MALE INFERTILITY part 2

MALE INFERTILITY

The Varicocele testis and the male accessory gland infections

Comprehensive Review Article

Part 2

Prof. Dr. Semir. A. Salim. Al Samarrai

At present, the clinical management of varicocele is still mainly based on physical examination; nevertheless, scrotal colour Doppler US is useful in assessing venous reflux and diameter, when palpation is unreliable and/or in detecting recurrence/persistence after surgery [1]. Definitive evidence of reflux and venous diameter may be utilised in the decision to treat.

Scrotal US is able to detect changes in the proximal part of the seminal tract due to obstruction. Especially for CBAVD patients, scrotal US is a favourable option to detect the abnormal appearance of the epididymis. Given that, three types of epididymal findings are described in CBAVD patients: tubular ectasia (honeycomb appearance), meshwork pattern, and complete or partial absence of the epididymis [2,3].

Transrectal US:

For patients with a low seminal volume, acidic pH and severe oligozoospermia or azoospermia, in whom obstruction is suspected, scrotal and transrectal US are of clinical value in detecting CBAVD and presence or absence of the epididymis and/or seminal vesicles (SV) (e.g., abnormalities/agenesis). Likewise, transrectal US (TRUS) has an important role in assessing obstructive azoospermia (OA) secondary to CBAVD or anomalies related to the obstruction of the ejaculatory ducts, such as ejaculatory duct cysts, seminal vesicular dilatation or hypoplasia/atrophy, although retrograde ejaculation should be excluded as a differential diagnosis [1,4].

Special Conditions and Relevant Clinical Entities:

• Cryptorchidism

Cryptorchidism is the most common congenital abnormality of the male genitalia; at 1 year of age nearly 1% of all full-term male infants have cryptorchidism [5]. Approximately 30% of undescended testes are nonpalpable and may be located within the abdominal cavity. These guidelines will only deal with management of cryptorchidism in adults.

• Classification

The classification of cryptorchidism is based on the duration of the condition and the anatomical position of the testes. If the undescended testis has been identified from birth, then it is termed congenital while diagnosis of acquired cryptorchidism refers to men that have been previously noted to have testes situated within the scrotum. Cryptorchidism is categorised on whether it is bilateral or unilateral and the location of the testes (inguinal, intra-abdominal or ectopic).

• Aetiology and pathophysiology

It has been postulated that cryptorchidism may be a part of the so-called testicular dysgenesis syndrome (TDS), which is a developmental disorder of the gonads caused by environmental and/or genetic influences early in pregnancy, including exposure to endocrine disrupting chemicals. Besides cryptorchidism, TDS includes hypospadias, reduced fertility, increased risk of malignancy, and Leydig/Sertoli cell dysfunction [6]. Cryptorchidism has also been linked with maternal gestational smoking [7] and premature birth [8].

Pathophysiological effects in maldescended testes:

• Degeneration of germ cells

The degeneration of germ cells in maldescended testes is apparent even after the first year of life and varies, depending on the position of the testes [9]. During the second year, the number of germ cells declines. Early treatment is therefore recommended (surgery should be performed within the subsequent year) to conserve spermatogenesis and hormone production, as well as to decrease the risk for tumours [10]. Surgical treatment is the most effective. Meta-analyses on the use of medical treatment with GnRH and hCG have demonstrated poor success rates [11,12]. It has been reported that hCG treatment may be harmful to future spermatogenesis; therefore, the Nordic Consensus Statement on treatment of undescended testes does not recommend it use on a routine basis [13]. See also the EAU Guidelines on Paediatric Urology [14]. There is increasing evidence to suggest that in unilateral undescended testis, the contralateral normal descended testis may also have structural abnormalities, including smaller volume, softer consistency and reduced markers of future fertility potential (spermatogonia/tubule ratio and dark spermatogonia) [15,16]. This implies that unilateral cryptorchidism may affect the contralateral testis and patients and parents should be counselled appropriately.

• Relationship with fertility

Semen parameters are often impaired in men with a history of cryptorchidism [17]. Early surgical treatment may have a positive effect on subsequent fertility [18]. In men with a history of unilateral cryptorchidism, paternity is almost equal (89.7%) to that in men without cryptorchidism (93.7%). In men with bilateral cryptorchidism, oligozoospermia can be found in 31% and azoospermia in 42%. In cases of bilateral cryptorchidism, the rate of paternity falls to 35-53% [19]. It is also important to screen for hypogonadism, as this is a potential long-term sequela of cryptorchidism and could contribute to impaired fertility and potential problems such as testosterone deficiency and MetS [20].

• Germ cell tumours

As a component of TDS, cryptorchidism is a risk factor for testicular cancer and is associated with testicular microcalcifications and intratubular germ cell neoplasia in situ (GCNIS), formerly known as carcinoma in situ (CIS) of the testes. In 5-10% of testicular cancers, there is a history of cryptorchidism [21]. The risk of a germ cell tumour is 3.6-7.4 times higher than in the general population and 2-6% of men with a history of cryptorchidism will develop a testicular tumour [5]. Orchidopexy performed before the onset of puberty has been reported to decrease the risk of testicular cancer [22]. However, there is evidence to suggest that even men who undergo early orchidopexy still harbour a higher risk of testicular cancer than men without cryptorchidism [23]. Therefore, all men with a history of cryptorchidism should be warned that they are at increased risk of developing testicular cancer and should perform regular testicular self-examination [24]. There is also observational study data suggesting that cryptorchidism may be a risk factor for worsening clinical stage of seminoma but this needs to be substantiated with future prospective studies [25].

Disease management:

• Hormonal treatment

Human chorionic gonadotropin or GnRH is not recommended for the treatment of cryptorchidism in adulthood. Although some studies have recommended the use of hormonal stimulation as an adjunct to orchidopexy to improve fertility preservation, there is a lack of long-term data and concerns regarding impairment to spermatogenesis with the use of these drugs [26].

• Surgical treatment

In adolescence, removal of an intra-abdominal testis (with a normal contralateral testis) can be recommended, because of the risk of malignancy [27]. In adults, with a palpable undescended testis and a normal functioning contralateral testis (i.e., biochemically eugonadal), an orchidectomy may be offered as there is evidence that the undescended testis confers a higher risk of GCNIS and future development of GCT [28] and regular testicular self-examination is not an option in these patients. In patients with unilateral undescended testis (UDT) and impaired testicular function on the contralateral testis as demonstrated by biochemical hypogonadism and/or impaired sperm production (infertility), an orchidopexy may be offered to preserve androgen production and fertility.

Germ cell malignancy and male infertility:

• Testicular germ cell cancer and reproductive function

Sperm cryopreservation is considered standard practice in patients with cancer overall, and not only in those with testicular cancer [29,30]. As such, it is important to stress that all men with cancer must be offered sperm cryopreservation prior to the therapeutic use of gonadotoxic agents or ablative surgery that may impair spermatogenesis or ejaculation (i.e., chemotherapy, radiotherapy or retroperitoneal surgery).

Men with testicular germ cell cancer (TGCT) have decreased semen quality, even before cancer treatment. Azoospermia has been observed in 5–8% of men with TGCT [31] and oligospermia in 50% [32]. Given that the average 10-year survival rate for testicular cancer is 98% and it is the most common cancer in men of reproductive potential, it is mandatory to include counselling regarding fertility preservation prior to any gonadotoxic treatment [32,33]. Semen analysis and cryopreservation are therefore recommended prior to any gonadotoxic cancer treatment and all patients should be offered cryopreservation of ejaculated sperm or sperm extracted surgically (e.g., c/mTESE) if shown to be azoospermic or severely oligozoospermic. Given that a significant number of men with testicular cancer at the time of first presentation have severe semen abnormalities (i.e., severe oligozoospermia/azoospermia) even prior to any treatment [34], it is recommended that men should undergo sperm cryopreservation prior to orchidectomy.

• Testicular microcalcification (TM)

Microcalcification inside the testicular parenchyma can be found in 0.6-9% of men referred for testicular US [35,36]. Although the true incidence of TM in the general population is unknown, it is most probably rare. Ultrasound findings of TM have been seen in men with TGCT, cryptorchidism, infertility, testicular torsion and atrophy, Klinefelter syndrome, hypogonadism, male pseudo hermaphroditism and varicocele [7]. The incidence reported seems to be higher with high-frequency US machines [37]. The relationship between TM and infertility is unclear, but may relate to testicular dysgenesis, with degenerate cells being sloughed inside an obstructed seminiferous tubule and failure of the Sertoli cells to phagocytose the debris. Subsequently, calcification with hydroxyapatite occurs. Testicular microcalcification is found in testes at risk of malignant development, with a reported incidence of TM in men with TGCT of 6-46% [38–40]. A recent systematic review and meta-analysis of case-control studies indicated that the presence of TM is associated with a ~18-fold higher odds ratio for testicular cancer in infertile men (pooled OR: 18.11, 95% CI: 8.09, 40.55; p < 0.0001) [41].

Testicular microcalcification should therefore be considered pre-malignant in this setting and patients counselled accordingly. Testicular biopsies from men with TM have found a higher prevalence of GCNIS, especially in those with bilateral microcalcifications [42].

• Varicocele

Varicocele is a common congenital abnormality, that may be associated with the following andrological conditions:

• male sub-fertility;

• failure of ipsilateral testicular growth and development;

• symptoms of pain and discomfort;

• hypogonadism.

• Classification

The following classification of varicocele [43] is useful in clinical practice:

• Subclinical: not palpable or visible at rest or during Valsalva manoeuvre, but can be shown by special tests (Doppler US).

• Grade 1: palpable during Valsalva manoeuvre.

• Grade 2: palpable at rest.

• Grade 3: visible and palpable at rest.

Overall, the prevalence of varicocele in one study was 48%. Of 224 patients, 104 had unilateral and 120 had bilateral varicocele; 62 (13.30%) were grade 3, 99 (21.10%) were grade 2, and 63 (13.60%) were grade 1 [44]. Worsening semen parameters are associated with a higher grade of varicocele and age [45,46].

• Diagnostic evaluation

The diagnosis of varicocele is made by physical examination and Scrotal Doppler US is indicated if physical examination is inconclusive or semen analysis remains unsatisfactory after varicocele repair to identify persistent and recurrent varicocele [43,47]. A maximum venous diameter of > 3 mm in the upright position and during the Valsalva manoeuvre and venous reflux with a duration > 2 seconds correlate with the presence of a clinically significant varicocele [48,49]. To calculate testicular volume Lambert’s formula (V=L x W x H x 0.71) should be used, as it correlates well with testicular function in patients with infertility and/ or varicocele [50]. Patients with isolated, clinical right varicocele should be examined further for abdominal, retroperitoneal and congenital pathology and anomalies.

Basic considerations:

• Varicocele and fertility

Varicocele is present in almost 15% of the normal male population, in 25% of men with abnormal semen analysis and in 35-40% of men presenting with infertility [43,45,51,52]. The incidence of varicocele among men with primary infertility is estimated at 35–44%, whereas the incidence in men with secondary infertility is 45–81% [43,52]. The exact association between reduced male fertility and varicocele is unknown. Increased scrotal temperature, hypoxia and reflux of toxic metabolites can cause testicular dysfunction and infertility due to increased overall survival and DNA damage [52]. A meta-analysis showed that improvements in semen parameters are usually observed after surgical correction in men with abnormal parameters [53]. Varicocelectomy can also reverse sperm DNA damage and improve OS levels [51,52].

• Varicocelectomy

Varicocele repair has been a subject of debate for several decades. A meta-analysis of RCTs and observational studies in men with only clinical varicoceles has shown that surgical varicocelectomy significantly improves semen parameters in men with abnormal semen parameters, including men with NOA with hypo spermatogenesis or late maturation (spermatid) arrest on testicular pathology [51,54–57]. Pain resolution after varicocelectomy occurs in 48-90% of patients [58]. A recent systematic review has shown greater improvement in higher-grade varicoceles and this should be taken into account during patient counselling [59]. In RCTs, varicocele repair in men with a subclinical varicocele was ineffective at increasing the chances of spontaneous pregnancy [60]. Also, in randomised studies that included mainly men with normal semen parameters no benefit was found to favour treatment over observation. A Cochrane review from 2012 concluded that there is evidence to suggest that treatment of a varicocele in men from couples with otherwise unexplained subfertility may improve a couple’s chance of spontaneous pregnancy [61]. Two recent metaanalyses of RCTs comparing treatment to observation in men with a clinical varicocele, oligozoospermia and otherwise unexplained infertility, favoured treatment, with a combined OR of 2.39-4.15 (95% CI: 1.56-3.66 and 95% CI: 2.31-7.45, respectively) [57,61]. Average time to improvement in semen parameters is up to two spermatogenic cycles [62,63] with spontaneous pregnancy occurring between 6 and 12 months after varicocelectomy [64,65]. A further meta-analysis has reported that varicocelectomy may improve outcomes following ART in oligozoospermic men with an OR of 1.69 (95% CI: 0.95-3.02) [66].

• Prophylactic varicocelectomy

In adolescents with a varicocele, there is a significant risk of over-treatment because most adolescents with a varicocele have no problem achieving pregnancy later in life [67]. Prophylactic treatment is only advised in case of documented testicular growth deterioration confirmed by serial clinical or Doppler US examinations and/or abnormal semen analysis [68,69].

• Varicocelectomy and NOA

Several studies have suggested that varicocelectomy may lead to sperm appearing in the ejaculate in men with azoospermia. In one such study, microsurgical varicocelectomy in men with Non‐obstructive azoospermia (NOA) led to sperm in the ejaculate post-operatively with an increase in ensuing natural or assisted pregnancies [70].

• Varicocelectomy and hypogonadism

Evidence also suggests that men with clinical varicoceles who are hypogonadal may benefit from varicocele intervention. One meta-analysis studied the efficacy of varicocele intervention by comparing the pre-operative and post-operative serum testosterone of 712 men. The combined analysis of seven studies demonstrated that the mean post-operative serum testosterone improved by 34.3 ng/dL (95% CI: 22.57-46.04, p < 0.00001, I² = 0%) compared with their pre-operative levels. An analysis of surgery vs. untreated control results showed that mean testosterone among hypogonadic patients increased by 105.65 ng/dL (95% CI: 77.99-133.32 ng/dL), favouring varicocelectomy [71].

• Varicocelectomy for assisted reproductive technology and raised DNA fragmentation

Varicocelectomy can improve sperm DNA integrity, with a mean difference of -3.37% (95% CI: -2.65% to -4.09%) [67]. There is now increasing evidence that varicocele treatment may improve DNA fragmentation and outcomes from ART [66,67]. As a consequence, more recently it has been suggested that the indications for varicocele intervention should be expanded to include men with raised DNA fragmentation. If a patient has failed ART (e.g., failure of implantation, embryogenesis or recurrent pregnancy loss) there is an argument that if DNA damage is raised, consideration could be given to varicocele intervention after extensive counselling [72], and exclusion of other causes of raised DNA fragmentation [67,73]. The dilemma is whether varicocele treatment is indicated in men with raised DNA fragmentation and normal semen parameters.

• Disease management

Several treatments are available for varicocele (Table 1). Current evidence indicates that microsurgical varicocelectomy is the most effective among the different varicocelectomy techniques [67,74]. Unfortunately, there are no large prospective RCTs comparing the efficacy of the various interventions for varicocele. However, microsurgical repair results in fewer complications and lower recurrence rates compared to the other techniques based upon case series [75]; however, this procedure requires microsurgical training. The various other techniques are still considered viable options, although recurrences and hydrocele formation appear to be higher [76]. Radiological techniques (sclerotherapy and embolisation) are minimally invasive widely used approaches, although higher recurrence rates compared to microscopic varicocelectomy have been reported (4-27%) [52]. Robot-assisted varicocelectomy has a similar success rate compared to the microscopic varicocelectomy technique, although larger prospective randomised studies are needed to establish the most effective method [77–79].

Table 1: Recurrence and complication rates associated with treatments for varicocele

Male accessory gland infections and infertility:

• Introduction

Infection of the male urogenital tract is a potentially curable cause of male infertility [80–82]. The WHO considers urethritis, prostatitis, orchitis and epididymitis to be male accessory gland infections (MAGIs) [83]. The effect of symptomatic or asymptomatic infections on sperm quality is contradictory [83]. A systematic review of the relationship between sexually transmitted infections, such as those caused by Chlamydia trachomatis, genital mycoplasmas, Neisseria gonorrhoeae, Trichomonas vaginalis and viruses, and infertility was unable to draw a strong association between sexually transmitted infections and male infertility due to the limited quality of reported data [84].

Diagnostic evaluation:

• Semen analysis

Semen analysis clarifies whether the prostate is involved as part of a generalised MAGI and provides information regarding sperm quality. Leukocyte analysis allows differentiation between inflammatory and non-inflammatory chronic pelvic pain syndrome (CP/CPPS) (NIH IIa vs. NIH 3b National Institutes of Health classification for CP/CPPS).

• Microbiological findings

After exclusion of UTI (including urethritis), > 106 peroxidase-positive white blood-cells (WBCs) per millilitre of ejaculate indicate an inflammatory process. In these cases, a semen culture or polymerase chain reaction (PCR) analysis should be performed for common urinary tract pathogens. A concentration of > 103 CFU/mL urinary tract pathogens in the ejaculate is indicative of significant bacteriospermia [85]. The sampling should be delivered the same day to the laboratory because the sampling time can influence the rate of positive microorganisms in semen and the frequency of isolation of different strains [86]. The ideal diagnostic test for isolating C. trachomatis in semen has not yet been established [87], but the most accurate method is PCR [88–90].

Historical data show that Ureaplasma urealyticum is pathogenic only in high concentrations (> 103 CFU/mL ejaculate). Fewer than 10% of samples analysed for Ureaplasma exceeded this concentration []. Normal colonisation of the urethra hampers the significance of mycoplasma-associated urogenital infections, using samples such as the ejaculate [92].

A meta-analysis indicated that Ureaplasma parvum and Mycoplasma genitalium were not associated with male infertility, but a significant relationship existed between U. urealyticum (OR: 3.03 95% CI: 1.02–8.99) and Mycoplasma hominis (OR: 2.8; 95% CI: 0.93– 3.64) [93].

The prevalence of human papilloma virus (HPV) in the semen ranges from 2 to 31% in the general population and is higher in men with unexplained infertility (10-35.7%) [94,95]. Recent systematic reviews have reported an association between male infertility, poorer pregnancy outcomes and semen HPV positivity [96–98]. However, data still needs to be prospectively validated to clearly define the clinical impact of HPV infection in semen. Additionally, seminal presence of Herpes Simplex virus (HSV)-2 in infertile men may be associated with lower sperm quality compared to that in HSV-negative infertile men [83]. However, it is unclear if anti-viral therapy improves fertility rates in these men.

• White blood cells

The clinical significance of an increased concentration of leukocytes in the ejaculate is controversial [99]. Although leukocytospermia is a sign of inflammation, it is not necessarily associated with bacterial or viral infections, and therefore cannot be considered a reliable indicator [100]. According to the WHO classification, leukocytospermia is defined as > 106 WBCs/mL. Only two studies have analysed alterations of WBCs in the ejaculate of patients with proven prostatitis [101,102]. Both studies found more leukocytes in men with prostatitis compared to those without inflammation (CPPS, type NIH 3b). Furthermore, leukocytospermia should be further confirmed by performing a peroxidase test on the semen. There is currently no evidence that treatment of leukocytospermia alone without evidence of infective organisms improves conception rates [103].

• Sperm quality

The deleterious effects of chronic prostatitis (CP/CPPS) on sperm density, motility and morphology have been demonstrated in a recent systematic review based on case-controlled studies [104]. Both C. trachomatis and Ureoplasma spp. can cause decreased sperm density, motility, altered morphology and increased DNA damage. Data from a recent retrospective cross-sectional study showed that U. urealyticum was the most frequent single pathogen in semen of asymptomatic infertile men; a positive semen culture was both univariably (p < 0.001) and multi-variably (p = 0.04) associated with lower sperm concentration [105]. Human papilloma virus can also induce changes in sperm density, motility and DNA damage [94,95]. Mycoplasma spp. can cause decreased motility and development of antisperm antibodies [83].

• Seminal plasma alterations

Seminal plasma elastase is a biochemical indicator of polymorphonuclear lymphocyte activity in the ejaculate [82,106,107]. Various cytokines are involved in inflammation and can influence sperm function. Several studies have investigated the association between interleukin (IL) concentration, leukocytes, and sperm function through different pathways, but no correlations have been found [108–110].

The prostate is the main site of origin of IL-6 and IL-8 in the seminal plasma. Cytokines, especially IL-6, play an important role in the male accessory gland inflammatory process [111]. However, elevated cytokine levels do not depend on the number of leukocytes in expressed prostatic secretion [112].

• Glandular secretory dysfunction

The secretory function of the prostate gland can be evaluated by measuring seminal plasma pH, citric acid, or γ-glutamine transpeptidase levels; the seminal plasma concentrations of these factors are usually altered during infection and inflammation. However, they are not recommended as diagnostic markers for MAGIs [113].

• Reactive oxygen species

Reactive oxygen species may be increased in infertile patients with asymptomatic C. trachomatis and M. hominis infection, with subsequent decrease in ROS upon antibiotic treatment. However, the levels of ROS in infertile patients with asymptomatic C. trachomatis and M. hominis in the semen are low, making it difficult to draw any firm conclusions [114]. Chronic urogenital infections are also associated with increased leukocyte numbers [115]. However, their biological significance in prostatitis remains unclear [83].

• Disease management

Treatment of CP/CPPS is usually targeted at relieving symptoms [116,117]. The indications and aims of therapy are:

• reduction or eradication of micro-organisms in prostatic secretions and semen.

• normalisation of inflammatory (e.g., leukocytes) and secretory parameters.

• improvement of sperm parameters associated with fertility impairment [118].

Only antibiotic therapy of chronic bacterial prostatitis (NIH II according to the classification) has provided symptomatic relief, eradication of micro-organisms, and a decrease in cellular and humoral inflammatory parameters in urogenital secretions. Although antibiotics might improve sperm quality [118], there is no evidence that treatment of CP/CPPS increases the probability of natural conception [82,119]. Asymptomatic presence of C. trachomatis and M. hominis in the semen can be correlated with impaired sperm quality, which recovers after antibiotic treatment. However further research is required to confirm these findings [114].

• Epididymitis

Inflammation of the epididymis causes unilateral pain and swelling, usually with acute onset. Among sexually active men aged < 35 years, epididymitis is most often caused by C. trachomatis or N. gonorrhoea [120,121]. Sexually transmitted epididymitis is usually accompanied by urethritis. Non-sexually transmitted epididymitis is associated with UTIs and occurs more often in men aged > 35 years [122].

• Diagnostic evaluation

Ejaculate analysis according to WHO Laboratory Manual for the Examination and Processing of Human Semen (6th edn) criteria, may indicate persistent inflammatory activity. Transient reductions in sperm counts and progressive motility can be observed [120,123,124]. Semen culture might help to identify pathogenic micro-organisms. Development of stenosis of the epididymal ducts, reduction of sperm count, and azoospermia are more important potential sequelae to consider in the follow-up of bilateral epididymitis.

• Disease management

Treatment of epididymitis results in:

• microbiological cure of infection.

• improvement of clinical signs and symptoms.

• prevention of potential testicular damage; • prevention of transmission.

• decrease of potential complications (e.g., infertility or chronic pain).

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Author Correspondence:

Prof. Dr. Semir A. Salim. Al Samarrai

Medical Director of Professor Al Samarrai Medical Center.

Dubai Healthcare City, Al-Razi Building 64, Block D, 2nd Floor, Suite 2018

E-mail: semiralsamarrai@hotmail.com

Tel: +97144233669