Special characteristics, reproductive, and clinical profile of women with unexplained infertility versus other causes of infertility: a comparative study

Purpose To investigate whether women with unexplained infertility (UI) demonstrate different demographic and IVF characteristics compared to those with other causes of infertility.

Data on 245 couples that underwent a total of 413 IVF/ICSI cycles were analyzed (UI 114 cycles, 73 women; anovulation (PCO/PCOS) 83 cycles, 51 women; tubal factor 85 cycles, 47 women; male factor 131 cycles, 74 women). Features of UI were compared versus other infertility groups, after adjustment for multiple comparisons. Generalized least squares (GLS) and random-effects logistic regression analysis were also performed.

Live birth rates, consisting of the primary outcome, were similar in all compared infertility groups. Compared to male infertility, UI was associated with woman’s older age at cycle, lower body mass index (BMI), and higher follicle-stimulating hormone (FSH). Compared to tubal infertility, UI was linked to lower endometrial thickness at oocyte retrieval and lower BMI; compared to anovulatory infertility related to PCO/PCOS, UI was linked to woman’s older age, more frequent smoking, and poorer ovarian reserve tests (FSH and antral follicle count). After adjustment for other types of infertility, woman’s age, age at menarche, and FSH levels, anovulatory infertility presented with higher odds of clinical pregnancy compared to UI (adjusted OR = 2.13, 95% C: 1.01–4.52).

Infertile women with UI undergoing assisted reproduction demonstrate different demographic and clinical characteristics compared to those of other causes of infertility, albeit live birth rates are similar.

Unexplained infertility, Ovarian reserve, Assisted Reproduction, Live birth, Male infertility, tubal infertility.

Unexplained infertility (UI) refers to a diagnosis made in couples in whom standard investigations including semen analysis, tests of ovulation, and tubal patency are normal [1]. It is a term used to describe 30–40% of infertile couples [2], while its etiology seems heterogeneous [3]. Knowledge from the past has demonstrated that additional investigations in couples with UI have failed to improve pregnancy rates [4, 5]. Instead, age and duration of infertility should be taken into account by clinicians, when scheduling both diagnostic and therapeutic plans, with emphasis on individualization [1, 6–9]. Regarding treatment, there is insufficient evidence of a difference in live birth between expectant management and other interventions, including IVF/ICSI [10, 11], whereas no specific markers exist to recommend one intervention over another [12]. There is an ongoing clinical uncertainty among fertility specialists in managing couples with UI [8]. It appears that part of the solution may be hidden in the basis of the pathophysiology and etiology of the disease. Its existence, as a term, has been debated more than a decade ago [1, 13]: according to debates, its clinical sustainability as an independent diagnosis has been questioned and related to its “dependency on which diagnostic tests have been performed (or have been omitted) and at what level of quality, together with its association with endometriosis, tubal infertility (especially distal and peritubal disease), premature ovarian ageing, and immunological infertility.” The opposite view was “that, although scientifically unsatisfying, the diagnosis of UI is sustainable from a clinical and practical perspective.” In this respect, we endorse a “pragmatic” theory, according to which this type of infertility is closely linked with different baseline characteristics of the couples, and especially women, who are involved. Thus, special and different characteristics of women/couples with the diagnosis of UI as compared to those with other types of infertility or fertile women have been reported, such as different hormonal profiles, endometrial gene expression patterns at the time of embryo implantation, laboratory manifestations of altered baseline ovarian reserve tests, or response to ovarian stimulation during assisted reproduction treatments [14–18]. In this context, we used a dataset of a previously diagnosed infertile population, containing detailed data on demographics, medical/reproductive history for both partners, and previous IVF/ICSI cycle parameters and outcomes. This study aims to evaluate any distinct clinical and reproductive features of UI versus other types of infertility, namely male factor, tubal, and anovulation, linked to PCO and PCOS.

Study population The present study was designed as a retrospective cohort study to deal with the specific research question. Data was collected on a previously diagnosed infertile population of 256 infertile couples who underwent 430 IVF/ICSI cycles, at the Assisted Reproduction Unit of the Third Department of Obstetrics and Gynecology, “Attikon” University Hospital in Greece, from July 2010 to February 2017. This was the same sample used to construct and validate an artificial neural network based on parameters with statistical correlation to live birth, in patients undergoing IVF/ICSI [19]. Conclusive data was available on demographics, medical/reproductive history for both partners, and previous IVF/ICSI cycle parameters and outcomes. Consent to use anonymous data for research purposes was obtained from all participants, and the research protocol was approved by the Scientific Council and the Bioethics Committee of the Hospital, prior to study initiation (EVD 1172/26-11-15; 593/17-09-19). The population of the cohort had been previously diagnosed with infertility (tubal factor, male factor, anovulation linked with PCO/PCOS and UI) and met the criteria for undergoing ovarian stimulation protocols. Exclusion criteria included woman’s age (> 43 years), increased levels of FSH on the third day of the menstrual cycle (> 15 IU/L), other factors of infertility than the reported and previous poor ovarian response, ovarian cystectomy or oophorectomy, history of pathology affecting the endometrial cavity and/or receptivity, and hereditary or acquired thrombophilia. No other interventions were applied during cycles, apart from the routine protocols described in the regular practice of the IVF Unit, that conform to International trends and European standards for appropriate medical management. Both the GnRH antagonist and the long-21 GnRH agonist protocols were used to promote ovarian stimulation, which have been described in one of our previous studies [20]. All procedures and culture conditions, along with medical and paramedical personnel were stable throughout the years of the more than 10 years function of the Unit, all of which were under standard operating procedures. ICSI was performed in cases of male infertility. Culture medium used was the Sydney IVF Cleavage Medium (COOK) and embryo transfer took place 3 days after the oocyte retrieval; the maximum of embryos placed was two, according to the Hellenic legislation. The study group included women with UI, which was diagnosed through the combination of (i) verified ovulation, demonstrated by menstrual cycles between 23 and 35 days and ovulatory progesterone levels; (ii) normal uterine cavity and patent tubes, demonstrated by hysterosalpingography and/or laparoscopy; and (iii) a normal semen analysis according to the World Health Organization (WHO) reference values [21]. Other infertility groups studied included tubal factor infertility diagnosed by hysterosalpingography and/or laparoscopy, male factor infertility, and anovulation (PCO/PCOS) treated in our unit during the same time interval. Parameters studied and analyses The initial dataset included 430 IVF/ICSI cycles performed in 256 women. We excluded 17 cycles (11 women) as they demonstrated combined tubal and male infertility. From the remaining 413, we included as follows: (1) UI 114 cycles, 73 women; (2) male infertility 131 cycles, 74 women; (3) tubal infertility: 85 cycles, 47 women; and (4) anovulatory infertility (PCO/PCOS): 83 cycles, 51 women. A database was generated with Microsoft Excel and used for data storage and pre-processing, including medical and reproductive history, lifestyle information and demographics linked to fertility dynamics, pathology linked to infertility factors for both partners, age at cycle, parity, hormonal profile along with selected information on menstrual cycle characteristics for the female partner, and ultrasonographic tests, such as antral follicle count (AFC) and sperm analysis for the male partner. Conventional IVF and/or ICSI were performed according to the cause of infertility. Detailed descriptions of the procedures during IVF/ICSI have been reported previously [22]. Outcome measures and sample size The primary outcome measure was a priori set as live birth (yes vs. no). Secondary outcomes were the following: biochemical pregnancy (yes vs. no), clinical pregnancy (yes vs. no), top quality embryos (≥ 2 vs. < 2), number of follicles (≥ 8 vs. < 8) , number of retrieved oocytes (≥ 6 vs. < 6), and number of embryos (≥ 2 vs. < 2). Assuming four infertility groups (six comparisons) and a homoscedastic setting, for a study power of 80% at a significance level of 0.05/6 = 0.008 (Bonferroni correction), the study sample (n = 413 cycles) would allow the detection of mean difference equal to (0.49*standard deviation) for numeric variables in equally sized groups. Power calculation was performed using the G*Power 3.1.9.2 software (University of Düsseldorf, Germany). Statistical analysis A cycle-based approach was adopted throughout the study. Results were presented as mean ± standard deviation (SD) for numeric variables and as percentages for categorical variables. At the univariate analysis examining differences between infertility groups, Pearson’s chi-squared test was performed for categorical variables. For numeric variables, given the deviation from normality, non-parametric tests were implemented, specifically Mann-Whitney-Wilcoxon test for independent samples and Kruskal-Wallis test, as appropriate. In order to adjust for multiple comparisons, the Bonferroni correction was applied in the post hoc evaluation of differences between UI and other infertility groups. The multivariate analysis focused on the independent associations between primary/secondary outcomes and UI, taking into account the effects of confounders. Whenever the univariate analysis showed that prevalence of the outcome differed in any infertility group versus UI, generalized least squares (GLS), random-effects logistic regression analysis was performed setting this outcome as the dependent variable, taking into account the intercorrelation between cycles and examining as independent variables the confounders presenting with p < 0.05 at the univariate analysis. The level of significance was set at 0.05, unless otherwise specified. Statistical analysis was performed with STATA/SE version 13 statistical software (Stata Corp. College Station, TX, USA).

Differences between infertility groups—univariate analysis The characteristics of 413 IVF/ICSI cycles, stemming from a total of 245 infertile couples, are presented in Table 1, by type of infertility. UI was associated with woman’s older age (37.0 ± 3.6 years) as compared to anovulatory and male factor infertility (34.0 ± 4.0 years, BA-p < 0.001 and 35.3 ± 4.4 years, BA-p = 0.013, respectively) and lower FSH levels (BA-p < 0.001 and BA-p = 0.006, respectively) versus the aforementioned two groups. UI was associated with lower BMI (22.9 ± 3.9 kg/m2) as compared to tubal factor (23.5 ± 2.8 kg/m2, BA-p = 0.019) and male factor infertility (24.1 ± 3.9 kg/m2, BA-p = 0.005). Women with UI were smoking more frequently as compared to those with anovulatory infertility (43.0% vs. 21.7%, BA-p = 0.012). Endometrial thickness was higher in cycles with tubal factor infertility (10.4 ± 2.2 mm) versus UI (9.5 ± 1.8 mm, BA-p = 0.038). AFC levels were significantly lower in UI compared to anovulatory infertility (7.96 ± 3.64 vs. 11.54 ± 5.34, BA-p < 0.001). No differences were noted regarding age at menarche, AMH levels, and day of embryo transfer. Table 1. | Parameters | Unexplained infertility (n = 114) | Anovulation (PCO/PCOS) (n = 83) | Tubal factor (n = 85) | Male factor (n = 131) | p | |---|---|---|---|---|---| | Age (years) | 37.0 (3.6) | 34.0 (4.0)* | 36.4 (4.1) | 35.3 (4.4)* | 0.0001KW | | Age at menarche (years) | 12.52 (1.42) | 12.54 (2.38) | 12.44 (2.14) | 12.33 (1.44) | 0.679KW | | BMI (kg/m2) | 22.9 (3.9) | 24.6 (5.2) | 23.5 (2.8)* | 24.1 (3.9)* | 0.004KW | | Current smoking, % (frequency) | 43.0% (49) | 21.7% (18)* | 38.8% (33) | 29.8% (39) | 0.009C | | Endometrial thickness (mm) | 9.5 (1.8) | 9.6 (1.9) | 10.4 (2.2)* | 9.7 (1.8) | 0.038KW | | AFC | 7.96 (3.64) | 11.54 (5.34)* | 7.54 (3.38) | 8.92 (3.9) | 0.0001KW | | AMH | 4.14 (3.14) | 5.56 (4.25) | 4.6 (3.33) | 4.85 (4.18) | 0.132KW | | FSH | 8.37 (3.43) | 6.54 (3.52)* | 8.01 (3.14) | 6.93 (2.51)* | 0.0001KW | | Day of embryo transfer | 2.94 (0.80) | 3.02 (0.84) | 2.91 (0.70) | 2.96 (0.78) | 0.884KW | | Outcomes | p | |||| | Live birth, % (frequency) | 17.5% (20) | 26.5% (22) | 21.2% (18) | 21.4% (28) | 0.512C | | Biochemical pregnancy, % (frequency) | 34.2% (39) | 51.8% (43) | 35.3% (30) | 38.9% (51) | 0.065C | | Clinical pregnancy, % (frequency) | 22.8% (26) | 42.2% (35)** | 27.1% (23) | 31.3% (41) | 0.029C | | Top quality embryos | 0.61 (0.91) | 1.09 (1.43) | 0.92 (1.45) | 1.01 (1.43) | 0.149KW | | Number of follicles | 8.14 (4.31) | 10.49 (5.14)* | 8.12 (4.22) | 9.31 (4.82) | 0.001KW | | Number of retrieved oocytes | 7.02 (3.84) | 8.66 (4.55)* | 6.78 (3.50) | 8.13 (4.11) | 0.005KW | | Number of embryos | 2.11 (0.54) | 2.01 (0.37) | 2.14 (0.54) | 2.15 (0.53) | 0.208KW | Cp value derived from Chi-squared test; KWp value derived from Kruskal-Wallis test; *groups differing significantly versus unexplained infertility (Bonferroni-adjusted p value, derived from Mann-Whitney-Wilcoxon test, p < 0.05); **groups differing significantly versus unexplained infertility (Bonferroni-adjusted p-value, derived from Pearson’s chi-squared test, p < 0.05). FSH, follicle-stimulating hormone; RIF, repeated implantation failures; 2 PN, 2 pronuclei; MII, metaphase II oocytes; AFC, antral follicle count; IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection Regarding outcomes, no significant differences were noted in live birth rates (p = 0.512, Kruskal-Wallis test), biochemical pregnancy rates (p = 0.065), top quality embryos (p = 0.149), and number of embryos (p = 0.208) between all groups. However, UI was associated with lower clinical pregnancy rates (22.8% vs. 42.2%, BA-p = 0.024), lower number of follicles (8.14 ± 4.31 vs. 10.49 ± 5.14, BA-p = 0.004), and lower number of retrieved oocytes compared to anovulatory infertility (7.02 ± 3.84 vs. 8.66 ± 4.55, BA-p = 0.032). Unexplained infertility and study outcomes—multivariate analysis Given the associations noted at the univariate analysis, generalized least squares (GLS) and random-effects multivariate logistic regression analyses were performed; relevant results are presented in Table 2. After adjustment for other types of infertility, woman’s age, age at menarche, and FSH levels, anovulatory infertility cycles still presented with higher odds of clinical pregnancy versus UI (adjusted OR = 2.13, 95% CI 1.01–4.52). Table 2. | Predictors of clinical pregnancy | Compared categories | Crude OR (95% CI) | Multivariate OR (95% CI) | |---|---|---|---| | Type of infertility | ||| | Unexplained | Ref. | 1.00 | | | Anovulation (PCO/PCOS) | 2.54 (1.28–5.03) | 2.13 (1.01–4.52) | | | Tubal factor | 1.30 (0.64–2.67) | 1.23 (0.57-2.67) | | | Male factor | 1.55 (0.83–2.91) | 1.34 (0.67–2.66) | | | Age (years) | > 37 vs. ≤ 37 | 0.43 (0.25–0.73) | 0.49 (0.28–0.86) | | Age at menarche (years) | > 12 vs. ≤ 12 | 1.92 (1.14–3.25) | 2.01 (1.18–3.42) | | BMI (kg/m2) | ≥ 25 vs. < 25 | 0.82 (0.47–1.40) | Not entered | | Current smoking | Yes vs. no | 0.79 (0.47–1.32) | Not entered | | Endometrial thickness (mm) | ≥ 8 vs. 4 vs. ≤ 4 | 1.91 (0.92–3.98) | Not entered | | AMH | ≥ 4 vs. < 4 | 1.04 (0.65–1.67) | Not entered | | FSH | ≥ 12 vs. 3 vs. ≤ 3 | 1.96 (0.92–4.18) | Not entered | BMI, body mass index; FSH, follicle-stimulating hormone; IU, international units; RIF, repeated implantation failures; 2 PN, 2 pronuclei; MII, metaphase II oocytes; AFC, antral follicle count; STDs, sexually transmitted diseases; OR, oocyte retrieval; ICSI, intracytoplasmic sperm injection; AMH, antimullerian hormone; TSH, thyroid stimulating hormone; IVF in vitro fertilization On the other hand, the difference in number of follicles between UI and anovulatory infertility dissipated (adjusted OR = 1.20, 95% CI 0.35–4.10) at the multivariate analysis, adjusting for other types of infertility, woman’s age, endometrial thickness, AFC, AMH, and FSH (Table 3). Similarly, the difference in number of retrieved oocytes between UI and anovulatory infertility did not persist at the multivariate, random-effects GLS logistic regression analysis adjusting for other types of infertility, woman’s age, endometrial thickness, AFC, AMH, and day of embryo transfer (Table 4). Table 3. | Predictors of higher number of follicles (≥ 8 vs. < 8) | Compared categories | Crude OR (95% CI) | Multivariate OR (95% CI) | |---|---|---|---| | Type of infertility | ||| | Unexplained | Ref. | 1.00 | | | Anovulation (PCO/PCOS) | 4.31 (1.20–15.46) | 1.20 (0.35–4.10) | | | Tubal factor | 0.85 (0.25–2.97) | 0.48 (0.14–1.66) | | | Male factor | 1.90 (0.63–5.73) | 1.05 (0.36–3.09) | | | Age (years) | > 37 vs. ≤ 37 | 0.15 (0.07–0.32) | 0.72 (0.29–1.76) | | Age at menarche (years) | > 12 vs. ≤ 12 | 1.69 (0.76–3.79) | Not entered | | BMI (kg/m2) | ≥ 25 vs. < 25 | 0.59 (0.23–1.51) | Not entered | | Current smoking | Yes vs. no | 0.96 (0.39–2.41) | Not entered | | Endometrial thickness (mm) | ≥ 8 vs. 4 vs. ≤ 4 | 10.97 (4.29–28.06) | 5.25 (1.63–16.89) | | AMH | ≥ 4 vs. < 4 | 9.01 (3.93–20.67) | 4.67 (1.88–11.61) | | FSH | ≥ 12 vs. 3 vs. ≤ 3 | 3.43 (0.95–12.34) | Not entered | Table 4. | Predictors of higher number of retrieved oocytes (≥ 6 vs. < 6) | Compared categories | Crude OR (95% CI) | Multivariate OR (95% CI) | |---|---|---|---| | Type of infertility | ||| | Unexplained | Ref. | 1.00 | | | Anovulation (PCO/PCOS) | 1.72 (0.68–4.36) | 0.64 (0.24–1.73) | | | Tubal factor | 0.63 (0.26–1.56) | 0.41 (0.16–1.08) | | | Male factor | 1.50 (0.66–3.43) | 0.93 (0.39–2.21) | | | Age (years) | > 37 vs. ≤ 37 | 0.26 (0.15–0.46) | 1.24 (0.59–2.60) | | Age at menarche (years) | > 12 vs. ≤ 12 | 1.22 (0.67–2.24) | Not entered | | BMI (kg/m2) | ≥ 25 vs. < 25 | 0.75 (0.38–1.47) | Not entered | | Smoking | Yes vs. no | 0.83 (0.43–1.60) | Not entered | | Endometrial thickness (mm) | ≥ 8 vs. 4 vs. ≤ 4 | 11.85 (5.31–26.47) | 6.80 (2.50–18.46) | | AMH | ≥ 4 vs. < 4 | 5.65 (2.99–10.66) | 3.21 (1.55–6.66) | | FSH | ≥ 12 vs. 3 vs. ≤ 3 | 4.48 (1.32–15.23) | 26.24 (1.41–488.96) |

The current analysis demonstrated different baseline and clinical characteristics in infertile women undergoing IVF/ICSI diagnosed with UI when compared to those suffering from other types of infertility. In specific, compared to male infertility, UI was linked to woman’s older age, lower BMI, and higher FSH during screening; compared to tubal infertility, UI was linked to lower endometrial thickness at oocyte retrieval and lower BMI; compared to anovulatory infertility related to PCO/PCOS, UI was linked to woman’s older age, more frequent smoking, and poorer ovarian reserve tests (FSH and AFC). Of note, live birth rates, set as the primary outcome of this study, were found similar in all comparisons. This finding is consistent with previous reports, although data toward this objective is limited [14, 23]. It appears that women with UI decide to proceed with IVF/ICSI at an advanced age, probably because they have tried other treatment options before, such as expectant management and intrauterine insemination. They also have less healthy life style habits (smoking), but they try more to get pregnant, either naturally or through IVF/ICSI, also experiencing more failures. It has been previously shown that UI was linked to lower values in cycle length, a hypothesis that was not tested in our study, but it might imply an additional negative impact of the specific type of infertility on the rate and quality of follicular growth [24, 25]. Principally, a shorter cycle length may be a sign of a more advanced ovarian aging, which differs from that of chronological aging [26], while, secondly, it can be used as a marker of IVF/ICSI success [25]. As a result, although women with UI demonstrated inferior ovarian reserve parameters, ultimately, they exhibited similar IVF/ICSI results, with the exception of clinical pregnancy; after multivariate adjustment for various confounders, UI presented with lower odds of clinical pregnancy versus anovulatory infertility due to PCO/PCOS. The current literature links UI to a defective ovarian reserve. Women with UI demonstrate subtle alterations in hormones measured across the menstrual cycle [17] and different endometrial gene expression patterns at the time of embryo implantation, when compared with fertile ones [16]. Similarly, compared with either male or tubal infertility, they display lower AMH and AFC levels [27]; in our study, no differences in AMH levels were noted in all comparisons, apart from the AFC levels that were expectedly lower in UI, especially when compared to PCO/PCOS. Likewise, according to a recent report with a relative small sample size, women with UI of ≤ 37 years of age, demonstrated clear manifestations of sub-optimal ovarian reserve [14]; these authors along with many others attributed this finding to various parameters, such as FSH receptor polymorphisms, abnormalities in the pulsatile GnRH secretion, or in the pituitary sensitivity to GnRH or in the negative feedback from the ovary to the pituitary gland [28, 29]. In contrast, these causative etiologies were not able to affect neither the IVF/ICSI cycle performance nor the primary outcome in all comparisons, namely live birth. Compared to tubal infertility, women with UI displayed lower endometrial thickness at oocyte retrieval. Conversely, live birth rates were comparable; in contrast, Omland et al, using a similar sample size, reported an improved clinical outcome for the UI group with respect to live birth, twin birth, and early abortion rates compared to the tubal factor infertility group, further suggesting that this difference could guide patient counseling and selection for single embryo transfer [30]. Moreover, there has been published evidence for a distinct impairment of fertilization and cleavage, but not implantation and pregnancy rates due to oocyte dysfunction, when UI was compared with tubal infertility [31]. Compared to anovulatory infertility related to PCO/PCOS, UI was linked to older woman’s age, more frequent smoking, and inferior ovarian reserve tests, such as FSH and AFC, lower numbers of follicles, and retrieved oocytes at the univariate analysis, as well as lower clinical pregnancy rates. At the multivariate analysis, however, all differences dissipated, apart from clinical pregnancy rates, being higher in anovulatory infertility. Age, as an independent parameter of ovarian reserve tests, can predict (time to) ongoing pregnancy in patients with UI and mild male infertility [15, 32]. In all comparisons, expect from the tubal factor, the group of UI was at an older age. The point that has been raised, concerning UI, is that infertility owing to advanced age often leads to a misleading grouping of women with advanced age in UI, and, thus, reproductive management is skewed [3]. Accordingly, age per se should be presumed as an independent infertility factor, while some subpopulations are wrongly assigned with UI and thus should be reconsidered, in terms of type of infertility [27]; indeed, in our multivariate analyses, women’s age at cycle was a confounder consistently taken into account. Unfortunately, since fecundity declines with age, discerning between UI and age-related infertility becomes increasingly difficult as the woman’s age advances. It has been shown, with the use of a mathematical model, that the rate of false positive diagnoses of UI increases rapidly after 35 years of age, exceeding 50% in women starting seeking pregnancy after 37 years [3]. Differences in the clinical profile can probably be attributed to the background of the etiology of UI per se, where various parameters have been addressed in the literature, including the capacitation and/or ability of spermatozoa to negotiate with the uterotubal junction; inability of acrosome reaction and penetration of the zona pellucida; and quality of oocytes and impaired bidirectional tubal motility [33]. The main limitation of our study includes its retrospective design. In addition, although we encompassed various parameters, several were not available, such as mutation analyses in genes and proteins, so possible further relationships with severe diseases were lost, e.g., thrombophilia [34]. Correspondingly, we have not furhter investigated the male factor infertility, in terms of further reproductive and metabolic abnormalities, such as insulin resistance [35]. In conclusion, this study unraveled various demographic and clinical characteristics of infertile women undergoing IVF/ICSI, as compared to the other types of infertility, although live birth rates were similar. Results could help clinicians to select targeted strategy managements and treatments, tailored to the needs of an individual couple suffering from UI. Parameters associated with UI could be incorporated into prognostic models for the evaluation of treatment effects, or guide randomized controlled trials and individual patient data meta-analyses in fertility treatments and/or the construction of clinical tools for the management of UI. Footnotes Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

- 1.Siristatidis C, Bhattacharya S. Unexplained infertility: does it really exist? Does it matter? Hum Reprod. 2007;22(8):2084–2087. doi: 10.1093/humrep/dem117. [DOI] [PubMed] [Google Scholar] - 2.Collins JA, Crosignani PG. Unexplained infertility: a review of diagnosis, prognosis, treatment efficacy and management. Int J Gynaecol Obstet. 1992;39(4):267–275. doi: 10.1016/0020-7292(92)90257-j. [DOI] [PubMed] [Google Scholar] - 3.Somigliana E, Paffoni A, Busnelli A, Filippi F, Pagliardini L, Vigano P, Vercellini P. Age-related infertility and unexplained infertility: an intricate clinical dilemma. Hum Reprod. 2016;31(7):1390–1396. doi: 10.1093/humrep/dew066. [DOI] [PubMed] [Google Scholar] - 4.Zayed F, Abu-Heija A. The management of unexplained infertility. Obstet Gynecol Surv. 1999;54(2):121–130. doi: 10.1097/00006254-199902000-00022. [DOI] [PubMed] [Google Scholar] - 5.Taylor PJ, Collins JA. Unexplained infertility. Oxford: Oxford University Press; 1992. [Google Scholar] - 6.Buckett W, Sierra S. The management of unexplained infertility: an evidence-based guideline from the Canadian Fertility and Andrology Society. Reprod BioMed Online. 2019;39:633–640. doi: 10.1016/j.rbmo.2019.05.023. [DOI] [PubMed] [Google Scholar] - 7.Gunn DD, Bates GW. Evidence-based approach to unexplained infertility: a systematic review. Fertil Steril. 2016;105(6):1566–1574. doi: 10.1016/j.fertnstert.2016.02.001. [DOI] [PubMed] [Google Scholar] - 8.Nandi A, Gudi A, Shah A, Homburg R. An online survey of specialists’ opinion on first line management options for unexplained subfertility. Hum Fertil (Camb) 2015;18(1):48–53. doi: 10.3109/14647273.2014.948081. [DOI] [PubMed] [Google Scholar] - 9.Evers JL, de Haas HW, Land JA, Dumoulin JC, Dunselman GA. Treatment-independent pregnancy rate in patients with severe reproductive disorders. Hum Reprod. 1998;13(5):1206–1209. doi: 10.1093/humrep/13.5.1206. [DOI] [PubMed] [Google Scholar] - 10.Wang R, Danhof NA, Tjon-Kon-Fat RI, Eijkemans MJ, Bossuyt PM, Mochtar MH, et al. Interventions for unexplained infertility: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2019;9:CD012692. doi: 10.1002/14651858.CD012692.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar] - 11.van den Boogaard NM, Bensdorp AJ, Oude Rengerink K, Barnhart K, Bhattacharya S, Custers IM, Coutifaris C, Goverde AJ, Guzick DS, Hughes EC, Factor-Litvak P, Steures P, Hompes PGA, van der Veen F, Mol BWJ, Bossuyt P. Prognostic profiles and the effectiveness of assisted conception: secondary analyses of individual patient data. Hum Reprod Update. 2014;20(1):141–151. doi: 10.1093/humupd/dmt035. [DOI] [PubMed] [Google Scholar] - 12.Tjon-Kon-Fat RI, Tajik P, Zafarmand MH, Bensdorp AJ, Bossuyt PMM, Oosterhuis GJE, van Golde R, Repping S, Lambers MDA, Slappendel E, Perquin D, Pelinck MJ, Gianotten J, Maas JWM, Eijkemans MJC, van der Veen F, Mol BW, van Wely M, on behalf of the INeS study group†. Koks CAM, Hoek A, Hompes PGA, Broekmans FJM, Verhoeve HR, de Bruin JP, Cohlen BJ, van Bommel PF, Smeenk JM, Hoozemans DA. IVF or IUI as first-line treatment in unexplained subfertility: the conundrum of treatment selection markers. Hum Reprod. 2017;32(5):1028–1032. doi: 10.1093/humrep/dex037. [DOI] [PubMed] [Google Scholar] - 13.Gleicher N, Barad D. Unexplained infertility: does it really exist? Hum Reprod. 2006;21(8):1951–1955. doi: 10.1093/humrep/del135. [DOI] [PubMed] [Google Scholar] - 14.Abrahami N, Izhaki I, Younis JS. Do young women with unexplained infertility show manifestations of decreased ovarian reserve? J Assist Reprod Genet. 2019;36(6):1143–1152. doi: 10.1007/s10815-019-01467-0. [DOI] [PMC free article] [PubMed] [Google Scholar] - 15.Goverde AJ, McDonnell J, Schats R, Vermeiden JP, Homburg R, Lambalk CB. Ovarian response to standard gonadotrophin stimulation for IVF is decreased not only in older but also in younger women in couples with idiopathic and male subfertility. Hum Reprod. 2005;20(6):1573–1577. doi: 10.1093/humrep/deh827. [DOI] [PubMed] [Google Scholar] - 16.Altmae S, Martinez-Conejero JA, Salumets A, Simon C, Horcajadas JA, Stavreus-Evers A. Endometrial gene expression analysis at the time of embryo implantation in women with unexplained infertility. Mol Hum Reprod. 2010;16(3):178–187. doi: 10.1093/molehr/gap102. [DOI] [PubMed] [Google Scholar] - 17.Leach RE, Moghissi KS, Randolph JF, Reame NE, Blacker CM, Ginsburg KA, Diamond MP. Intensive hormone monitoring in women with unexplained infertility: evidence for subtle abnormalities suggestive of diminished ovarian reserve. Fertil Steril. 1997;68(3):413–420. doi: 10.1016/s0015-0282(97)00222-7. [DOI] [PubMed] [Google Scholar] - 18.Hull MG, Glazener CM, Kelly NJ, Conway DI, Foster PA, Hinton RA, Coulson C, Lambert PA, Watt EM, Desai KM. Population study of causes, treatment, and outcome of infertility. Br Med J (Clin Res Ed) 1985;291(6510):1693–1697. doi: 10.1136/bmj.291.6510.1693. [DOI] [PMC free article] [PubMed] [Google Scholar] - 19.Vogiatzi P, Pouliakis A, Siristatidis C. An artificial neural network for the prediction of assisted reproduction outcome. J Assist Reprod Genet. 2019;36(7):1441–1448. doi: 10.1007/s10815-019-01498-7. [DOI] [PMC free article] [PubMed] [Google Scholar] - 20.Siristatidis C, Askoxylaki M, Varounis C, Kassanos D, Chrelias C. E-selectin, resistin and reactive oxygen species levels in GnRH -agonist and -antagonist protocols in IVF/ICSI: a prospective cohort study. J Assist Reprod Genet. 2015;32(6):959–967. doi: 10.1007/s10815-015-0489-z. [DOI] [PMC free article] [PubMed] [Google Scholar] - 21.Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16(3):231–245. doi: 10.1093/humupd/dmp048. [DOI] [PubMed] [Google Scholar] - 22.Siristatidis C, Dafopoulos K, Christoforidis N, Anifandis G, Pergialiotis V, Papantoniou N. Corifollitropin alfa compared with follitropin beta in GnRH-antagonist ovarian stimulation protocols in an unselected population undergoing IVF/ICSI. Gynecol Endocrinol. 2017;33(12):968–971. doi: 10.1080/09513590.2017.1323203. [DOI] [PubMed] [Google Scholar] - 23.Murto T, Bjuresten K, Landgren BM, Stavreus-Evers A. Predictive value of hormonal parameters for live birth in women with unexplained infertility and male infertility. Reprod Biol Endocrinol. 2013;11:61. doi: 10.1186/1477-7827-11-61. [DOI] [PMC free article] [PubMed] [Google Scholar] - 24.Kolstad HA, Bonde JP, Hjollund NH, Jensen TK, Henriksen TB, Ernst E, et al. Menstrual cycle pattern and fertility: a prospective follow-up study of pregnancy and early embryonal loss in 295 couples who were planning their first pregnancy. Fertil Steril. 1999;71(3):490–496. doi: 10.1016/s0015-0282(98)00474-9. [DOI] [PubMed] [Google Scholar] - 25.Brodin T, Bergh T, Berglund L, Hadziosmanovic N, Holte J. Menstrual cycle length is an age-independent marker of female fertility: results from 6271 treatment cycles of in vitro fertilization. Fertil Steril. 2008;90(5):1656–1661. doi: 10.1016/j.fertnstert.2007.09.036. [DOI] [PubMed] [Google Scholar] - 26.te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002;8(2):141–154. doi: 10.1093/humupd/8.2.141. [DOI] [PubMed] [Google Scholar] - 27.Yücel B, Kelekci S, Demirel E. Decline in ovarian reserve may be an undiagnosed reason for unexplained infertility: a cohort study. Arch Med Sci. 2016;14(3):527–531. doi: 10.5114/aoms.2016.58843. [DOI] [PMC free article] [PubMed] [Google Scholar] - 28.Simoni M, Nieschlag E, Gromoll J. Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction. Hum Reprod Update. 2002;8(5):413–421. doi: 10.1093/humupd/8.5.413. [DOI] [PubMed] [Google Scholar] - 29.Randolph JF, Ginsburg KA, Leach RE, Blacker CM, Moghissi KS, Diamond MP, et al. Elevated early follicular gonadotropin levels in women with unexplained infertility do not provide evidence for disordered gonadotropin-releasing hormone secretion as assessed by luteinizing hormone pulse characteristics. Fertil Steril. 2003;80(2):320–327. doi: 10.1016/s0015-0282(03)00612-5. [DOI] [PubMed] [Google Scholar] - 30.Omland AK, Abyholm T, Fedorcsak P, Ertzeid G, Oldereid NB, Bjercke S, et al. Pregnancy outcome after IVF and ICSI in unexplained, endometriosis-associated and tubal factor infertility. Hum Reprod. 2005;20(3):722–727. doi: 10.1093/humrep/deh664. [DOI] [PubMed] [Google Scholar] - 31.Hull MG, Williams JA, Ray B, McLaughlin EA, Akande VA, Ford WC. The contribution of subtle oocyte or sperm dysfunction affecting fertilization in endometriosis-associated or unexplained infertility: a controlled comparison with tubal infertility and use of donor spermatozoa. Hum Reprod. 1998;13(7):1825–1830. doi: 10.1093/humrep/13.7.1825. [DOI] [PubMed] [Google Scholar] - 32.van Rooij IA, Broekmans FJ, Hunault CC, Scheffer GJ, Eijkemans MJ, de Jong FH, et al. Use of ovarian reserve tests for the prediction of ongoing pregnancy in couples with unexplained or mild male infertility. Reprod BioMed Online. 2006;12(2):182–190. doi: 10.1016/s1472-6483(10)60859-0. [DOI] [PubMed] [Google Scholar] - 33.Ray A, Shah A, Gudi A, Homburg R. Unexplained infertility: an update and review of practice. Reprod BioMed Online. 2012;24(6):591–602. doi: 10.1016/j.rbmo.2012.02.021. [DOI] [PubMed] [Google Scholar] - 34.Fatini C, Conti L, Turillazzi V, Sticchi E, Romagnuolo I, Milanini MN, Cozzi C, Abbate R, Noci I. Unexplained infertility: association with inherited thrombophilia. Thromb Res. 2012;129(5):e185–e188. doi: 10.1016/j.thromres.2012.02.012. [DOI] [PubMed] [Google Scholar] - 35.Mansour R, El-Faissal Y, Kamel A, Kamal O, Aboulserour G, Aboulghar M, et al. Increased insulin resistance in men with unexplained infertility. Reprod BioMed Online. 2017;35(5):571–575. doi: 10.1016/j.rbmo.2017.08.020. [DOI] [PubMed] [Google Scholar]