Empiric therapy for idiopathic oligoasthenoteratozoospermia | Actas Urológicas Españolas (English Edition)

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Cádiz, España). E2: estradiol; Fragm: fragmentación; T*: testosterona; TRA: técnica de reproducción asistida. ** Medido mediante SCSA, al no disponer de métodos de medición de niveles de ROS, se realiza una estimación indirecta del estrés oxidativo mediante los niveles de fragmentación del ADN." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. García-Baquero, C.M. Fernández-Ávila, J.L. Álvarez-Ossorio" "autores" => array:3 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "García-Baquero" ] 1 => array:2 [ "nombre" => "C.M." "apellidos" => "Fernández-Ávila" ] 2 => array:2 [ "nombre" => "J.L." 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García-Baquero, C.M. Fernández-Ávila, J.L. Álvarez-Ossorio" "autores" => array:3 [ 0 => array:4 [ "nombre" => "R." "apellidos" => "García-Baquero" "email" => array:1 [ 0 => "rgbaquero@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "C.M." "apellidos" => "Fernández-Ávila" ] 2 => array:2 [ "nombre" => "J.L." "apellidos" => "Álvarez-Ossorio" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Andrología y Cirugía Reconstructiva Urogenital, Servicio de Urología, Hospital Universitario Puerta del Mar, Cádiz, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento empírico de la oligoastenoteratozoospermia idiopática" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1551 "Ancho" => 2175 "Tamanyo" => 250815 ] ] "descripcion" => array:1 [ "en" => "Therapeutic algorithm in patients with idiopathic oligoasthenoteratozoospermia (Puerta del Mar University Hospital. Cádiz, Spain). E2: estradiol; Fragm: fragmentation; T*: testosterone; ART: assisted reproductive technology. ** Measured by SCSA, as there are no methods for measuring ROS levels, an indirect estimation of oxidative stress is made using DNA fragmentation levels." ] ] ] "textoCompleto" => "IntroductionIt is estimated that 15% of couples are infertile, understanding infertility as the inability of a sexually active, non-contracepting couple to achieve pregnancy in one year.<a class="elsevierStyleCrossRef" href="#bib0205">1</a> According to the WHO, 190 million people worldwide suffer from infertility and the number of couples that demand medical assistance in this regard is constantly growing.<a class="elsevierStyleCrossRef" href="#bib0210">2</a> Alone or combined with alterations in their partners, the male factor is present in 50% of couples that are unable to conceive.<a class="elsevierStyleCrossRef" href="#bib0215">3</a>Most causes of male infertility are related to an alteration in the classic parameters of the spermiogram,<a class="elsevierStyleCrossRef" href="#bib0215">3</a> and the oligoasthenoteratozoospermia syndrome (OAT) has a combination of the main alterations. In the OAT, oligozoospermia (sperm concentration <15million/mL sperm), asthenozoospermia (<32% of progressive motile sperm) and teratozoospermia (<4% of normal sperm) are presented simultaneously in 2 separate spermiograms within at least 3 weeks.<a class="elsevierStyleCrossRef" href="#bib0220">4</a>An exhaustive andrology assessment is essential in the clinical management of the infertile male, in order to identify etiological factors and propose specific treatment when it is possible.<a class="elsevierStyleCrossRef" href="#bib0225">5</a> However, idiopathic male infertility, or of unknown cause, accounts for 30–50% of overall male infertility.<a class="elsevierStyleCrossRef" href="#bib0215">3</a> The group of patients with idiopathic infertility is considered a heterogeneous cohort, with possible implication of etiopathogenic factors such as endocrine disrupting chemicals on patient's embryonic development or genetic alterations at the molecular level.<a class="elsevierStyleCrossRef" href="#bib0230">6</a> Although this type of infertility does not have a specific treatment by definition, there are situations in which empirical treatments, or probability treatments, can be considered.<a class="elsevierStyleCrossRef" href="#bib0215">3</a> In these situations, the proposed treatment is off-label and patients should previously sign an informed consent in this regard.Treatment on infertile men should take into account several aspects in order to be considered clinically relevant.<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Spermatogenesis. As the spermatogenic cycle has a normal duration of 72 days, treatment should be continued for at least 3 months.<a class="elsevierStyleCrossRef" href="#bib0230">6</a></li><li class="elsevierStyleListItem" id="lsti0010">•Treatment duration. If seminal quality has been improved, it is advisable to maintain treatment until a spontaneous pregnancy is achieved (main objective of the treatment), or the sample is cryopreserved.</li><li class="elsevierStyleListItem" id="lsti0015">•Intraindividual variability of the spermiogram. Sperm parameters within the same individual may have a wide variability (26.8% for concentration, 18.4% for motility), although they usually fluctuate around a virtual homeostatic set point.<a class="elsevierStyleCrossRef" href="#bib0235">7</a></li><li class="elsevierStyleListItem" id="lsti0020">•Female factor. The joint assessment of the couple is essential to correctly interpret the effectiveness of treatment.</li><li class="elsevierStyleListItem" id="lsti0025">•Spontaneous pregnancy rate. Without any other measure, the probability of spontaneous pregnancy increases with the time of exposure to unprotected intercourse, being 10–15% in the second year.<a class="elsevierStyleCrossRef" href="#bib0240">8</a></li></ul>The empirical treatments mentioned below come from all available evidence. Treatments such as androgens, bromocriptine, kallikrein, alpha-blockers, growth hormone, or oxytocin, without proven evidence to support their use, have not been included in this review.Hormone treatmentsSpermatogenesis has a hormonal regulation based on the hypothalamic-pituitary-gonadal axis. In addition to pure hormonal regulation, there are multiple paracrine factors that participate in this process.<a class="elsevierStyleCrossRef" href="#bib0230">6</a> Through empirical hormonal treatment, it is intended to achieve direct or indirect stimulation of the germinal epithelium, modifying the concentrations of hormones at the hypothalamic, pituitary, or intratesticular level (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>GonadotropinsExogenous gonadotropins replace endogenous gonadotropins, directly enhancing the testicular functions of spermatogenesis and steroidogenesis.<a class="elsevierStyleCrossRef" href="#bib0230">6</a>Empirical treatment with gonadotropins (FSHp [purified] 150IU/24h, FSHr [recombinant] 100–300IU/24–48h, hCG 2.500IU/72h, hMG 150IU/48h) increases live birth rates (odds ratio [OR] 9.31, 95% confidence interval [CI]: 1.17–73.75; p=0.03) and pregnancy rate (11.3% with treatment vs. 1.5% without treatment, OR 4.94, 95% CI: 2.13–11.44; p=0.0002) according to data extracted from a recently published meta-analysis.<a class="elsevierStyleCrossRef" href="#bib0245">9</a> Likewise, they improve the total sperm count (mean difference [MD] 2.66, 95% CI: 0.47–4.84; p=0.02) according to another recent meta-analysis.<a class="elsevierStyleCrossRef" href="#bib0250">10</a> Side effects, such as local injection site irritation, gynecomastia, and increased breast soreness, were rare and mild. The main limitations of these 2 published meta-analyses are the heterogeneity in terms of the included patients and treatment schedules, in addition to the relatively low number of studies and of treated patients.<a class="elsevierStyleCrossRefs" href="#bib0245">9,10</a> In turn, the high cost of treatment limits its application in daily clinical practice.AntiestrogensAntiestrogens are estrogen receptor antagonists at the hypothalamic level, increasing GnRH secretion, and at the pituitary level, increasing FSH and LH gonadotropins, by blocking the negative feedback of estrogens, generated mainly after aromatization of testosterone, thus stimulating spermatogenesis and steroidogenesis.<a class="elsevierStyleCrossRef" href="#bib0230">6</a>Empirical treatment with antiestrogens (tamoxifen 20mg/24h, clomiphene 50mg/24–48h) increases the pregnancy (OR 2.42, 95% CI 1.47–3.94; p=0.0004), concentration (MD 5.24, 95% CI: 2.12–88.37; p=0.001) and sperm motility (MD 4.55, 95% CI: 0.73–8.37; p=0.03) rates according to a published meta-analysis.<a class="elsevierStyleCrossRef" href="#bib0255">11</a> Another recent meta-analysis, less methodologically rigorous, confirms these results.<a class="elsevierStyleCrossRef" href="#bib0260">12</a> The incidence of side effects does not differ from that of placebo, although gynecomastia, headache and hot flushes are possible.<a class="elsevierStyleCrossRef" href="#bib0255">11</a> The advantages of using antiestrogens in clinical practice are their low cost and their reasonable safety profile.Aromatase inhibitorsAromatase inhibitors block the synthesis of estradiol from intratesticular and adipose tissue testosterone. Decreased estrogen production reduces the negative effect on spermatogenesis and testosterone biosynthesis, in addition to blocking negative feedback at the hypothalamic and pituitary levels, thus increasing endogenous testosterone synthesis through gonadotrophin secretion, without increasing circulating estrogens, unlike antiestrogens.<a class="elsevierStyleCrossRef" href="#bib0230">6</a>Treatment with aromatase inhibitors (anastrozole 1mg/24h, letrozole 2.5mg/24h) optimizes the hormonal profile (increases testosterone and gonadotropins, and reduces estradiol) and improves sperm concentration and motility in patients with a testosterone/estradiol ratio (ng/dL and pg/mL) <10.<a class="elsevierStyleCrossRefs" href="#bib0265">13–15</a> However, there are no data in the literature regarding pregnancy rates. Side effects are generally mild and relatively infrequent (<10%) such as edema, changes in libido, breast soreness, headache or asthenia,<a class="elsevierStyleCrossRefs" href="#bib0270">14,15</a> without forgetting increased bone resorption and reduced mineralization in extended treatments.<a class="elsevierStyleCrossRef" href="#bib0230">6</a> Results regarding its effectiveness are extracted from intervention studies without a control group.<a class="elsevierStyleCrossRefs" href="#bib0270">14,15</a> To date, there are no published clinical trials in patients with OAT, therefore its use cannot be widely recommended as there is not sufficient scientific evidence. The only published RCT was performed in patients with non-obstructive azoospermia or cryptozoospermia with good results supporting treatment.<a class="elsevierStyleCrossRef" href="#bib0280">16</a>AntioxidantsIt is known that 30–80% of infertile patients have higher levels of seminal reactive oxygen species (ROS) than fertile patients.<a class="elsevierStyleCrossRef" href="#bib0285">17</a> However, ROS are necessary for a multitude of sperm-specific cellular processes, such as spermatogenesis, capacitation, and acrosome reaction.<a class="elsevierStyleCrossRef" href="#bib0285">17</a> The harmful effect of ROS lies in their elevated concentration, when it is not compensated by natural antioxidant mechanisms and leads to seminal oxidative stress.<a class="elsevierStyleCrossRefs" href="#bib0290">18,19</a> The main sources of ROS are seminal leukocytes and cytoplasm, as mature and morphologically normal sperm generates less ROS in relation to immature or teratozoospermic forms.<a class="elsevierStyleCrossRef" href="#bib0300">20</a> Sperm cells are very susceptible to damage from oxidative stress due to the high concentration of polyunsaturated fatty acids in its membrane that tend to lipid peroxidation. Alterations in sperm affect its structural and functional integrity (concentration, motility, morphology),<a class="elsevierStyleCrossRefs" href="#bib0305">21,22</a> implying changes in the acrosome reaction and reducing their fertilizing capacity. Furthermore, high ROS concentrations are related with increased DNA fragmentation,<a class="elsevierStyleCrossRef" href="#bib0315">23</a> associated in turn with a low rate of spontaneous pregnancies and worse outcomes of assisted reproductive techniques (ART)<a class="elsevierStyleCrossRefs" href="#bib0320">24,25</a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The rational basis for the administration of antioxidant therapy is based on the premise that seminal oxidative stress is due, at least in part, to a deficiency in seminal antioxidants.<a class="elsevierStyleCrossRef" href="#bib0330">26</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>In a global way, the most widely used antioxidants (zinc, selenium, folic acid, N-acetylcysteine, coenzyme Q10 [ubiquinol], vitamins E and C, carnitine, docosahexaenoic acid [DHA], among others) increase the rate of live births (expected in the subfertile population in 12 to 14–26%; OR 1.79, 95% CI: 1.20–2.67; p=0.005) and pregnancy rate (expected in the subfertile population in 7 to 12–26%; OR 2.97, 95% CI: 1.91–4.63, p<0.001). In terms of sperm parameters, their concentration (MD 7.51, 95% CI: 4.23–10.79, p<0.000001, at 3 months; MD 7.49, 95% CI: 4.76–10.23, p<0.0001 at 6 months; MD 3.61, 95% CI: 0.17–7.06, p=0.04 at 9 months) and progressive motility (MD 6.11, 95% CI: 0.57–11.66; p=0.003, at 6 months) increase, and sperm DNA fragmentation decreases (MD −5.00, 95% CI: −12.61 to 2.61, p<0.0001), according to data from a recently published meta-analysis.<a class="elsevierStyleCrossRef" href="#bib0335">27</a> Side effects compared to placebo are similar, except for the most frequent gastrointestinal symptoms (2–9%) with treatment (OR 2.51, 95% CI: 1.25–5.03, p=0.01). However, the limitations of this systematic review, such as the paucity of data regarding the birth/pregnancy rate, the high heterogeneity of the administered treatments and the extended use of combinations, limit the quality of the evidence extracted in this regard.<a class="elsevierStyleCrossRef" href="#bib0335">27</a>In relation to seminal oxidative stress, it has been proposed to measure the oxidation–reduction potential in order to identify the so-called “male oxidative stress infertility” within those cataloged as idiopathic.<a class="elsevierStyleCrossRef" href="#bib0285">17</a> The identification of this type of infertility would allow selecting patients with higher seminal oxidative stress and with more probabilities of successful antioxidant therapy.<a class="elsevierStyleCrossRefs" href="#bib0285">17,28</a> Furthermore, this selection would avoid the indiscriminate use of antioxidants which can generate a harmful paradoxical effect on sperm quality by inducing a state of reductive stress<a class="elsevierStyleCrossRef" href="#bib0345">29</a> when used in patients without oxidative stress.Lifestyle changesRegardless of following a specific or empirical treatment, the consideration of advising the patient to modify his lifestyle in order to improve his fertile capacity should be evaluated. Among the modifiable factors related to poor seminal quality, we highlight the following:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0030">•An unhealthy diet, that is, rich in fats and poor in fruits and vegetables, is related to low sperm concentration.<a class="elsevierStyleCrossRef" href="#bib0350">30</a></li><li class="elsevierStyleListItem" id="lsti0035">•Obesity is associated with an increased risk of having oligozoospermia or azoospermia.<a class="elsevierStyleCrossRef" href="#bib0355">31</a></li><li class="elsevierStyleListItem" id="lsti0040">•Tobacco smoking is associated with a reduction in seminal volume and sperm concentration, motility and morphology, with a dose-dependent relationship; the greatest effect has been seen in heavy smokers compared to more moderate ones.<a class="elsevierStyleCrossRefs" href="#bib0360">32,33</a></li><li class="elsevierStyleListItem" id="lsti0045">•Excessive alcohol consumption is associated with lower sperm volume.<a class="elsevierStyleCrossRef" href="#bib0365">33</a></li><li class="elsevierStyleListItem" id="lsti0050">•High stress levels are associated with a reduction in seminal volume and sperm motility and morphology.<a class="elsevierStyleCrossRef" href="#bib0365">33</a></li><li class="elsevierStyleListItem" id="lsti0055">•Regarding air pollution and pollutants, certain trends have shown negative effects of exposure to air pollutants on semen quality, but without statistical significance.<a class="elsevierStyleCrossRef" href="#bib0370">34</a> The diversity of environmental pollutants and seminal parameters makes it difficult to obtain reliable data.<a class="elsevierStyleCrossRef" href="#bib0375">35</a></li></ul>These data are extracted from systematic reviews of observational or cross-sectional studies, which have shown relationship between factors but do not provide conclusions about a real cause–effect relationship. In addition to the possibility of bias with other factors (weight, age, active medication or physical activity). To date, there are hardly any published data regarding the effectiveness of intervention measures on this patient profile.<a class="elsevierStyleCrossRef" href="#bib0380">36</a>DiscussionDespite the publication of several meta-analyses that support the use of empirical treatments, the evidence in this regard is generally low, mainly due to the small sample size of the included studies and the heterogeneity of the patients and treatment regimens (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). According to the recommendations of the main clinical guidelines, in the absence of studies with more precise selection criteria, clear recommendations cannot be given in terms of the use of empirical treatment with gonadotropins, antiestrogens and antioxidants (weak grade of recommendation, very low level of evidence).<a class="elsevierStyleCrossRefs" href="#bib0215">3,5</a> However, these same guidelines state that empirical treatment can be considered before the immediate application of an ART,<a class="elsevierStyleCrossRefs" href="#bib0215">3,5</a> due to its good safety profile and, generally, its low cost.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The most adequate path is to propose empirical treatment only to those patients with optimal conditions.Optimal hormonal conditions. Despite the fact that the results of studies with empirical hormonal treatments are obtained from patients with normogonadotropic normogonadic infertility, performing a comprehensive analysis of their inclusion and exclusion criteria,<a class="elsevierStyleCrossRefs" href="#bib0245">9–15</a> it is more than likely that the best results are obtained in patients with a more favorable hormonal profile and more susceptible to optimization, that is, in those whose testosterone concentration is at the lower limit of normal (<400ng/dL) and with normal or low gonadotropin concentration (FSH≤7IU/L, LH≤6IU/L), with FSH levels never exceeding 12IU/L.<a class="elsevierStyleCrossRefs" href="#bib0245">9–12</a> In addition, a testosterone/estradiol ratio of <10 appears to be the key factor for indicating treatment with aromatase inhibitors.<a class="elsevierStyleCrossRefs" href="#bib0265">13–15</a>Optimal seminal conditions. After analyzing the effectiveness of empirical treatments, it is known that the seminal parameters that can be improved are sperm concentration and motility and DNA fragmentation (>30%), but not morphology.Optimal reproductive conditions, that is, patients with a partner of <35 years, without associated female infertility factor, with a waiting time to try natural conception which does not imply a significant reduction in the success rate of the application of an ART.Aa a proposal, we present the medical empirical treatment protocol followed in our center, based on the greatest scientific evidence available to date and the most widely used diagnostic means in daily clinical practice (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Finally, it should be reminded that, in the absence of effective treatment, the application of ART is recommended in patients with OAT, in order to improve their chances of achieving a pregnancy (strong recommendation, high level of evidence).<a class="elsevierStyleCrossRef" href="#bib0225">5</a> An underexplored possibility is to combine the improvement of seminal parameters induced by empirical treatment together with the application of ART in order to achieve better outcomes or to use a less invasive or expensive ART. In this sense, studies with gonadotropins<a class="elsevierStyleCrossRefs" href="#bib0385">37,38</a> and antioxidants<a class="elsevierStyleCrossRefs" href="#bib0395">39,40</a> show promising results.ConclusionsAlthough acceptable scientific evidence is limited, recently published systematic reviews and meta-analyses show that treatments with gonadotropins, antiestrogens, and antioxidants result in increased pregnancy and live births rates and improved semen parameters. That is why medical empirical treatment can be considered in specific situations of idiopathic infertility, with the aim of improving seminal quality and consequently, spontaneous fertility.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1362029" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1252167" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1362030" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1252166" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Hormone treatments" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Gonadotropins" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Antiestrogens" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Aromatase inhibitors" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Antioxidants" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Lifestyle changes" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-09-03" "fechaAceptado" => "2019-10-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1252167" "palabras" => array:3 [ 0 => "Empiric treatment" 1 => "Idiopathic male infertility" 2 => "Idiopathic oligoasthenoteratozoospermia" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1252166" "palabras" => array:3 [ 0 => "Tratamiento empírico" 1 => "Infertilidad masculina idiopática" 2 => "Oligoastenoteratozoospermia idiopática" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Male infertility accounts for 50% of the causes of infertile couples, being more than 30% of unknown etiology. In these cases, empiric treatment can be an option prior to the application of assisted reproduction techniques. Empiric treatment can be categorized as hormonal, such as gonadotropins, antiestrogens and aromatase inhibitors, and antioxidant, with vitamins, trace elements and carnitine, among others. Although scientifically acceptable evidence is limited due to the absence of large randomized and controlled clinical trials, recent systematic reviews and meta-analyses show that treatment with gonadotropins, antiestrogens and antioxidants increases pregnancy and live birth rates and improves seminal parameters. Empiric medical treatment for idiopathic infertility can be considered in specific cases in order to improve semen quality and spontaneous fertility." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El factor masculino supone el 50% de las causas de infertilidad en parejas infértiles, siendo en más del 30% de origen desconocido. En estos casos, el tratamiento médico empírico puede plantearse como una opción previa a la aplicación de una técnica de reproducción asistida. El tratamiento empírico puede dividirse en 2 categorías: hormonal, tales como gonadotropinas, antiestrógenos e inhibidores de la aromatasa, y antioxidante, tales como vitaminas, oligoelementos y carnitinas, entre otros. Aunque la evidencia científicamente aceptable es limitada debido a la ausencia de grandes ensayos clínicos aleatorizados y controlados, revisiones sistemáticas y metaanálisis recientemente publicados muestran que el tratamiento con gonadotropinas, antiestrógenos y antioxidantes resulta en un aumento de la tasa de embarazos y nacidos vivos y en una mejora en los parámetros seminales. Es por ello que, en determinadas situaciones, el tratamiento médico empírico para la infertilidad idiopática puede considerarse con el objetivo de mejorar la calidad seminal y consecuentemente el potencial fértil espontáneo." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: García-Baquero R, Fernández-Ávila CM, Álvarez-Ossorio JL. Tratamiento empírico de la oligoastenoteratozoospermia idiopática. Actas Urol Esp. 2020;44:281–288." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1549 "Ancho" => 2175 "Tamanyo" => 203135 ] ] "descripcion" => array:1 [ "en" => "hypothalamic pituitary gonadal axis. Red solid arrows indicate stimulation, blue dashed arrows indicate inhibition. * GnRH: gonadotropin-releasing hormone: FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin (LH function); hMG: human menopausal gonadotropin (FSH and LH function); LH: luteinizing hormone." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1590 "Ancho" => 2183 "Tamanyo" => 235391 ] ] "descripcion" => array:1 [ "en" => "Pathophysiology of sperm oxidative stress." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1551 "Ancho" => 2175 "Tamanyo" => 250815 ] ] "descripcion" => array:1 [ "en" => "Therapeutic algorithm in patients with idiopathic oligoasthenoteratozoospermia (Puerta del Mar University Hospital. Cádiz, Spain). E2: estradiol; Fragm: fragmentation; T*: testosterone; ART: assisted reproductive technology. ** Measured by SCSA, as there are no methods for measuring ROS levels, an indirect estimation of oxidative stress is made using DNA fragmentation levels." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Statistically significant data is bolded.According to the GRADE-Working Group scale:" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gonadotropins \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Antiestrogens \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Antioxidants \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FSHp150IU/24hFSHr100–300IU/24–48hhCG2.500IU/72hhMG150IU/48h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tamoxifen 20mg/24hClomiphene 50mg/24–48h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vitamin C 200–1.000mg/24Vitamin E 400–600mg/24hDHA 400–1.000mg/24hN-acetylcysteine 600mg/24hCoenzyme Q10 100mg/12h 200–300mg/24hl-Carnitine 1–3g/24hFolic acid 0.05–5mg/24hZinc 200–250mg/12hSelenium 100–225μg/24hMagnesium 3.000mg/24h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treatment duration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3–6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3–12 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3–24 months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Live births \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 9.31 (1.17–73.75)p=0.03 (1 RCTn=30)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No data \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 1.79 (1.20–2.67)p=0.005 (7 RCTn=750)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Spontaneous pregnancies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 4.94 (2.13–11.44)p=0.002 (5 RCTn=412)<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 2.42 (1.47–3.94) p=0.0004 (9 RCT n=590)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 2.97 (1.91–4.63)p<0.001 (11 RCTn=786)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sperm concentration (million/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD 2.66 (0.47–4.84)p=0.02 (11 RCTn=947) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD 5.24 (2.12–88.37)p=0.001 (8 RCTn=492) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD 7.51 (4.23–10.79)p<0.000001 (3 months) (20 RCTn=1.244) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD 7.49 (4.76–10.23)p<0.00001 (6 months) (11 RCTn=1.430) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD 3.61 (0.17–7.06)p=0.04 (9 months) (5 RCTn=583) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD 6.11 (0.57–11.66)p=0.003 (6 months) (5 RCTn=521) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Progressive sperm motility (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD 1.22 (−0.07 to 2.52) p=0.06 (6 RCT n=629) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD 4.55 (0.73–8.37)p=0.03 (7 RCTn=448) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sperm morphology (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No data \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD 0.28 (0.63–0.06) p=0.11 (5 RCT n=393)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No data \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Side effects \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Puncture site irritation, gynecomastia, breast soreness \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Headache, gynecomastia, skin rash, visual disturbances, asthenia, erectile dysfunction, changes in libido \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vomiting, nausea, stomach upset (p=0.01) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">References \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attia et al. (2013), 6 RCT n=456 patients<a class="elsevierStyleCrossRef" href="#bib0245">9</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chua et al. (2013), 11 RCT n=903<a class="elsevierStyleCrossRef" href="#bib0255">11</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smits et al. (2019), 61 RCT n=6.264<a class="elsevierStyleCrossRef" href="#bib0335">27</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Santi et al. (2015), 15 RCT n=1275 (FSH exclusively)<a class="elsevierStyleCrossRef" href="#bib0250">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2339896.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Very low quality of evidence." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Low quality of evidence." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "Moderate quality of evidence." ] ] ] "descripcion" => array:1 [ "en" => "Most relevant published meta-analysis results." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib0205" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The international glossary on infertility and fertility care, 2017" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. 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Review article

Empiric therapy for idiopathic oligoasthenoteratozoospermia

Tratamiento empírico de la oligoastenoteratozoospermia idiopática

R. García-Baquero

Corresponding author

rgbaquero@hotmail.com

Corresponding author.

, C.M. Fernández-Ávila, J.L. Álvarez-Ossorio

Unidad de Andrología y Cirugía Reconstructiva Urogenital, Servicio de Urología, Hospital Universitario Puerta del Mar, Cádiz, Spain

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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Therapeutic algorithm in patients with idiopathic oligoasthenoteratozoospermia &#40;Puerta del Mar University Hospital&#46; C&#225;diz&#44; Spain&#41;&#46;</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">E2&#58; estradiol&#59; Fragm&#58; fragmentation&#59; T&#42;&#58; testosterone&#59; ART&#58; assisted reproductive technology&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42; Measured by SCSA&#44; as there are no methods for measuring ROS levels&#44; an indirect estimation of oxidative stress is made using DNA fragmentation levels&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">It is estimated that 15&#37; of couples are infertile&#44; understanding infertility as the inability of a sexually active&#44; non-contracepting couple to achieve pregnancy in one year&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">1</span></a> According to the WHO&#44; 190 million people worldwide suffer from infertility and the number of couples that demand medical assistance in this regard is constantly growing&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> Alone or combined with alterations in their partners&#44; the male factor is present in 50&#37; of couples that are unable to conceive&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Most causes of male infertility are related to an alteration in the classic parameters of the spermiogram&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a> and the oligoasthenoteratozoospermia syndrome &#40;OAT&#41; has a combination of the main alterations&#46; In the OAT&#44; oligozoospermia &#40;sperm concentration &#60;15<span class="elsevierStyleHsp" style=""></span>million&#47;mL sperm&#41;&#44; asthenozoospermia &#40;&#60;32&#37; of progressive motile sperm&#41; and teratozoospermia &#40;&#60;4&#37; of normal sperm&#41; are presented simultaneously in 2 separate spermiograms within at least 3 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">An exhaustive andrology assessment is essential in the clinical management of the infertile male&#44; in order to identify etiological factors and propose specific treatment when it is possible&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a> However&#44; idiopathic male infertility&#44; or of unknown cause&#44; accounts for 30&#8211;50&#37; of overall male infertility&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a> The group of patients with idiopathic infertility is considered a heterogeneous cohort&#44; with possible implication of etiopathogenic factors such as endocrine disrupting chemicals on patient&#39;s embryonic development or genetic alterations at the molecular level&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a> Although this type of infertility does not have a specific treatment by definition&#44; there are situations in which empirical treatments&#44; or probability treatments&#44; can be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a> In these situations&#44; the proposed treatment is off-label and patients should previously sign an informed consent in this regard&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Treatment on infertile men should take into account several aspects in order to be considered clinically relevant&#46;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Spermatogenesis</span>&#46; As the spermatogenic cycle has a normal duration of 72 days&#44; treatment should be continued for at least 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Treatment duration&#46;</span> If seminal quality has been improved&#44; it is advisable to maintain treatment until a spontaneous pregnancy is achieved &#40;main objective of the treatment&#41;&#44; or the sample is cryopreserved&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Intraindividual variability of the spermiogram</span>&#46; Sperm parameters within the same individual may have a wide variability &#40;26&#46;8&#37; for concentration&#44; 18&#46;4&#37; for motility&#41;&#44; although they usually fluctuate around a virtual homeostatic set point&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Female factor</span>&#46; The joint assessment of the couple is essential to correctly interpret the effectiveness of treatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Spontaneous pregnancy rate</span>&#46; Without any other measure&#44; the probability of spontaneous pregnancy increases with the time of exposure to unprotected intercourse&#44; being 10&#8211;15&#37; in the second year&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a></p></li></ul></p><p id="par0050" class="elsevierStylePara elsevierViewall">The empirical treatments mentioned below come from all available evidence&#46; Treatments such as androgens&#44; bromocriptine&#44; kallikrein&#44; alpha-blockers&#44; growth hormone&#44; or oxytocin&#44; without proven evidence to support their use&#44; have not been included in this review&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Hormone treatments</span><p id="par0055" class="elsevierStylePara elsevierViewall">Spermatogenesis has a hormonal regulation based on the hypothalamic-pituitary-gonadal axis&#46; In addition to pure hormonal regulation&#44; there are multiple paracrine factors that participate in this process&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a> Through empirical hormonal treatment&#44; it is intended to achieve direct or indirect stimulation of the germinal epithelium&#44; modifying the concentrations of hormones at the hypothalamic&#44; pituitary&#44; or intratesticular level &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Gonadotropins</span><p id="par0060" class="elsevierStylePara elsevierViewall">Exogenous gonadotropins replace endogenous gonadotropins&#44; directly enhancing the testicular functions of spermatogenesis and steroidogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Empirical treatment with gonadotropins &#40;FSHp &#91;purified&#93; 150<span class="elsevierStyleHsp" style=""></span>IU&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; FSHr &#91;recombinant&#93; 100&#8211;300<span class="elsevierStyleHsp" style=""></span>IU&#47;24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#44; hCG 2&#46;500<span class="elsevierStyleHsp" style=""></span>IU&#47;72<span class="elsevierStyleHsp" style=""></span>h&#44; hMG 150<span class="elsevierStyleHsp" style=""></span>IU&#47;48<span class="elsevierStyleHsp" style=""></span>h&#41; increases live birth rates &#40;odds ratio &#91;OR&#93; 9&#46;31&#44; 95&#37; confidence interval &#91;CI&#93;&#58; 1&#46;17&#8211;73&#46;75&#59; <span class="elsevierStyleItalic">p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span></span>0&#46;03&#41; and pregnancy rate &#40;11&#46;3&#37; with treatment vs&#46; 1&#46;5&#37; without treatment&#44; OR 4&#46;94&#44; 95&#37; CI&#58; 2&#46;13&#8211;11&#46;44&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;0002&#41; according to data extracted from a recently published meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">9</span></a> Likewise&#44; they improve the total sperm count &#40;mean difference &#91;MD&#93; 2&#46;66&#44; 95&#37; CI&#58; 0&#46;47&#8211;4&#46;84&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;02&#41; according to another recent meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a> Side effects&#44; such as local injection site irritation&#44; gynecomastia&#44; and increased breast soreness&#44; were rare and mild&#46; The main limitations of these 2 published meta-analyses are the heterogeneity in terms of the included patients and treatment schedules&#44; in addition to the relatively low number of studies and of treated patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">9&#44;10</span></a> In turn&#44; the high cost of treatment limits its application in daily clinical practice&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antiestrogens</span><p id="par0070" class="elsevierStylePara elsevierViewall">Antiestrogens are estrogen receptor antagonists at the hypothalamic level&#44; increasing GnRH secretion&#44; and at the pituitary level&#44; increasing FSH and LH gonadotropins&#44; by blocking the negative feedback of estrogens&#44; generated mainly after aromatization of testosterone&#44; thus stimulating spermatogenesis and steroidogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Empirical treatment with antiestrogens &#40;tamoxifen 20<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; clomiphene 50<span class="elsevierStyleHsp" style=""></span>mg&#47;24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#41; increases the pregnancy &#40;OR 2&#46;42&#44; 95&#37; CI 1&#46;47&#8211;3&#46;94&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;0004&#41;&#44; concentration &#40;MD 5&#46;24&#44; 95&#37; CI&#58; 2&#46;12&#8211;88&#46;37&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and sperm motility &#40;MD 4&#46;55&#44; 95&#37; CI&#58; 0&#46;73&#8211;8&#46;37&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;03&#41; rates according to a published meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">11</span></a> Another recent meta-analysis&#44; less methodologically rigorous&#44; confirms these results&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a> The incidence of side effects does not differ from that of placebo&#44; although gynecomastia&#44; headache and hot flushes are possible&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">11</span></a> The advantages of using antiestrogens in clinical practice are their low cost and their reasonable safety profile&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Aromatase inhibitors</span><p id="par0080" class="elsevierStylePara elsevierViewall">Aromatase inhibitors block the synthesis of estradiol from intratesticular and adipose tissue testosterone&#46; Decreased estrogen production reduces the negative effect on spermatogenesis and testosterone biosynthesis&#44; in addition to blocking negative feedback at the hypothalamic and pituitary levels&#44; thus increasing endogenous testosterone synthesis through gonadotrophin secretion&#44; without increasing circulating estrogens&#44; unlike antiestrogens&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Treatment with aromatase inhibitors &#40;anastrozole 1<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; letrozole 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#41; optimizes the hormonal profile &#40;increases testosterone and gonadotropins&#44; and reduces estradiol&#41; and improves sperm concentration and motility in patients with a testosterone&#47;estradiol ratio &#40;ng&#47;dL and pg&#47;mL&#41; &#60;10&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">13&#8211;15</span></a> However&#44; there are no data in the literature regarding pregnancy rates&#46; Side effects are generally mild and relatively infrequent &#40;&#60;10&#37;&#41; such as edema&#44; changes in libido&#44; breast soreness&#44; headache or asthenia&#44;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">14&#44;15</span></a> without forgetting increased bone resorption and reduced mineralization in extended treatments&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a> Results regarding its effectiveness are extracted from intervention studies without a control group&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">14&#44;15</span></a> To date&#44; there are no published clinical trials in patients with OAT&#44; therefore its use cannot be widely recommended as there is not sufficient scientific evidence&#46; The only published RCT was performed in patients with non-obstructive azoospermia or cryptozoospermia with good results supporting treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Antioxidants</span><p id="par0090" class="elsevierStylePara elsevierViewall">It is known that 30&#8211;80&#37; of infertile patients have higher levels of seminal reactive oxygen species &#40;ROS&#41; than fertile patients&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a> However&#44; ROS are necessary for a multitude of sperm-specific cellular processes&#44; such as spermatogenesis&#44; capacitation&#44; and acrosome reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a> The harmful effect of ROS lies in their elevated concentration&#44; when it is not compensated by natural antioxidant mechanisms and leads to seminal oxidative stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">18&#44;19</span></a> The main sources of ROS are seminal leukocytes and cytoplasm&#44; as mature and morphologically normal sperm generates less ROS in relation to immature or teratozoospermic forms&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a> Sperm cells are very susceptible to damage from oxidative stress due to the high concentration of polyunsaturated fatty acids in its membrane that tend to lipid peroxidation&#46; Alterations in sperm affect its structural and functional integrity &#40;concentration&#44; motility&#44; morphology&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">21&#44;22</span></a> implying changes in the acrosome reaction and reducing their fertilizing capacity&#46; Furthermore&#44; high ROS concentrations are related with increased DNA fragmentation&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a> associated in turn with a low rate of spontaneous pregnancies and worse outcomes of assisted reproductive techniques &#40;ART&#41;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">24&#44;25</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The rational basis for the administration of antioxidant therapy is based on the premise that seminal oxidative stress is due&#44; at least in part&#44; to a deficiency in seminal antioxidants&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">In a global way&#44; the most widely used antioxidants &#40;zinc&#44; selenium&#44; folic acid&#44; N-acetylcysteine&#44; coenzyme Q10 &#91;ubiquinol&#93;&#44; vitamins E and C&#44; carnitine&#44; docosahexaenoic acid &#91;DHA&#93;&#44; among others&#41; increase the rate of live births &#40;expected in the subfertile population in 12 to 14&#8211;26&#37;&#59; OR 1&#46;79&#44; 95&#37; CI&#58; 1&#46;20&#8211;2&#46;67&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;005&#41; and pregnancy rate &#40;expected in the subfertile population in 7 to 12&#8211;26&#37;&#59; OR 2&#46;97&#44; 95&#37; CI&#58; 1&#46;91&#8211;4&#46;63&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; In terms of sperm parameters&#44; their concentration &#40;MD 7&#46;51&#44; 95&#37; CI&#58; 4&#46;23&#8211;10&#46;79&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;000001&#44; at 3 months&#59; MD 7&#46;49&#44; 95&#37; CI&#58; 4&#46;76&#8211;10&#46;23&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001 at 6 months&#59; MD 3&#46;61&#44; 95&#37; CI&#58; 0&#46;17&#8211;7&#46;06&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;04 at 9 months&#41; and progressive motility &#40;MD 6&#46;11&#44; 95&#37; CI&#58; 0&#46;57&#8211;11&#46;66&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;003&#44; at 6 months&#41; increase&#44; and sperm DNA fragmentation decreases &#40;MD &#8722;5&#46;00&#44; 95&#37; CI&#58; &#8722;12&#46;61 to 2&#46;61&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41;&#44; according to data from a recently published meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a> Side effects compared to placebo are similar&#44; except for the most frequent gastrointestinal symptoms &#40;2&#8211;9&#37;&#41; with treatment &#40;OR 2&#46;51&#44; 95&#37; CI&#58; 1&#46;25&#8211;5&#46;03&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; However&#44; the limitations of this systematic review&#44; such as the paucity of data regarding the birth&#47;pregnancy rate&#44; the high heterogeneity of the administered treatments and the extended use of combinations&#44; limit the quality of the evidence extracted in this regard&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In relation to seminal oxidative stress&#44; it has been proposed to measure the oxidation&#8211;reduction potential in order to identify the so-called &#8220;male oxidative stress infertility&#8221; within those cataloged as idiopathic&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a> The identification of this type of infertility would allow selecting patients with higher seminal oxidative stress and with more probabilities of successful antioxidant therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">17&#44;28</span></a> Furthermore&#44; this selection would avoid the indiscriminate use of antioxidants which can generate a harmful paradoxical effect on sperm quality by inducing a state of reductive stress<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">29</span></a> when used in patients without oxidative stress&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Lifestyle changes</span><p id="par0105" class="elsevierStylePara elsevierViewall">Regardless of following a specific or empirical treatment&#44; the consideration of advising the patient to modify his lifestyle in order to improve his fertile capacity should be evaluated&#46; Among the modifiable factors related to poor seminal quality&#44; we highlight the following&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0110" class="elsevierStylePara elsevierViewall">An unhealthy diet&#44; that is&#44; rich in fats and poor in fruits and vegetables&#44; is related to low sperm concentration&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">30</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Obesity is associated with an increased risk of having oligozoospermia or azoospermia&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a></p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0120" class="elsevierStylePara elsevierViewall">Tobacco smoking is associated with a reduction in seminal volume and sperm concentration&#44; motility and morphology&#44; with a dose-dependent relationship&#59; the greatest effect has been seen in heavy smokers compared to more moderate ones&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">32&#44;33</span></a></p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0125" class="elsevierStylePara elsevierViewall">Excessive alcohol consumption is associated with lower sperm volume&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a></p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0130" class="elsevierStylePara elsevierViewall">High stress levels are associated with a reduction in seminal volume and sperm motility and morphology&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a></p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0135" class="elsevierStylePara elsevierViewall">Regarding air pollution and pollutants&#44; certain trends have shown negative effects of exposure to air pollutants on semen quality&#44; but without statistical significance&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a> The diversity of environmental pollutants and seminal parameters makes it difficult to obtain reliable data&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a></p></li></ul></p><p id="par0140" class="elsevierStylePara elsevierViewall">These data are extracted from systematic reviews of observational or cross-sectional studies&#44; which have shown relationship between factors but do not provide conclusions about a real cause&#8211;effect relationship&#46; In addition to the possibility of bias with other factors &#40;weight&#44; age&#44; active medication or physical activity&#41;&#46; To date&#44; there are hardly any published data regarding the effectiveness of intervention measures on this patient profile&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Discussion</span><p id="par0145" class="elsevierStylePara elsevierViewall">Despite the publication of several meta-analyses that support the use of empirical treatments&#44; the evidence in this regard is generally low&#44; mainly due to the small sample size of the included studies and the heterogeneity of the patients and treatment regimens &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; According to the recommendations of the main clinical guidelines&#44; in the absence of studies with more precise selection criteria&#44; clear recommendations cannot be given in terms of the use of empirical treatment with gonadotropins&#44; antiestrogens and antioxidants &#40;weak grade of recommendation&#44; very low level of evidence&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">3&#44;5</span></a> However&#44; these same guidelines state that empirical treatment can be considered before the immediate application of an ART&#44;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">3&#44;5</span></a> due to its good safety profile and&#44; generally&#44; its low cost&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">The most adequate path is to propose empirical treatment only to those patients with optimal conditions&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Optimal hormonal conditions&#46; Despite the fact that the results of studies with empirical hormonal treatments are obtained from patients with normogonadotropic normogonadic infertility&#44; performing a comprehensive analysis of their inclusion and exclusion criteria&#44;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">9&#8211;15</span></a> it is more than likely that the best results are obtained in patients with a more favorable hormonal profile and more susceptible to optimization&#44; that is&#44; in those whose testosterone concentration is at the lower limit of normal &#40;&#60;400<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&#41; and with normal or low gonadotropin concentration &#40;FSH<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>7<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#44; LH<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#41;&#44; with FSH levels never exceeding 12<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">9&#8211;12</span></a> In addition&#44; a testosterone&#47;estradiol ratio of &#60;10 appears to be the key factor for indicating treatment with aromatase inhibitors&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">13&#8211;15</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Optimal seminal conditions&#46; After analyzing the effectiveness of empirical treatments&#44; it is known that the seminal parameters that can be improved are sperm concentration and motility and DNA fragmentation &#40;&#62;30&#37;&#41;&#44; but not morphology&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Optimal reproductive conditions&#44; that is&#44; patients with a partner of &#60;35 years&#44; without associated female infertility factor&#44; with a waiting time to try natural conception which does not imply a significant reduction in the success rate of the application of an ART&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Aa a proposal&#44; we present the medical empirical treatment protocol followed in our center&#44; based on the greatest scientific evidence available to date and the most widely used diagnostic means in daily clinical practice &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">Finally&#44; it should be reminded that&#44; in the absence of effective treatment&#44; the application of ART is recommended in patients with OAT&#44; in order to improve their chances of achieving a pregnancy &#40;strong recommendation&#44; high level of evidence&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a> An underexplored possibility is to combine the improvement of seminal parameters induced by empirical treatment together with the application of ART in order to achieve better outcomes or to use a less invasive or expensive ART&#46; In this sense&#44; studies with gonadotropins<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">37&#44;38</span></a> and antioxidants<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">39&#44;40</span></a> show promising results&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0180" class="elsevierStylePara elsevierViewall">Although acceptable scientific evidence is limited&#44; recently published systematic reviews and meta-analyses show that treatments with gonadotropins&#44; antiestrogens&#44; and antioxidants result in increased pregnancy and live births rates and improved semen parameters&#46; That is why medical empirical treatment can be considered in specific situations of idiopathic infertility&#44; with the aim of improving seminal quality and consequently&#44; spontaneous fertility&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of interest</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "identificador" => "xres1362029"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Hormone treatments"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Gonadotropins"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Antiestrogens"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Aromatase inhibitors"
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        6 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Antioxidants"
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        7 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Lifestyle changes"
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          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2019-09-03"
    "fechaAceptado" => "2019-10-28"
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          "clase" => "keyword"
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          "identificador" => "xpalclavsec1252167"
          "palabras" => array:3 [
            0 => "Empiric treatment"
            1 => "Idiopathic male infertility"
            2 => "Idiopathic oligoasthenoteratozoospermia"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1252166"
          "palabras" => array:3 [
            0 => "Tratamiento emp&#237;rico"
            1 => "Infertilidad masculina idiop&#225;tica"
            2 => "Oligoastenoteratozoospermia idiop&#225;tica"
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        ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Male infertility accounts for 50&#37; of the causes of infertile couples&#44; being more than 30&#37; of unknown etiology&#46; In these cases&#44; empiric treatment can be an option prior to the application of assisted reproduction techniques&#46; Empiric treatment can be categorized as hormonal&#44; such as gonadotropins&#44; antiestrogens and aromatase inhibitors&#44; and antioxidant&#44; with vitamins&#44; trace elements and carnitine&#44; among others&#46; Although scientifically acceptable evidence is limited due to the absence of large randomized and controlled clinical trials&#44; recent systematic reviews and meta-analyses show that treatment with gonadotropins&#44; antiestrogens and antioxidants increases pregnancy and live birth rates and improves seminal parameters&#46; Empiric medical treatment for idiopathic infertility can be considered in specific cases in order to improve semen quality and spontaneous fertility&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El factor masculino supone el 50&#37; de las causas de infertilidad en parejas inf&#233;rtiles&#44; siendo en m&#225;s del 30&#37; de origen desconocido&#46; En estos casos&#44; el tratamiento m&#233;dico emp&#237;rico puede plantearse como una opci&#243;n previa a la aplicaci&#243;n de una t&#233;cnica de reproducci&#243;n asistida&#46; El tratamiento emp&#237;rico puede dividirse en 2 categor&#237;as&#58; hormonal&#44; tales como gonadotropinas&#44; antiestr&#243;genos e inhibidores de la aromatasa&#44; y antioxidante&#44; tales como vitaminas&#44; oligoelementos y carnitinas&#44; entre otros&#46; Aunque la evidencia cient&#237;ficamente aceptable es limitada debido a la ausencia de grandes ensayos cl&#237;nicos aleatorizados y controlados&#44; revisiones sistem&#225;ticas y metaan&#225;lisis recientemente publicados muestran que el tratamiento con gonadotropinas&#44; antiestr&#243;genos y antioxidantes resulta en un aumento de la tasa de embarazos y nacidos vivos y en una mejora en los par&#225;metros seminales&#46; Es por ello que&#44; en determinadas situaciones&#44; el tratamiento m&#233;dico emp&#237;rico para la infertilidad idiop&#225;tica puede considerarse con el objetivo de mejorar la calidad seminal y consecuentemente el potencial f&#233;rtil espont&#225;neo&#46;</p></span>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Please cite this article as&#58; Garc&#237;a-Baquero R&#44; Fern&#225;ndez-&#193;vila CM&#44; &#193;lvarez-Ossorio JL&#46; Tratamiento emp&#237;rico de la oligoastenoteratozoospermia idiop&#225;tica&#46; Actas Urol Esp&#46; 2020&#59;44&#58;281&#8211;288&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">hypothalamic pituitary gonadal axis&#46; Red solid arrows indicate stimulation&#44; blue dashed arrows indicate inhibition&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">&#42; GnRH&#58; gonadotropin-releasing hormone&#58; FSH&#58; follicle-stimulating hormone&#59; hCG&#58; human chorionic gonadotropin &#40;LH function&#41;&#59; hMG&#58; human menopausal gonadotropin &#40;FSH and LH function&#41;&#59; LH&#58; luteinizing hormone&#46;</p>"
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        "figura" => array:1 [
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            "imagen" => "gr2.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Pathophysiology of sperm oxidative stress&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Therapeutic algorithm in patients with idiopathic oligoasthenoteratozoospermia &#40;Puerta del Mar University Hospital&#46; C&#225;diz&#44; Spain&#41;&#46;</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">E2&#58; estradiol&#59; Fragm&#58; fragmentation&#59; T&#42;&#58; testosterone&#59; ART&#58; assisted reproductive technology&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42; Measured by SCSA&#44; as there are no methods for measuring ROS levels&#44; an indirect estimation of oxidative stress is made using DNA fragmentation levels&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Statistically significant data is bolded&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">According to the GRADE-Working Group scale&#58;</p>"
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            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gonadotropins&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Antiestrogens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Antioxidants&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FSHp<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>IU&#47;24<span class="elsevierStyleHsp" style=""></span>hFSHr<span class="elsevierStyleHsp" style=""></span>100&#8211;300<span class="elsevierStyleHsp" style=""></span>IU&#47;24&#8211;48<span class="elsevierStyleHsp" style=""></span>hhCG<span class="elsevierStyleHsp" style=""></span>2&#46;500<span class="elsevierStyleHsp" style=""></span>IU&#47;72<span class="elsevierStyleHsp" style=""></span>hhMG<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>IU&#47;48<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tamoxifen 20<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>hClomiphene 50<span class="elsevierStyleHsp" style=""></span>mg&#47;24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vitamin C 200&#8211;1&#46;000<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>Vitamin E 400&#8211;600<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>hDHA 400&#8211;1&#46;000<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>hN-acetylcysteine 600<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>hCoenzyme Q10 100<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h 200&#8211;300<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleSmallCaps">l</span>-Carnitine 1&#8211;3<span class="elsevierStyleHsp" style=""></span>g&#47;24<span class="elsevierStyleHsp" style=""></span>hFolic acid 0&#46;05&#8211;5<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>hZinc 200&#8211;250<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>hSelenium 100&#8211;225<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;24<span class="elsevierStyleHsp" style=""></span>hMagnesium 3&#46;000<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Treatment duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#8211;6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#8211;12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#8211;24 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Live births&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">OR 9&#46;31 &#40;1&#46;17&#8211;73&#46;75&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;03 &#40;1 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">30&#41;</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No data&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">OR 1&#46;79 &#40;1&#46;20&#8211;2&#46;67&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;005 &#40;7 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">750&#41;</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Spontaneous pregnancies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">OR 4&#46;94 &#40;2&#46;13&#8211;11&#46;44&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;002 &#40;5 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">412&#41;</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OR 2&#46;42 &#40;1&#46;47&#8211;3&#46;94&#41; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;0004 &#40;9 RCT <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>590&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">OR 2&#46;97 &#40;1&#46;91&#8211;4&#46;63&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;001 &#40;11 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">786&#41;</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sperm concentration &#40;million&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MD 2&#46;66 &#40;0&#46;47&#8211;4&#46;84&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;02 &#40;11 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">947&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MD 5&#46;24 &#40;2&#46;12&#8211;88&#46;37&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;001 &#40;8 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">492&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MD 7&#46;51 &#40;4&#46;23&#8211;10&#46;79&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;000001 &#40;3 months&#41; &#40;20 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">1&#46;244&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MD 7&#46;49 &#40;4&#46;76&#8211;10&#46;23&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;00001 &#40;6 months&#41; &#40;11 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">1&#46;430&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MD 3&#46;61 &#40;0&#46;17&#8211;7&#46;06&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;04 &#40;9 months&#41; &#40;5 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">583&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MD 6&#46;11 &#40;0&#46;57&#8211;11&#46;66&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;003 &#40;6 months&#41; &#40;5 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">521&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Progressive sperm motility &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MD 1&#46;22 &#40;&#8722;0&#46;07 to 2&#46;52&#41; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;06 &#40;6 RCT <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>629&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MD 4&#46;55 &#40;0&#46;73&#8211;8&#46;37&#41;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;03 &#40;7 RCT</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">n</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">448&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sperm morphology &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No data&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MD 0&#46;28 &#40;0&#46;63&#8211;0&#46;06&#41; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>0&#46;11 &#40;5 RCT <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>393&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No data&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Side effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Puncture site irritation&#44; gynecomastia&#44; breast soreness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Headache&#44; gynecomastia&#44; skin rash&#44; visual disturbances&#44; asthenia&#44; erectile dysfunction&#44; changes in libido&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Vomiting&#44; nausea&#44; stomach upset &#40;</span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">p</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><span class="elsevierStyleBold">&#61;</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;01&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">References&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attia et al&#46; &#40;2013&#41;&#44; 6 RCT <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>456 patients<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chua et al&#46; &#40;2013&#41;&#44; 11 RCT <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>903<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smits et al&#46; &#40;2019&#41;&#44; 61 RCT <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>6&#46;264<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Santi et al&#46; &#40;2015&#41;&#44; 15 RCT <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#61;</span><span class="elsevierStyleHsp" style=""></span>1275 &#40;FSH exclusively&#41;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2339896.png"
              ]
            ]
          ]
          "notaPie" => array:3 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Very low quality of evidence&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Low quality of evidence&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Moderate quality of evidence&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Most relevant published meta-analysis results&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:40 [
            0 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The international glossary on infertility and fertility care&#44; 2017"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Zegers-Hochschild"
                            1 => "G&#46;D&#46; Adamson"
                            2 => "S&#46; Dyer"
                            3 => "C&#46; Racowsky"
                            4 => "J&#46; de Mouzon"
                            5 => "R&#46; Sokol"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
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                      "doi" => "10.1016/j.fertnstert.2017.06.005"
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