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. Author manuscript; available in PMC: 2018 Feb 1.
Published in final edited form as: Reprod Biomed Online. 2016 Nov 16;34(2):154–161. doi: 10.1016/j.rbmo.2016.11.002

Does elevated progesterone on day of oocyte maturation play a role in the racial disparities in IVF outcomes?

Micah J Hill a, G Donald Royster IV a, Mansi Taneja c, Mae Wu Healy a, Shvetha M Zarek a, Alicia Y Christy a, Alan H DeCherney a, Eric Widra b, Kate Devine b
PMCID: PMC5292078  NIHMSID: NIHMS830397  PMID: 27887992

Abstract

The aim of this study was to evaluate if premature progesterone elevation on the last day of assisted reproduction technique stimulation contributes to racial disparities. A total of 3289 assisted reproduction technique cycles were evaluated in Latino, Asian, African American, and white women. Live birth was more likely in white women (42.6%) compared with Asian (34.8%) and African American women (36.3%), but was similar to Latino women (40.7%). In all racial groups, progesterone was negatively associated with live birth and the negative effect of progesterone persisted when adjusting for confounders. Although the effect of elevated progesterone was similar in all racial groups, the prevalence of elevated progesterone differed. P > 1.5 ng/ml occurred in only 10.6% of cycles in white women compared with 18.0% in Latino and 20.2% in Asian women. P > 2 ng/ml occurred in only 2.3% of cycles in white women compared with 6.3% in Latino, 5.9% in Asian and 4.4% in African American women. The increased prevalence of premature elevated progesterone persisted when controlling for IVF stimulation parameters. In conclusion, premature progesterone elevation had a negative effect on live birth in all racial groups studied. The prevalence of elevated progesterone was higher in racial minorities.

Keywords: serum progesterone level, ethnicity, racial disparity, ART outcomes

Introduction

Racial disparities in assisted reproductive techniques demonstrate decreased pregnancy and live birth in African American, Asian, and Latino women compared with white women (Sharara 2000; Bendikson 2005; Dayal 2009; Butts, 2010; Fujimoto 2010; Csokmay, 2011; Nichols 2001; James 2012; Dhillon 2015; Humphries 2015; Kan 2015). Potential causes for racial disparities with assisted reproduction techniques include uterine leiomyomas, tubal disease, Fragile X gene mutation, obesity, hormonal milieu, access to care, parental consanguinity, vitamin D deficiency and socioeconomic status (Seher et al., 2015; Bosdou et al., 2016). Interestingly, controlling for these potential confounders in assisted reproduction technique outcomes does not ameliorate racial disparities among the outcomes, suggesting other unrecognized causes.

Recently published studies have shown that premature elevated progesterone on the day of ovulation trigger results in lower pregnancies and live births in fresh assisted reproduction technique cycles (Papanikolaou 2009; Bosch, 2010; Xu 2012; Hill, 2015). This phenomenon is most likely a result of the advancement of the endometrium, leading to embryo–endometrial asynchrony and resulting in failure of implantation (Bosch, 2010; Hill, 2015). Gene expression studies demonstrate differential expression of global and implantation genes when premature elevated progesterone levels are present (Rong, 2011; Lahoud, 2012). The implementation of cryopreserved embryo transfer cycles may represent a method of ameliorating the effect of elevated progesterone on live birth (Healy, 2016).

Premature progesterone elevations may differentially affect races. To our knowledge, premature elevated progesterone has not been explored as a potential factor for racial disparities in assisted reproduction technqiues. Our objective was to assess if premature progesterone elevations were associated with racial disparities in assisted reproduction technique outcomes.

Materials and methods

Study design

This retrospective cohort study was conducted between 2009 and 2013 at Shady Grove Reproductive Science Center. This time frame was chosen as collected, verified live birth data were available at the time this retrospective study was initiated. The study was designed to determine the effect of progesterone on the last day of assisted reproduction technique stimulation and its effect on assisted reproduction technique outcomes in Latino, Asian, African American, and white women. The study was carried out under an exempt IRB protocol at Shady Grove Fertility Center for outcomes analysis of de-identified data collected under routine clinical care, approved by Schulman IRB on 4 March 2016 (IRB reference no. 200912670).

Study population

Inclusion criteria were women undergoing assisted reproduction techniques with fresh autologous embryo transfer. Cycles with donor oocytes, frozen transfers or no embryo transfers were excluded. Preimplantation genetic screening cycles were excluded as they require frozen embryo transfer in our practice. A total of 3289 cycles met inclusion criteria. Patients self-identified race upon enrolment into the clinic. Self-identified races other than Latino, Asian, African American and white women were excluded owing to inadequate numbers for analysis (Supplemental Figure 1). All fresh autologous cycles with a progesterone value on the last day of stimulation were included if they were from any of the four identified racial groups.

Stimulation protocol

For ovarian stimulation, mixed FSH and LH (Gonal-F Merck USA, Menopur Ferring USA, Bravelle Ferring, USA) protocols under GnRH antagonist or GnRH agonist pituitary suppression were used (Hill, 2015). The stimulation protocols used Menopur in all patients for LH activity and either Bravelle or Gonal F for additional FSH activity. In general, oral contraceptive pills were started 21 days before stimulation. For antagonist protocols, the antagonist (Ganirelix) was started when the dominant follicle was 14 mm in size. Ovarian stimulation was achieved with mixed protocols using both recombinant FSH and HMG. When the dominant follicle was 18 mm or wider, final oocyte maturation was triggered with 10,000 IU of HCG or 4 mg of GnRH agonist. The GnRH agonist trigger was used in patients clinically determined to be at risk of ovarian hyperstimulation syndrome in a GnRH antagonist cycle. Serum progesterone levels were obtained on day of trigger. Oocyte retrieval occurred 36 h later. Fertilization was achieved with conventional IVF or intracytoplasmic sperm injection as clinically indicated. Sperm was obtained by masturbation or surgical extraction. If three or more high-quality embryos were available on day 3, embryos were placed into extended culture and transferred on day 5. Otherwise, the embryos were transferred on day 3. Embryos were graded as good, fair, or poor according to the simplified Society for Assisted Reproductive Technology scoring system (Heitmann et al., 2014). Luteal support was given generally with vaginal progesterone in HCG trigger cycles or intramuscular progesterone with exogenous oestrogen in GnRH agonist triggers. Serum HCG levels were assessed at 4 weeks’ gestational age followed by ultrasonography confirmation of a gestational sac obtained in all pregnant patients.

Hormone assay

Serum progesterone levels were measured using a solid-phase, competitive chemiluminescent enzyme immunoassay (Immulite 2000 Progesterone assay; SiemensMedical Solutions Diagnostic). During the study period, no changes in the progesterone assay occurred. The lower limit of detection for the assay was 0.2 ng/ml, and the analytical sensitivity of the assay was 0.1 ng/ml. The intra-assay and inter-assay coefficients of variation for the assay were 6.7% and 7.2%, respectively, within ovulatory ranges of progesterone. Within the ranges of progesterone measured during ovarian stimulation, the intra-assay and inter-assay coefficients of variation were as follows: 0.4 ng/ml 17.4% and 21.7%; 1.4 ng/ml 8.8% and 12.5%; 2.5 ng/ml 10.2% and 10.6%, respectively. The laboratory regularly carried out calibration verifiers (linearity) during the study period. Assay precision was monitored with three levels of control with progesterone control samples from a third party (Bio-Rad Laboratories).

Statistical analysis

The primary outcome was live birth, defined as a live born infant after the 23 week of gestation. All cycles with an embryo transfer were assessed for live birth. The secondary outcome was the prevalence of elevated progesterone. All cycles were included in this analysis, regardless of whether embryo transfer occurred. Generalized estimating equations (GEE) were used to evaluate the association of progesterone with live birth and progesterone elevation. The GEE models accounted for multiple cycles within a single patient and for confounding variables. Univariate GEE models were used to assess for variables associated with live birth and serum progesterone. Variables with a P < 0.05 were included in the adjusted model. Adjusted models for live birth included age, body mass index, infertility diagnosis, type of trigger medication, peak oestradiol, progesterone, oocytes retrieved, embryo stage, embryo quality, and the number of embryos transferred. Adjusted models for progesterone elevation prevalence included patient age, total gonadotrophin dose, days of gonadotrophin stimulation, GnRH antagonist cycles, oestradiol levels on the day of trigger, all follicles measured on the day of trigger, follicles 14 mm or wider on the day of trigger and the number of oocytes retrieved. Follicle numbers were assessed for all follicles measured, and follicles 12 mm or wider, 14 mm or wider and 16 mm or wider. Each follicular threshold was associated with serum progesterone, but in multivariate analysis, only follicles 14 mm or wider were significantly associated with serum progesterone (P < 0.001). Interaction tests of progesterone by racial groups with live birth were carried out to determine if progesterone had a similar effect on live birth across the range of progesterone values. Progesterone was treated as a continuous variable in these models. The GEE model used a robust estimator for the covariance matrix and an exchangeable structure for the working correlation matrix. All variables were assessed as continuous variables, except for subject race (four categorical variables), primary infertility diagnosis (seven categorical variables), and GnRH agonist trigger use (two categorical variables). Live birth was analysed as a dichotomous outcome.

For graphical purposes, arbitrary progesterone levels and ovarian response levels were used to visually illustrate the effect of progesterone across the range of data. The live birth rate for each racial group was calculated at each progesterone range using unadjusted GEE models accounting for multiple cycles. To asses for variables associated with serum progesterone, GEE models and Pearson correlation were used. Pearson correlations cannot account for repeated cycles, which occurred in 10% of the analysed cycles, so GEE models were used to confirm the Pearson correlations. Adjusted models for comparing the prevalence of progesterone elevation between races accounted for patient age, total gonadotrophin dose, GnRH antagonist cycles, oestradiol levels on the day of trigger, follicles 14 mm or wider on the day of trigger and the number of oocytes retrieved, as these variables were associated with serum progesterone.

The progesterone cut-off thresholds used were 0.8, 0.9, 1.2, 1.5, 1.75, 2.0 or over, and 2.25 ng/ml, as these levels have been published as having a detrimental effect on assisted reproduction technique outcomes (Bosch, 2010; Venetis, 2013; Hill, 2015; Healy 2016). The prevalence of progesterone above these thresholds was calculated for each racial group. Normality of data distribution was assessed with the Shapiro–Wilk test and non-normally distributed data expressed as median with interquartile range. Results were expressed as odds ratios with 95% confidence intervals. P< 0.05 was considered statistically significant. SPSS (IBM, Armonk, NY) was used for statistical analysis.

Results

A total of 4073 assisted reproduction technique cycles with progesterone measured on the last day of stimulation were assessed for eligibility (Supplemental Figure 1). A total of 436 cycles were excluded owing to a racial group identified other than the four studied groups. A total of 3637 autologous fresh assisted reproduction technique cycles in 3263 patients were assessed for the prevalence of elevated progesterone on the day of trigger. A total of 3289 autologous fresh assisted reproduction techqnie cycles in 2956 patients had an embryo transfer and were analysed for live birth. A total of 2019 cycles were carried out among white women, 639 in Asian women, 468 in African American women and 163 in Latino women. Baseline characteristics and assisted reproduction technique parameters are shown in Table 1. In general, the three racial minority groups were older than white women and had a higher number of embryos transferred. Asian women had a higher serum oestradiol on the last day of assisted reproduction technique stimulation, fewer follicles on ultrasound and fewer oocytes retrieved compared with white women. African American women required more gonadotrophins but had a higher serum oestradiol on the last day of assisted reproduction technique stimulation compared with white women. Progesterone was not correlated with anti-Müllerian hormone or antral follicle count. Progesterone was correlated with oestradiol levels on the day of trigger (r = 0.26), total dose of gonadotrophins administered (r = 0.08), follicles 14 mm or wider on the day of trigger (r = 0.16) and the number of oocytes retrieved (r = 0.15) (P < 0.001 for all). The GEE models accounting for multiple cycles confirmed the associations of these variables with serum progesterone.

Table 1.

Comparison of baseline characteristics and assisted reproduction technique parameters between the racial groups. Data expressed as median and interquartile range, except for embryos transferred, which are expressed as mean with 95% CI of the mean.

Variable Latino Asian African American White
Age (years) 36.5 (33–39)a 36 (33–39)a 37 (33–37)a 35 (32–38)
Body mass index (kg/m2) 24.5 (23–27) 23 (21–26)a 28 (25–32)a 24 (22–29)
Antral follicle count 11 (9–14) 12 (9–16) 12 (8–17) 12 (9–19)
Anti-Müllerian hormone 1.2 (0.2–3.0) 1.7 (0.3–2.9) 1.3 (0.3–2.3) 1.2 (0.2–2.4)
Gonadotrophins (IUs) 4123 (2914–6393) 3825 (2512–5700) 4275 (2624–5925)a 3787 (2550–6000)
Oestradiol (pg/ml) 2276 (1229–3472) 2342 (1611–3080)a 2434 (1627–3176)a 2041 (1482–2807)
Progesterone (ng/ml) 1.11 (0.85–1.73)a 1.26 (0.96–1.61)a 1.27 (0.91–1.58) 1.17 (0.91–1.37)
Progesterone–oestrogen ratio (x1000) 0.54 (0.3–0.8) 0.62 (0.3–0.8)a 0.49 (0.3–0.8) 0.52 (0.4–0.8)
Follicles >14 mm 9 (6–11.5) 9 (6–11)a 10 (7–13) 10 (7–12)
Oocytes retrieved 11 (7–16.5) 11 (7–16)a 12 (8–19) 13 (8–18)
Embryos transferred 1.9 (1.7–2.0)a 1.9 (1.8–2.0)a 1.8 (1.7–1.9)a 1.7 (1.7–1.8)
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a

P < 0.05 compared with white women.

In unadjusted and adjusted models, serum progesterone on the last day of assisted reproduction technique stimulation was higher in Latino women (mean 1.34) and Asian women (mean 1.32) compared with white women (mean 1.18, P < 0.01 compared with both). The median progesterone values were low and within the normal clinical range for all racial groups (Table 1).

The effect of progesterone on live birth was similar in all racial groups, with OR ranging from 0.54 to 0.73 (Table 2). The negative effect of progesterone on live birth persisted in all racial groups when confounding variables were accounted for, except in Latino women (OR 0.70, 95% CI 0.49 to 1.01). Live birth was more likely in white women (42.6%) compared with Asian (34.8%) and African American women (36.3%) (P < 0.05 for each compared with white women ), but was similar to Latino women (40.7%). Live birth frequency remained stable as progesterone increased in all racial groups until progesterone was 1.5–1.9 ng/ml, at which point live birth dropped in all ethnicities (Figure 1). When progesterone was 2 ng/ml or over, live birth declined to 10% in Latino women, 5% in Asian women, 14% in African American women, and 18% in white women (Figure 1). Interaction testing of live birth and progesterone by racial group was non-significant, indicating progesterone had a similar effect on live birth in all racial groups.

Table 2.

The association of progesterone on the last day of stimulation and live birth among the racial groups. Adjusted generalized estimating equations models included age, body mass index, infertility diagnosis, type of trigger medication, peak oestradiol, oocytes retrieved, embryo stage, embryo quality and the number of embryos transferred.

Ethnicity Unadjusted OR (95% CI) P-value Adjusted OR (95% CI) P-value
Latino 0.65 (0.46 to 0.90) 0.01 0.70 (0.49 to 1.01) 0.05
Asian 0.56 (0.46 to 0.69) <0.001 0.53 (0.43 to 0.65) <0.001
African American 0.54 (0.41 to 0.70) <0.001 0.50 (0.39 to 0.66) <0.001
Caucasian 0.73 (0.61 to 0.87) 0.001 0.59 (0.48 to 0.70) <0.001
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Figure 1.

Figure 1

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Mean live birth plotted against progesterone values for the four racial groups. Error bars represent 95% CI for the live birth proportion.

Although the effect of elevated progesterone was similar in all racial groups, the prevalence of elevated progesterone differed. P > 1.5 ng/ml occurred in only 10.6% of cycles in white women with 18.0% in Latino and 20.2% in Asian women (Table 3) (P < 0.05 for all compared with white women ). P > 1.5 ng/ml occurred at a similar frequency in white women and African American women (10.6% versus 12.2%, respectively). P > 2 ng/ml occurred in only 2.3% of cycles in white women compared with 6.3% in Latino women, 5.9% in Asian women, and 4.4% in African American women (P < 0.05 for all compared with white women). At lower progesterone thresholds of over 0.8, 0.9, and 1.2 ng/ml, only Asian women had a higher prevalence of elevated progesterone and African American women had a lower prevalence of elevated progesterone compared with white women at progesterone thresholds over 0.8 and 0.9 ng/ml.

Table 3.

Prevalence and likelihood of progesterone elevation above various published thresholds between the racial groups. Unadjusted prevalence was estimated using generalized estimating equations models accounting for multiple cycles within a patient. Adjusted prevalence was estimated using generalized estimating equations models accounting for multiple cycles within a patient for comparing the prevalence of progesterone elevation between races and adjusting for variables which were significantly associated with progesterone (P < 0.05). Adjusted models included patient age, total gonadotrophin dose, days of gonadotrophin stimulation, GnRH antagonist cycles, oestradiol levels on the day of trigger, all follicles measured on the day of trigger, follicles 14 mm or wider on the day of trigger and the number of oocytes retrieved, as these variables were associated with serum progesterone.

Progesterone > 0.8 ng/ml
Ethnicity Unadjusted prevalence (%) Unadjusted OR (95% CI) P-value Adjusted prevalence (%) Adjusted OR (95% CI) P-value
Latino 61.8 1.08 (0.77 to 1.50) NS 79.6 1.48 (0.82 to 2.67) NS
Asian 72.8 1.79 (1.46 to 2.19) <0.001 81.3 1.65 (1.22 to 2.23) 0.001
African American 50.9 0.69 (0.53 to 0.85) <0.001 58.5 0.54 (0.39 to 0.74) <0.001
White 60.0 Reference Reference 72.4 Reference Reference
Progesterone >0.9 ng/ml
Ethnicity Unadjusted prevalence (%) Unadjusted OR (95% CI) P-value Adjusted prevalence (%) Adjusted OR (95% CI) P-value
Latino 53.5 1.10 (0.79 to 1.52) NS 71.1 1.54 (0.92 to 2.57) NS
Asian 63.3 1.72 (1.42 to 2.08) <0.001 71.5 1.57 (1.19 to 2.07) 0.001
African American 41.4 0.69 (0.56 to 0.85) 0.001 45.3 0.52 (0.38 to 0.70) <0.001
White 50.1 Reference Reference 61.4 Reference Reference
Progesterone >1.2 ng/ml
Ethnicity Unadjusted prevalence (%) Unadjusted OR (95% CI) P-value Adjusted prevalence (%) Adjusted OR (95% CI) P-value
Latino 29.3 1.27 (0.88 to 18.2) NS 36.2 1.34 (0.81 to 2.22) NS
Asian 38.8 1.94 (1.60 to 2.35) <0.001 46.5 2.06 (1.59 to 2.69) <0.001
African American 25.3 1.04 (0.82 to 1.31) NS 26.9 0.87 (0.63 to 1.12) NS
White 24.6 Reference Reference 29.6 Reference Reference
Progesterone >1.5 ng/ml
Ethnicity Unadjusted prevalence (%) Unadjusted OR (95% CI) P-value Adjusted prevalence (%) Adjusted OR (95%CI) P-value
Latino 18.0 1.84 (1.19 to 2.85) 0.006 21.2 2.16 (1.25 to 3.72) 0.006
Asian 20.2 2.13 (1.66 to 2.72) <0.001 24.7 2.64 (1.90 to 3.65) <0.001
African American 12.2 1.16 (0.85 to 1.60) NS 13.4 1.24 (0.83 to 1.85) NS
White 10.6 Reference Reference 11.0 Reference reference
Progesterone >1.75 ng/ml
Ethnicity Unadjusted prevalence (%) Unadjusted OR (95% CI) P-value Adjusted prevalence (%) Adjusted OR (95% CI) P-value
Latino 11.8 2.45 (1.46 to 4.13) 0.001 14.7 3.30 (1.72 to 6.35) <0.001
Asian 11.1 2.29 (1.66 to 3.17) <0.001 12.6 2.76 (1.80 to 4.24) <0.001
African American 6.1 1.19 (0.77 to 1.84) NS 6.9 1.41 (0.84 to 2.23) NS
White 5.1 Reference Reference 4.9 Reference Reference
Progesterone >2 ng/ml
Ethnicity Unadjusted prevalence (%) Unadjusted OR (95% CI) P-value Adjusted prevalence (%) Adjusted OR (95% CI) P-value
Latino 6.3 2.73 (1.35 to 5.52) 0.005 10.5 5.71 (2.65 to 12.3) <0.001
Asian 5.9 2.57 (1.65 to 4.00) <0.001 6.7 3.52 (1.95 to 6.34) <0.001
African American 4.4 1.86 (1.09 to 3.18) 0.02 5.0 2.57 (1.35 to 4.89) 0.004
White 2.3 Reference Reference 2.0 Reference Reference
Progesterone >2.25 ng/ml
Ethnicity Unadjusted prevalence (%) Unadjusted OR (95% CI) P-value Adjusted prevalence (%) Adjusted OR (95% CI) P-value
Latino 4.2 3.43 (1.64 to 8.05) 0.005 7.4 8.28 (3.15 to 21.7) <0.001
Asian 3.4 2.73 (1.55 to 4.85) 0.001 3.5 3.81 (1.71 to 8.52) 0.001
African American 2.7 2.19 (1.11 to 4.30) 0.02 2.8 3.02 (1.25 to 7.24) 0.01
White 1.2 Reference Reference 0.9 Reference Reference
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Adjusted GEE models for live birth were conducted to further determine if disparities among the racial groups could be explained by the available confounding variables (Supplemental Table 1). In unadjusted models, there was a lower likelihood of live birth in Asians (OR 0.73, 95% CI 0.60 to 0.90) and African Americans (OR 0.77, 95% CI 0.61 to 0.96). No difference in live birth, however, was found between any of the racial groups when age, body mass index, infertility diagnosis, type of trigger medication, peak oestradiol, progesterone, oocytes retrieved, embryo stage, embryo quality, and the number of embryos transferred were accounted for. In these adjusted models, Latino (OR 1.54–95% CI 0.97 to 2.45), Asian (OR 0.82, 95% CI 0.59 to 1.13) and African American women (OR 1.03, 95% CI 0.73 to 1.46) all had similar live birth to white women (Supplemental Table 1).

Discussion

These results support other studies that found a negative effect of premature elevated progesterone on the day of trigger on assisted reproduction technique outcomes (Bosch 2010; Healy 2015; Hill 2015). These data refine our understanding of this phenomenon by demonstrating this negative effect on live birth is consistent across various racial groups. Although the negative effect of premature elevated progesterone was consistent among races in this study, the prevalence of elevated progesterone differed, with white women having a lower likelihood of progesterone elevation compared with racial minorities. Increased prevalence of elevated progesterone might play a role in the racial disparities seen in this study and others. Controlling for differences in progesterone in the model predicting live birth improved outcomes in ethnic minorities, but did not restore them to the same rate as white women. This demonstrates that progesterone is a contributor to ethnic disparity but only partially explains the differences in live birth outcomes. It is interesting that at higher progesterone elevation thresholds of over 1.5, 2.0, and 2.5 ng/ml, the greatest racial disparity in the prevalence of progesterone elevation was seen. These disparities, however, did not occur at lower thresholds in Latino women and were reversed at lower thresholds in African American women (progesterone thresholds of >0.8 and 0.9 ng/ml). The data reported in the present study show no adverse effect with rising progesterone levels at these lower thresholds (Figure 1). The decrease in live birth became apparent with P > 1.5 and higher.

Possible explanations for racial differences in progesterone elevation include iatrogenic stimulation effects of downregulation protocols and stimulation medication or may reflect underlying differences in steroid pathway activity. It is speculative that polymorphisms in CYP17, aromatase, FSH and LH receptor genes could lead to differential relative serum levels of progesterone in response to gonadotrophin stimulation. Racial disparities in CYP17 polymorphisms have been correlated with uterine leiomyomas and breast cancer, potentially through alteration in steroid production (Catherino, 2013). CYP17 polymorphisms also have been associated with the need for menopausal hormone replacement, with varying frequencies amongst racial groups, further suggesting differential propensities for steroid pathway functionality based on the frequencies of these polymorphisms (Feigelson, 1999). Polymorphisms of the FSH and LH receptors have been shown to predict assisted reproduction technique outcomes and determine the amount of gonadotrophin needed for assisted reproduction technique stimulation (Lazaros, 2013; Lasik-Podar 2015; Lindgren 2016). Polymorphisms in aromatase have been associated with differences in oestradiol and follicle response to ovarian stimulation (Lazaros, 2013). Given that CYP17 and LH receptor activity are necessary for conversion of progesterone to androgens and that FSH receptor and aromatase activity is necessary for conversion of androgens to oestrogen, it is biologically plausible that polymorphisms in these genes could affect the relative serum expression of progesterone in response to gonadotrophin stimulation. Such possibilities are purely speculative. It would be interesting to study the expression of these enzymes and their polymorphisms in patients with and without elevated progesterone.

The strengths of our study include the large sample size at a single centre, providing adequate power to detect differences in the prevalence of premature elevated progesterone. Race was self-identified, which is the gold standard for race reporting (Chin, 2015) and collected in a manner outlined by the Institute of Medicine (Ulmer, 2009). The GEE modelling controlled for possible confounding, which is inherent to analysing multiple cycles from the same patient. The GEE models also accounted for confounding variables associated with live birth, which are not otherwise controlled for in a retrospective analysis. Leiomyomas have been implicated to play a role in assisted reproduction technique racial disparities, with a higher prevalence of leiomyomas in African American women (Baird 2003; Wellons, 2012). Our data set did not have quality data on the number, size or location of leiomyomas to include this as a confounding variable. Patients included in the dataset, however, did have a normal endometrial cavity on saline sonogram before proceeding with IVF. Recent data have suggested that cumulative progesterone exposure over several days may be more significant than a single progesterone value on the day of oocyte maturation (Huang, 2012); however, this study was not able to address racial disparities within the context of cumulative progesterone exposure. In the study, there were fewer Latino women compared with other races, which may have limited our power to detect actual differences in this population. Gonadotrophin dosing and exposure of granulosa cells to stimulation is known to be associated with progesterone levels and was therefore accounted for in the multivariate GEE models (Fillicori et al., 2002; Bosch, et al., 2010; Hill et al., 2015, Lawrenz et al., 2016). Despite this modelling, we cannot completely exclude the risk that bias in the stimulation protocols affected the results. The retrospective design of the study has additional weaknesses that could be overcome with a prospective design where all confounding variables could be collected. Confounding variables not available in this retrospective data set include the exact LH–FSH ratio used on each patient for stimulation, the individual sizes of all follicles, socioeconomic status, smoking status, and surgically extracted sperm. A prospective study design would allow for the collection of all potential confounding variables for the prevalence of progesterone elevation and live birth. It is also possible that measuring serum progesterone over several days of IVF stimulation would provide more helpful information in estimating live birth. Unfortunately, that was beyond the scope of this study to investigate. Racial minorities were under represented in this data set compared with white women and may further contribute to bias. Finally, the finding of different prevalence of premature progesterone elevation was a secondary end-point of the study and not the primary hypothesis. It is possible that this finding was the result of type I error and should be confirmed in future studies.

In conclusion, these data demonstrate evidence that premature elevated progesterone has a similar negative effect across various racial groups. The mean serum progesterone values, however, and more importantly the prevalence of premature elevated progesterone was higher in racial minorities and partially contributed to the lower live birth outcomes that were observed. Further research is needed to confirm the findings of disparate prevalence of elevated progesterone, identify the physiologic causes of this disparity and determine if assisted reproduction technique protocols can be modified to change these outcomes.

Supplementary Material

1. Supplemental Figure 1.

Cycles assessed for eligibility.

2

Biography

graphic file with name nihms830397b1.gif

Dr Hill is Director of Research and Associate Professor at the Combined Federal Fellowship in REI. He has published over 150 research papers, book chapters and abstracts.

Footnotes

Declaration The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U. S. Government.The authors report no financial or commercial conflicts of interest. This research was supported, in part, by Intramural research program of the Program in Reproductive and Adult Endocrinology, NICHD, NIH.

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References

  1. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am Jour Obstet Gynecol. 2003;188:100–107. doi: 10.1067/mob.2003.99. [DOI] [PubMed] [Google Scholar]
  2. Bendikson K, Cramer DW, Vitonis A, Hornstein MD. Racial background and in vitro fertilization outcomes. Int J Gynaecol Obstet. 2005;88:342–6. doi: 10.1016/j.ijgo.2004.11.022. [DOI] [PubMed] [Google Scholar]
  3. Xu Bei, PhD, Li Zhou, PhD, Zhang Hanwang, PhD, Jin Lei, PhD, Li Yufeng, PhD, Ai Jihui, PhD, Zhu Guijin., MD Serum progesterone level effects on the outcome of in vitro fertilization in patients with different ovarian response: an analysis of more than10,000 cycles. Fertility and Steril. 2012;97:1321–7. doi: 10.1016/j.fertnstert.2012.03.014. [DOI] [PubMed] [Google Scholar]
  4. Bosdou JK, Kolibianakis EM, Tarlatzis BC, Fatemi HM. Sociocultural influences on fertility in the Middle East: the role of paternal consanguinity, obesity and vitamin D definciency. Fertil Steril. 2016;106:269–60. doi: 10.1016/j.fertnstert.2016.04.010. [DOI] [PubMed] [Google Scholar]
  5. Bosch E, Labarta E, Crespo J, Simón C, Remohí J, Jenkins J, et al. Circulating P levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4,000 cycles. Hum Reprod. 2010;25:2092–100. doi: 10.1093/humrep/deq125. [DOI] [PubMed] [Google Scholar]
  6. Butts SF, Seifer DB. Racial and racial differences in reproductive potential across the life cycle. Fertil Steril. 2010;93:681–90. doi: 10.1016/j.fertnstert.2009.10.047. [DOI] [PubMed] [Google Scholar]
  7. Catherino WH, Eltoukhi HM, Al-Hendy A. Racial and racial differences in the pathogenesis of clinical manifestations of uterine leiomyoma. Semin Reprod Med. 2013;31:370–9. doi: 10.1055/s-0033-1348896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chin MH. Using patient race, ethnicity, and language data to achieve health equity. J General Inter Med. 2015;30:703–5. doi: 10.1007/s11606-015-3245-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Csokmay JM, Hill MJ, Maguire M, Payson MD, Fujimoto VY, Armstrong AY. Are there racial differences in pregnancy rates in African-American versus white women undergoing frozen blastocyst transfers? Fertil Steril. 2011;95(1):89–93. doi: 10.1016/j.fertnstert.2010.03.050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dayal MB, Gindoff P, Dubey A, Spitzer TL, Bergin A, Peak D, Frankfurter D. Does raciality influence in vitro fertilization (IVF) birth outcomes? Fertil Steril. 2009;91:2414–8. doi: 10.1016/j.fertnstert.2008.03.055. [DOI] [PubMed] [Google Scholar]
  11. Dhillon RK, Smith PP, Malhas R, Harb HM, Gallos ID, Dowell K, Fishel S, Deeks JJ, Coomarasamy A. Investigating the effect of raciality on IVF outcome. Reprod Biomed Online. 2015;31:356–63. doi: 10.1016/j.rbmo.2015.05.015. [DOI] [PubMed] [Google Scholar]
  12. Feigelson HS, McKean-Cowdin R, Pike MC, Coetzee GA, Kolonel LN, Nomura AM, Marchaud LL, Henderson BE. Cytochrome P45017α Gene (CYP17) polymorphism predicts use of hormone replacement therapy. Cancer Research. 1999;59:3908–10. [PubMed] [Google Scholar]
  13. Filicori M, Cognigni GE, Samara A, Melappioni S, Perri T, Cantelli B, Parmegiani L, Pelusi G, DeAloysio D. The use of LH activity to drive folliculogenesis: exploring uncharted territories in ovulation induction. Hum Reprod Update. 2002;8:543–57. doi: 10.1093/humupd/8.6.543. [DOI] [PubMed] [Google Scholar]
  14. Fujimoto VY, Luke B, Brown MB, Jain T, Armstrong A, Grainger DA. Racial and racial disparities in assisted reproductive technology in assisted reproductive technology outcomes in the United States. Fertil Steril. 2010;93:382–90. doi: 10.1016/j.fertnstert.2008.10.061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Heitmann RJ, Hill MJ, Richter KS, DeCherney AH, Widra EA. The simplified SART embryo scoring system is highly correlated to implantation and live birth in single blastocyst transfers. J Assist Reprod Genet. 2013;30:563–7. doi: 10.1007/s10815-013-9932-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Healy MW, Patounakis George, Connell Matt T, Devine Kate, DeCherney Alan H, Levy Michael J, Hill Micah J. Does a frozen embryo transfer ameliorate the effect of elevated progesterone seen in fresh transfer cycles? Fertil Steril. 2016;105:93–99. doi: 10.1016/j.fertnstert.2015.09.015. [DOI] [PubMed] [Google Scholar]
  17. Hill MJ, Royster GD, 4th, Healy MW, Richter KS, Levy G, DeCherney AH, Levens ED, Suthar G, Widra E, Levy MJ. Are good patient and embryo characteristics protective against the negative effect of elevated progesterone level on the day of oocyte maturation? Fertil Steril. 2015;103:1477–84. doi: 10.1016/j.fertnstert.2015.02.038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Huang CC, Lien YR, Chen HF, et al. The duration of pre-ovulatory serum progesterone elevation before hCG administration affects the outcome of IVF/ICSI cycles. Hum Reprod. 2012;27:2036–45. doi: 10.1093/humrep/des141. [DOI] [PubMed] [Google Scholar]
  19. Humphries LA, Chang O, Humm K, Sakkas D, Hacker MR. Influence of race and raciality on in vitro fertilization outcomes: systematic review. Am J Obstet Gynecol. 2015 Sep 9; doi: 10.1016/j.ajog.2015.09.002. pii: S0002-9378(15)01026-1. [DOI] [PubMed] [Google Scholar]
  20. James C, Hammond KR, Steinkampf MP. Race and assisted reproduction: a case-controlled study of outcomes in African-American and Caucasian women. Fertil Steril. 2012;78:s123. [Google Scholar]
  21. Kan A, Leung P, Luo K, Fay L, Tan CL. Do Asian women do as well as their Caucasian counterparts in IVF treatment: Cohort study. J Obstet Gynaecol Res. 2015;41:946–51. doi: 10.1111/jog.12643. [DOI] [PubMed] [Google Scholar]
  22. Lahoud R, Kwik M, Ryan J, Al-Jefout M, Foley J, Illingworth P. Elevated progesterone in GnRH agonist down regulated in vitro fertilisation (IVFICSI) cycles reduces live birth rates but not embryo quality. Archives of Gynecol and Obstet. 2012;285:535–40. doi: 10.1007/s00404-011-2045-0. [DOI] [PubMed] [Google Scholar]
  23. Lasik-Podar T, Kaart T, Peters M, Salumets A. Genetic variants associated with female reproductive ageing- potential markers for assessing ovarian function and ovarian stimulation outcome. Reprod Biomed Online. 2015;31:199–09. doi: 10.1016/j.rbmo.2015.05.001. [DOI] [PubMed] [Google Scholar]
  24. Lawrenz B, Beligotti F, Engelmann N, Gates D, Fatemi HM. Impact of gonadotropin type on progesterone elevation during ovarian stimulation in GnRH antagonist cycles. Hum Reprod. 2016 doi: 10.1093/humrep/dew213. in press. [DOI] [PubMed] [Google Scholar]
  25. Lazaros L, Hatzi E, Xita N, Takenaka A, Sofiktis N, Zikopoulos K, Georgiou I. Inflence of FSHR diplotypes on ovarian response to standard gonadotropin stimulation for IVF/ICSI. J Reprod Med. 2013:395–401. [PubMed] [Google Scholar]
  26. Lazaros L, Xita N, Hatzi E, Takenaka A, Kapomis A, Makrydimas G, Sofikitis N, Stefos mT, Sikopoulos K, Georgiou I. CYP19 gene variants affect the assisted reproduction outcome of women with polycystic ovarian syndrome. Gynecol Endocrinol. 2013;29:478–82. doi: 10.3109/09513590.2013.774359. [DOI] [PubMed] [Google Scholar]
  27. Lindgren I, Baath M, Uvebrant K, Dejmek A, Kjaer L, Henic E, Bungum M, Cilio C, Leiojonhufvud I, Skouby S, Andersen CY, Giwercman YL. Combined assessment of polymorphisms in the LHCGR and FSHR genes predict chance of pregnancy after in vitro fertilization. Hum Reprod. 2016 doi: 10.1093/humrep/dev342. in press. [DOI] [PubMed] [Google Scholar]
  28. Nichols JE, Jr, Higdon HL, 3rd, Crane MM, 4th, Boone WR. Comparison of implantation and pregnancy rates in African American and white women in an assisted reproductive technology practice. Fertil Steril. 2001;76:80–4. doi: 10.1016/s0015-0282(01)01853-2. [DOI] [PubMed] [Google Scholar]
  29. Papanikolaou EG, Kolibianakis EM, Pozzobon C, Tank P, Tournaye H, Bourgain C, Van Steirteghem A, Devroey P. Progesterone rise on the day of humanchorionic gonadotropin administration impairs pregnancy outcome in day 3 single-embryo transfer, while it has no effect on day 5 single blastocyst transfer. Fertil Steril. 2009;91:949–952. doi: 10.1016/j.fertnstert.2006.12.064. [DOI] [PubMed] [Google Scholar]
  30. Li Rong, 1, Qiao Jie, 1, Wang Lina, 1, Li Li, 1, Zhen Xiumei, 1, Liu Ping, 1, Zheng Xiaoying., 2 MicroRNA array and microarray evaluation of endometrial receptivity in patients with high serum progesterone levels on the day of hCG administration. Reprod Bio and Endocrinol. 2011;9:29. doi: 10.1186/1477-7827-9-29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Seher T, Thiering E, al Azemi M, Heinrich J, Schmidt-Weber CB, Kivlahan C, Gutermuth J, ZFatemi HM. Is parental consanguinity associated with ovarian reserve. Repro BioMed Online. 2015;31:427–33. doi: 10.1016/j.rbmo.2015.06.003. [DOI] [PubMed] [Google Scholar]
  32. Sharara FI, McClamrock HD. Differences in in vitro fertilization (IVF) outcome between white and black women in an inner-city, university-based IVF program. Fertil Steril. 2000;73:1170–3. doi: 10.1016/s0015-0282(00)00524-0. [DOI] [PubMed] [Google Scholar]
  33. Ulmer C, McFadden B, Nerenz DR. Race, thnicity, and language data: Standardization of health care quality improvement. National Academies Press; Washington DC: 2009. [PubMed] [Google Scholar]
  34. Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and the probability of pregnancy after IVF: a systematic review and meta-analysis of over 60,000 cycles. Hum Reprod Update. 2013;19:433–57. doi: 10.1093/humupd/dmt014. [DOI] [PubMed] [Google Scholar]
  35. Wellons MF, Fujimoto VY, Baker VL, Barrington DS, Broomfield D, Catherino WH, Richard-Davis G, Ryan M, Thornton K, Armstrong AY. Race matters: a systematic review of racial/ethnic disparity in Society for Assisted Reproductive Technology reported outcomes. Fert Stert. 2012;98:406–9. doi: 10.1016/j.fertnstert.2012.05.012. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1. Supplemental Figure 1.

Cycles assessed for eligibility.

NIHMS830397-supplement-1.doc (30KB, doc)
2
NIHMS830397-supplement-2.doc (29.5KB, doc)

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