Abstract
STUDY QUESTION
Do oral contraceptives (OCs) and progestins impact live birth rate of IVF when used for cycle scheduling in women with polycystic ovary syndrome (PCOS)?
SUMMARY ANSWER
OCs used for scheduling IVF cycle were associated with lowered rates of pregnancy and live birth after fresh embryo transfer, whereas progestins used for this purpose yield higher rates of pregnancy and live birth than OCs.
WHAT IS KNOWN ALREADY
Due to oligo-menorrhea in PCOS, OCs and progestin are extensively used to schedule the start of an IVF cycle in women with PCOS. Little is known about the effect of such pretreatments on outcomes, especially, the rate of live birth.
STUDY DESIGN, SIZE, DURATION
This was a nested cohort study and secondary analysis of a multicenter randomized trial, which was designed to compare live birth rate after fresh embryo transfer vs frozen embryo transfer (FET) in women with PCOS (Frefro-PCOS). A total of 1508 women were enrolled from 14 centers between June 2013 and May 2014.
PARTICIPANTS/MATERIALS, SETTING, METHODS
At the discretion of local investigators, subjects were instructed to wait for spontaneous menses (Control group, n = 323), or were prescribed progestins (P group, n = 283) or OCs (OCs group, n = 902) to induce menstruation prior to the start of ovarian stimulation. GnRH antagonist protocol was initiated at Day 2 or 3 of induced or spontaneous menses cycle. The rates of pregnancy, pregnancy loss and live birth after either fresh embryo transfer or FET were compared among these three groups.
MAIN RESULTS AND THE ROLE OF CHANCE
With fresh embryo transfer, women with OC-induced menses had lower rates of clinical pregnancy (48.8% vs 63.6%, relative rate (RR): 0.77, 95% CI: 0.66–0.89) and live birth (36.1% vs 48.1%, RR: 0.75, 95% CI: 0.61–0.92) than women with spontaneous menses. With freeze-all and deferred FET, women with OC-induced menses had a similar pregnancy rate but a higher pregnancy loss rate (27.7% vs 13.0%, RR: 2.13, 95% CI: 1.28–3.52) after FET than women with spontaneous menses. The live birth rate after FET in women with OC-induced menses, progestin-induced menses and spontaneous menses was 49.4%, 50.7% and 60.2%, respectively (P = 0.06). Progestin-induced menses was associated with similar rates of pregnancy, pregnancy loss and live birth after transfer of either fresh or frozen embryos compared with spontaneous menses. Multivariate logistic regression analysis showed that OCs used for menses induction was associated with lower rate of live birth.
LIMITATIONS, REASONS FOR CAUTION
The methods for menses induction were not assigned randomly, thus selection bias was highly likely because of the study design and significant differences that were observed in the baseline characteristics of the women in the different groups. The mean BMI in this study population was relatively normal; the applicability of this result to obese PCOS women needs to be evaluated in further study.
WIDER IMPLICATIONS OF THE FINDINGS
Our results suggest that either waiting for a spontaneous menses or using progestin is a better option than using OCs to induce menses in women with PCOS prior to ovarian stimulation using GnRH antagonist protocol for IVF. Further randomized controlled studies are needed to confirm our findings.
STUDY FUNDING/COMPETING INTEREST(S)
This study was funded by National Basic Research Program of China (973 Program) (2012CB944700), the State Key Program of National Natural Science Foundation of China (81430029), National Natural Science Foundation of China (81471428) and Thousand Talents Program (Drs Legro and Zhang H). Dr Legro reports receiving consulting fees from Euroscreen, Kindex, Bayer and Millendo Pharmaceuticals and research funding from Ferring. Others report no disclosures.
TRIAL REGISTRATION NUMBER
Frefro-PCOS was registered at Clinicaltrials.gov: NCT01841528.
Keywords: oral contraceptives, progestin, polycystic ovary syndrome, live birth, embryo transfer
Introduction
Polycystic ovary syndrome (PCOS) is characterized by ovulatory dysfunction, hyperandrogenism and polycystic ovary morphology on ultrasonography (Lizneva et al., 2016). Oral contraceptives (OCs) are commonly used to resolve the classic symptom(s) of PCOS, such as hirsutism, acne and irregular menses (McCartney and Marshall, 2016). Progestins are also widely used to induce withdrawal bleed before infertility treatment (Diamond et al., 2012). However, there has been increasing concern about potential adverse effects of their use on pregnancy outcomes after infertility treatment (Diamond et al., 2012; Legro et al., 2015, 2016; Jones et al., 2016). IVF is a common infertility treatment for women with PCOS, and is often used in those who fail to conceive with ovulation induction and those who have concomitant infertility factors.
Due to the feature of oligo-menorrhea and unpredictability of menstrual bleeding in women with PCOS, OCs and progestins are extensively used to schedule the start of an IVF cycle. However, the effects of OCs or progestins pretreatment on outcome of IVF cycle remain inconclusive (Smulders et al., 2010), especially in PCOS which was often an exclusion criterion in many previous randomized trials investigating such effects (Cedrin-Durnerin et al., 2007; Huirne et al., 2006; Kolibianakis et al., 2006; Rombauts et al., 2006). OCs used for cycle scheduling in women with regular menses were suggested to have a remnant adverse effect on outcomes after fresh embryo transfer (Griesinger et al., 2010; Smulders et al., 2010). Frozen embryo transfer (FET) has been increasingly used and an elective freeze-all strategy has recently been advocated (Shapiro et al., 2014; Weinerman and Mainigi, 2014). However, the effect of OCs or progestin use prior to ovarian stimulation on outcome of FET is unclear. We recently completed a large multicenter randomized controlled trial of fresh embryo transfer vs elective FET in women with PCOS (Frefro-PCOS) (Chen et al., 2016), during which the methods used for cycle scheduling were prospectively documented. In the present study, a secondary analysis was performed to see whether the primary outcome of live birth was affected by OCs or progestins pretreatment before ovarian stimulation.
Materials and Methods
Study population
Frefro-PCOS was conducted during June 2013 and July 2015 across 14 centers in China. The conduct of the original study was approved by the ethics committees of Reproductive Medical Center of Shandong University and other study sites. The rationale, design and conduct of this trial and main outcomes have been previously reported in detail (Chen et al., 2016; Shi et al., 2014). Briefly, 1508 infertile women with PCOS undergoing their first cycle of IVF or ICSI were enrolled. PCOS was diagnosed by the presence of menstrual disturbance combined with either hyperandrogenism (hirsutism or hyperandrogenemia) or polycystic ovary on ultrasonography (defined as either an ovary that contains ≥12 antral follicles or ovarian volume >10 cm3), and exclusion of other causes of hyperandrogenism and ovulation dysfunction (Shi et al., 2014). Subjects with a history of unilateral oophorectomy, recurrent spontaneous abortion (defined as three or more previous spontaneous pregnancy losses), congenital or acquired uterine malformations, abnormal parental karyotypes or medical conditions that contraindicated assisted reproductive technology and/or pregnancy were excluded.
Study procedures
At the discretion of local investigators, subjects were instructed to wait for spontaneous menses, or were prescribed progestins for 6–10 days or low-dose monophasic combined OC pills daily for 21–25 days to induce menstruation. The assignment was not randomized, but was based on physicians’ habitual practice and/or patients’ preference. Two kinds of progestin were used: micronized progestin 200 mg/d or dydrogesterone 20 mg/d. Three kinds of OCs were used: ethinyl estradiol (0.03 mg) and desogestrel (0.15 mg), ethinyl estradiol (0.035 mg) and cyproterone acetate (2 mg), ethinyl estradiol (0.03 mg) and drospirenone (3 mg). There was not a standard for choosing the types of OCs or progestins and the choices were mainly based on local physicians’ habitual practice and patients’ preference. GnRH antagonist protocol was used for ovarian stimulation in all subjects. The detailed regimen for ovarian stimulation had been previously described (Chen et al., 2016; Shi et al., 2014). Briefly, recombinant FSH (Gonal-f; Merck Serono, Geneva, Switzerland) was initiated at Days 2–3 of the induced or spontaneous menstrual cycle. HMG (Menopur, Ferring, Switzerland) could be added by the discretion of local investigators, and the indication to do so was not standardized. GnRH antagonist (Cetrorelix; Merck Serono, Darmstadt, Germany) at a daily dose of 250 μg was started when the largest follicle exceeded 12 mm. hCG was administered to trigger oocyte maturation when two or more follicles were ≥18 mm. Oocyte retrieval was performed 34–36 h after hCG injection. Subjects in the fresh embryo transfer arm underwent Day-3 fresh embryos transfer. Subjects in the FET arm had all embryos cryopreserved and underwent a transfer of Day-3 frozen embryos into the endometrium prepared by artificial cycle (Chen et al., 2016). Up to two embryos were transferred for both arms. Endometrial preparation started from Day 2 to 3 of the second menstruation after oocyte retrieval. Again, at the discretion of local investigators, women were instructed to wait for spontaneous menses or prescribed with OCs or progestin to induce menses before endometrial preparation. Oral estradiol valerate (Progynova, Delpharm Lille) and subsequent intramuscular progesterone were used to prepare the endometrium. The procedure of embryo transfer was the same in both groups and performed by experienced physicians. Luteal phase support was administered in both fresh embryo transfer and FET groups till 10 weeks after conception.
Outcome
The outcomes included the rates of live birth, clinical pregnancy and pregnancy loss after the first transfer. The parameters of ovarian response were also analyzed. The definitions of these outcomes were described previously (Chen et al., 2016).
Statistical analysis
We compared the IVF outcomes among women with spontaneous menses (control group), women with progestins-induced menses (P group) and women with OC-induced menses (OCs group). The interaction effect between method for menses and type of transfer was tested to assess whether the effect of OCs or progestin pretreatment varies between the fresh embryo transfer and FET arms. Chi-square test was used to compare the distributions of categorical variables among study groups, and Fisher's exact test was used when a cell count was <5. Continuous variables were summarized as the mean ± standard deviation for normally distributed variables and as median and range for non-normally distributed variables in each group and were compared by one-way ANOVA test or by Kruskal–Wallis test when necessary. Multivariate logistic regression was used to adjust the effect of baseline characteristics and treatment arms. Two-sided alpha level of 0.05 was considered statistically significant without correction for multiple comparisons. All analyses were performed with the use of SPSS software (SPSS Inc., Version 21.0, Chicago, USA).
Results
Baseline characteristics
Of these 1508 women, 323 had spontaneous menses, 283 had progestin-induced menses and 902 had OC-induced menses before ovarian stimulation (Supplementary Fig. S1). Women with OC-induced menses were slightly younger than the other two groups (Table I). The duration of infertility, BMI and total antral follicle count were higher in women with progestin-induced menses than the other two groups. The level of total testosterone was lower in women with spontaneous menses than the other two groups. The major indication for IVF was concomitant tubal factor in all groups.
Table I.
Baseline characteristics.
| Characteristics | Control groupa | P groupa | OCs groupa | P-value |
|---|---|---|---|---|
| N | 323 | 283 | 902 | |
| Age (year) | 28.4 ± 3.0 | 28.4 ± 3.1 | 28.0 ± 3.0c | 0.015 |
| Duration of infertility (year)b | 3.0 [13.0] | 4.0 [11.0]c | 3.0 [13.0] | 0.013 |
| BMI | 23.7 ± 3.7 | 24.4 ± 3.8c | 23.7 ± 3.6 | 0.025 |
| Primary infertility, no. (%) | 217 (67.2) | 204 (72.1) | 629 (69.7) | 0.422 |
| Total antral follicle countd | 28.5 ± 8.3 (294) | 30.9 ± 8.6 (263)c | 28.9 ± 7.9 (801) | 0.001 |
| LH/FSH ratio | 1.20 [6.65] | 1.49 [4.90] | 1.27 [7.80] | 0.087 |
| Total testosterone (ng/dl)d | 38.1 ± 18.7 (316)c | 43.1 ± 19.5 (283) | 43.1 ± 18.1 (841) | <0.001 |
| Indication for IVF treatment, no. (%) | 0.022 | |||
| Ovulation dysfunction only | 64 (19.8) | 67 (23.7) | 148 (16.4) | |
| Concomitant tubal factor | 186 (57.6) | 152 (53.7) | 486 (53.9) | |
| Concomitant male factor | 57 (17.6) | 47 (16.6) | 211 (23.4) | |
| Concomitant tubal and male factors | 16 (5.0) | 17 (6.0) | 57 (6.3) | |
aControl group represents women with spontaneous menses before ovarian stimulation. P group represents women with progestogen-induced menses. OCs group represents women with oral contraceptive-induced menses.
bNon-normally distributed variables were described as median [range].
cPost hoc analyses showed significant differences compared with the other two groups. The other comparison was not significant.
dThe number in brackets following mean ± standard deviation indicates the number of complete observations which is below the number of the group.
Ovarian response
The duration of exogenous gonadotropin stimulation and the total dose of gonadotropin consumed were comparable among these three groups (Table II). The levels of estradiol and LH on the day of hCG trigger were different between groups, which were highest in women with progestin-induced menses and lowest in women with OC-induced menses. The endometrial thickness on the day of hCG trigger was lower in women with OC-induced menses than the other two groups. The numbers of oocyte retrieved, embryos on Day 3, and embryos transferred and the incidence of moderate or severe ovarian hyperstimulation syndrome (OHSS) were comparable among these three groups (Table II).
Table II.
Ovarian response.
| Variables | Control groupa | P groupa | OCs groupa | P-value |
|---|---|---|---|---|
| N | 323 | 283 | 902 | |
| Duration of ovarian stimulation (day) | 10.4 ± 2.1 | 10.4 ± 2.3 | 10.2 ± 2.1 | 0.280 |
| Gonadotropin dose consumed (IU)b | 1350.0 [4000.0] | 1350.0 [4850.0] | 1350.0 [4300.0] | 0.406 |
| Estradiol level on day of hCG trigger (pg/ml)b | 3955.9 [13 376.3] | 4283.0 [14 249.5] | 3713.0 [15 170.1] | <0.001c |
| LH on day of hCG trigger (IU/l)b | 2.2 [27.6] | 3.0 [23.1] | 1.6 [37.0] | <0.001c |
| Progesterone on day of hCG trigger (ng/ml)b | 0.95 [3.59] | 1.00 [5.42] | 0.91 [3.56] | 0.153 |
| Endometrial thickness on day of hCG trigger (mm) | 11.2 ± 2.0 | 11.3 ± 2.0 | 9.9 ± 2.0d | <0.001 |
| No. of oocytes | 14.5 ± 5.7 | 14.7 ± 5.8 | 14.1 ± 6.0 | 0.251 |
| No. of embryo on Day 3b | 6.0 [22.0] | 6.0 [19.0] | 6.0 [25.0] | 0.243 |
| No. of embryo transferredb | 2.0 [1.0] | 2.0 [1.0] | 2.0 [1.0] | 0.325 |
| Moderate or severe OHSS | 15/323 (4.6%) | 16/283 (5.7%) | 33/902 (3.7%) | 0.321 |
aControl group represents women with spontaneous menses before ovarian stimulation. P group represents women with progestogen-induced menses. OCs group represents women with oral contraceptive-induced menses.
bNon-normally distributed variables were described as median [range].
cPost hoc analyses showed significant differences between any two groups.
dPost hoc analyses showed significant differences compared with the other two groups. The other comparison was not significant.
OHSS, ovarian hyperstimulation syndrome.
Rates of pregnancy, pregnancy loss and live birth
Seven women with spontaneous menses (2.2%), six women with progestin-induced menses (2.1%) and twenty-one women with OC-induced menses (2.3%) did not undergo embryo transfer mainly due to no embryos obtained or personal issues (Supplementary Fig. S1).
There were significant interaction effects between methods for menses and the type of transfer (fresh or frozen embryo) on conception rate (P = 0.006) and clinical pregnancy rate (P = 0.008), indicating that the effects of OCs pretreatment on conception and pregnancy differed between fresh embryo transfer and FET. Such interaction effects were not significant on the rates of pregnancy loss (P = 0.207) or live birth (P = 0.143).
With fresh embryo transfer, the rates of conception (59.0% vs 68.8%, relative rate (RR): 0.86, 95% CI: 0.75–0.98; number needed treat (NNT): 10, 95% CI: 5–81), clinical pregnancy (48.8% vs 63.6%, RR: 0.77, 95% CI: 0.66–0.89; NNT: 7, 95% CI: 4–17) and live birth (36.1% vs 48.1%, RR: 0.75, 95% CI: 0.61–0.92; NNT: 8, 95% CI: 5–35) were significantly lower in women with OC-induced menses than that in women with spontaneous menses (Figs 1A and 2A). Women with progestin-induced menses had similar rates of conception (74.1% vs 68.8%, RR: 1.08, 95% CI: 0.93–1.24), clinical pregnancy (66.9% vs 63.6%, RR: 1.05, 95% CI: 0.89–1.24) and live birth (51.8% vs 48.1%, RR: 1.08, 95% CI: 0.86–1.36) to women with spontaneous menses (Figs 1A and 2B). The pregnancy loss rate after fresh embryo transfer was similar among these three groups (29.2%, 29.1% and 34.6% for control group, P group and OCs group, respectively, P = 0.458, Fig. 1A).
Figure 1.
Rates of pregnancy, live birth and pregnancy loss after either fresh or frozen embryo transfer (FET) among women with spontaneous menses (Control group), progestin-induced menses (P group) and oral contraceptive (OC)-induced menses (OCs group). (A) Rates after fresh embryo transfer; (B) Rates after FET; * represented the difference among three groups was statistically significant.
Figure 2.
Relative risk (RR) of pregnancy, live birth and pregnancy loss compared with women with spontaneous menses (Control group). (A) RR after fresh embryo transfer in women with OC-induced menses (OCs group) compared with control. (B) RR after fresh embryo transfer in women with progestin-induced menses (P group) compared with control. (C) RR after FET in OCs group compared with control. (D) RR after FET in P group compared with control.
With freeze-all and FET, the rates of conception (71.0%, 65.2% and 70.5% for control group, P group and OCs group, respectively, P = 0.461) and clinical pregnancy (68.5%, 58.0% and 61.1% for control group, P group and OCs group, respectively, P = 0.136) were similar among these three groups (Fig. 1B). Nonetheless, women with OC-induced menses had a higher rate of pregnancy loss after FET than women with spontaneous menses and progestin-induced menses (27.7% vs 13.0% and 18.9%, P = 0.004, Figs 1B and 2C and D). The live birth rate after FET in women with OC-induced menses, progestin-induced menses and spontaneous menses approached a significant difference (49.4%, 50.7% and 60.2% respectively, P = 0.06, Fig. 1B). Post hoc analyses showed that the live birth rate in women with OC-induced menses was lower than women with spontaneous menses (RR: 0.82, 95% CI: 0.70–0.96).
For women who underwent FET, OCs or progestins were prescribed again in some to induce menses before endometrial preparation. To distinguish the confounding effect of OCs or progestins used before endometrial preparation for FET from effect of usages before ovarian stimulation, we subdivided each group into three subgroups according to menses-induction methods before endometrial preparation (Supplementary Table S1). We found that OC-induced menses before endometrial preparation was associated with a thinner endometrium before FET. However, the rates of pregnancy, pregnancy loss and live birth were all comparable among subgroups with spontaneous menses, progestin or OC-induced menses before endometrial preparation.
In women with OC-induced menses, freeze-all and FET resulted in significantly higher rates of conception, clinical pregnancy and live birth compared with fresh embryo transfer (Table III). In women with progestin-induced menses, the rates of conception, clinical pregnancy, pregnancy loss and live birth were comparable between fresh embryo transfer and FET (Table III).
Table III.
Comparison between fresh vs frozen embryo transfer among women with spontaneous menses, progestin-induced menses or OC-induced menses.
| Variables | Fresh embryo transfer | Frozen embryo transfer | P-value |
|---|---|---|---|
| Women with spontaneous menses | |||
| N | 154 | 162 | |
| Conception rate, no. (%)a | 106 (68.8) | 115 (71.0) | 0.676 |
| Clinical pregnancy rate, no. (%)b | 98 (63.6) | 111 (68.5) | 0.359 |
| Pregnancy loss rate, no. (%)c | 31/106 (29.2) | 15/115 (13.0) | 0.003 |
| Live birth rate, no. (%)d | 74 (48.1) | 97/161 (60.2) | 0.030 |
| Women with progestin-induced menses | |||
| N | 139 | 138 | |
| Conception rate, no. (%)a | 103 (74.1) | 90 (65.2) | 0.108 |
| Clinical pregnancy rate, no. (%)b | 93 (66.9) | 80 (58.0) | 0.125 |
| Pregnancy loss rate, no. (%)c | 30/103 (29.1) | 17/90 (18.9) | 0.098 |
| Live birth rate, no. (%)d | 72 (51.8) | 70 (50.7) | 0.858 |
| Women with OC-induced menses | |||
| N | 441 | 440 | |
| Conception rate, no. (%)a | 260 (59.0) | 310 (70.5) | <0.001 |
| Clinical pregnancy rate, no. (%)b | 215 (48.8) | 269 (61.1) | <0.001 |
| Pregnancy loss rate, no. (%)c | 90/260 (34.6) | 86/310 (27.7) | 0.077 |
| Live birth rate, no. (%)d | 159/440 (36.1) | 216/437 (49.4) | <0.001 |
aConception was defined by a serum hCG of >10 mIU/ml.
bClinical pregnancy was defined by observation of intrauterine gestational sac on ultrasonography.
cPregnancy loss was defined as conceptions that did not result in live birth with exception of ectopic pregnancy.
dLive birth was defined as delivery of any viable infant ≥28 weeks gestation.
In our multivariable logistic regression, we adjusted for age, duration of infertility, BMI, primary or secondary infertility, total antral follicle count, LH/FSH ratio, total testosterone, indications for IVF and fresh embryo transfer or FET group. OCs use for menses induction was still significantly related with lower rates of clinical pregnancy and live birth as well as a higher rate of pregnancy loss compared with spontaneous menses (Supplementary Table S2). Progestin use for menses induction was not significantly related to any of these outcomes.
Discussion
In women with PCOS, we found that OCs used for menses induction before ovarian stimulation were associated with lower rates of clinical pregnancy and live birth after fresh embryo transfer; however, progestins for this purpose were not related with adverse effects on these outcomes compared with spontaneous menses. By performing freeze-all and FET, the adverse effect of OCs pretreatment on the live birth rate was greatly reduced though it was still associated with a higher pregnancy loss rate.
OCs and progestin inhibit endogenous gonadotropin secretion through negative feedback (Cohen and Katz, 1979). Although it was suggested that gonadotropin secretion recovered as early as 5 days after pill cessation (Cedrin-Durnerin et al., 2007), there was evidence that the conception rate in the first 3 months was lower after cessation of OCs use than that after discontinuation of other contraceptive methods, which suggested lasting effect on the following cycles after OCs use (Linn et al., 1982). We found that OCs used for menses induction had a remnant adverse effect on the subsequent fresh embryo transfer cycle. During ovarian stimulation, serum levels of LH and estradiol and endometrial thickness remained lower in women with OC-induced menses than those with spontaneous menses or progestin-induced menses. This finding was consistent with a previous study, which reported the lower level of LH related with OCs pretreatment persisted from the beginning of ovarian stimulation till the day of hCG trigger (Kolibianakis et al., 2006).
OC-induced menses was associated with decreased endometrium thickness in the ensuing cycle, which was evidenced by thinner endometrium on day of hCG trigger and before FET. We found that rates of pregnancy and live birth after FET were not affected by OCs used for scheduling endometrial preparation, though it was related to a thinner endometrium. This finding was consistent with another study, which found no effect of OCs used for scheduling FET cycle on pregnancy rate (Ozgur et al., 2016). The underlying mechanism was unclear. However, it has been reported that OCs treatment induces a maturation advance in endometrium histological dating (Creus et al., 2003). Ovarian stimulation was also associated with advancement of endometrium maturation (Shapiro et al., 2011). Speculatively, the remnant effect of OCs may aggravate the effect of ovarian stimulation on the asynchrony between endometrium and embryo during fresh embryo transfer, which consequently resulted in lowered rate of clinical pregnancy. However, during FET, with the recovery from the supra-physiological hormone exposure, the remnant effect of OCs used for scheduling endometrial preparation alone may not be enough to affect endometrial maturation or the ensuing pregnancy rate. However, the increased pregnancy loss rate after FET suggested that OCs pretreatment may also adversely affect oocyte and/or embryo quality. LH was shown to be essential for normal follicle development and oocyte maturation in a natural cycle (Hillier, 2001). In GnRH antagonist cycles, lower LH levels were found to be associated with a higher rate of early pregnancy loss in patients with OCs pretreatment (Meldrum et al., 2009).
Progestin-induced menses was associated with similar rates of pregnancy and live birth after either fresh embryo transfer or FET compared with spontaneous menses. A meta-analysis showed in GnRH agonist cycles that progestin pretreatment was associated with higher clinical pregnancy rate than placebo or no pretreatment (Smulders et al., 2010). Our results showed that progestin-induced menses was associated with higher levels of estradiol and LH and comparable endometrial thickness on the day of hCG trigger than spontaneous menses. However, the mechanism is unclear and warrants further studies.
The present study had the following strengths. The data were prospectively collected from 14 centers and thus enhanced the extrapolation of the results. The long-term follow-up of the cohort allowed us to provide information on the most clinically important outcomes, i.e. live birth rate, which has been recommended by expert consensus in infertility studies (Legro et al., 2014a).
There are also limitations of our study. First, OCs or progestins administration was not randomly assigned, but given at the discretion of local investigators, selection bias was highly likely as suggested by the baseline differences in our post hoc groups. However, compared with women with spontaneous menses, women with OC-induced menses were slightly younger and had higher levels of testosterone. Women with progestin-induced menses had a longer duration of infertility, higher BMI, more antral follicles and higher testosterone levels. In general, given these differences in baseline characteristics, women with progestin-induced menses were expected to have lowest rate of live birth. In contrast, our results revealed that the rate of live birth was lowest in women with OC-induced menses. Thus, the differences in outcomes were unlikely solely related to selection bias. Nonetheless, our results need to be confirmed by randomized controlled trial. Second, the mean BMI of the studied population was relatively normal, which was lower than that in some other ethnic PCOS populations (Legro et al., 2014b), such that there may have been relatively increased serum levels of synthetic hormones (Edelman et al., 2009). However, a recent Cochrane meta-analysis did not find increasing BMI that impacted the effectiveness of hormonal contraceptives (Lopez et al., 2016). The applicability of our results to obese PCOS women needs to be confirmed in future studies. Third, three types of OCs with different components of progestin were used in this study. Whether the effect of different OC types was varied is unclear due to the small sample size in each OCs subgroup. The interactions between OCs pretreatment and FET vs fresh embryo transfer on rates of live birth were not statistically significant, and the difference in live birth rate after FET was not statistically significant between OCs group and control group, which may due to the insufficient sample size. Additionally, multiple tests performed in this study increase the risk of Type I error. Further studies are needed to reinforce our findings.
In summary, our results suggest that either waiting for a spontaneous menses or using progestin is a better option than using OCs to induce menses in women with PCOS prior to ovarian stimulation using GnRH antagonist protocol for IVF. PCOS women using OCs had a lower live birth rate after fresh embryo transfer when compared with women using progestin for inducing menses or those with spontaneous menses. This difference, however, was not observed in the group who received an FET. These results should be interpreted with caution, as there is a high likelihood of selection bias because of the study design and significant differences that were observed in the characteristics of the women in the different groups.
Supplementary Material
Acknowledgements
In addition to the authors, other people who participated in data collection and site monitoring were as following: Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University: Z. Wang, L. Zhang, P. Li, M. Xia, T. Ni, T. Chen, C. Zhang; Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University: F. Diao, C. Wu; Reproductive Medicine Center, the Sixth Affiliated Hospital of Sun Yat-sen University: Y. Deng, B. Wang; Center for Reproductive Medicine, the First Affiliated Hospital of Anhui Medical University: Y. Xu, D. Chen; Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University: X.Ji, Y. He, Y. Wang; Center for Reproductive Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University: X. Chen; Center for Reproduction and Genetics, Suzhou Municipal Hospital: H.Li; Center for Reproductive Medicine, Maternal and Child Health Hospital in Guangxi_ H. Zhou; Center for Reproductive Medicine, Wuhan University: D. Cheng; Center for Reproductive Medicine of Yantai Yuhuangding Hospital: L. Zhuang; Jiangxi Maternal and Child Health Hospital: Q.Wu; Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine: S. Zhang; Assisted Reproduction Center, Maternal and Child Health Care Hospital of Shanxi Province: H. Bai; Reproductive Medicine Center of Jinghua Hospital: L. Liu, N Zhou; Resman database manager: T Wu; Data and Safety Monitoring Committee: J. Simpson (Chair), TC. Li, J. Zhang, G. Sun, Y. Li. We would also like to thank the NIH U10 Reproductive Medicine Network Steering Committee for sharing the protocol and case report forms from the Pregnancy in Polycystic Ovary Syndrome II study.
Supplementary data
Supplementary data are available at Human Reproduction online.
Authors’ roles
D.W., Y.S., H.Z., R.S.L., and Z.-J.C. were involved in study concept and design. D.W., L.Z. and H.Z. analyzed data. D.W., H.Z., R.S.L. and Z.-J.C. drafted the manuscript, and Z.-J.C. had a primary responsibility for final content. All authors were involved in acquisition of the data collection, interpreted the data, provided critical input to the manuscript and approved the final manuscript.
Funding
National Basic Research Program of China (973 Program) (2012CB944700); The State Key Program of National Natural Science Foundation of China (81430029); National Natural Science Foundation of China (81471428); Thousand Talents Program (Drs. Legro and H. Zhang).
Conflict of interest
Dr. Legro reports receiving consulting fees from Euroscreen, Kindex, Bayer and Millendo Pharmaceuticals and research funding from Ferring. Others report no disclosures.
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