Keywords

14.1 Varicocele

Varicocele is an abnormal dilatation, elongation, and tortuosity of the pampiniform plexus of veins draining the testicles and is associated with venous reflux. Varicocele is diagnosed on ultrasound by the demonstration of venous diameter of >3 mm in the upright position, and during the Valsalva maneuver, and venous reflux duration is >2 s [1, 2]. The prevalence of varicocele is estimated to be approximately 20% in the general population, 40% among men with primary infertility, and 80% among men with secondary infertility [3]. A prevalence trial on 816 infertile men report that 74.6% of them had primary infertility while 25.4% secondary infertility. The overall prevalence of varicocele was 32.0% and varicocele accounted for 32.2% of patients with primary infertile, and 28.5% with secondary infertile [4].

Since the early report by Tulloch [5], extensive research has been done to explore the role of varicocele in male infertility. However, the topic of varicocele remains as one of the most controversial issues among andrologists and reproductive scientists. Several mechanisms have been postulated to explain the pathogenesis of infertility in men with varicocele, including scrotal hyperthermia, testicular hypoxia, hormonal disturbances, and the backflow of toxic metabolites [6] (Fig. 14.1). Elevated scrotal temperature in varicocele patients results from venous stasis and retrograde flow, which compromises the testicular heat exchange system [7, 8]. Testicular hypoxia in patients with varicocele is caused by vasoconstriction of pre-capillary arterioles, a compensatory mechanism to maintain the physiological intra-testicular pressure [9].

Fig. 14.1
figure 1

Mechanism of action of varicocele on male infertility

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Scrotal hyperthermia, testicular hypoperfusion, and reflux of toxic metabolites enhance the generation of reactive oxygen species (ROS) that can overwhelm the antioxidant capacity of the sperm resulting in the status of oxidative stress (OS). The latter is thought to play a central role in the pathogenesis of male infertility in general and in varicocele in particular [10]. A meta-analysis indicated significantly higher levels of seminal ROS and lower antioxidant capacity in varicocele patients compared to healthy controls [11]. High seminal OS in infertile men with varicocele has been associated with low conventional sperm parameters [12, 13] and increased sperm DNA fragmentation (SDF) [12, 14].

Additionally, a lower percentage of sperm DNA methylation and an altered sperm DNA integrity have been observed in varicocele patients compared to fertile controls [15, 16]. Furthermore, the gene variants that cause protamine deficiency have been reported at higher frequencies in varicocele patients with abnormal sperm parameters [17]. Recent studies showed altered seminal plasma proteomic profiles of varicocele patients in association with increased generation of ROS and pro-oxidant proteins, and up-regulation of antioxidant systems [18,19,20]. Varicocele patients show alteration in the expression of 253 proteins that are involved in sperm functions, including sperm motility, capacitation, hyperactivation, acrosome reaction, and fertilization [21]. Furthermore, the latter study indicated higher protein alterations among patients with bilateral varicoceles than those with unilateral varicocele.

Experimental animal studies with induced varicoceles indicated progressive decline of semen quality [22], and impairment of the fertilizing capacity of the haploid male gamete [23]. In infertile men, varicoceles may be associated with abnormal semen quality [24], or even complete azoospermia [25]. The current treatment options for infertile men with varicocele include varicocele repair (VR), empirical therapies, and assisted reproductive technology (ART).

In clinical practice, the decision to conduct VR during the management of infertile men with clinical varicocele is challenging in many aspects. First, the selection of patients that will benefit most from varicocele treatment and the timing of treatment may be difficult [26, 27]. Second, the outcome of VR may be a subject of great variability as it relies on several factors, including patient’s age, varicocele grade, testicular volume, pretreatment semen parameters, and reproductive hormone levels [26,27,28]. Last but not least is the method of VR, as the evidence is not satisfactory enough to suggest the optimum method [1].

In addition, there is no consensus as to the management of infertile men with subclinical varicocele. However, a recent systematic review and meta-analysis found no improvement in pregnancy rate after surgical repair of subclinical varicoceles [29]. Moreover, the current guidelines by the European Association of Urology (EAU) offers a “weak” suggestion to not treat varicocele in infertile men who have normal semen analysis or with a sub-clinical varicocele [1]. Once again, EAU guidelines [1] and the American Urological Association (AUA)/the American Society for Reproductive Medicine (ASRM) guidelines [30] do not mention specific measures for the management of varicocele associated with isolated sperm defects such as oligozoospermia, asthenozoospermia, necrozoospermia, or teratozoospermia, and do not determine which technique to choose for the management of recurrent varicoceles.

VR can be either surgical (varicolectomy) or through angiographic embolization. Surgical repair of varicocele includes open non-microsurgical techniques whether inguinal (Ivanissevich) or high retroperitoneal ligation (Palomo), open microsurgical techniques (inguinal or sub-inguinal) or laparoscopic [31, 32]. In a recent systematic review, the highest spontaneous pregnancy rate was found following subinguinal microsurgical VR (41%) as compared to inguinal (26%), retroperitoneal (37%), laparoscopic transperitoneal (26%), and percutaneous embolization (36%) [33]. However, a previous meta-analysis indicated no specific technique to be the most effective in improving the outcome [34]. The EAU guidelines report the microsurgical technique as having the lowest risk of recurrence (evidence level 2a) compared to non-microscopic approaches while highlighting the need for microsurgical training and expertise [1]. Using optical magnification helps avoid postoperative complications such as testicular devascularization or hydrocele with sparing of arteries and lymphatics, and decreased potential of recurrence rates [35]. Additionally, the microsurgical subinguinal VR has the advantage of a short postoperative recovery because no major muscles are dissected [36]. However, microsurgery necessitates the presence of expensive equipment and special surgical skills. Alternative methods for identifying the spermatic artery during VR include the use of intraoperative Doppler or direct visualization of arterial pulsations with or without the use of a vasodilator such as papaverine [37]. Percutaneous embolization of varicoceles may result in less post-procedural pain than surgical repairs. However, this latter approach is limited by technical difficulties and higher recurrence rates [38, 39].

The accumulating evidence suggests that VR can improve conventional sperm parameters (sperm concentration, motility, and morphology), seminal OS, SDF [40,41,42], and serum testosterone concentrations [43]. Although the positive impact of VR on semen quality is evident for all surgical techniques [26, 44, 45], the microsurgical approach appears to provide superior results [40]. Studies exploring the impact of VR on spontaneous pregnancy outcomes yielded equivocal results [40, 44, 46,47,48,49,50,51]. However, a meta-analysis revealed significantly higher clinical pregnancy rates (OR = 1.59) and live birth rates (OR = 2.17) among patients who underwent intracytoplasmic sperm injection (ICSI) following VR [52].

The impact of VR on seminal OS markers and SDF has been extensively investigated over the last two decades with conflicting results. Positive outcome of VR included reduction of 8-hydroxydeoxyguanosine (8-OhdG), a known marker for oxidative DNA damage, as well as an increase in seminal thiols and ascorbic acid (Vitamin C) 6 months after surgery [53]. Similarly, inguinal varicocelectomy with loop magnification resulted in a significant reduction of seminal ROS, and a rise in total antioxidant capacity (TAC) and SDF [54].

Using microsurgical retroperitoneal high ligation technique, a significant reduction in seminal malonaldehyde (MDA), a lipid peroxidation product, was observed at 3 and 6 months following varicocelectomy [55]. Furthermore, spermatic vein ligation caused a significant increase in seminal TAC levels at 3 and 6 months following surgery, particularly in patients with grade II and III varicoceles [56]. However, no significant change was observed in TAC levels at 10 and 24 months post-varicocelectomy, despite a positive impact on TAC regulation and associated improvement of sperm motility [57].

Varicocele repair has also been shown to reduce SDF and enhance the chance of spontaneous pregnancy and ART outcomes [58]. A meta-analysis concluded that VR is associated with a significant reduction of SDF with a mean difference of −3.37% (95% CI −4.09 to −2.65, p < 0.00001) [59]. Another recent meta-analysis including 11 studies (a total of 394 patients) demonstrated a significant reduction in SDF levels by 5.79% following VR [60].

A different meta-analysis, including 1070 infertile men with clinical varicocele indicated a significant reduction of SDF rates following VR. The effect was more evident among the patients with elevated pre-operative SDF values [61]. The ASRM 2015 guidelines recommend VR and antioxidants as valuable methods in reducing SDF [62]. The EAU guidelines also recommend VR in infertile men with high SDF and/or unexplained infertility [63].

Given the paramount role of OS in the pathogenesis of varicocele-mediated infertility, there is significant interest in the use of antioxidants in the management of varicocele as a sole therapy or combined with VR [32, 64]. Additionally, the fact that antioxidants are non-invasive and relatively cheap may encourage their prescription by practitioners for the treatment of varicocele prior to surgical intervention or ART [32]. This has been reflected in a recent global survey of clinical practice patterns in which 39% of reproductive specialists stated that they recommend antioxidant therapy for infertile men with varicocele [65].

A recent monocentric, randomized, double-blind, placebo-controlled trial investigated the effect of 6 months of supplementation with L-carnitine, acetyl-l-carnitine, and other micronutrients on sperm quality in infertile men with oligo- and/or astheno- and/or teratozoospermia with or without varicocele [66]. Sperm concentration, total sperm count, progressive motility, and total motility were significantly increased in the patients that received supplementation, and the positive outcome was more evident in those diagnosed with varicocele. Interestingly, 10/12 spontaneous pregnancies were reported in the supplementation group. Therapy with a combination of pentoxifylline, zinc, and folic acid improved sperm morphology in infertile men with varicocele [67]. Also, zinc supplementation in infertile males with or without VR resulted in a significant increase in sperm motility after two months of therapy, particularly in patients with low seminal zinc concentrations [68].

Microsurgical VR resulted in significantly higher sperm concentration and pregnancy outcomes compared to a combination therapy consisting of clomiphene citrate, vitamin A, vitamin E, selenium, l-carnitine, and pentoxifylline [69]. Administration of vitamin C for 6 months following VR improved sperm morphology and motility, but not sperm count [70]. The intake of N-acetylcysteine, post-varicocelectomy, significantly improved SDF and pregnancy rates [71]. A combination of folic acid and zinc sulfate following VR improved sperm parameters and serum inhibin-B levels, compared to surgery alone or the intake of zinc sulfate or folic acid alone [72].

These results indicate that using antioxidants combined with VR in infertile patients may provide additional benefits to the surgery alone [73]. However, administration of l-carnitine for six months following inguinal varicocelectomy did not benefit the sperm parameters or the SDF compared to surgery alone or placebo [74]. The role of antioxidants therapy in infertile men with varicocele is not clear due to the lack of well-designed studies and the absence of guidelines [75,76,77,78,79]. Future studies are warranted to clarify the role of antioxidants in the management of varicocele-associated male infertility, and to answer many queries related to the type, dose, and duration of antioxidants, as well as the potential complications including reductive stress [75].

Finally, ART is an additional option offered to infertile couples with varicocele under certain circumstances such as failure of natural pregnancy following surgery or advanced female partner’s age. ART outcomes in infertile men with clinical varicocele may be enhanced by surgical and/or antioxidant treatment [32].

14.2 Cryptorchidism

Cryptorchidism, undescended testis, is a common birth defect of the male genital tract that is usually diagnosed before male puberty. It is defined as the absence of one or both testes in normal scrotal position. During initial clinical evaluation, it may refer to palpable or nonpalpable testes, which are either cryptorchid or absent. Even if cryptorchidism is generally considered congenital, some cases occur beyond the neonatal period (acquired cryptorchidism). Most common risk factors for congenital cryptorchidism are prematurity, low weight at birth, small gestational age size, breech presentation, and maternal diabetes, while for acquired one, the main risk is retractile testis [80]. Genetic studies report a hereditary risk, but the susceptibility is polygenic and multifactorial. Clustering of undescended testis has been observed in some families affecting different individuals in the same generation with variable phenotype [81, 82]. The most studied genes for nonsyndromic cryptorchidism are INSL3, RXFP2, HOXA10, and HOXA11 [83]. Environmental risk factors include maternal excessive alcohol consumption, smoking (the most debated), increased use of anti-inflammatory/painkillers, and endocrine-disrupting chemicals consumption (particularly diethylstilbestrol) [84,85,86,87]. Testicular hormones also regulate testicular descent, and a defective production or action may contribute to the pathogenesis of cryptorchidism. Persistent Mullerian duct syndrome, Klinefelter syndrome (47,XXY), central nervous system, and gastrointestinal disorders are even associated with a higher incidence of cryptorchidism [88,89,90]. It was also postulated that cryptorchidism is a part of testicular dysgenesis syndrome along with hypospadias, testis cancer, and reduced semen quality [91].

The development of gonads starts during the fifth week of gestation, and cells arise from the posterior abdominal wall of the embryo [92]. Cells’ differentiation and their organization proceed to create the histologic compartments within the testicle, and at the same time, the scrotum develops together with the connection to the prostate, creating the sperm route [92]. The most common alteration, occurring during the first trimester and resulting in an extra-inguinal localization of testis, is reported during the migration of germ cells from the posterior abdominal wall toward the inguinal canals and the scrotum [92]. Certain regulatory genes have been identified in animal models to drive gonads descent: insulin-like 3 (INSL3), laxin/insulin-like family peptide receptor 2 (LGRF8), anti-Müllerian hormone (AMH), and HOX gene family [93]. All these genes can be involved in testis descent alteration, and infertility due to impaired spermatogenesis can be associated. Even androgens are required to induce regression of the cranial suspensory ligament and allow testis descent [93].

When an alteration in any of these processes is reported, cryptorchidism can occur. Incidence is 4% of newborns, and in the first year of age 1.5%, unilateral cryptorchidism is more common and is almost twice bilateral [94]. Undescended testis is related with male infertility, but there is an important difference between who has unilateral (treated during first years of life) and those with bilateral and treated later. Studies underling this difference, and paternity ranges from 96% between unilateral treated cryptorchidism to 70% in bilateral cryptorchidism. In these patients, inhibin-B levels differed between unilateral and bilateral undescended testis while testosterone levels were almost similar [95]. These differences are significant to underline that fertility is impaired more because of alteration in seminiferous epithelium than Leydig cell steroidogenesis. Even analysis performed with electron microscopy found higher ultrastructural defects in men with bilateral cryptorchidism than in the control group’s unilateral ones [96].

The diagnostic process is not often easy and should start with the physical examination performed in supine, upright cross-legged and standing position that are the best to determine the localization of testis. Scrotal asymmetry is a common clinical sign usually reported in unilateral cryptorchidism [97]. More than 75% of undescended testes are palpable and more than 60% are unilateral usually involving the right side [98, 99]. Analyzing metanalysis and biggest single center series, after surgery, 3–34% of testis were localized in the abdomen, 12% near internal ring, 16–63% canalicular, and all the others near to the external ring [98, 100,101,102]. Undescended testis can be palpable when are localized along the line of normal descent between the abdomen and scrotum or anterior to the rectus abdominus muscle or, more rarely, in a perirenal, prepubic, femoral, peripenile, perineal, or contralateral scrotal position [101] (Figs. 14.2 and 14.3). Nonpalpable testis are reported when localized in abdominal or transinguinal position, in case complete atrophy or vanishing testis, and when an extra abdominal localization is reported [101]. Hypospadias can be associated with cryptorchidism in 12% to 24% of cases and even small penis can be reported when cryptorchidism is due to hypogonadotropic hypogonadism [101].

Fig. 14.2
figure 2

True and ectopic undescended testis localizations

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Fig. 14.3
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Risks of undescended testis causing infertility

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The dosage of hormones is important in cases of suspected bilateral atrophy or vanishing testes because elevated basal serum gonadotropin levels (FSH and LH), undetectable AMH and inhibin B levels, and no response to hCG stimulation are common [103]. When doubts remain, surgical abdominal exploration is suggested. Diagnostic evaluation often is completed with inguino-scrotal ultrasonography and magnetic resonance imaging, particularly in cases of nonpalpable testis [104, 105]. The first has a sensitivity and specificity of 45% and 78% while the latter of 65% and 100% [104, 106, 107]. There is no specific imaging evaluation for vanishing and atrophic testes that requires initial scrotal exploration because often are near the scrotum, but this approach is useless when a vanishing testis is intraabdominal. Laparoscopy should be performed to confirm or exclude the presence of a viable or remnant abdominal testis, unless a prominent scrotal nubbin is palpable [108, 109]. Usually, diagnostic laparoscopy and contemporary orchidopexy is the preferable approach for all nonpalpable testis [108, 109].

The management of cryptorchism is based on surgical correction. The surgical approach for palpable undescended testis is inguinal orchidopexy with eventual repair of concomitant hernia [110]. Scrotal surgical approach is a viable alternative [111]. For nonpalpable undescended testis, surgical approach can be open or laparoscopic, in one or two stages and possibly with spermatic vessel transection. In some cases, orchiectomy is required (testis abdominal localization, impossibility of mobilization, or high neoplastic risk) [112]. The surgery is performed to optimize testicular function and cosmesis, prevent testicular malignancy, maintain fertility, and avoid hernia or torsion. After six months of postnatal observation, to allow spontaneous testicular descent, orchidopexy is indicated. This approach is suggested because after six months, spontaneous descent is uncommon, and after the surgery, testis growth is restored [113, 114]. After orchidopexy, studies report that size of the undescended testis is like those of normal contralateral testis [115]. However, final recommendations cannot be made because some series report a difference in size of testes, even if the treatment is performed before puberty [116]. There are not conclusive reports on contralateral fixation of a solitary testis in cases of monarchism. Medical therapy with hormones (hCG or LHRH), to stimulate testes descent and germ cell maturation is no longer suggested because of the lack of conclusive data. The majority of studies report no difference or a slight difference with placebo [117, 118].

Analyzing data regarding fertility in later life, the perfect timing of orchidopexy remains still inconclusive. In general, surgery is suggested before puberty because there is the belief that germ cells development remains quiescent till puberty, causing no remarkable difference if orchidopexy is performed at an earlier age [119]. Negri et al. reported that retrieval of sperm from 30 azoospermic men, affected by undescended bilateral testis and treated with orchidopexy, was not affected by the timing of surgery (overall success rate was 73%) [120]. Another experience with 42 azoospermic patients, once again, does not underline the difference in sperm retrieval success rate if orchidopexy is performed before or after ten years of age (61.9% and 57.1%, respectively) [121]. On the other side, there is a trial with 38 azoospermic men where sperm retrieval success rate was 94% for those who performed orchidopexy up to 10 years of age, 43% between 11 and 20 years, and 44% for those older than 20 years [122]. Finally, in EAU guidelines, it is stated that “paternity in men with unilateral cryptorchidism is almost equal to men without cryptorchidism” (LE:1B). Last but not least, even though it is considered experimental, some centers worldwide offer testicular tissue cryopreservation to children with undescended testis to restore fertility in adulthood [123, 124].

14.3 Inflammation and Seminal Tract Infections

Male accessory gland infections (MAGI) indicate infection and/or inflammation of accessory glands such as the prostate, seminal vesicles, and Cowper’s glands. Male genital tract infections (MGTI) is commonly used to indicate the eventual involvement of the complete male genital tract. During MGTI and MAGI, the presence of an elevated number of leukocytes and/or pathogens in semen, together with inflammatory signs, are common.

Male infertility is often linked with MGTIs and is one of the most common cause of male infertility, accounting for approximately 15% of cases. An abnormal leukocyte count is reported in the ejaculate and Chlamydia trachomatis, Escherichia coli, and Neisseria gonorrhoeae are the most common causes of infection [125, 126].

The impaired accessory glands function and genital tract inflammation can affect semen quality, leading to deterioration of spermatogenesis, sperm function alteration, and seminal tract obstruction [127, 128]. Inflammatory response is led by pro-inflammatory cytokines: tumor necrosis factor-α (TNF-α), IL-1α, IL-6 or IL-8 [129, 130].

The most common reported infections are prostatitis and epididymitis, both different between acute and chronic presentation and can lead to seminal tract obstruction. In severe cases, involvement of the testis can cause orchitis with high rates of infertility and sometimes can be a cause of testicular atrophy and spermatogenic impairment [131, 132]. Also, there is a broad spectrum of urethritis caused by both sexually transmitted and non-sexually transmitted pathogens [133, 134].

Usually, pathogens reported for seminal tract infections are bacteria including Chlamydia trachomatis, Urea plasma urealyticum, Neisseria gonorrhoeae, Mycoplasma hominis, and Mycoplasma genitalium [125]. Between Gram negatives, Escherichia coli is the most common and is responsible for most prostatitis and epididymo-orchitis [125]. All pathogens, and especially Chlamydia, can affect semen parameters and sperm function [135,136,137]. Even if MGTI/MAGI are common, often present asymptomatically (50% of cases) [125], and these silent infections may remain undetected and untreated leading to female partner transmission, severe complications and/or infertility [136,137,138].

Bacterial prostatitis are classified in accordance with the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) and should be distinguished by chronic pelvic pain syndrome (CPPS). The classification include type I—Acute bacterial prostatitis (ABP), type II—Chronic bacterial prostatitis (CBP), type III - Chronic non-bacterial prostatitis (CPPS) divided in IIIA and IIIB (Inflammatory CPPS and Non-inflammatory CPPS), and type IV—Asymptomatic inflammatory prostatitis (histological prostatitis) [139, 140]. Acute bacterial prostatitis is characterized by voiding symptoms and perineal pain that can be associated with malaise and fever. Chronic bacterial prostatitis is defined by symptoms that persist for at least three months. Analyzing prostatitis syndrome, a retrospective trial on more than 1400 patients found that an infectious etiology was found in 74.2% of cases (C. trachomatis 37.2%, T. vaginalis 10.5%, E. coli 6.6%, and U. urealyticum 5%) [141]. Diagnostic evaluation is based on culture of mid-stream urine and the Meares and Stamey test to determine the bacterial strain and choose antibiotic therapies [142, 143]. Further test can include transrectal ultrasound and PSA dosage, and in rare cases prostate biopsy. Therapeutic management is mainly dependent on bacterial strain, inflammation status and symptoms. Fluoroquinolones are the most used antibiotics with second and third generations (ciprofloxacin, levofloxacin, and prulifloxacin) reported to be similarly effective in microbiological eradication [144]. Different antibiotics such doxycycline, azithromycin, and metronidazole have been reported to be effective [144]. Further than antibiotics, phytotherapy or PDE5i can be used in association and may improve symptom relief and quality of life, particularly in patients with chronic prostatitis [145, 146].

Epididymitis, as the second most common MAGI, is characterized by pain, swelling, and increased temperature of the epididymis, which may involve the testis and scrotal skin. The mechanism underlying epididymitis is retrograde reflux of infectious agents. The most common pathogens are C. trachomatis, Enterobacteriaceae (E. coli), and N. gonorrhoeae [147]. Other less commonly seen agents are mumps virus, tuberculosis, or Brucella and Candida spp. Culture of a mid-stream urine is the most used test for diagnosis, while sexually transmitted infections like C. trachomatis or N. gonorrhoeae should be detected by nucleic acid amplification techniques on first voided urine or urethral swab. The management usually consists of empirical antimicrobial therapy that could be varied when a pathogen is identified. The most commonly used antibiotics are doxycycline and fluoroquinolones. Even azithromycin is effective against C. trachomatis. A single high parenteral dose of a third-generation cephalosporin can be used against N. gonorrhoeae [148,149,150]. Rare cases require surgical intervention to drain abscesses or debride tissue.

Urethritis, sometimes involved in male fertility problems, can be divided in infectious or non-infectious, and in gonococcal urethritis (GU) or non-gonococcal urethritis (NGU) if caused by Neisseria gonorrhoeae or not. Between non-gonococcal ones, most common pathogens are Chlamydia trachomatis, Mycoplasma genitalium, Ureaplasma urealyticum, and Trichomonas vaginalis. Reported symptoms, even useful for correct diagnosis, are mucopurulent or purulent discharge, dysuria, and urethral pruritus. Gram or methylene-blue stain of urethral secretions demonstrate inflammation and the presence of ≥10 polymorphonuclear leucocytes per high power field in the sediment from first-void urine sample or a positive leukocyte esterase test are considered positive for urethritis [151, 152]. When a urethritis is suspected, C. trachomatis, M. genitalium, and N. gonorrhoea should be tested with nucleic acid amplification techniques. Usually for gonococcal urethritis, a combination therapy with two antimicrobials is recommended [152]. Ceftriaxone in association with azithromycin should be used as first-line treatment, alternatively ceftriaxone can be substituted with cefixime while doxycycline is an alternative to macrolides [152]. Non-gonococcal urethritis, when a pathogen is not identified, can be treated empirically with doxycycline or alternatively with azithromycin [151]. Moxifloxacine can be used for resistant M. genitalium and pristinamycin and josamycin are another alternative [153]. Fluoroquinolones can be considered an alternative to doxycycline and azitromicin when a resistant Clamydia infection is reported [154].