Abstract
Objective
This study aimed to compare the pregnancy outcomes between women receiving frozen embryo transfer (FET) with hormone replacement treatment (HRT) with and without gonadotropin-releasing hormone agonist (GnRHa) pretreatment.
Methods
All consecutive women undergoing HRT cycles (2936 cycles) or HRT with GnRHa pretreatment (HRT + GnRHa, 303 cycles) at our reproductive center between January 2015 and December 2017 were analyzed retrospectively.
Results
The average age was higher in the HRT + GnRHa compared with the HRT group (34.0 ± 4.8 vs. 31.3 ± 4.4). However, the pregnancy outcomes were comparable between the two groups. The clinical pregnancy rate was significantly increased in younger women (≤35 years) in the HRT + GnRHa group compared with the HRT group (56.8% vs. 48.7%), but the live birth rates were similar in the two groups (44.2% vs. 38.4%). The HRT + GnRHa protocol significantly increased the clinical pregnancy rate (55.6% vs. 43.2%) and live birth rate (43.5% vs. 33.5%) compared with the HRT group among women with endometriosis, and significantly decreased the abortion rate in women with polycystic ovarian syndrome (3.1% vs. 16.4%).
Conclusions
GnRHa pretreatment may improve pregnancy outcomes in women with endometriosis and polycystic ovarian syndrome.
Keywords: Frozen–thawed embryo transfer, gonadotropin-releasing hormone agonist, endometriosis, pregnancy outcome, hormone replacement treatment, in vitro fertilization
Introduction
The use of fresh or frozen embryo transfer for in vitro fertilization (IVF) has been a hot topic for debate in recent decades. However, there has been no definitive answer to date, given that the use of fresh or frozen cycles may depend on the cause of the infertility.1,2 Frozen–thawed embryo transfer (FET) is no longer considered as merely a supplement to fresh embryo transfer, and a “freeze-all” protocol has become routine procedure in IVF treatment, owing to the application of progestin-primed ovarian stimulation protocols and pre-implantation genetic diagnosis/screening, and the higher risk of ovarian hyperstimulation syndrome, higher levels of progesterone or estrogen, and abnormal endometrial status in fresh cycles.3,4 The current priority is thus to identify factors that could improve pregnancy outcomes in patients undergoing FET cycles.
Endometrial preparation protocols for FET cycles can be natural or artificial. Natural cycles are suitable for younger women with regular ovulation, and involve several courses of hormone testing and ultrasound monitoring without medical intervention; however, this protocol is less easy to control and less flexible, and carries a risk of asynchronization between the embryo and endometrium due to advanced ovulation or anovulation.5 Artificial or hormone replacement treatment (HRT) cycles are usually recommended in older women and women with ovarian function disorders, irregular menstruation cycles, or ovulation disorders. HRT cycles are more flexible than natural cycles and are generally suitable for women with or without regular ovulation. Although this protocol is controlled by estrogen supplementation, it has been proved to be as successful as natural cycles.5
Programmed cycles using a gonadotropin-releasing hormone agonist (GnRHa) before HRT aim to achieve pituitary down-regulation and avoid spontaneous ovulation and cycle cancellation.6 However, GnRHa administration increases the cost and number of treatment cycles, and its effect on pregnancy outcomes remains controversial. Several studies claimed no difference in pregnancy outcomes between HRT and HRT with GnRHa pretreatment,7–9 and other prospective studies showed that pregnancy outcomes were significantly improved by GnRHa pretreatment in HRT cycles.10,11 We therefore retrospectively analyzed the outcomes of patients treated with FET cycles in our reproductive center and compared outcomes between HRT and HRT + GnRHa cycles.
Materials and methods
Study design
This was a retrospective cohort analysis of women undergoing FET with HRT cycles at the Centre for Reproductive Medicine, Renmin Hospital of Wuhan University, between 1 January 2015 and 31 December 2017. All FET cycles in women receiving HRT or HRT + GnRHa cycles were included, regardless of age, diagnosis, stimulation protocol, embryo stage, or embryo transfer number.
Embryo cryopreservation and thawing
Embryos were cryopreserved on day 3, 5, or 6 of embryo culture. The embryos were placed into equilibrium solution (Kitazato Corporation, Tokyo, Japan) for 6 minutes in room temperature, transferred to vitrification solution (Kitazato Corporation) for 30 s, and then loaded on a Cryotop (Kitazato Corporation) and plunged into liquid nitrogen within 60 s, for no longer than 90 s after initial exposure to vitrification solution. For thawing, the Cryotop was removed from liquid nitrogen and placed immediately into thawing solution (Kitazato Corporation) at 37°C for 1 minute, followed by a three-step rehydration protocol: dilution solution for 3 minutes, followed by two steps of washing solution for 5 minutes, respectively. The embryos were then transferred into a droplet of blastocyst medium in a pre-balanced culture dish in 37°C and 6.0% CO2.
Endometrial preparation protocol
Artificial preparation of the endometrium consisted of treatment with estradiol valerate (Progynova®; Bayer-Schering Pharma AG, Berlin, Germany) 2 mg twice daily for 7 days, followed by two mg three times daily for 6 days. Progesterone supplementation was started on day 13 if the endometrium was at least 7 mm thick, a triple-line endometrium was present, and serum progesterone levels were <1.5 ng/mL. Day 3 embryos were transferred on the fourth day of progesterone exposure, and the blastocysts were transferred on the sixth day of progesterone exposure.
For HRT + GnRHa cycles, 3.75 mg leuprorelin acetate (Diphereline®, Ipsen, France) or 3.75 mg triptorelin acetate (Decapeptyl®, Ferring, Switzerland) was administered during the early follicular phase of the previous menstrual cycle (day one or two), and the HRT protocol was started 28 days later.
Assessment of pregnancy outcomes
Serum β-human chorionic gonadotropin levels were measured 12 days after embryo transfer. If the test was positive, daily estradiol valerate and progesterone supplementation was continued until the 12th week of pregnancy. An ultrasound scan was performed to determine fetal viability 30 days after embryo transfer. Clinical pregnancy was defined as the presence of at least one fetus with a heart beat on ultrasound 45 days after embryo transfer. Pregnancy outcomes, including information on abortion, ectopic pregnancy, delivery conditions, and neonatal status, were collected at clinic visits and by telephone follow-up.
Ethical approval
This was a retrospective study that analyzed the electronic and paper databases in our hospital. All the participating partners signed informed consent for controlled ovarian hyperstimulation, oocyte and sperm collection, IVF or intracytoplasmic sperm injection treatment, embryo cryopreservation, embryo transfer, and follow-up visits. All the procedures complied with the Regulation of Human Assisted Reproductive Technology in China. The data collection and analysis were exempt from the need for ethical approval because the Ethical Review Board confirmed that it was a retrospective study with no extra interventions or bias in treatment. Patient consent for data collection and analysis was not required because the personal information was de-identified for tracking and searching.
Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics for Windows, version 19.0 (IBM Corp., Armonk, NY, USA). Continuous variables were analyzed using independent t-tests or Mann–Whitney U tests, depending on the normality of the distribution. Categorical variables were analyzed by Pearson’s χ2 or Fisher’s exact tests. P<0.05 indicated statistical significance.
Results
Baseline characteristics
A total of 3239 FET cycles were evaluated and included in this study, including 2936 HRT cycles and 303 HRT + GnRHa cycles. The baseline characteristics of both groups are presented in Table 1. The average age was significantly higher in the HRT + GnRHa compared with the HRT group (P<0.0001) and the proportion of older women (>35 years) was also significantly higher in the HRT + GnRHa group (P<0.0001). The proportion of women with endometriosis was significantly higher and the endometrial thickness on the progesterone-administration day was significantly lower in the HRT + GnRHa compared with the HRT group (both P < 0.0001). The type of infertility, number of FET cycles, number of transferred embryos and type of embryos, and serum estradiol level on the progesterone-administration day were all similar in both groups.
Table 1.
Baseline characteristics of women receiving HRT or HRT + GnRHa.
| Characteristic |
Study group |
P value | |
|---|---|---|---|
| HRT | HRT + GnRHa | ||
| Transfer cycles (n) | 2936 | 303 | |
| Age at transfer (years) | 31.3 ± 4.4 | 34.0 ± 4.8 | <0.0001a |
| ≤35 | 2455 (83.6) | 190 (62.7) | <0.0001b |
| >35 | 481 (16.4) | 113 (37.3) | |
| Type of infertility | 0.28b | ||
| Primary infertility, n (%) | 1291 (44.0) | 143 (47.2) | |
| Secondary infertility, n (%) | 1645 (56.0) | 160 (52.8) | |
| Indication for fertility treatment | <0.0001b | ||
| Tubal factor, n (%) | 1892 (64.4) | 121 (39.9) | <0.0001b |
| Male factor, n (%) | 352 (12.0) | 23 (7.6) | 0.03b |
| PCOS, n (%) | 354 (12.1) | 32 (10.6) | 0.05b |
| Endometriosis, n (%) | 206 (7.0) | 108 (35.6) | <0.0001b |
| POF, n (%) | 27 (0.9) | 4 (1.3) | 0.71 |
| Other, n (%) | 105 (3.6) | 25 (5.0) | 0.0001 |
| Number of FET cycles | 1.3 ± 0.6 | 1.3 ± 0.7 | 0.19a |
| Endometrial thickness (cm) | 0.94 ± 0.19 | 0.85 ± 0.27 | <0.0001a |
| Embryo transfer | 2.0 ± 0.4 | 2.0 ± 0.4 | 0.94a |
| Embryo transfer type | 0.14b | ||
| Day 3, n (%) | 2332 (79.4) | 229 (75.6) | |
| Blastocyst, n (%) | 604 (20.6) | 74 (24.4) | |
| E2 level (pg/mL) | 339.5 ± 14.0 | 355.0 ± 443.0 | 0.13a |
Data presented as mean ± standard error or n (%).aStudent’s t-test;bPearson’s χ2 test. HRT, hormone replacement treatment; GnRHa, gonadotropin-releasing hormone agonist; PCOS, polycystic ovarian syndrome; POF, premature ovarian failure; FET, frozen-thawed embryo transfer; E2, estradiol.
Pregnancy outcomes in the HRT and HRT + GnRHa groups
The pregnancy outcomes are presented in Table 2. The overall clinical pregnancy rate (CPR) and live birth rate (LBR) were similar in the two groups. However, among younger women (≤35 years), the CPR was significantly higher in the HRT + GnRHa group (P = 0.04), but the LBR remained similar in both groups. Among older women, the LBR was slightly lower in the HRT + GnRHa compared with the HRT group, but the difference was not significant. The abortion rate and sex ratio at birth (female versus male) were similar in both groups.
Table 2.
Pregnancy outcomes in women receiving HRT or HRT + GnRHa in relation to age.
| Characteristic |
Study group |
P valuea | |
|---|---|---|---|
| HRT | HRT + GnRHa | ||
| Transfer cycles (n) | 2936 | 303 | |
| Clinical pregnancy rate (per transfer cycle) | 46.1% (1353/2936) | 48.5% (147/303) | 0.45 |
| ≤35 years old | 48.7% (1196/2455) | 56.8% (108/190) | 0.04 |
| >35 years old | 32.6% (157/481) | 34.5% (39/113) | 0.74 |
| Abortion rate (per transfer cycle) | 8.5% (249/2936) | 11.2% (34/303) | 0.13 |
| ≤35 years old | 8.5% (209/2455) | 10.0% (19/190) | 0.60 |
| >35 years old | 8.3% (40/481) | 13.3% (15/113) | 0.11 |
| Live birth rate (per transfer cycle) | 35.8 (1051/2936) | 35.0% (106/303) | 0.83 |
| ≤35 years old | 38.4% (942/2455) | 44.2% (84/190) | 0.13 |
| >35 years old | 22.6% (109/481) | 19.5% (22/113) | 0.53 |
| Sex ratio at birth(female: male) | 1: 1.20 (598: 718) | 1: 1.22 (59: 72) | >0.95 |
Data presented as mean ± standard error. aPearson’s χ2 test. HRT, hormone replacement treatment; GnRHa, gonadotropin-releasing hormone agonist.
The pregnancy outcomes in women with endometriosis and polycystic ovarian syndrome (PCOS) are shown in Table 3. Among women with endometriosis, the CPR and LBR were both significantly higher in the HRT + GnRHa group compared with the HRT group (P=0.04 and P = 0.02, respectively). Among women with PCOS, the CPR and LBR were comparable in the two groups, but the abortion rate was significantly lower in the HRT + GnRHa group (P = 0.04).
Table 3.
Pregnancy outcomes in women with endometriosis or PCOS receiving HRT or HRT + GnRHa.
| Characteristic |
Study group |
P value | |
|---|---|---|---|
| HRT | HRT + GnRHa | ||
| Endometriosis | 206 | 108 | |
| Age (years) | 30.8 ± 4.2 | 31.4 ± 3.66 | 0.21a |
| Clinical pregnancy rate | 43.2% (89/206) | 55.6% (60/108) | 0.04b |
| Abortion rate | 7.8% (16/206) | 9.3% (10/108) | 0.67b |
| Live birth rate | 33.5% (69/206) | 43.5% (47/108) | 0.02b |
| PCOS | 354 | 32 | |
| Age (years) | 30.1 ± 3.9 | 31.3 ± 2.8 | 0.11a |
| Clinical pregnancy rate | 51.4% (182/354) | 50.0% (16/32) | 0.85b |
| Abortion rate | 16.4% (58/354) | 3.1% (1/32) | 0.04b |
| Live birth rate | 34.5% (122/354) | 46.9% (14/32) | 0.18b |
Data presented as mean ± standard error. aStudent’s t-test; bPearson’s χ2 test. HRT, hormone replacement treatment; GnRHa, gonadotropin-releasing hormone agonist; PCOS, polycystic ovarian syndrome.
Discussion
In this study, we analyzed 3239 FET cycles to compare the pregnancy outcomes between women receiving HRT cycles and HRT + GnRHa cycles. CPR and LBR were similar in both HRT protocols, with or without GnRHa pretreatment. However, given that this was a retrospective study with significant differences in participants’ ages and infertility diagnoses, the results must be interpreted with caution.
GnRHa may be given in addition to HRT to suppress hormone production by the ovaries and inhibit spontaneous ovulation in artificial cycles. In this study, the average age was significantly higher in the HRT + GnRHa group compared with the HRT group. According to feedback from clinic physicians, this was partly because GnRHa pretreatment could prolong the menstruation cycle and decrease the cycle cancellation rate in older women. A previous retrospective study also found that the average age of women undergoing FET cycles with GnRHa pretreatment was higher than that for women undergoing cycles without GnRHa, because physicians preferred to use GnRHa to prevent cancellation in women of advanced age.8
Natural and artificial FET cycles can achieve equivalent pregnancy outcomes in women with regular ovulation and well-preserved ovarian function.12,13 A prospective randomized clinical trial found no difference in pregnancy outcomes between HRT cycles with and without GnRHa pretreatment in women with regular menstrual cycles.7 HRT cycles can therefore be applied in younger women with normal ovulation and ovarian reserve function, to minimize clinic visiting times and costs. However, the LBR was slightly lower and the abortion rate was higher among older women (>35 years) receiving HRT + GnRHa compared with HRT. Likewise, in controlled hyperstimulation ovulation, a long pituitary-suppression protocol with GnRHa did not produce favorable results in older women or women with poor ovarian reserve, possibly because GnRHa may cause over-suppression of hypothalamic-pituitary-ovarian function and negatively affect uterine receptivity.14–16 The effect of GnRHa pretreatment on pregnancy outcomes in women older than 35 years needs to be further validated.
Endometriosis is a main reason for sub-fertility and failure of embryo implantation.13,17 GnRHa has been used to treat endometriosis by long-term pituitary suppression to improve uterine receptivity.18–20 In this study, HRT cycles with GnRHa pretreatment significantly increased the CPR and LBR in women with endometriosis. Previous results also suggested that FET following GnRHa treatment tended to increase the pregnancy rate in women with endometriosis or adenomyosis.21,22
Infertile women with PCOS have an increased risk of early pregnancy loss, possibly as a result of hyperandrogenism, aberrant uterine receptivity, insulin resistance, and high body mass index.23–25 In terms of IVF treatment, women with PCOS are usually transferred to FET cycles because of a high risk of ovarian hyperstimulation syndrome, and it is important to decrease the rate of pregnancy loss in women with PCOS.26 In this study, although the abortion rate among women with PCOS was significantly higher in the HRT group compared with the HRT + GnRHa group, the LBR was similar in both groups, possibly because of the small sample size in the HRT + GnRHa group. A previous retrospective study showed that GnRHa pretreatment during FET significantly increased the ongoing pregnancy rate in women with hyperandrogenic PCOS.27 However, testosterone levels were not monitored in women with PCOS to determine the mechanism of GnRHa in the prevention of pregnancy loss.
Conclusion
We recommend that women undergoing FET be treated individually in terms of endometrial preparation, based on their diagnosis and age. GnRHa pretreatment could significantly increase CPR and LBR in women with endometriosis and decrease the abortion rate in women with PCOS. However, this was a retrospective clinical study with a limited sample size in the HRT + GnRHa group, and further prospective, randomized clinical studies are needed to validate the optimal protocol for FET cycles.
Declaration of conflicting interest
The authors declare that there is no conflict of interest.
Funding
This work was supported by the fund program: Guide Funding from Renmin Hospital of Wuhan University (RMYD2018M42, 2018; RMYD2018Z13, 2018).
ORCID iD
Qianrong Qi https://orcid.org/0000-0003-0276-7187
References
- 1.Shi Y, Sun Y, Hao C, et al. Transfer of fresh versus frozen embryos in ovulatory women. N Engl J Med 2018; 378: 126–136. [DOI] [PubMed] [Google Scholar]
- 2.Chen ZJ, Legro RS. Fresh versus frozen embryos in polycystic ovary syndrome. N Engl J Med 2016; 375: e42. [DOI] [PubMed] [Google Scholar]
- 3.Blockeel C, Drakopoulos P, Santos-Ribeiro S, et al. A fresh look at the freeze-all protocol: a SWOT analysis. Hum Reprod 2016; 31: 491–497. [DOI] [PubMed] [Google Scholar]
- 4.Casper RF, Yanushpolsky EH. Optimal endometrial preparation for frozen embryo transfer cycles: window of implantation and progesterone support. Fertil Steril 2016; 105: 867–872. [DOI] [PubMed] [Google Scholar]
- 5.Mackens S, Santos-Ribeiro S, van de Vijver A, et al. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Hum Reprod 2017; 32: 2234–2242. [DOI] [PubMed] [Google Scholar]
- 6.Greco E, Litwicka K, Arrivi C, et al. The endometrial preparation for frozen-thawed euploid blastocyst transfer: a prospective randomized trial comparing clinical results from natural modified cycle and exogenous hormone stimulation with GnRH agonist. J Assist Reprod Genet 2016; 33: 873–884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Azimi Nekoo E, Chamani M, Shahrokh Tehrani E, et al . Artificial endometrial preparation for frozen-thawed embryo transfer with or without pretreatment with depot gonadotropin releasing hormone agonist in women with regular menses. J Family Reprod Health 2015; 9: 1–4. [PMC free article] [PubMed] [Google Scholar]
- 8.Groenewoud ER, Cohlen BJ, Al-Oraiby A, et al. A randomized controlled, non-inferiority trial of modified natural versus artificial cycle for cryo-thawed embryo transfer. Hum Reprod 2016; 31: 1483–1492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Yovich JL, Conceicao JL, Hinchliffe PM. GnRH agonist is not required for frozen embryo transfers conducted under artificial hormone therapy. Reprod Biomed Online 2015; 30: 560. [DOI] [PubMed] [Google Scholar]
- 10.Hebisha SA, Adel HM. GnRH agonist treatment improves implantation and pregnancy rates of frozen-thawed embryos transfer. J Obstet Gynaecol India 2017; 67: 133–136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.El-Toukhy T, Taylor A, Khalaf Y, et al. Pituitary suppression in ultrasound-monitored frozen embryo replacement cycles. A randomised study. Human Reprod 2004; 19: 874–879. [DOI] [PubMed] [Google Scholar]
- 12.Groenewoud ER, Macklon NS, Cohlen BJ. Cryo-thawed embryo transfer: natural versus artificial cycle. A non-inferiority trial. (ANTARCTICA trial). BMC Women’s Health 2012; 12: 27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Agha-Hosseini M, Hashemi L, Aleyasin A, et al. Natural cycle versus artificial cycle in frozen-thawed embryo transfer: a randomized prospective trial. Turk J Obstet Gynecol 2018; 15: 12–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Fabregues F, Creus M, Penarrubia J, et al. Effects of recombinant human luteinizing hormone supplementation on ovarian stimulation and the implantation rate in down-regulated women of advanced reproductive age. Fertil Steril 2006; 85: 925–931. [DOI] [PubMed] [Google Scholar]
- 15.Check JH, Choe JK, Cohen R, et al. A study to determine the efficacy of controlled ovarian hyperstimulation regimen using a gonadotropin releasing hormone agonist versus antagonist in women of advanced reproductive age with varying degrees of oocyte reserve on outcome following in vitro fertilization-embryo transfer. Clin Exp Obstet Gynecol 2013; 40: 191–192. [PubMed] [Google Scholar]
- 16.Haahr T, Esteves SC, Humaidan P. Individualized controlled ovarian stimulation in expected poor-responders: an update. Reprod Biol Endocrinol 2018; 16: 20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Yang H, Yin J, Ficarrotta K, et al. Aberrant expression and hormonal regulation of Galectin-3 in endometriosis women with infertility. J Endocrinol Invest 2016; 39: 785–791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Wu B, Yang Z, Tobe RG, et al. Medical therapy for preventing recurrent endometriosis after conservative surgery: a cost-effectiveness analysis. BJOG 2018; 125: 469–477. [DOI] [PubMed] [Google Scholar]
- 19.Kim MK, Chon SJ, Lee JH, et al. Postoperative levonorgestrel-releasing intrauterine system insertion after gonadotropin-releasing hormone agonist treatment for preventing endometriotic cyst recurrence: a prospective observational study. Reprod Sci 2018; 25: 39–43. [DOI] [PubMed] [Google Scholar]
- 20.Tamura H, Takasaki A, Nakamura Y, et al. A pilot study to search possible mechanisms of ultralong gonadotropin-releasing hormone agonist therapy in IVF-ET patients with endometriosis. J Ovarian Res 2014; 7: 100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Niu Z, Chen Q, Sun Y, et al. Long-term pituitary downregulation before frozen embryo transfer could improve pregnancy outcomes in women with adenomyosis. Gynecol Endocrinol 2013; 29: 1026–1030. [DOI] [PubMed] [Google Scholar]
- 22.Surrey ES, Katz-Jaffe M, Kondapalli LV, et al. GnRH agonist administration prior to embryo transfer in freeze-all cycles of patients with endometriosis or aberrant endometrial integrin expression. Reprod Biomed Online 2017; 35: 145–151. [DOI] [PubMed] [Google Scholar]
- 23.Yang X, Quan X, Lan Y, et al. Serum chemerin level in women with PCOS and its relation with the risk of spontaneous abortion. Gynecol Endocrinol 2018; 34: 864–867. [DOI] [PubMed] [Google Scholar]
- 24.Sheng Y, Lu G, Liu J, et al. Effect of body mass index on the outcomes of controlled ovarian hyperstimulation in Chinese women with polycystic ovary syndrome: a multicenter, prospective, observational study. J Assist Reprod Genet 2017; 34: 61–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Abu Hashim H. Twenty years of ovulation induction with metformin for PCOS; what is the best available evidence? Reprod Biomed Online 2016; 32: 44–53. [DOI] [PubMed] [Google Scholar]
- 26.Jakubowicz DJ, Essah PA, Seppala M, et al. Reduced serum glycodelin and insulin-like growth factor-binding protein-1 in women with polycystic ovary syndrome during first trimester of pregnancy. J Clin Endocrinol Metab 2004; 89: 833–9. [DOI] [PubMed] [Google Scholar]
- 27.Tsai HW, Wang PH, Lin LT, et al. Using gonadotropin-releasing hormone agonist before frozen embryo transfer may improve ongoing pregnancy rates in hyperandrogenic polycystic ovary syndrome women. Gynecol Endocrinol 2017; 33: 686–689. [DOI] [PubMed] [Google Scholar]