PROOF COVER SHEET Author(s):
Salvatore Gizzo, Alessandra Andrisani, Federica Esposito, Marco Noventa, Stefania Di Gangi, Stefano Angioni, Pietro Litta, Michele Gangemi, and Giovanni Battista Nardelli
Article title: Which luteal phase support is better for each IVF stimulation protocol to achieve the highest pregnancy rate? A superiority randomized clinical trial Article no:
DGYE_A_964638
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1
Salvatore
Gizzo
2
Alessandra
Andrisani
3
Federica
Esposito
4
Marco
Noventa
5
Stefania
Di Gangi
6
Stefano
Angioni
7
Pietro
Litta
8
Michele
Gangemi
9
Giovanni Battista
Nardelli
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67 68 69 Gynecol Endocrinol, Early Online: 1–7 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.964638 70 71 72 73 ORIGINAL ARTICLE 74 75 76 77 78 79 80 81 Salvatore Gizzo1, Alessandra Andrisani1, Federica Esposito1, Marco Noventa1, Stefania Di Gangi1, Stefano Angioni2, 82 Pietro Litta1, Michele Gangemi1, and Giovanni Battista Nardelli1 83 84 1 2 Department of Woman and Child Health, University of Padua, Padova, Italy and Department of Surgical Sciences, University of Cagliari, 85 Cagliari, Italy 86 87 88 Abstract Keywords In vitro fertilization (IVF) cycles generate abnormalities in luteal-phase sex steroid concentra- Endometrium, estradiol, GnRH agonist, GnRH 89 90 tions and this represent an important limiting factor to achieve a good pregnancy rate. antagonist, IVF protocol, luteal phase 91 Although there are evidences about the usefulness of luteal phase support (LPS) after IVF support, pregnancy rate, progesterone 92 cycles, no consensus exist about the best dose and way of progesterone (PG) administration, 93 the advantages of estradiol (E2) supplementation and which IVF protocol could benefit from History one more than other LPS scheme. Aim of the study was to assess the best LPS (low-dose PG, 94 high-dose PG, high-dose PG and E2 supplementation) to achieve the highest clinical/ongoing Received 15 May 2014 95 pregnancy rate according to stimulation protocol, E2 at ovulation induction, endometrial Revised 8 September 2014 96 thickness at pick-up and women’s age. We conducted a randomized trial on 360 women Accepted 9 September 2014 97 2 2 2 Published online undergoing IVF (180 treated by long-GnRH agonist, 90 by short-GnRH agonist and 90 by short98 GnRH antagonist protocol) and stimulated by recombinant follicle-stimulating hormone alone. 99 Our data demonstrated that high-dose PG is better than low-dose to increase both clinical and 100 ongoing pregnancy rate. E2 supplementation are mandatory in case of short-GnRH antagonist 101 protocol and strongly suggested in all protocols when E2max 55 nmol/l and endometrial 102 thickness 510 mm. In long-GnRH agonist protocols, as well as in patients 435 years, the real 103 advantages of E2 supplementation remain debatable and require further confirmation. 104 105 Introduction Although there is a consensus about the usefulness of LPS to 106 improve both clinical and ongoing pregnancy rate after in vitro 107 Despite substantial progress and numerous advances have been fertilization (IVF) cycles, no general agreement is available 108 made in ARTs treatment over the last two decades, at now the concerning the best protocol to use. Nowadays many controversies 109 ‘‘take-home baby rate’’ remains 20–30% per treatment [1]. exist: it is not well-defined and accepted the best therapeutic 110 The main reason still remains the implantation failure. Despite the scheme [prostaglandin (PG) alone or in combination with 111 amount of studies conducted on human embryos implantation, estradiol (E2)], the most appropriate daily dose (high or low 112 only little progress has been made in the development of dose) and administration way (vaginal and/or intramuscular for 113 therapeutic strategies. Many studies have been carried out to PG; oral or vaginal for E2). In addition, poor data are available 114 improve the implantation rate (such as the selection of ‘‘highconcerning the most appropriated LPS for each ARTs protocol 115 quality embryos’’) but most of all, proposing ‘‘empirical’’ and peculiar clinical conditions. A recent meta-analysis showed 116 treatments, ended with inconclusive and debatable recommendasignificant positive effects of PG for LPS after IVF. However, the 117 tions [1–4]. available studies included in statistical analysis did not permit to 118 Postulated that the implantation failure is an important limiting prove strong evidences about the best dose and way of PG 119 factor in the ARTs outcomes, the most accredited evidences 120 administration and the advantages of E2 supplementation [8]. demonstrated that ARTs protocols [either using gonadotropinThe aim of this study is to assess the best LPS (drugs 121 releasing hormone (GnRH) agonist (ag) or antagonist (ant)] are association, daily dose and administration way) after IVF cycles 122 affected by abnormalities in luteal-phase sex steroid concentrain order to achieve the highest clinical and ongoing pregnancy 123 tions and that an adequate luteal phase support (LPS) may rate considering the stimulation protocol, the E2 serum value at 124 increase the overall pregnancy rate [5–7]. ovulation induction, the endometrial thickness at pick-up and the 125 126 maternal age at treatment. 127 128 Methods 129 130 We conducted a perspective, superiority, randomized open-label Address for correspondence: Stefano Angioni, Department of Surgical Sciences, University of Cagliari, SS554, Monserrato, Cagliari 09042, study on idiopathic infertile patients referred to Assisted 131 Reproductive Unit of Gynecologic and Obstetric Clinic, 132 Italy. Tel: +39-0705103399. E-mail:
[email protected]
Which luteal phase support is better for each IVF stimulation protocol to achieve the highest pregnancy rate? A superiority randomized clinical trial
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133 Department of Woman and Child Health, University of Padua, 134 between January 2010 and September 2013. 135 At recruitment, all patients were properly informed about the 136 aim of the study and they were enrolled only if they agree to the 137 aim of the study and to the use of their data according to Italian 138 Privacy Law (675/96). 139 We considered women aged between 18 and 50 years with 140 BMI between 18 and 30 as eligible for the study. We excluded 141 patients with previous ovarian surgery to avoid any possible 142 interference of decreased ovarian reserve or patients with a 143 previous diagnosis of endometriosis [9–11]. In addition, patients 144 treated for benign endouterine disease (such as endometrial 145 polyps, submucous myomas, intrauterine synechiae and/or 146 uterine septus) in the 6 months before IVF cycle [12–14], 147 history of abnormalities in thyroid pattern [15] or alteration in 148 basal serum prolactin value and E2 peak at ovulation induction 149 513 nmol/l were not included. Other criteria of exclusion were 150 the following: history of smoking; untreated uterine myomas 151 [16–18]; absence of major systemic disease such as diabetes 152 [19], multiple sclerosis, adrenal diseases, karyotype abnormal153 ities, mutations of the cystic fibrosis gene, acquired or inherited 154 thrombophilia and immunological disorders; previous or actual 155 neoplasia; previous chemo and/or radio treatment for neoplasia; 156 severe qualitative and quantitative alteration in semen (accord157 ing to World Health Organization guidelines) [20]; absence of 158 retrieved oocytes at pick-up and absence of at least one 159 fertilized oocyte. 160 According to pretreatment ovarian reserve assessment [21], all 161 patients received the most adequate stimulation protocol accord162 ing to our Units Protocol. In detail, all patients were treated by 163 recombinant follicle-stimulating hormone (rFSH) and classified in 164 three groups according to the protocol used: Group A, if treated 165 by long-agonist protocol (long-GnRH-ag); Group B, if treated by 166 short-agonist protocol (short-GnRH-ag) and Group C, if treated 167 by flexible scheme short-antagonist protocol (short-GnRH-ant). 168 GnRH-ag daily dose (0.1 mg) of triptorelin acetate (Fertipeptil, 169 Ferring S.p.A.Õ , Milano, Italy) was administered in both long170 GnRH-ag and short-GnRH-ag while GnRH-ant daily dose 171 (0.25 mg/0.5 ml) of ganirelix (Orgalutran, N.V. OrganonÕ , BH 172 Oss, Nederland) was administered in short-GnRH-ant. 173 Concerning the controlled ovarian hyperstimulation, we used 174 rFSH (Gonal-FÕ, Merck-Serono, Geneva, Switzerland) with a 175 starting dose (maintained for the first 5 days) of 100, 225 and 176 300 UI per day in estimated high, normo and poor responders, 177 respectively. The subsequent dose adjustment was decided by the 178 clinicians during the cycles according to the biochemical and 179 ultrasound [transvaginal sonography (TVS)] features of ovarian 180 response. The rFSH was administered in third day after spontan181 eous menstruation (pending the basal E250.3 nmol/l) in both 182 short protocol and at achievement of hypothalamic suppression in 183 long protocol. In short-GnRH-ant protocol, the daily dose of 184 ganirelix was administered starting from the TVS detection of at 185 least one follicle 414 mm in diameter and continued until hCG 186 administration (flexible protocol). 187 All women performed subcutaneous injection of 250 mg rhCG 188 for ovulation induction. 189 For all patients, we collected the following data: age, BMI, 190 ovarian reserve test [bFSH, bLH, bAMH (anti-Mu¨llerian hor191 mone) and bAFC (antral follicle count)], total dose of rFSH 192 administered, E2 at ovulation induction, endometrial thickness at 193 pick-up, number and quality of obtained embryos [20], clinical 194 pregnancy rate (serum bhCG test positive 2 weeks after embryo 195 transfer) and ongoing pregnancy rate (uncomplicated pregnancy 196 over 12 gestational weeks). 197 After oocyte fertilization, according to the casual envelopes 198 produced by software randomization, in each Group (A, B and C)
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patients were randomly assigned (with a randomization of 1:1) to one of three different subgroups (A1, A2 and A3; B1, B2 and B3 and C1, C2 and C3) in relation to the different pharmacological LPS starting from the first day after pick-up: subgroups A1 (60 patients), B1 (30 patients) and C1 (30 patients) received low-dose PG (200 mg vaginal capsule twice daily) and subgroups A2 (60 patients), B2 (30 patients) and C2 (30 patients) received high-dose PG (200 mg vaginal capsule three times daily plus 100 mg intramuscular daily). Subgroups A3 (60 patients), B3 (30 patients) and C3 (30 patients) received high-dose PG (200 mg vaginal capsule three times daily plus 100 mg intramuscular daily) in association with valerate E2 (2 mg vaginal tablet twice daily). Endpoints Primary outcome was to detect the best LPS for each stimulation protocol in terms of clinical pregnancy (calculated as percentage of embryo transfer) and ongoing pregnancy rate (calculated as percentage of clinical pregnancy). Secondary outcome was to detect differences between the different LPS schemes (considering all protocols) in term of odds ratio (OR) to achieve clinical and ongoing pregnancy in cases of E2max at ovulation induction 55 nmol/l, endometrial thickness at pick-up 510 mm and woman age 435 years. Statistical analysis Statistical analysis was performed by Statistical Package for the Social Sciences (SPSS) (SPSS Inc., Chicago, IL) software for Windows version 19, using parametric and non-parametric tests, when appropriate. We performed the Kolmogorov–Smirnov to test normality of distribution. Continuous data were tested with the t-test or analysis of variance test while categorical variables were tested with the 2 test or Fisher’s exact test, when appropriate. The results obtained from the data collection were expressed in absolute numbers and percentages for discrete variables and in mean ± standard deviation for continuous variables. We provided also to calculate the OR to achieve clinical and ongoing pregnancy for each subgroups (LPS) according to stimulation protocol used: woman age, E2max at ovulation induction and endometrial thickness at pick-up. The statistical significance was defined as p50.05.
Results In the interval time considered, 360 women resulted eligible for the study. Of these, 180 patients entered in Group A, 90 in Group B and the remaining 90 in Group C. Considering all patients, the mean age at ovarian stimulation was 37.59 ± 4.52 years (range 24–48) and the mean BMI was 23.16 ± 2.56 (range 19–27). Concerning the ovarian reserve test, we found mean values of bFSH of 7.86 ± 2.54 UI (range 3.60– 15.30), bLH of 5.91 ± 2.37 UI (1.39–14.70), bAMH of 2.21 ± 1.42 nmol/l (range 0.1–5.50) and bAFC of 13.61 ± 7.46 (range 2–43). During controlled ovarian stimulation, we used a mean dose of rFSH of 2786.18 ± 1192.55 UI (range 1012.5– 7875). At ovulation induction, we found an E2max mean value of 6.11 ± 2.33 nmol/l (range 2.16–13.7) and at pick-up day, an endometrial thickness mean value of 10.02 ± 1.84 mm (range 7–16). Considering the obtained embryos quality, we found that good quality (Grade 1 and 2) was achieved in 225 cases (62.5%) and poor quality (Grade 3–5) in the remaining 135 cases (37.5%). Clinical pregnancy was obtained in 123 cases (34.2%); of these, 64 cases (52%) resulted in on-going pregnancy and the remaining
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265 59 cases (48%) resulted in miscarriage/biochemical/extra-uterine 266 pregnancy. 267 The comparison between the groups for general features 268 showed statistical significant differences in terms of patients age 269 (35.80 ± 4.35 versus 40.79 ± 3.68 versus 37.97 ± 3.73, respect270 ively; p50.001), bFSH of Group A versus Group B and Group C 271 (7.29 ± 2.13 versus 8.60 ± 2.40 versus 8.28 ± 3.14; p50.001), 272 bAMH (2.61 ± 1.4 versus 1.48 ± 0.99 versus 2.12 ± 1.53; 273 p50.001) and bAFC (15.49 ± 6.9 versus 8.87 ± 4.05 versus 274 14.58 ± 9.01; p50.001) of Group A and Group C versus Group 275 B. The comparison between the groups showed significant 276 differences (Group A and Group C versus Group B) in terms of 277 mean value of total rFSH administered dose (2488.26 ± 961.02 278 versus 3650.55 ± 1470.36 versus 2517.63 ± 842.14; p50.001), 279 mean value of E2max at ovulation induction (Group A and Group 280 B versus Group C) (6.31 ± 2.48 versus 6.43 ± 2.41 versus 281 5.37 ± 1.72; p50.01), mean value of endometrial thickness at 282 pick-up day (Group A versus Group B and Group C) (10.36 ± 1.83 283 versus 9.59 ± 1.85 versus 9.76 ± 1.71; p50.001). 284 Regarding to the embryos quality, we found that Group B 285 patients obtained a lower rate of good quality embryos respect to 286 Group A and Group C (44.4 versus 28.9 versus 46.7%; p50.01). 287 Concerning clinical pregnancy rate (33.3 versus 32.2 versus 288 35.6%) and on-going pregnancy rate (63.3 versus 55.2 versus 289 59.4%) no differences were found between the groups [p value not 290 shown (n.s.)]. 291 Considering clinical pregnancy outcome, the stratification 292 data according to the different LPS (considering as control in 293 each group patients treated by low-dose PG) permit us to detect 294 that in Group A: the subgroup A2 showed higher rate than A1 295 (p50.01) and the A3 showed higher rate than A2 (p50.05); in 296 Group B: the subgroup B2 showed higher rate than B1 (p50.01) 297 but no differences were found between B2 and B3 [p value: n.s.] 298 and in Group C: the subgroup C2 showed higher rate than C1 299 [p50.001], and C3 showed higher rate than C2 (p50.001) 300 (Figure 1). 301 Considering ongoing pregnancy outcome, we detect that in 302 Group A: the subgroup A2 showed higher rate than A1 (p50.05) 303 but no differences were found between A3 and A2 (p value: n.s.); 304 in Group B: the subgroup B2 showed higher rate than B1 305 (p50.05) as well as B3 with respect to B2 (p50.05); in Group C: 306 the subgroup C2 showed no differences with respect to C1 307 (p50.001) but both significantly differed from the C3 (p50.001) 308 (Figure 2). 309 In patients aged 435 years (241 women), we found 81 clinical 310 pregnancies (33.6%) and 41 ongoing pregnancies (51.25%). 311 Considering patients treated with low-dose PG as control group, 312 in patients treated by high-dose PG we found OR: 2.29 and OR: 313 1.8 to achieve clinical and ongoing pregnancies, respectively, 314 while OR: 3.68 and OR: 2.47 were found in patients treated by E2 315 plus high-dose PG. 316 In patients with E2max at ovulation induction 55 nmol/l (131 317 women), we found 39 clinical pregnancies (29.77%) and 19 318 ongoing pregnancies (48.71%). Considering patients treated with 319 low-dose PG as control group, in patients treated by high-dose PG 320 we found OR: 2.78 and OR: 1.5 to achieve clinical and ongoing 321 pregnancies, respectively, while OR: 4.88 and OR: 2.75 were 322 found in patients treated by E2 plus high-dose PG. 323 Finally, in patients with endometrial thickness at pick-up 324 510 mm (196 women) we found 57 clinical pregnancies (29.08%) 325 and 29 ongoing pregnancies (50.87%). Considering patients 326 treated with low dose of PG as control group, in patients treated 327 by high-dose PG we found OR: 2.07 and OR: 2.33 to achieve 328 clinical and ongoing pregnancies, respectively, while OR: 6.75 329 and OR: 4.71 were found in patients treated by E2 plus high-dose 330 PG (Figure 3).
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Discussion It is universally accepted and demonstrated that, despite some differences in timing and severity, all IVF protocols induce an abnormal luteal phases. The most accredited theory postulated that the multi-follicular development achieved during ovarian stimulation induce a supraphysiological concentrations of steroids secreted by the high number of corpora lutea during the early luteal phase. An adequate E2 and PG concentration is fundamental to have a good endometrial receptivity and consequently to achieve pregnancy [22]. Because the corpus luteum produces not only PG but also E2 and other steroid hormones, some researchers have questioned whether adding E2 to PG could further improve implantation rates [5–8,22–26]. The rationale to use PG in LPS is uncomfortable. A lot of studies analyzed the usefulness of LPS by PG after ART cycles and the most recently meta-analysis concluded that it has a significant positive effect on clinical pregnancy, ongoing pregnancy and live birth rates. Unfortunately, the researchers did not report any conclusive evidences about the best administration way and daily dose for each ART protocol [8]. Despite PG are available in different formulations (oral, vaginal, rectal and intramuscular), in our study we use only micronized PG administered in low dose (vaginally) or in high dose (both vaginally and intramuscular), excluding the oral administration way (to avoid the pre-hepatic and first pass hepatic metabolism) and the rectal one (to avoid patients’ discomfort and disagreement). Probably for this reason, in our study we do not collect any cases of patients’ therapy drop nor adverse or side effects (i.e. painful injections, rash, inflammatory reactions and infection in injection sites). In agreement with previous evidences, our data confirm that low-dose PG scheme is a less effective support in each ART protocols both in term of clinical and ongoing pregnancy. In fact, high-dose PG scheme resulted better than low dose in terms of clinical pregnancy in some of ART protocols and comparable to the scheme with E2 addition in short-GnRH-ag protocols. According to our results and in agreement with previous data [1], it is possible to postulate that in short-GnRH-ag protocols the addiction of E2 to high-dose PG does not increase the clinical pregnancy rate. This result is probably related to the fact that this protocol inhibits less hypothalamic gonadotropin production than the other ones, resulting in a less early/mild-luteal E2 serum level deprivation [27–29]. Concerning ongoing pregnancy outcome, our data showed that patients treated by high-dose PG reported a higher rate than patients treated by low-dose PG only if treated by agonist protocols. Whereas in antagonist protocols, two PG schemes resulted comparable and real advantages and were found only after LPS by high-dose PG associated to E2. Unfortunately, this IVF protocol induces a strong pituitary suppression in late follicular phase other than a direct reduction in ovarian E2 production probably via GnRH receptors inhibition on granulosa cells [30]. Minaretzis et al. [31] demonstrated that this mechanism is responsible of the differences in E2 production between women treated by GnRH-ant or GnRH-ag. The GnRH-ag administrations usually have an agonistic effect on ovarian E2 production during luteal phase other than a direct positive effect in endometrial thickening due to granulosa and endometrial GnRH receptors stimulation [31]. This spread between GnRH-ag and GnRH-ant protocols in E2 production and endometrial thickness could results more evident in cases of older and poor responder women.
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Figure 1. Clinical pregnancy: stratification data according to the different LPS (for all IVF protocol we considered as control patients treated by low PG dose).
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Figure 2. Ongoing pregnancy: stratification data according to the different LPS (for all IVF protocol we considered as control patients treated by low PG dose).
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397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 Figure 3. Clinical pregnancy: stratification data according to the different LPS in case of women’s age 435 years, E2max at ovulation induction 428 55 nmol/l and endometrial thickness at pick-up 510 mm (we considered as control patients treated by low PG dose). 429 430 431 Evidences by Tavaniotou et al. [32] in oocyte donors suggested in all protocols when low E2max and endometrial 432 underlined that GnRH-ant induced a severe luteal-phase E2 thickness occur. In long-GnRH-ag protocols and in patients 435 433 reduction in younger women also. Surprisingly researchers found years, the real advantages of E2 supplementation remain debat434 that, despite without LPS, this protocol induced luteal PG levels able and require further confirmations. In all the other conditions, 435 higher than that of spontaneous cycle. These evidences are LPS with high-dose PG alone seems a reasonable cost-effective 436 strongly in agreement with our data demonstrating that women scheme to achieve a good pregnancy outcome after IVF. 437 treated by GnRH-ant cycles do not benefit from high-dose PG In our knowledge, our study represents the first large-scale 438 administration in term of on-going pregnancy but get real randomized study aimed to detect the best LPS scheme for each 439 advantages only from E2 supplementation. IVF protocols in usual and peculiar conditions. In addition, our 440 Anyway, our data demonstrated that LPS with high-dose PG in study shows as strength point: strictly patients’ selection criteria, 441 association to E2 supplementation positively increase both the performance of all treatments in a Single Unit by the same 442 clinical and ongoing pregnancy rate in some peculiar condition: Clinicians and well-defined internal guidelines, all serum sample 443 in women aged 435 years, with E2max serum levels at ovulation were analyzed by a single laboratory as well all the endometrial 444 induction 55 nmol/l and endometrial thickness 510 mm, indethickness measurements were performed by two skilled sono445 pendently from the IVF protocol. graphers blinded to patients’ treatment. 446 In these conditions, even if the high-dose PG administration As limitations we report: lack of placebo/no-treatment group 447 alone result better than low-dose PG in terms of OR to achieve (in our opinion unethical), the exclusion of cases treated by rLH 448 clinical pregnancy (OR: 2.3) and on-going pregnancy rate (OR: supplementation or non-recombinant gonadotropins during ovar449 1.9), the E2 supplementation seems to further increase the OR in ian stimulation, the lack of data about hCG or GnRH-ag LPS 450 all cases. Certainly, the advantages in terms of clinical and support (these LPS are unusual in our Unit), statistical significant 451 ongoing pregnancy differ according to the condition (one or more differences in embryos quality between the groups, the lack of 452 together) and to the IVF protocol. We found that the E2 data about live birth rate, the impossibility to blind patients and 453 supplementation to high-dose PG offer minimal advantages in clinicians to the treatment, the exclusive use of micronized 454 case of advanced age (OR: 3.68 for clinical and OR: 2.47 for progesterone and valerate oral estradiol. 455 ongoing pregnancy), quite advantages in case of E2max at 456 ovulation induction 55 nmol/l (OR: 4.88 and OR: 2.75, respectAcknowledgements 457 ively) and the more advantages in case of endometrial thickness The authors acknowledge Dr Stefano Gava, Dr Capuzzo Denise, 458 510 mm at pick-up (OR: 6.75 and OR: 4.61, respectively). Dr Elena Poli and Dr Manfe` Serena, for the precious collaboration 459 Our data strongly demonstrated independently from the IVF in patients recruitment and data collection. The authors acknowledge 460 protocol that LPS with high-dose PG is better than low dose in also the biologist team (Dr Maria Lia Coronella, Dr Cecilia Zicchina 461 increasing clinical and ongoing pregnancy rate. E2 supplemenand Dr Alessandra Oliva) for the daily collaboration in the patient’s treatment. 462 tation is mandatory in case of GnRH-ant protocols and strongly
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Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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