; 231

13 Letrozole and gonadotropins versus luteal estradiol and gonadotropinreleasing hormone antagonist protocol in women with a prior low response to ovarian stimulation Elassar, F&S, 2011 Is High dose gonadotropin treatment detrimental? In animal models, COH results in a dose dependent affect on oocyte and embryo quality(van der Auwera, Hum Reprod. 2001) Comparing natural vs stimulated cycles in humans, no difference has been seen in embryo quality or aneuploidy(labara, 2012, 2014)

14 Modified natural in vitro fertilization cycle in patients with genuine poor response 111 patients who fulfilled two of the three Bologna criteria and also yielded a maximum of three oocytes after COH MNC IVF: natural cycles with GnRH antagonist supplementation (0.25 mg/day; started when a follicle of 13 mm was present IU of hmg were coadministered daily during the antagonist treatment Kedem, F&S, 2014, 101:1624 Kedem, F&S, 2014, 101:1624

15 A controlled trial of natural cycle versus microdose gonadotropin releasing hormone analog flare cycles in poor responders undergoing in vitro fertilization Morgia, F&S, 2004 Parameters Natural cycle COH P No. of patients No. of cycles Cycles with oocytes (%) Cycles with transfer (%) ` NS No. of embryos/transfer 1.8 NS Pregnancy/cycle (%) NS Pregnancy/transfer (%) NS Implantation rate (%) Natural cycle in vitro fertilization in poor responder patients: a survey of 500 consecutive cycles Inclusion criteria in the study were patient < 44, and a previous IVF cycle performed in our IVF center that was canceled due to no follicle activation or only one follicle recruited Mean age was 39.3 years (range: 30 to 43 years), their duration of infertility was 4.6years Schimberni, IVF with natural cycle in poor responder women. Fertil Steril 2008.

16 Natural cycle in vitro fertilization in poor responder patients: a survey of 500 consecutive cycles Conventional vs. minimal ovarian stimulation in poor responder women according to the Bologna criteria. Poor responders(bologna criteria) underwent both one conventional antagonist (cos) (n=46) and one mininal stimulation (mos) protocol (n=46) mos was performed with 50mg daily clomiphene citrate and low amounts of gonadotrophins every other day from 4th day of stimulation Mean age was 40.4 years, FSH of 11.3, AFC: 5.3, AMH: 0.79 abarta, F&S, September, 2015

17 Labarta, F&S, September, 2015 Strategies to manage poor responders: Increase FSH levels(increased FSH dose, letrozole, Clomiphene, Agonist flare, Antagonists Increasing follicle sensitivity to FSH Testosterone DHEA Dexamethasone Growth Hormone

18 Why Would Androgens Impact Folliculogenesis? Weil et al., J Clin Endocrinol Metab 1998;83: Circulating DHEA SO4 levels, which reflect androgen production, decrease by 50% between ages % of follicular androgens are produced from circulating DHEA DHEA may act by increasing IGF 1 expression to enhance gonadotropin action Carson et al, Fertil Steril 1998;70: Impact on FSH receptors FSH receptor density is reduced in low responders Local androgens induce FSH receptor up regulation Vendola in the subhuman primate model showed that an amount of systemically applied T (50 mg/kg per day for 5 days), which raised the circulating T concentration into the low male range, was capable of increasing preantral and antral follicles

Basal Day 3 Testosterone Level and IVF Outcome 60 53.1 Pregnancy rate (%) 50 40 30 20 10 N=43 * p<.05 11.1 * 0 < 20 > 20 Testosterone (ng/dl) Frattarelli et al.

19 Basal Day 3 Testosterone Level and IVF Outcome Pregnancy rate (%) N=43 * p< * 0 < 20 > 20 Testosterone (ng/dl) Frattarelli et al., Fertil Steril 2004;81: The follicular hormonal profile in low responder patients undergoing unstimulated cycles: is it hypoandrogenic? De los Santos, Hum. Reprod. (2013) 28 (1):

20 Dehydroepiandrosterone administration does not increase pregnancy rates in poor responders: a meta analysis Kolibianakis, O 084,Eshre abstract, 2016 DHEA administration in poor responders undergoing ovarian stimulation for IVF is not associated with an increase in the probability of pregnancy. Randomized controlled trials (RCTs) evaluating DHEA administration exclusively in poor responders Seven eligible RCTs evaluating a total of 576 patients were meta analyzed DHEA did not improve the probability of clinical pregnancy (RR: 1.10; 95% CI: ) or live birth (RR: 1.18; 95% CI: ) as compared to no DHEA treatment Although No significant differences were observed in the number of COCs retrieved, in the number of 2 pronuclei oocytes and in the number of embryos transferred Transdermal testosterone may improve ovarian response to gonadotropins in low responder IVF patients Fábregues et al, Hum Reprod : RCT of 62 infertile women whose first IVF cycle was cancelled due to poor follicular response. Group 1 (n = 31): Transdermal application of testosterone preceding standard gonadotropin ovarian stimulation with GnRHa suppression. Daily single patch with 2.5 mg/day nominal testosterone delivery rate (Androderm 2.5 mg) applied on the thigh at night and removed at 9:00 each morning (20 mcg/kg per day for 5 days) Group 2 (n = 31): High dose gonadotropins with a mini dose GnRHa protocol.

21 Transdermal Testosterone in Poor Responders (cont.) Fabregues et al, Hum Reprod 2009;24: Percentage of cycles with poor response lower in Gr. 1 (32.2% vs. 71%, p<.05) Trend towards lower cancellation rate in Gr. 1 (19.4% vs. 41.9%, p=.09) Lower cancellation rate in Gr. 1 among subset of patients with normal baseline FSH levels (18.8% vs. 58.9%, p<.05) Transdermal Testosterone Priming Kim et al, Fertil Steril 2011;95: Prospective randomized trial of 110 low responders ( 3 oocytes retrieved despite use of >2500 IU gonadotropins in prior cycle) Study group: E2 valerate 1 mg/d + norethindrone 5mg/d x 21 days + transdermal testosterone gel (TTG) (Testo gel 1%) 12.5 mg daily beginning day 6 of E+P x 21 days prior to FSH 300 IU daily with flexible GnRH ant protocol Control group: E+P and COH as above without TTG No differences in patient characteristics between groups Significant in # mature and fer lized oocytes, good quality embryos (all p<.001), implantation and clinical pregnancy rates (both p<.05) with TTG No adverse effects with TTG use

22 Despite no adequately powered clinical trials, there are already three meta analyses advocating the benefits of Testosterone pretreatment(bosdou, 2012, Gonzalez Comadran, 2012, Sunkara, 2011) Growth Hormone for Poor Responders GH stimulates granulosa cell proliferation and ovarian response to FSH through IFG 1 synthesis Higher intrafollicular GH levels have been correlated with oocyte and embryo competence Poor responders have low IFG 1 levels

23 GH and Poor Responders: Meta Analysis Kolibianakis et al, Hum Reprod Update 2009; 15: RCTs including 169 patients 17% live birth rate (95% CI: 5-30); NNT: 6 (95% CI: 3-20) 22% % in patients undergoing ET (95% CI: 7-30) High degree of heterogeneity makes interpretation difficult: Definition of poor responders, GH dose, ovarian stimulation protocol Comparison of rlh and rfsh versus rfsh alone for COH in GnRH agonist dowregulated IVF/CSI cycles in poor responders, Outcome: Ongoing pregnancy per woman randomized.

yield, (<50%) number of oocytes retrieved per number of follicles > 14 mm in diameter on day of hcg administration

24 Lower apoptosis rate in human cumulus cells after administration of recombinant luteinizing hormone to women undergoing ovarian stimulation for in vitro fertilization procedures Ruvolo F&S, 2007 Patients with poor oocytes yield, (<50%) number of oocytes retrieved per number of follicles > 14 mm in diameter on day of hcg administration Given double trigger(hcg and agonist) in subsequent cycle Haas J, J Ovarian Res Aug 2;7:77. doi: /

Dual trigger with gonadotropin releasing hormone agonist and standard dose human chorionic gonadotropin to improve oocyte maturity rates Griffin, Fertility and Sterility, Vol.

25 Dual trigger with gonadotropin releasing hormone agonist and standard dose human chorionic gonadotropin to improve oocyte maturity rates Griffin, Fertility and Sterility, Vol. 102, Issue 2, p Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation Patients with reduced ovarian reserve AMH level of 1.5 ng/ml, AFC 6 follicles, and/or 5 oocytes retrieved in a previous cycle Blastocyst stage CCS Mean age: 39.2 Mean FSH: 12.3 Mean AMH 0.7 Mean antral follicle count: 5.2 Ubaldi, F&S, 2016

26 Ubaldi, F&S, June 2016, 105, 6, Data according to follicular and luteal phase stimulation. Follicular Luteal P value Days of stimulation NS Oocytes NS Blastocysts NS Euploid Blastocyst NS Euploid Blast/M 2 oocyte 16.2% 15% NS Implantion Rate 71.4% 62.5% Ubaldi, F&S, June 2016, 105, 6,

27 Poor Responders: Summary The lack of a uniform definition of the poor responder makes comparison of results from trials difficult Among GnRH agonist protocols, microdose agonist flare with brief OC pre treatment seem most effective Whether microdose flare protocols are more effective than specific GnRH antagonist protocols is unclear Growth hormone appears to improve outcomes although the ideal patient population has not been defined More data are needed on the role of androgen pre treatment (DHEA, T) Conclusions No evidence to support luteal estrogen priming, luteal antagonist, or Aromatase inhibitors LH, Testosterone and growth hormone are adjuncts that demonstrate benefit Clomid protocols may hold promise in the era of vitrification/embryo banking

Best practices of ASRM and ESHRE

Best practices of ASRM and ESHRE Late submission Cortina d Ampezzo, Italy 1-3 March 2012 A joint meeting between the American Society for Reproductive Medicine and the European Society of Human Reproduction