Approach
The treatment goal for male infertility is to achieve pregnancy and restore normal reproductive function for the man. Despite advances in understanding the causes of male infertility, many medical and surgical treatments remain of undemonstrated effectiveness. The choice of treatment for men should take into account their partner's age, because there is a natural decline in female fertility that accelerates after the age of 35 years.
Medical and surgical therapy
Obstructive azoospermia[24][47]
If transrectal ultrasound demonstrates ejaculatory duct obstruction and dilation of the seminal vesicles, transurethral resection of the ejaculatory ducts may be performed to restore patency.
Microsurgical vasovasostomy or epididymovasostomy may be performed in circumstances of obstruction due to iatrogenic vasal injury during inguinal or scrotal surgery (i.e., herniorrhaphy), vasectomy, or isolated vasal obstruction (i.e., trauma, infection). In instances of multifocal obstruction, reconstruction may not be possible.
Sperm retrieval may be performed in lieu of reconstruction or in the setting of reconstructive failures. Sperm retrieval methods include both percutaneous and open techniques from both the epididymis and the testicle and are followed by IVF/intracytoplasmic sperm injection (ICSI).
Gonadotropin or gonadotropin-releasing hormone (GnRH) deficiencies
Medical treatment is effective in cases of secondary hypogonadism and other endocrine causes of male infertility.
Men with secondary hypogonadism, such as gonadotropin deficiency or genetic conditions such as Kallmann syndrome, can be treated with gonadotropins or pulsatile GnRH.[48][49] If human chorionic gonadotropin (hCG) is used for secondary hypogonadism and sperm is not induced after 6 months of therapy, follitropin alfa (follicle-stimulating hormone [FSH]) should be added to the regimen.
Primary hypogonadism
Testosterone is essential for maintaining spermatogenesis and male fertility. Low testosterone levels can lead to the absence of secondary sex characteristics, infertility, muscle wasting, and other abnormalities.[50]
Clomiphene has been used for the treatment of low testosterone levels with minimal adverse effects, and it has been shown not to interfere with spermatogenesis.[51] Clomiphene was originally approved for the treatment of ovulatory dysfunction in women; it inhibits the negative feedback of the estradiol hypothalamic-pituitary-gonadal axis at the level of the hypothalamus. This leads to release of luteinizing hormone (LH) and FSH from the anterior pituitary, which stimulates Leydig cells, leading to testosterone production.[51] Common adverse effects include headache, dizziness, nausea, vomiting, gynecomastia, weight gain, and hypertension.[52] Clomiphene is expected to significantly increase testosterone, but only in a small percentage of men; therefore, it is recommended to evaluate bioavailable testosterone 3 weeks following initiation of clomiphene to assess the need for dose titration.[53] Clomiphene is off-label for this indication.
Clomiphene has been used in patients with azoospermia and spermatogenic dysfunction, with the hypothesis that increases in intratesticular testosterone level will potentially lead to increased sperm in the ejaculation or to improve the success rate of successful testicular sperm extraction. One study showed that 57.7% of patients prescribed clomiphene had a successful microsurgical sperm retrieval, compared with 33.6% of the control group.[54]
hCG induces testosterone production by stimulating Leydig cells directly. hCG has been an effective regimen in the treatment of men with hypogonadotropic hypogonadism.[55] Its use among men with low testosterone and low to normal LH and FSH is not well studied.
High estrogen levels in combination with low testosterone
High estrogen levels in combination with low testosterone levels have been shown to impair spermatogenesis.[56] Elevated levels of estrogen result in a decrease in LH, which is necessary for testosterone production, and a decrease in FSH, which is essential for sperm production.[57]
The use of aromatase inhibitors (e.g., anastrozole) in men with infertility and testosterone <300 nanograms/dL with a testosterone/estradiol ratio <10:1 improved hormonal profile and semen parameters.[58] Aromatase inhibitors block the conversion of testosterone and androstenedione into estradiol and estrone, respectively. This effect indirectly increases GnRH; the GnRH increase, in turn, increases FSH release, which will act on the Sertoli cells to enhance spermatogenesis, and LH release, which will act on the Leydig cell to secrete testosterone.[59] Adverse effects are rare. One study reported that anastrozole improved endocrine parameters in 95.3% of men with hyperandrogenism with low T/E (testosterone/epitestosterone) ratio and a subset of patients displayed significantly improved sperm parameters.[60]
Selective estrogen receptor modulators (e.g., clomiphene) might play an important role in these patients. In select hypoandrogenic subfertile men, a combination of an aromatase inhibitor and a selective estrogen receptor modulator has proven to be safe and effective.[61] Combination therapy is often indicated when axis stimulation by selective estrogen receptor modulators results in an elevation of testosterone but also a resultant disproportionate increase in the aromatization to estradiol.
Hyperprolactinemia due to pituitary adenoma
Men with secondary hypogonadism due to hyperprolactinemia from a pituitary tumor are treated with bromocriptine or cabergoline.
Presence of antisperm antibodies
Corticosteroids are advocated in the presence of antisperm antibodies. However, their effectiveness is uncertain given methodologic concerns in the published literature that make study comparisons and definitive conclusions difficult.[62] As such, men with antisperm antibodies are better treated with assisted reproductive techniques (ART); artificial insemination with sperm wash or IVF with ICSI are better options.
Presence of varicocele and no other cause of infertility detected
Reviews of randomized clinical trials have been controversial as to the benefit of varicocele treatment in subfertile men.
Varicocele should be treated for infertility only after a full discussion with the infertile opposite-sex couple about the controversy of treatment benefit and after ruling out other causes of male and female infertility.[10] Varicocele treatment may improve the chances for pregnancy; however, it is uncertain whether any treatment has a benefit on live birth rates as evidence is limited.[63] Varicocele repair may "upgrade" semen parameters to reduce the need for IVF and intrauterine insemination (IUI).[64] Some studies suggest improved sperm count in men with azoospermia resulting from late maturation arrest and hypospermatogenesis after varicocele repair.[65]
In general, varicocelectomy has been found to improve various sperm parameters, to reduce sperm DNA damage, to reduce seminal oxidative stress, and to improve sperm ultramorphology.[66] Microsurgical repair is associated with better outcomes compared with other methods of repair.[63]
Idiopathic male infertility
Idiopathic male infertility refers to abnormalities in semen parameters without a known etiology. Medical treatment of opposite-sex couples with unexplained subfertility is of unclear effectiveness.[67] Such treatment should be given in the context of clinical trials. Meta-analyses suggest that gonadotropin treatment for men with idiopathic male subfertility or infertility may improve live birth rate and pregnancy rate; quality of evidence was variable, with high risk of bias.[68][69] [
]
The American Urological Association (AUA) guidelines recommend consideration for FSH therapy in idiopathic infertility.[29]Alternative means of hormonal manipulation (e.g., hCG, aromatase inhibitors, selective estrogen receptor modulators) have inconclusive evidence of their benefit in idiopathic infertility.
Men with idiopathic infertility may benefit from antioxidant therapy.[70][71] Low-quality evidence suggests that antioxidants may improve pregnancy rates and live birth rates in subfertile opposite-sex couples.[71] [
]
Unexplained infertility
Unexplained infertility refers to normal male and female evaluations but an inability to conceive. Randomized controlled trials have shown that empiric treatment of unexplained male infertility using gonadotropins is not effective.[72]
Assisted reproductive techniques (ART)
These techniques are recommended when medical/surgical intervention is ineffective, contraindicated, or unlikely to succeed.
The aim of ART is to facilitate oocyte fertilization and to produce a pregnancy. ART includes insemination with or without controlled ovarian stimulation. It also includes IVF with or without intracytoplasmic sperm injection (ICSI).[73]
[ ]
Intrauterine insemination (IUI) is a minimally invasive ART that can be considered for men with low post-wash total motile sperm counts (TMSC). Pregnancy rates with IUI are optimized with post-wash TMSC of at least 9 million; however, as there is a gradual decline in pregnancy rates at lower counts, a hard threshold above which IUI ought to be recommended is not available.[74] If antisperm antibodies are present, the ejaculate is collected directly into sterile sperm wash media in an effort to immediately dilute antibodies present in the seminal fluid. In the case of retrograde ejaculation, sperm can be retrieved from the urine. The sperm should be immediately removed from the urine to preserve sperm viability and then washed in sperm wash media for insemination. Other pretreatments may be offered to alkalize the urine before ejaculation or treatment with phenylpropanolamine or pseudoephedrine to increase the constrictive force of the bladder neck. Double insemination may increase pregnancy rates in cases with male factor infertility, but the evidence is inconsistent.[75]
If artificial insemination is not successful, then the opposite-sex couple should be referred for IVF.
ICSI should be used for azoospermia or severe oligozoospermia (≤5 million sperm/mL). Some programs advocate ICSI for sperm penetration defects. In the case of azoospermia, sperm can be retrieved from the reproductive tract by microsurgical testicular sperm extraction or microsurgical epididymal sperm aspiration (MESA).[76] MESA can only be used for obstructive azoospermia. IUI for male subfertility has also been studied, with low-quality trials failing to detect a difference in pregnancy rates.[73]
[ ]
However, meta-analysis of trials of IUI in opposite-sex couples with unexplained subfertility concluded that IUI with ovarian hyperstimulation probably results in a higher cumulative live birth rate.[77] Large, high-quality randomized controlled trials, comparing the effectiveness of a gradient and/or a swim-up and/or wash and centrifugation technique on clinical outcome of IUI, are lacking.[78] There is insufficient evidence to recommend a single method of sperm retrieval.[79] ART is also linked to a small increased risk of poor pregnancy outcome and birth defects; however, an increased risk related to infertility itself cannot be excluded.[80][81]
Donor insemination can be an option for men with severe oligozoospermia/azoospermia who decline ART or men with absent spermatogenesis.
Use of this content is subject to our disclaimer