Journal of Assisted Reproduction and Genetics (2019) 36:1143–1152 https://doi.org/10.1007/s10815-019-01467-0 ASSISTED REPRODUCTION TECHNOLOGIES Do young women with unexplained infertility show manifestations of decreased ovarian reserve? Noa Abrahami1,2 & Ido Izhaki3 & Johnny S. Younis1,2 Received: 7 February 2019 /Accepted: 28 April 2019 /Published online: 21 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose To investigate whether unexplained infertility at a young age demonstrates manifestations of decreased ovarian reserve. Methods A total of 100 women were divided into two equally sized groups. The study group comprised women aged ≤ 37 years diagnosed with unexplained infertility, and the control group included age-matched women with either mechanical factor or severe male factor infertility. Results Both groups were comparable in their basic characteristics. Overall, women with unexplained infertility presented with inferior ovarian reserve results set against women of the control group. The number of ≥ 14-mm follicles on the day of hCG administration was significantly lower in the study compared with the control group (7.0 ± 4.5 vs. 10.4 ± 4.1 follicles, respec- tively, P < 0.001). Likewise, basal serum FSH was higher in the study compared with the control group (8.4 ± 5.5 vs. 6.4 ± 1.7 IU/ L, respectively, P = 0.015), while antral follicle count was lower (10.9 ± 6.6 vs. 16.2 ± 6.6 follicles, respectively, P <0.001). Furthermore, women with unexplained infertility required a higher total dose of FSH for ovarian stimulation (2,923 ± 1,701 vs. 2,196 ± 941 IU/L, respectively, P = 0.010), but exhibited a lower number of retrieved oocytes (9.3 ± 6.3 vs. 15.6 ± 7.9 oocytes, respectively, P < 0.001), alongside a lower number of achieved embryos (5.3 ± 4.0 vs. 8.0 ± 4.7 embryos, respectively, P = 0.002). Interestingly, the cumulative clinical pregnancy rate was not significantly different between the two groups (44% vs. 58%, respectively, P =0.163). Conclusions Young women ≤ 37 years of age with unexplained infertility have clear manifestations of sub-optimal ovarian reserve set against controls. Our findings suggest that unexplained infertility at a young age may be a risk factor for developing poor ovarian response, specifically as a quantitative, rather than a qualitative, risk factor. Keywords Unexplained infertility . Ovarian reserve . (Basal) Ovarian reserve tests . Ovarian hyperstimulation . Bologna criteria Introduction of ovulation, tubal patency, and normal semen parameters [2]. Without treatment, couples with unexplained infertility expe- Up to 30% of couples who are unable to conceive are deter- rience both diminished and delayed fecundity with an average mined to have unexplained infertility [1]. It is generally live birth of 1.8–3.8% per cycle [3]. Moreover, pregnancy established as a diagnosis of exclusion in women who have rates in these couples are lower with increasing age of the tried to conceive for 1 year without success, despite evidence female partner and duration of infertility [4]. Several steps of the fertility process are not thoroughly explored or cannot be accurately investigated when reaching the diagnosis of unexplained infertility. Consequently, this * Johnny S. Younis diagnosis may encompass a heterogeneous group of condi- [email protected] tions [5]. These may include a potential malfunction of the 1 The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, cervical [6], endometrial [7], tubal [8], peritoneal [9], or male Safed, Israel [10] concealed factors that could be involved, albeit normal 2 Reproductive Medicine Unit, Department of Obstetrics & basic evaluation. Gynecology, Baruch-Padeh Medical Center, Poriya, Israel Except for age, risk factors for POR in women undergoing 3 Department of Evolutionary and Environmental Biology, University controlled ovarian stimulation (COS) for assisted reproduc- of Haifa, Haifa, Israel tion are still poorly defined [11]. The publication of the 1144 J Assist Reprod Genet (2019) 36:1143–1152 Bologna criteria in 2011 provided the minimal criteria re- according to the World Health Organization (WHO) ref- quired to define POR. At least two of the three following erence values [35] The control group included women criteria must exist to establish POR: (1) Advanced maternal with either mechanical factor infertility or severe male age (>40 years) or any other risk factor for POR. (2) A previ- factor infertility treated at our unit during the same time ous POR (≤3 oocytes with a conventional stimulation proto- interval. Mechanical factor infertility was defined in col). (3) An abnormal ovarian reserve test [i.e. antral follicle women following bilateral salpingectomy or with bilat- count (AFC) <5-7 follicles or Anti-Müllerian hormone eral tubal occlusion diagnosed by hysterosalpingography (AMH) <0.5-1.1 ng/mL]. They did not, however, delineate and/or laparoscopy. Severe male factor infertility was the risk factors included in the first out of three advocated defined in couples with a pre-wash total motile sperm criteria [12]. Several suggestions were made for more specific of <5×106 in accordance with Hamilton et al. [16]or risk factors; among these and the least studied was unex- previously failed fertilization in conventional in vitro plained infertility in women under the age of 40 years [13]. fertilization treatment. To the best of our knowledge, since the publication of the Women with hypogonadotropic hypogonadism, poly- Bologna criteria, no study has been performed to target the cystic ovarian syndrome, or endometriosis or cases potential implication of unexplained infertility on the devel- employing testicular sperm were excluded from the opment of POR. Moreover, the literature lack targeted studies study. In addition, women who underwent ovarian sur- that explored the association between unexplained infertility gery (cystectomy or oophorectomy), known FMR1 pre- and decreased ovarian reserve (DOR) in young infertile mutation, or following chemotherapy and/or radiothera- women. py were excluded. To minimize the effect of potential With the ongoing postponement of first birth in modern causative Bhidden^ conditions, women who had more societies [14], it seems that the higher the woman’sage,the than five unsuccessful trials of IVF-ET were also omit- harder it becomes to distinguish between unexplained infertil- ted from this study. The included women in both the ity and age-related infertility [5]. Female’s age is one factor study and control groups could participate in the study that does contribute to the unexplained category. When a only once. woman’s age of more than 37 years is the only reason for Data were collected in two separate stages in order to infertility, test results are likely to be normal [15]. That is to increase the reliability of this case-control study. The first suggest that only younger women < 37 years of age may ad- stage aimed to look for infertile women who met the in- equately be referred to as having Bgenuine^ unexplained clusion and exclusion criteria. All women who were infertility. reviewed during this stage were treated in our unit be- The present study aims to evaluate whether young wom- tween April 2015 and November 2016. To ensure similar en aged < 37 years, with an established diagnosis of unex- basal characteristics of both the study and control groups, plained infertility, demonstrate manifestations of DOR, as specifically age and duration of infertility, management of compared to adequate matched controls, in an assisted re- the initial selection was blinded to clinical results. production setting. Following completion of the first stage, the second stage included the collection of all related clinical parameters relevant to ovarian reserve, in both groups. Materials and methods Study conduct Study population This study was authorized beforehand by the Institutional The present study was designed as a retrospective, case- Review and Ethical Committee of Poriya Medical control study. It included young infertile women aged < Center. The first and last authors, NA and JSY, conducted 37 years eligible for in vitro fertilization (IVF)-embryo the search, as well as inclusion and exclusion of women to transfer (ET) at our center chosen by a consecutive sys- the study or control groups. All women participating in the tematic review of patients’ data on files. All included study underwent ovarian reserve evaluation in a natural cycle women had normal cycles with no symptoms of dys- prior to treatment initiation by means of endocrine and ultra- menorrhea or dyspareunia. The study group comprised sonographic (US) tests. Endocrine tests included basal serum women meticulously diagnosed with unexplained infer- follicle-stimulating hormone (FSH) level, serum luteinizing tility who had all of the following: (1) Verified ovula- hormone (LH) level, serum estradiol (E2) level, and FSH/ tion, demonstrated by regular menstrual cycles and ovu- LH ratio. US tests included antral follicle count (AFC) and latory mid-luteal progesterone level, (2) A normal uter- ovarian volume. The sonographic assessment was performed ine cavity and patent tubes, demonstrated by hysterosal- by two US technicians, both of whom are highly proficient pingography, and (3) A normal semen analysis with more than 25 years of experience in reproductive US J Assist Reprod Genet (2019) 36:1143–1152 1145 evaluation. Of note, both technicians were blinded to the strat- [20]. To demonstrate a statistical power of at least 80%, a total egy, as well as the target of the study, as it was retrospective in of 78 women, i.e., 39 in each group, is required to detect a nature. difference in means of 1.3 follicles ≥ 14 mm in diameter on the COS was individually prescribed on a case-to-case basis day of hCG administration, with a standard deviation of 2 according to standard clinical practice. The employment of the follicles using a two-sample t test with a 0.05 two-sided sig- long/short GnRH agonist or the GnRH antagonist protocols nificance level.