Progesterone level on the day of hCG administration in relation to the pregnancy rates of patients undergoing assisted reproduction techniques

Renato de Oliveira Fernanda Godoy Cabral Waldemar de Almeida Pereira Carvalho Emerson Barchi Cordts Bianca Bianco Caio Parente Barbosa About the authors

ABSTRACT

Objective

To evaluate the predictive capacity for pregnancy of the progesterone level on the day of administering human chorionic gonadotropin, in women submitted to assisted reproductive techniques.

Methods

An observational study with 914 women submitted to assisted reproductive techniques from August 2014 to June 2016.

Results

Total pregnancy rate was 34.58%; in that, the pregnancy rate in women <35 years, between 35 and 38, and >38 years was, respectively, 42.3%, 38.7% and 16.1% (p<0.001). For embryo transfer in the same cycle, and progesterone of 1.3ng/dL, sensitivity was 4.78%, specificity, 84.18%, accuracy, 56.72%, positive likelihood ratio of 0.3019, and negative likelihood ratio of 1.1312, with receiver operating characteristic curve of 0.46 (95%CI: 0.42-0.49).

Conclusion

The progesterone level on the day of administering human chorionic gonadotropin of 1.3ng/dL differs from that empirically adopted at the study site (1.7ng/dL), and has a better predictive capacity for pregnancy in the patients studied. However, the low sensitivity of this examination raises questions about its real importance.

Pregnancy; Chorionic gonadotropin; Progesterone; Reproductive techniques, assisted

RESUMO

Objetivo

Avaliar a capacidade preditiva para gravidez do valor de progesterona no dia da administração da gonadotrofina coriônica humana em mulheres submetidas às técnicas de reprodução assistida.

Métodos

Estudo observacional com 914 mulheres submetidas a reprodução assistida de agosto de 2014 até junho de 2016.

Resultados

Engravidaram 34,58% das mulheres, sendo a taxa de gravidez naquelas >35 anos, entre 35 e 38 anos e >38 anos, respectivamente, de 42,3%, 38,7% e 16,1% (p<0,001). Para o valor de progesterona até 1,3ng/dL visando à transferência embrionária no mesmo ciclo, encontraram-se sensibilidade de 4,78%, especificidade de 84,18%, acurácia de 56,72%, razão de verossimilhança positiva de 0,3019 e razão de verossimilhança negativa de 1,1312, com área sob a curva característica de operação do receptor de 0,46 (IC95%: 0,42-0,49).

Conclusão

O valor de progesterona no dia da administração de gonadotrofina coriônica humana até 1,3ng/dL difere daquele empiricamente adotado no local do estudo (1,7ng/dL) e apresenta melhor capacidade preditiva para gravidez nas pacientes estudadas. No entanto, a baixa sensibilidade deste exame abre questionamentos sobre sua real importância.

Gravidez; Gonadotropina coriônica; Progesterona; Técnicas de reprodução assistida

INTRODUCTION

The results of assisted reproductive techniques (ART) depend on both patient-related clinical aspects and embryo cleavage and development.(11. Wang JX, Yap YY, Matthews CD. Frozen-thawed embryo transfer: influence of clinical factors on implantation rate and risk of multiple conception. Hum Reprod. 2001;16(11):2316-9.)

In this process, searching for success predictors of high-complexity ART, such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), is key to enable single embryo transfer with acceptable pregnancy rate and reduction of multiple pregnancy-related risks.(22. Hydén-Granskog C, Unkila-Kallio L, Halttunen M, Tiitinen A. Single embryo transfer is an option in frozen embryo transfer. Hum Reprod. 2005;20(10): 2935-8.)

Several studies(33. Fanchin R, de Ziegler D, Castracane VD, Taieb J, Olivennes F, Frydman R. Physiopathology of premature progesterone elevation. Fertil Steril. 1995; 64(4):796-801.

4. Givens CR, Schriock ED, Dandekar PV, Martin MC. Elevated serum progesterone levels on the day of human chorionic gonadotrophin administration do not predict outcome in assisted reproduction cycles. Fertil Steril. 1994;62(5): 1011-7.
-55. Check JH, Hourani C, Choe JK, Callan C, Adelson HG. Pregnancy rates in donors versus recipients according to the serum progesterone level at the time of human chorionic gonadotropin in a shared oocyte program. Fertil Steril. 1994;61(2):262-4.) reported that increased serum progesterone levels in high-complexity ART, measured on the day that human chorionic gonadotropin (hCG) is administered, leads to poorer reproductive results.

This higher progesterone level, even when comparing hCG-triggered ovulation and the gonadotropin-releasing hormone agonist (GnRH), also has a negative effect on pregnancy rate,(66. Connell MT, Patounakis G, Healy MW, DeCherney AH, Devine K, Widra E, et al. Is the effect of premature levated progesterone augmented by human chorionic gonadotropin versus gonadotropin-releasing hormone agonist trigger? Fertil Steril. 2016;106(3):584-9.e1.) corroborating the importance of such evaluation.

The level of ≥1.0ng/mL is considered a premature increase in progesterone or early luteinization.(77. Harada T, Yoshida S, Katagiri C, Takao N, Ikenari T, Toda T, et al. Reduced implantation rate associated with a subtle rise in serum progesterone concentration during the follicular phase of cycles stimulated with a combination of gonadotrophin-releasing hormone agonist and gonadotrphin. Hum Reprod. 1995;10(5):1060-4.,88. Bosch E, Valencia I, Escudero E, Crespo J, Simón C, Remohí J, et al. Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. Fertil Steril. 2003;80(6):1444-9.) This increase correlates with greater response to controlled ovarian hyperstimulation (COH), greater number of oocytes captured and higher estradiol levels (E2).(99. Ozçakir HT, Levi R, Tavmergen E, Göker EN. Premature luteinization defined as progesterone estradiol ratio >1 on hCG administration day seems to adversely affect clinical outcome in long gonadotropin-releasing hormone agonist cycles. J Obstet Gynaecol Res. 2004;30(2):100-4.) The higher E2 level would stimulate granulosa cells to produce more progesterone, but at insufficient levels to trigger ovulation.(1010. Al-Azemi M, Kyrou D, Kolibianakis EM, Humaidan P, Van Vaerenbergh I, Devroey P, et al. Elevated progesterone during ovarian stimulation for IVF. Reprod Biomed Online. 2012;24(4):381-8. Review.)

Although routine use of ART provides better knowledge about cycles, early luteinization occurs in approximately 5 to 50% of cases.(1111. Huang B, Li Z, Zhu L, Hu D, Liu Q, Zhu G, et al. Progesterone elevation on the day of HCG administration may affect rescue ICSI. Reprod Biomed Online. 2014;29(1):88-93.

12. Edelstein MC, Seltman HJ, Cox BJ, Robinson SM, Shaw RA, Muasher SJ. Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropin-releasing hormone agonist suppression are not predictive of pregnancy outcome. Fertil Steril. 1990;54(5):853-7.
-1313. Huang B, Ren X, Wu L, Zhu L, Xu B, Li Y, et al. Elevated progesterone levels on the day of oocyte maturation may affect top Quality Embryo IVF Cycles. PLoS One. 2016;11(1):e0145895. eCollection 2016.)

The increase in progesterone could have a negative effect both on ovaries in terms of oocyte maturation, fertilization and embryonic cleavage,(1212. Edelstein MC, Seltman HJ, Cox BJ, Robinson SM, Shaw RA, Muasher SJ. Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropin-releasing hormone agonist suppression are not predictive of pregnancy outcome. Fertil Steril. 1990;54(5):853-7.

13. Huang B, Ren X, Wu L, Zhu L, Xu B, Li Y, et al. Elevated progesterone levels on the day of oocyte maturation may affect top Quality Embryo IVF Cycles. PLoS One. 2016;11(1):e0145895. eCollection 2016.

14. Kiliçdag EB, Haydardedeoglu B, Cok T, Hacivelioglu SO, Bagis T. Premature progesterone elevation impairs implantation and live birth rates in GnRH-agonist IVF/ICSI cycles. Arch Gynecol Obstet. 2010;281(4):747-52.

15. Martinez F, Barri PN, Coroleu B, Tur R, Sorsa-Leslie T, Harris WJ, et al. Women with poor response to IVF have lowered circulating gonadotropin surge-attenuating factor (GnSAF) bioactivity during spontaneous and stimulated cycles. Hum Reprod. 2002;17(3):634-40.
-1616. Ubaldi F, Camus M, Smitz J, Bennink HC, Van Steirteghem A, Devroey P. Premature luteinization in in vitro fertilization cycles using gonadotropin-releasing hormone agonist (GnRH-a) and recombinant follicle-stimulating hormone (FSH), and GnRH-a and urinary FSH. Fertil Steril. 1996;66(2):275-80.) and on endometrium, leading to inappropriate decidualization.(1717. Borman SM, Chaffin CL, Schwinof KM, Stouffer RL, Zelinski-Wooten MB. Progesterone promotes oocyte maturation, but not ovulation, in nonhuman primate follicles without a gonadotropin surge. Biol Reprod. 2004;71(1):366-73.)

In relation to values, the proposal is to consider up to 1.5ng/mL for poor responders, 1.75ng/mL for intermediate responders, and 2.25ng/mL to high responders.(1818. Xu B, Li Z, Zhang H, Jin L, Li Y, Ai J, et al. Serum progesterone level effects on the outcome of in vitro fertilization in patients with different ovarian response: an analysis of more than 10,000 cycles. Fertil Steril. 2012;97(6):1321-7.e1-4.) Additionally, extreme progesterone levels were associated to poor pregnancy outcome.(1919. Pal L, Kovacs P, Witt B, Jindal S, Santoro N, Barad D. Postthaw blastomere survival is predictive of the success of frozen-thawed embryo transfer cycles. Fertil Steril. 2004;82(4):821-6.)

Therefore, identifying the progesterone level to define embryo transfer and improve pregnancy rates justifies the importance of this investigation. In addition, there are scarce studies on highly miscegenated populations, like the Brazilian people. (2020. Giolo SR, Soler JM, Greenway SC, Almeida MA, de Andrade M, Seidman JG, et al. Brazilian urban population genetic structure reveals a high degree of admixture. Eur J Hum Genet. 2012;20(1):111-6.)

OBJECTIVE

To analyze progesterone level measured on measured on the day that human chorionic gonadotropin is administered, which predicts better pregnancy rates in patients undergoing assisted reproductive techniques.

METHODS

A cross-sectional study assessing 1,200 electronic records of patients submitted to ART from August 2014 to June 2016, at the Instituto Ideia Fértil, and approved by the Ethics Committee of Faculdade de Medicina do ABC through opinion no. 676.628, CAAE: 31010214.3.0000.0082.

A total of 914 patients were selected and 286 were excluded due to incomplete records.

Progesterone was tested by Elecsys 1010 Immunoanalyzer (Roche, Indianapolis, USA) only on the day of hCG administration, since the local protocol does not measure it on the beginning of the cycle. If progesterone level was >1.7ng/mL, all formed embryos were cryopreserved for subsequent transfer.

The characteristics evaluated were age, infertility (primary or secondary), smoking, body mass index (BMI), total antral follicle count (AFC), number of follicles >14mm, number of metaphase I (MI) and II (MII) oocytes, number of formed embryos, and a variable known as “response to treatment”, defined as number of follicles >14mm, divided by total AFC multiplied by 100, to evaluate and estimated quality of COH (in percentage).

The COH protocol was defined after initial investigation using follicle-stimulating hormone receptor (FSHr) (Puregon® or Gonal®, 100UI, 150UI or 200UI) and GnRH-antagonist (ORGALUTRAN®) or GnRH-agonists (both long-term and short-term protocols) taking clinical characteristics into consideration, total AFC and patient’s specific aspects, based on the local protocol. Ovulation was triggered through administration of hCG (Ovidrel®). After 35 hours, ovarian puncture was performed and luteal phase support was initiated with vaginal micronized progesterone (600mg per day).

For statistical analysis, Groups A and B were related to pregnancy or no pregnancy after ART, respectively.

The qualitative variables were evaluated by absolute and relative frequencies using the χ2 test. The quantitative variables by medians, 25% and 75% percentiles, confidence interval (CI) and Shapiro-Wilk and Mann-Whitney tests. Sensitivity and specificity were determined by the Receiver Operating Characteristic (ROC) curve, with likelihood ratio and a 95% confidence level. The statistical program used was Stata® 11.0.

RESULTS

The clinical characteristics of the groups are shown in table 1.

Table 1
Characterization of clinical data of evaluated patients

Table 2 displays the high-complexity treatment results. COH data included total AFC, number of follicles >14mm on the day of ovarian puncture, and treatment response. Data related to the procedure and laboratory progression results, such as MI, MII and number of embryos evolved until transfer or cryopreservation were also evaluated.

Table 2
Clinical laboratory parameters of assisted reproduction treatments

As to reproductive outcomes, total pregnancy rate was 34.6%. The evaluation of this rate considered the number of women by age group: patients under <35 years, between 35 and 38 years, and >38 years was 155 (42.3%), 126 (38.7%) and 36 (16.1%), respectively (p<0.001).

The median levels of progesterone in Groups A and B were 0.7ng/dL (95%CI: 0.65-0.71) and 0.69ng/dL (95%CI: 0.6-0.8), respectively (p=0.110).

In patients with BMI <25kg/m2, 356 (65.8%) from Group A had the same median progesterone (0.7ng/dL) as compared to Group B, which comprised 185 (34.2%) patients (p=0.056). Likewise, patients with BMI ≥25kg/m2 had the same median progesterone level (0.63ng/dL) both in Group A, with 243 (65.2%) patients, and in Group B, with 130 (34.8%) patients (p=0.407).

The progesterone level of 1.3ng/dL obtained by ROC curve was the most representative pregnancy predictor, considering sensitivity of 4.78%, specificity of 84.18%, accuracy of 56.72%, positive likelihood ratio of 0.301, negative likelihood ratio of 1.131 and area under the curve of 0.460 (95%CI: 0.421-0.498), as shown in figure 1.

Figure 1
Receiver operation characteristic curve of predictive progesterone capacity in relation to pregnancy rate

DISCUSSION

In spite of excluding approximately 84% of patients who would not get pregnant by ART, the level of 1.3ng/dL of progesterone would included only approximately 5% of those patients who got pregnant. This fact raises questions about its use.

No consensus was reached on the ideal progesterone level for embryo transfer.(2121. Yding Andersen C, Bungum L, Nyboe Andersen A, Humaidan P. Preovulatory progesterone concentration associates significantly to follicle number and LH concentration but not to pregnancy rate. Reprod Biomed Online. 2011;23(2):187-95.) However, an analysis of more than four thousand cycles demonstrated that levels >1.5ng/mL reduced pregnancy rate.(2222. Bosch E, Labarta E, Crespo J, Simón C, Remohí J, Jenkins J, et al. Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles. Hum Reprod. 2010;25(8):2092-100.)

There have been many attempts to select groups to define the best progesterone level. For example, cycles with only GnRH antagonists and progesterone level of ≤1.5ng/mL, obtained acceptable pregnancy rate only for normal responders (6 to 18 oocytes), but not for hyper-responders (>18 oocytes).(2323. Griesinger G, Mannaerts B, Andersen CY, Witjes H, Kolibianakis EM, Gordon K. Progesterone elevation does not compromise pregnancy rates in high responders: a pooled analysis of in vitro fertilization patients treated with recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in six trials. Fertil Steril. 2013;100(6):1622-8.e1-3.) A systematic review and a meta-analysis with more than 60 thousand cycles concluded that the high level of progesterone decreased the pregnancy rate in fresh embryo transfer, but not frozen-thawed embryos.(2424. Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles. Hum Reprod Update. 2013;19(5):433-57.)

The transfer of frozen-thawed embryos is a practice already used in many centers, considering that a hyperstimulated endometrium, which is typical of COH in the same cycle, would affect embryo implantation.(2525. Kofinas JD, Mehr H, Ganguly N, Biley Y, Bochkovsky S, McCulloh D, et al. Is it the egg or the endometrium? Elevated progesterone on day of trigger is not associated with embryo ploidy nor decreased success rates in subsequent embryo transfer cycles. J Assist Reprod Genet. 2016;33(9):1169-74.) The reduced progesterone level of 1.7ng/mL adopted is expected to increase the number of embryo transfers and, therefore, improve positive outcome.

Nonetheless, the new level progesterone of 1.3ng/mL suggests some reflection about its use.

First, it is worth mentioning this level was obtained through the analysis of Brazilian patients, and this could encourage national investigation on the topic. However, there are contradictions about its adoption, as previously mentioned, since it included 5% of patients that got pregnant.

The change in the empirically adopted progesterone level from 1.7 to 1.3ng/dL and based on international populations, considering the national population studied, allows excluding most patients who would not become pregnant. Thus, at an acceptable cost, there is an attempt to prevent miscarriage with improved pregnancy rate by transfer. Moreover, search for new gestational predictors is encouraged.

The decrease in pregnancy rate with ageing is corroborated by the literature and suggests effectiveness of treatments.(2626. Speroff L. The effect of aging on fertility. Curr Opin Obstet Gynecol. 1994; 6(2):115-20. Review.,2727. Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med. 2006;354(11):1139-46.)

As limiting factors of the study, we could mention the GnRH antagonist or agonist protocols were not evaluated separately. The lack of detailed information in evaluations is a bias. The expressive number of patients, however, minimizes differences between groups.

The major benefit of this study was the readjustment of progesterone level measured on the day of hCG administration, to define embryo transfer in the same cycle at the study site. This could also provide better results in other human reproduction centers in our country.

CONCLUSION

The progesterone level on the day of administering human chorionic gonadotropin of up to 1.3ng/dL differs from the level empirically adopted at the study center (1.7ng/dL). Although low sensitivity of this test enables arguing about its relevance, its permanence, associated with search for new pregnancy predictors, are considered essential to improve pregnancy rate per single embryo transfer.

ACKNOWLEGEMENTS

We would like to thank Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) support (project 2014/11655-0) for this research.

REFERENCES

  • 1
    Wang JX, Yap YY, Matthews CD. Frozen-thawed embryo transfer: influence of clinical factors on implantation rate and risk of multiple conception. Hum Reprod. 2001;16(11):2316-9.
  • 2
    Hydén-Granskog C, Unkila-Kallio L, Halttunen M, Tiitinen A. Single embryo transfer is an option in frozen embryo transfer. Hum Reprod. 2005;20(10): 2935-8.
  • 3
    Fanchin R, de Ziegler D, Castracane VD, Taieb J, Olivennes F, Frydman R. Physiopathology of premature progesterone elevation. Fertil Steril. 1995; 64(4):796-801.
  • 4
    Givens CR, Schriock ED, Dandekar PV, Martin MC. Elevated serum progesterone levels on the day of human chorionic gonadotrophin administration do not predict outcome in assisted reproduction cycles. Fertil Steril. 1994;62(5): 1011-7.
  • 5
    Check JH, Hourani C, Choe JK, Callan C, Adelson HG. Pregnancy rates in donors versus recipients according to the serum progesterone level at the time of human chorionic gonadotropin in a shared oocyte program. Fertil Steril. 1994;61(2):262-4.
  • 6
    Connell MT, Patounakis G, Healy MW, DeCherney AH, Devine K, Widra E, et al. Is the effect of premature levated progesterone augmented by human chorionic gonadotropin versus gonadotropin-releasing hormone agonist trigger? Fertil Steril. 2016;106(3):584-9.e1.
  • 7
    Harada T, Yoshida S, Katagiri C, Takao N, Ikenari T, Toda T, et al. Reduced implantation rate associated with a subtle rise in serum progesterone concentration during the follicular phase of cycles stimulated with a combination of gonadotrophin-releasing hormone agonist and gonadotrphin. Hum Reprod. 1995;10(5):1060-4.
  • 8
    Bosch E, Valencia I, Escudero E, Crespo J, Simón C, Remohí J, et al. Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. Fertil Steril. 2003;80(6):1444-9.
  • 9
    Ozçakir HT, Levi R, Tavmergen E, Göker EN. Premature luteinization defined as progesterone estradiol ratio >1 on hCG administration day seems to adversely affect clinical outcome in long gonadotropin-releasing hormone agonist cycles. J Obstet Gynaecol Res. 2004;30(2):100-4.
  • 10
    Al-Azemi M, Kyrou D, Kolibianakis EM, Humaidan P, Van Vaerenbergh I, Devroey P, et al. Elevated progesterone during ovarian stimulation for IVF. Reprod Biomed Online. 2012;24(4):381-8. Review.
  • 11
    Huang B, Li Z, Zhu L, Hu D, Liu Q, Zhu G, et al. Progesterone elevation on the day of HCG administration may affect rescue ICSI. Reprod Biomed Online. 2014;29(1):88-93.
  • 12
    Edelstein MC, Seltman HJ, Cox BJ, Robinson SM, Shaw RA, Muasher SJ. Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropin-releasing hormone agonist suppression are not predictive of pregnancy outcome. Fertil Steril. 1990;54(5):853-7.
  • 13
    Huang B, Ren X, Wu L, Zhu L, Xu B, Li Y, et al. Elevated progesterone levels on the day of oocyte maturation may affect top Quality Embryo IVF Cycles. PLoS One. 2016;11(1):e0145895. eCollection 2016.
  • 14
    Kiliçdag EB, Haydardedeoglu B, Cok T, Hacivelioglu SO, Bagis T. Premature progesterone elevation impairs implantation and live birth rates in GnRH-agonist IVF/ICSI cycles. Arch Gynecol Obstet. 2010;281(4):747-52.
  • 15
    Martinez F, Barri PN, Coroleu B, Tur R, Sorsa-Leslie T, Harris WJ, et al. Women with poor response to IVF have lowered circulating gonadotropin surge-attenuating factor (GnSAF) bioactivity during spontaneous and stimulated cycles. Hum Reprod. 2002;17(3):634-40.
  • 16
    Ubaldi F, Camus M, Smitz J, Bennink HC, Van Steirteghem A, Devroey P. Premature luteinization in in vitro fertilization cycles using gonadotropin-releasing hormone agonist (GnRH-a) and recombinant follicle-stimulating hormone (FSH), and GnRH-a and urinary FSH. Fertil Steril. 1996;66(2):275-80.
  • 17
    Borman SM, Chaffin CL, Schwinof KM, Stouffer RL, Zelinski-Wooten MB. Progesterone promotes oocyte maturation, but not ovulation, in nonhuman primate follicles without a gonadotropin surge. Biol Reprod. 2004;71(1):366-73.
  • 18
    Xu B, Li Z, Zhang H, Jin L, Li Y, Ai J, et al. Serum progesterone level effects on the outcome of in vitro fertilization in patients with different ovarian response: an analysis of more than 10,000 cycles. Fertil Steril. 2012;97(6):1321-7.e1-4.
  • 19
    Pal L, Kovacs P, Witt B, Jindal S, Santoro N, Barad D. Postthaw blastomere survival is predictive of the success of frozen-thawed embryo transfer cycles. Fertil Steril. 2004;82(4):821-6.
  • 20
    Giolo SR, Soler JM, Greenway SC, Almeida MA, de Andrade M, Seidman JG, et al. Brazilian urban population genetic structure reveals a high degree of admixture. Eur J Hum Genet. 2012;20(1):111-6.
  • 21
    Yding Andersen C, Bungum L, Nyboe Andersen A, Humaidan P. Preovulatory progesterone concentration associates significantly to follicle number and LH concentration but not to pregnancy rate. Reprod Biomed Online. 2011;23(2):187-95.
  • 22
    Bosch E, Labarta E, Crespo J, Simón C, Remohí J, Jenkins J, et al. Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles. Hum Reprod. 2010;25(8):2092-100.
  • 23
    Griesinger G, Mannaerts B, Andersen CY, Witjes H, Kolibianakis EM, Gordon K. Progesterone elevation does not compromise pregnancy rates in high responders: a pooled analysis of in vitro fertilization patients treated with recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in six trials. Fertil Steril. 2013;100(6):1622-8.e1-3.
  • 24
    Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles. Hum Reprod Update. 2013;19(5):433-57.
  • 25
    Kofinas JD, Mehr H, Ganguly N, Biley Y, Bochkovsky S, McCulloh D, et al. Is it the egg or the endometrium? Elevated progesterone on day of trigger is not associated with embryo ploidy nor decreased success rates in subsequent embryo transfer cycles. J Assist Reprod Genet. 2016;33(9):1169-74.
  • 26
    Speroff L. The effect of aging on fertility. Curr Opin Obstet Gynecol. 1994; 6(2):115-20. Review.
  • 27
    Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med. 2006;354(11):1139-46.

Publication Dates

  • Publication in this collection
    Jul-Sep 2017

History

  • Received
    26 Apr 2017
  • Accepted
    9 Aug 2017
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