Medication Strategies for the Male with Unexplained Infertility

Fig. 24.1

Table 24.1

Classes of medications used for empiric medical therapy

Antiestrogens

Clomiphene citrate

Tamoxifen

Aromatase inhibitors

Testolactone

Anastrazole

Gonadotropins

HCG

HMG

Recombinant human follicle stimulating hormone (FSH)

Androgens

Antiestrogens

Selective estrogen receptor modulators are the most commonly used medical therapies for unexplained infertility. These medications competitively bind estrogen receptors, especially at the level of the hypothalamus and pituitary. The effect is to inhibit the negative feedback of estrogen on the system, which leads to increased endogenous gonadotropin-releasing hormone secretion. This results in increases in the production of follicle stimulating hormone (FSH) and luteinizing hormone (LH) , ultimately promoting spermatogenesis. The most studied and prescribed medications of this type are clomiphene citrate and tamoxifen.

Clomiphene Citrate

Administration of clomiphene for idiopathic infertility varies in dosage, timing, and duration . Treatment doses range from clomiphene 25–100 mg daily or every other day. Common adverse effects of clomiphene therapy in men include nausea, headache, weight gain, alteration in libido, visual field changes, dizziness, gynecomastia, and allergic dermatitis; these side effects occur in less than 5 % of patients and are usually mild [5]. Clomiphene doses in excess of 200 mg/day can lead to suppression of spermatogenesis [7]. Serum gonadotropin and testosterone levels should be periodically monitored while on treatment. Additionally, a small number of patients may have decline in semen parameters, and as such, periodic semen analyses are indicated [5, 8].

One recent trial looked at a combination of clomiphene citrate and vitamin E in a prospective, randomized, placebo-controlled trial of 60 patients with idiopathic oligo-asthenospermia [9] . The trial showed this combination resulted in a significantly higher sperm count, increasing sperm count from a baseline of 10.2 +/− 4.14–18 million cells/ml +/− 15 ( p = 0.0025). In placebo recipients, pretreatment concentration was 11.3 + /− 7.13–12 million cells/ml +/− 8.6 ( p> 0.05). The progressive sperm motility also showed improvement in the treatment group. Additionally, the authors found a strong influence of this regimen on pregnancy rates, 36.7 % in the combination versus 13.3 % in the placebo group.

A second recent randomized trial showed a statistically significant increase in sperm count and motility for idiopathic infertility patients treated with clomiphene [10]. In this study, the treatment group had semen counts go from 20.38 +/− 16.2 to 42.51 +/− 29.4 million/ml ( p = 0.01). The motility percentage went from 23.78 +/− 17.5 to 43.38 +/− 20.1 %, where p = 0.01. Other placebo-controlled studies have also found a positive treatment effect for sperm counts and pregnancy rates for clomiphene [11–13].

However, the results from these trials are tempered with multiple other trials which have failed to show benefit from clomiphene therapy [14, 15]. A well-designed randomized and multicenter study by the WHO included 190 couples and showed no effect of clomiphene on pregnancy rates compared to placebo [16]. In a systematic meta-analysis, Cochrane review included ten studies involving 738 subfertile men with oligo-asthenozoospermia treated with at least 3 months of antiestrogen treatment [17]. They reported no difference in pregnancy rates with antiestrogen therapy .

Tamoxifen

Tamoxifen is known to have less estrogenic activity compared to clomiphene and has also been used as an oral agent to treat idiopathic male infertility. Treatment doses of tamoxifen range from 10 to 30 mg daily. The most common side effects are subjective flushing sensation (40–80 %) and risk of thrombus (1 %) [6]. Periodic lab analysis of liver function tests is recommended.

Initial uncontrolled trials reported improved sperm counts in men using tamoxifen [18, 19]. Subsequent controlled trials have all failed to show benefit from tamoxifen therapy for idiopathic male infertility [20, 21]. A meta-analysis of several randomized trials of tamoxifen demonstrated no significant treatment effect [22].

Additional evidence for the utilization of antiestrogens includes patients who will need intracytoplasmic sperm injection (ICSI) treatment. Hussein et al. looked at nonobstructive azoospermia patients who took antiestrogens for 3–9 months (mean duration of treatment 5.15 +/− 2.38 months). The authors found that 64 % of the patients responded to clomiphene and produced enough sperm in their ejaculate to allow for ICSI treatment, obviating the need for an extraction procedure [23]. It remains to be established which subpopulation of subfertile males will demonstrate the most benefit from these agents. Overall, antiestrogens are relatively inexpensive, well tolerated, and safe oral medications; however, there continues to be doubt about their efficacy and a lack of strong evidence to support their use.

Aromatase Inhibitors

Testolactone and Anastrazole

Aromatase is an enzyme which converts testosterone to estradiol and androstenedione to estrone . The peripheral aromatization of testosterone to an estrogen form has a negative feedback effect on gonadotropin production [24]. In 2001, Pavlovich et al. identified men with severe male factor infertility characterized by a decreased serum testosterone-to-estradiol ratio [25]. This physiology serves as the basis for the use of this class of agents as empiric therapy for male factor subfertility. Aromatase inhibitors have been used to treat idiopathic infertility by altering the inhibitory effects of estrogen; specifically, preventing the conversion of testosterone to estrogen will limit the estrogen-based inhibitory effects on spermatogenesis [24] .

Testolactone and anastrazole are both aromatase inhibitors which have been prescribed for this purpose. Testolactone is a steroidal inhibitor, whereas anastrazole is a more selective nonsteroidal aromatase inhibitor. Testolactone is contraindicated in men with a previous history of male breast cancer. Anastrazole can increase the risk of developing osteoporosis (11 %) and joint disorders (17 %) [26]. Further, practitioners should consider checking serum liver function tests when administering anastrazole as up to 10 % of the patients may experience elevated liver enzymes.

Raman and Schlegel evaluated the effects of testolactone and anastrozole on a heterogeneous population of patients with abnormal testosterone to estradiol ratios (T/E2 ratio < 10). The study included patients who were overweight, had Klinefelter’s syndrome, and varicoceles. The authors found that both medications statistically demonstrated significant improvements in hormone profiles and semen parameters. In men treated with testolactone, the T/E2 ratio increased from 5.3 +/− 0.2 to 12.4 +/− 1.1 ( p< 0.001). Additionally, there were improvements in sperm concentration, which increased from 5.5 to 11.2 million sperm per mL ( p< 0.01), and sperm motility increased from 14.7 to 21.0 % ( p< 0.05). For men treated with anastrazole, the T/E2 ratio increased from 7.2 +/− 0.3 to 18.1 +/− 1.0 ( p< 0.001), and sperm concentration increased from 5.5 to 15.6 million per mL ( p< 0.01) [27].

However, the Raman study was not specifically looking at idiopathic infertility patients, did not include a placebo group, and did not analyze pregnancy outcomes. Clark et al. performed a randomized, double blind, placebo-controlled trial looking at testolactone specifically in men with unexplained infertility [28]. These authors found no improvements in semen parameters or pregnancy rates compared to men taking placebo.

Gonadotropins

Human Chorionic Gonadotropin (HCG), Human Menopausal Gonadotropin (HMG), and Recombinant follicle stimulating hormone (FSH)

Human chorionic gonadotropin (HCG) and Human menopausal gonadotropin (HMG) have been used to treat idiopathic infertility . Recombinant FSH works via its primary mechanism, HCG works as an LH analog, and HMG displays both FSH and LH activity. All of these medications must be injected subcutaneously. Common side effects for these medications include pain at the injection site (6 %), nausea (2–3 %), fatigue (2 %), and gynecomastia (3 %). Serious venous and arterial thromboembolic events are rare but have been reported.

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