MALE INFERTILITY part 3

MALE INFERTILITY

Therapy of the Idiopathic Male Infertility and oligo-astheno-terato-zoospermia

Comprehensive Review Article

Part 3

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

Idiopathic male infertility and oligo-astheno-terato-zoospermia:

Oligo-astheno-terato-zoospermia (OAT) is a clinical condition with a reduced number of spermatozoa in the ejaculate, which is also characterised by reduced sperm motility and morphology; often referred to as OAT syndrome (OATS). Several conditions can cause OATS, although the aetiology may be unknown in a significant number of cases [1,2].

Empirical treatments:

• Life-style

Studies suggest that environmental and lifestyle factors may contribute to idiopathic infertility acting additively on a susceptible genetic background [1,2]. Hence, lifestyle improvement can have a positive effect on sperm parameters.

• Weight loss

Few authors have investigated the role of weight loss on male fertility outcomes. Non-controlled studies have suggested that weight loss can result in improved sperm parameters [1,3,4]. However, data derived from RCTs are more conflicting. A meta-analysis of 28 cohort studies and 1,022 patients, documented that bariatric surgery did not improve sperm quality and function in morbidly obese men [5]. Data on ART outcomes are lacking. However, it is important to recognise that weight loss can improve obesity-related secondary hypogonadism, which may result in better outcomes in couples seeking medical care for infertility, and is important for the general health of the male partner [3,5].

• Physical activity

Regular physical activity is recommended by the WHO in order to prevent and reduced the risk of several long-term chronic diseases [6]. A recent meta-analysis has documented that moderate-intensity (20–40 metabolic equivalents [METs]/week) or even high-intensity (40–80 METs-h/week) recreational physical activity can result in better semen parameters [7]. In addition, similar to what is observed from weight loss, improvements in hormonal profile have also been reported [3].

• Smoking

Epidemiological data indicates that about one in three men of reproductive age smokes, with the highest prevalence observed in Europe among all the WHO regions [8]. Data derived from a large meta-analysis of 20 studies with 5,865 participants clearly show a negative association between smoking and sperm parameters [8]. Experimental studies performed in rats have shown that nicotine has a dose-dependent deleterious effect on sperm, which can be improved by nicotine cessation [9]. Data in men are lacking and only one case report has indicated an improvement of sperm parameters after 3 months of a smoking cessation programme [10]. Similar data have been reported in a recent non-controlled study, which showed a possible benefit on ART after the male partner stopped smoking [11].

• Alcohol consumption

Data derived from a recent meta-analysis including 15 cross-sectional studies and 16,395 men suggested that moderate alcohol does not adversely affect semen parameters, whereas high alcohol intake can have a detrimental effect on male fertility [12]. Similar to what has been reported for weight loss; however, heavy chronic alcohol consumption (defined as > 2 drinks/day [13]) can reduce testosterone levels, which can be restored by alcohol cessation [14].

• Antioxidant treatment

Inflammation is a positive reaction of the human body to overcome potential noxious stimuli. However, chronic inflammation can induce several negative biochemical and metabolic effects that contribute to the development of several medical conditions. Oxidative stress is considered to be of the most important contributing factors in the pathogenesis of idiopathic infertility. Reactive oxygen species, the final products of OS, can impair sperm function acting at several levels, including plasma membrane lipid peroxidation, which can affect sperm motility, the acrosome reaction and chromatin maturation leading to increased DNA fragmentation [15]. Accordingly, seminal levels of ROS have been negatively associated with ART outcomes [16]. Despite this, evidence for the role of antioxidant therapy in male infertility is still conflicting. A Cochrane systematic review and meta-analysis including 34 RCTs and 2,876 couples using various antioxidant compounds, it was concluded that antioxidant therapy had a positive impact on live-birth and pregnancy rates in sub-fertile couples undergoing ART cycles [17]. Similar results were also reported in the most recent meta-analysis including 61 studies with 6,264 infertile men, aged 18-65 years [18]. More recently, the Males, Antioxidants, and Infertility (MOXI) trial found that antioxidants did not improve semen parameters or DNA integrity compared to placebo among infertile men with male factor infertility. Moreover, cumulative live-birth rate did not differ at 6 months between the antioxidant and placebo groups (15% vs. 24%) [19]. However, all the aforementioned studies also recognised important limitations: data were derived from low-quality RCTs with serious risk of bias due to poor methods of reporting randomisation; failure to report on the clinical outcomes including live-birth and clinical pregnancy rates; high attrition rates; and imprecision due to often low event rates and small overall sample sizes [18]. No clear conclusions were possible regarding the specific antioxidants to use or and/or therapeutic regimes for improving sperm parameters and pregnancy rate [18].

• Selective oestrogen receptor modulators

Selective oestrogen receptor modulators (SERMs) have been advocated as a possible empirical treatment in male idiopathic infertility. The proposed mechanism of action is based on the activity of these compounds to block oestrogen receptors at the level of the hypothalamus, which results in stimulation of GnRH secretion leading to an increase in pituitary gonadotropin release. The latter effect, by stimulating spermatogenesis, represents the rational basis for SERM administration to patients with reduced sperm count [20]. In an initial meta-analysis including 11 RCTs, in which only 5 were placebo-controlled, it was concluded that SERMs were not associated with an increased pregnancy rate in the 459 patients analysed [21]. In a subsequent Cochrane review published 1 year later, these findings were confirmed in a larger number of studies (n = 10 and 738 men), although positive effects on hormonal parameters were documented. More recently, Chua et al., meta-analysed data derived from 11 RCTs and showed that SERMs were associated with a significantly increased pregnancy rate [22]. Additionally, a significant improvement in sperm and hormonal parameters was detected. Similar results were confirmed in the latest updated meta-analysis of 16 studies [20]. However, it should be recognised that the quality of the papers included was low and only a few studies were placebo-controlled. In conclusion, although some positive results relating to the use of SERMs in men with idiopathic infertility have been reported, no conclusive recommendations can be drawn due to poor quality of the available evidence. Furthermore, complications from the use of SERMs were under-reported.

• Aromatase inhibitors

Aromatase, a cytochrome p450 enzyme, is present in the testes, prostate, brain, bone, and adipose tissue of men; it converts testosterone and androstenedione to oestradiol and oestrone, respectively. Oestradiol negatively feeds back on the hypothalamus and pituitary to reduce gonadotropic secretions, ultimately affecting spermatogenesis. In this context, aromatase inhibitors (AIs) may decrease oestrogen production by reversibly inhibiting cytochrome p450 isoenzymes 2A6 and 2C19 of the aromatase enzyme complex inhibiting the negative feedback of oestrogen on the hypothalamus resulting in stronger GnRH pulses that stimulate the pituitary to increase production of FSH [23-26]. Aromatase activity has been associated with male infertility characterised by testicular dysfunction with low serum testosterone and/or testosterone to oestradiol ratio. In this context, AIs have been reported to increase endogenous testosterone production and improve spermatogenesis in the setting of infertility as an off-label option for treatment [27]. Either steroidal (testolactone) and non-steroidal (anastrozole and letrozole) AIs significantly improve hormonal and semen parameters in infertile men, with a safe tolerability profile, although prospective RCTs are necessary to better define the efficacy of these medications in this clinical setting [25,27].

Hormonal therapy:

• Gonadotrophins

Follicle Stimulating Hormone is primarily involved in the initiation of spermatogenesis and testicular growth during puberty. The role of FSH post puberty has not been clearly defined. Luteinising hormone stimulates testosterone production in the testes, but due to its short half-life, it is not suitable for clinical use. Human Chorionic Gonadotrophin acts in a similar manner to LH and can be used pharmacologically to stimulate testosterone release in men with failure of their hypothalamic-pituitary-gonadal axis. Human Chorionic Gonadotrophin can adequately stimulate spermatogenesis in men whom have developed hypopituitarism after normal puberty. Therefore, the treatment of men with secondary hypogonadism depends on whether or not they developed hypothalamic-pituitary failure before or after puberty [28].

Secondary hypogonadism:

• Pre-Pubertal-Onset

Congenital causes resulting in low gonadotropin production are associated with testicular size < 4 mL and/or cryptorchidism. Testes size of < 4 mL occurs when they have not been exposed to any gonadotropins at all. These conditions require combination therapy with both hCG and FSH with subcutaneous administration or GnRH by pulsed delivery using a subcutaneous pump [29]. However, GnRH treatment requires a pulsatile secretion using specific devices for either intravenous or subcutaneous administration, which may limit patient compliance. Moreover, GnRH therapy should be limited to subjects with a residual pituitary gonadotropic activity [28]. As for the type of gonadotropin treatment, it is usual to commence hCG first and titrate the dose to achieve testosterone levels within the normal physiological range. However, FSH can be given first or in combination with hCG [30]. Human Chorionic Gonadotrophin is given twice weekly and in patients with congenital secondary hypogonadism in high dose, commencing at 1,000 IU twice weekly. Testosterone levels can be assayed every 2 weeks with dose increases until ideally mid-range testosterone is achieved. Dose increases can be to 2,000, 3,000, 4,000 and 5,000 IU two or three times a week, until normal testosterone levels are achieved [31–34]. Failure to achieve normal testosterone status at the high dose would indicate that primary testicular failure is present; probably as a result of cryptorchidism or failure of testicular development. Human Chorionic Gonadotrophin is also used to stimulate testicular descent into the scrotum in individuals with cryptorchidism. Once the hCG dose giving a normal level testosterone is established with the implication that intra-testicular testosterone has occurred, FSH 75-150 IU three times per week subcutaneously should be commenced. Usually, the higher 150 IU dose three times weekly is needed to be successful in men with testicular volume < 4mL. The trophic response of the testes to FSH is variable in these patients and it may range from no effect to achieving testicular sizes of 12-15 mL [35]. A trophic response is usually an indication of an increase in spermatogenesis. The production of new spermatogenesis may be evident after 3 months of FSH therapy, but could occur even after 18 months of treatment [33–35]. A low baseline sperm concentration does not indicate a poor response to gonadotropin therapy [36]. Semen analysis can be assessed at 3-monthly intervals. These patients can be fertile with low sperm counts < 20 million/mL as there is a high proportion of motile sperm. Follicle-stimulating hormone therapy prior to GnRH is also effective in stimulating testicular growth and fertility in men with congenital hypogonadotropic hypogonadism (HH) [37]. A larger initial testicular volume is the best prognostic factor for induction of successful spermatogenesis [38].

• Post-Pubertal Onset Secondary

If secondary hypogonadism develops after puberty, hCG alone is usually required first to stimulate spermatogenesis. Doses of subcutaneous hCG required may be lower than those used in individuals with pre-pubertal onset; therefore, a starting dose of 250 IU twice weekly is suggested, and if normal testosterone levels are reached, hCG doses may be increased up to 2,000 IU twice weekly as for pre-pubertal onset. Again, semen analysis should be performed every 3 months to assess response, unless conception has taken place. If there is a failure of stimulation of spermatogenesis, then FSH can be added (75 IU three times per week, increasing to 150 IU three times per week if indicated).

Similarly, combination therapy with FSH and hCG can be administered from the beginning of treatment, promoting better outcomes in men with HH [30]. No difference in outcomes were observed when urinary-derived, highly purified FSH was compared to recombinant FSH [30]. Greater baseline testicular volume is a good prognostic indicator for response to gonadotrophin treatment [38]. Data had suggested that previous testosterone therapy can have a negative impact on gonadotropin treatment outcomes in men with HH [38]. However, this observation has been subsequently refuted by a meta-analysis that did not confirm a real negative role of testosterone therapy in terms of future fertility in this specific setting [30]. In the presence of hyperprolactinaemia, causing suppression of gonadotrophins resulting in sub-fertility the treatment independent of aetiology (including a pituitary adenoma) is dopamine agonist therapy or withdrawal of the drug that causes the condition. Dopamine agonists used include bromocriptine, cabergoline and quinagolide.

• Primary Hypogonadism

There is no substantial evidence that gonadotrophin therapy has any beneficial effect in the presence of classical testicular failure. Likewise, there are no data to support the use of other hormonal treatments (including SERMs or AIs) in the case of primary hypogonadism to improve spermatogenesis [39,40].

• Idiopathic Male Factor Infertility

There is some evidence that FSH treatment increases sperm parameters in idiopathic oligozoospermic men with FSH levels within the normal range (generally 1.5 – 8 mIU/mL) [41]. It has also been reported that FSH may improve sperm DNA fragmentation rates as well as ameliorating AMH and inhibin levels [42–45]. High-dose FSH therapy is more effective in achieving a testicular response than lower doses are [46]. A Cochrane systematic review including six RCTs with 456 participants, different treatment protocols and follow-up periods concluded that FSH treatment resulted in higher live-birth and pregnancy rates compared with placebo or no treatment. However, no significant difference among groups was observed when ICSI or IUI were considered [47]. In a more recent meta-analysis including 15 trials with > 1,200 patients, similar findings after FSH treatment were observed in terms of both spontaneous pregnancies and pregnancies after ART [48]. A further study showed that in azoospermic men undergoing TESE-ICSI there were improved SRRs and higher pregnancy and fertilisation rates in men treated with FSH compared to untreated men [49]. In men with NOA, combination hCG/FSH therapy was shown to increase SRR in only one study [50]. Human chorionic gonadotrophin alone prior to TESE in NOA has not been found to have any benefit on SRRs [51]. Overall, the evidence for the use of hormone therapy prior to SSR is limited and treatment should be confined to clinical trials and not used routinely in clinical practice.

• Anabolic Steroid Abuse

Oligospermia or azoospermia as a result of anabolic abuse should be treated initially by withdrawal of the anabolic steroid. There is no common indication for treating this disorder; the management is based on case reports and clinical experience. Usually, adequate sperm numbers and quality will improve over a six to twelve-month period. If after this interval the condition persists, then hCG without or in combination with FSH as an alternative to clomiphene can be used to try and stimulate spermatogenesis [52].

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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