madman
Super Moderator
Medical management of male infertility: now and future (2022)
Grace Chena , Martin Kathrinsb , Samuel Ohlandera and Craig Niederberger
Purpose of review
Medical therapy for idiopathic male infertility has historically been empiric and based on small observational studies rather than larger well-designed clinical trials. This review is timely and relevant because of the recent publication of several studies that are less susceptible to bias because of being placebo-controlled and more highly powered.
Recent findings
The largest proportion of recent publications covered antioxidants, with eight randomized controlled trials (RCTs) included in this review. The Males, Antioxidants, and Infertility (MOXI) trial is of particular interest, being a large multicenter RCT, which demonstrated no improvement in semen parameters or live-birth rates with antioxidant use. In addition, phosphodiesterase-5 inhibitors (PDE5i) have been shown to improve semen parameters, while duloxetine use was not associated with any adverse effects on sperm. Progress was also made in the realm of regenerative medicine, with the realization of the first successful primate model of sperm production from pluripotent stem cells.
Summary
It may be time to stop recommending antioxidants for idiopathic male infertility given recent studies suggesting a lack of efficacy, but given their relative safety, it is reasonable to continue their use until the evidence is overwhelming. Otherwise, stem cell therapy is another anticipated area of research interest.
INTRODUCTION
Male factor infertility has many potential causes but is frequently multifactorial or idiopathic. If the cause is known, pharmacologic treatments tend to be well-established. However, up to a quarter of male infertility cases are idiopathic. For these cases, treatment options are empiric and have less definitive outcome data to support the use of these agents.
In this review, we summarize the most recent developments in the medical management of male infertility and speculate on developing therapies to look forward to. Most recent publications build upon existing treatment options, which are mainly drugs targeting the hypothalamic-pituitary-gonadal (HPG) axis. A large proportion of these studies focus on the effect of antioxidant use on semen parameters, as it has long been posited that increased oxidative stress may play a factor in idiopathic male infertility. An update on this topic is much needed, as previous data came from uncontrolled studies with variable designs. One experimental treatment under investigation that will also be given attention in this chapter is the use of stem cells to restore spermatogenesis in nonfunctioning testes.
MEDICAL TREATMENTS
Gonadotropins
Gonadotropins such as human chorionic gonadotropin (hCG), follicle-stimulating hormone (FSH), or human menopausal gonadotropin (hMG) have a proven benefit in men with hypogonadotropic hypogonadism who are unable to secrete their own gonadotropins. Traditional first-line therapy consists of hCG, though a consensus dosing regimen does not exist. After establishing a eugonadal state, recombinant FSH or hMG may be added for further spermatogenic stimulation. However, there is limited data on the use of these agents for otherwise normogonadotropic men with idiopathic infertility. Only two studies were published in the past 2 years on gonadotropin use for male infertility.
Aromatase inhibitor therapy
Aromatase inhibitors such as anastrozole work by competitively inhibiting the peripheral conversion of androgens to estrogens, thereby reducing the inhibitory effect of estrogen on the HPG axis and increasing intra -testicular testosterone and spermatogenesis. A recent study suggests an important additional effect of aromatase inhibitors on Leydig cell aromatase activity suggesting a potential therapeutic target for the intratesticular testosterone: estrogen ratio, which is independently associated with spermatogenesis [4& ]. Aromatase inhibitors have been used as an off-label drug for the treatment of idiopathic male infertility.
Selective estrogen receptor modulators
(SERMs) are a class of drugs that upregulate gonadotropin secretion from the pituitary, primarily by binding estrogen receptors and thereby preventing the negative feedback effect of estrogen on gonadotropin production. SERMs such as clomiphene citrate and tamoxifen have a well-established off-label role in the treatment of hypogonadal men with infertility. However, American Urological Association guidelines caution on the limited benefit of SERM therapy relative to assisted reproductive technologies (ART) [6].
Phosphodiesterase-5 Inhibitors
Phosphodiesterase-5 inhibitors (PDE5i) are the gold standard treatment for erectile dysfunction, and a few older studies exist that suggested an improvement in semen parameters with PDE5i use.
Antioxidants
Antioxidants are an attractive area for study as reactive oxygen species (ROS), and oxidative stress have long been proposed to play a role in idiopathic male infertility or subfertility. Of the many antioxidants under investigation, the ones that have historically shown some benefit for the treatment of male infertility include vitamin C, Coenzyme Q10 (CoQ10), L-carnitine, and glutathione. There have also been small-scale studies to evaluate the role of antioxidants in preventing damage to sperm during cryopreservation, which is an important component of in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) success. Some common problems cited for these studies include the high risk of bias because of poor reporting methods of randomization, lack of follow-up of live birth rates and pregnancy, high patient attrition, and small overall sample sizes, which prevents definitive consensus statements on the use of antioxidants for idiopathic male infertility [10& ].
Antidepressants
The impact of antidepressant use on male fertility is an avenue worth studying because of the increasing prevalence of these medications. There has historically been a paucity of research on the topic, though some in-vitro, animal, and observational studies have shown potential negative effects of selective serotonin reuptake inhibitors (SSRIs) on semen parameters [22]. This negative association was recently called into question by a double-blind placebo-controlled RCT from Cornell, which concluded that the administration of duloxetine had no effect on bulk semen parameters [23&&]. These results are encouraging as this is the first adequately powered human study to be published and suggests that at least duloxetine is well tolerated for use in men desiring fertility.
Stem cell therapy
Stem cell therapy is a promising avenue of scientific research that is increasingly being explored for male infertility. Although no human clinical trials have been conducted to date, there are promising results shown in many in-vitro and in-vivo studies on the topic [24&,25& ].
DISCUSSION AND FUTURE PERSPECTIVES
Antioxidant use for the treatment of male infertility has been a topic of interest for decades, and while we appear to be closer to a consensus opinion, there is still more work that needs to be done in this area. The sheer number of antioxidant agents available is so large that many drug combinations are possible, and there is high heterogeneity in trial design. To date, there are only a few studies, which may be considered good-quality placebo-controlled RCTs, and these tend to be small-scale. Many studies focus on the effect of drugs on semen parameters or sperm fragmentation, with only a few studies including reproductive outcomes (fertilization rate, pregnancy rate, and live birth rate) as a primary outcome. This makes it difficult to assess the clinical relevance of these studies, particularly given recent publications that have found a lack of correlation between factors like sperm DNA fragmentation and live pregnancy rates [29& ]. In addition, pregnancy occurrence is multifactorial, and it would be unrealistic to fully attribute any pregnancy outcome to the administration of antioxidant therapy alone. However, given the demonstrated safety of antioxidant use and the presence of many small-scale studies demonstrating improvement in the quality of sperm, it may be reasonable to recommend these drugs for use in idiopathic infertility.
On the more experimental front, stem cell therapy is an avenue, which holds promise for the treatment of idiopathic male infertility and has been shown to be viable in animal models. We look forward to further research into this potential treatment option.
CONCLUSION
Medical treatment for idiopathic male infertility remains largely provider-dependent and empiric. Clinicians may exercise their judgment on what medications to prescribe based on the patient’s individual characteristics and taking into account past medical history and baseline hormonal and semen function. Larger scale randomized trials are needed to definitively reach a consensus opinion on treatments.
Grace Chena , Martin Kathrinsb , Samuel Ohlandera and Craig Niederberger
Purpose of review
Medical therapy for idiopathic male infertility has historically been empiric and based on small observational studies rather than larger well-designed clinical trials. This review is timely and relevant because of the recent publication of several studies that are less susceptible to bias because of being placebo-controlled and more highly powered.
Recent findings
The largest proportion of recent publications covered antioxidants, with eight randomized controlled trials (RCTs) included in this review. The Males, Antioxidants, and Infertility (MOXI) trial is of particular interest, being a large multicenter RCT, which demonstrated no improvement in semen parameters or live-birth rates with antioxidant use. In addition, phosphodiesterase-5 inhibitors (PDE5i) have been shown to improve semen parameters, while duloxetine use was not associated with any adverse effects on sperm. Progress was also made in the realm of regenerative medicine, with the realization of the first successful primate model of sperm production from pluripotent stem cells.
Summary
It may be time to stop recommending antioxidants for idiopathic male infertility given recent studies suggesting a lack of efficacy, but given their relative safety, it is reasonable to continue their use until the evidence is overwhelming. Otherwise, stem cell therapy is another anticipated area of research interest.
INTRODUCTION
Male factor infertility has many potential causes but is frequently multifactorial or idiopathic. If the cause is known, pharmacologic treatments tend to be well-established. However, up to a quarter of male infertility cases are idiopathic. For these cases, treatment options are empiric and have less definitive outcome data to support the use of these agents.
In this review, we summarize the most recent developments in the medical management of male infertility and speculate on developing therapies to look forward to. Most recent publications build upon existing treatment options, which are mainly drugs targeting the hypothalamic-pituitary-gonadal (HPG) axis. A large proportion of these studies focus on the effect of antioxidant use on semen parameters, as it has long been posited that increased oxidative stress may play a factor in idiopathic male infertility. An update on this topic is much needed, as previous data came from uncontrolled studies with variable designs. One experimental treatment under investigation that will also be given attention in this chapter is the use of stem cells to restore spermatogenesis in nonfunctioning testes.
MEDICAL TREATMENTS
Gonadotropins
Gonadotropins such as human chorionic gonadotropin (hCG), follicle-stimulating hormone (FSH), or human menopausal gonadotropin (hMG) have a proven benefit in men with hypogonadotropic hypogonadism who are unable to secrete their own gonadotropins. Traditional first-line therapy consists of hCG, though a consensus dosing regimen does not exist. After establishing a eugonadal state, recombinant FSH or hMG may be added for further spermatogenic stimulation. However, there is limited data on the use of these agents for otherwise normogonadotropic men with idiopathic infertility. Only two studies were published in the past 2 years on gonadotropin use for male infertility.
Aromatase inhibitor therapy
Aromatase inhibitors such as anastrozole work by competitively inhibiting the peripheral conversion of androgens to estrogens, thereby reducing the inhibitory effect of estrogen on the HPG axis and increasing intra -testicular testosterone and spermatogenesis. A recent study suggests an important additional effect of aromatase inhibitors on Leydig cell aromatase activity suggesting a potential therapeutic target for the intratesticular testosterone: estrogen ratio, which is independently associated with spermatogenesis [4& ]. Aromatase inhibitors have been used as an off-label drug for the treatment of idiopathic male infertility.
Selective estrogen receptor modulators
(SERMs) are a class of drugs that upregulate gonadotropin secretion from the pituitary, primarily by binding estrogen receptors and thereby preventing the negative feedback effect of estrogen on gonadotropin production. SERMs such as clomiphene citrate and tamoxifen have a well-established off-label role in the treatment of hypogonadal men with infertility. However, American Urological Association guidelines caution on the limited benefit of SERM therapy relative to assisted reproductive technologies (ART) [6].
Phosphodiesterase-5 Inhibitors
Phosphodiesterase-5 inhibitors (PDE5i) are the gold standard treatment for erectile dysfunction, and a few older studies exist that suggested an improvement in semen parameters with PDE5i use.
Antioxidants
Antioxidants are an attractive area for study as reactive oxygen species (ROS), and oxidative stress have long been proposed to play a role in idiopathic male infertility or subfertility. Of the many antioxidants under investigation, the ones that have historically shown some benefit for the treatment of male infertility include vitamin C, Coenzyme Q10 (CoQ10), L-carnitine, and glutathione. There have also been small-scale studies to evaluate the role of antioxidants in preventing damage to sperm during cryopreservation, which is an important component of in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) success. Some common problems cited for these studies include the high risk of bias because of poor reporting methods of randomization, lack of follow-up of live birth rates and pregnancy, high patient attrition, and small overall sample sizes, which prevents definitive consensus statements on the use of antioxidants for idiopathic male infertility [10& ].
Antidepressants
The impact of antidepressant use on male fertility is an avenue worth studying because of the increasing prevalence of these medications. There has historically been a paucity of research on the topic, though some in-vitro, animal, and observational studies have shown potential negative effects of selective serotonin reuptake inhibitors (SSRIs) on semen parameters [22]. This negative association was recently called into question by a double-blind placebo-controlled RCT from Cornell, which concluded that the administration of duloxetine had no effect on bulk semen parameters [23&&]. These results are encouraging as this is the first adequately powered human study to be published and suggests that at least duloxetine is well tolerated for use in men desiring fertility.
Stem cell therapy
Stem cell therapy is a promising avenue of scientific research that is increasingly being explored for male infertility. Although no human clinical trials have been conducted to date, there are promising results shown in many in-vitro and in-vivo studies on the topic [24&,25& ].
DISCUSSION AND FUTURE PERSPECTIVES
Antioxidant use for the treatment of male infertility has been a topic of interest for decades, and while we appear to be closer to a consensus opinion, there is still more work that needs to be done in this area. The sheer number of antioxidant agents available is so large that many drug combinations are possible, and there is high heterogeneity in trial design. To date, there are only a few studies, which may be considered good-quality placebo-controlled RCTs, and these tend to be small-scale. Many studies focus on the effect of drugs on semen parameters or sperm fragmentation, with only a few studies including reproductive outcomes (fertilization rate, pregnancy rate, and live birth rate) as a primary outcome. This makes it difficult to assess the clinical relevance of these studies, particularly given recent publications that have found a lack of correlation between factors like sperm DNA fragmentation and live pregnancy rates [29& ]. In addition, pregnancy occurrence is multifactorial, and it would be unrealistic to fully attribute any pregnancy outcome to the administration of antioxidant therapy alone. However, given the demonstrated safety of antioxidant use and the presence of many small-scale studies demonstrating improvement in the quality of sperm, it may be reasonable to recommend these drugs for use in idiopathic infertility.
On the more experimental front, stem cell therapy is an avenue, which holds promise for the treatment of idiopathic male infertility and has been shown to be viable in animal models. We look forward to further research into this potential treatment option.
CONCLUSION
Medical treatment for idiopathic male infertility remains largely provider-dependent and empiric. Clinicians may exercise their judgment on what medications to prescribe based on the patient’s individual characteristics and taking into account past medical history and baseline hormonal and semen function. Larger scale randomized trials are needed to definitively reach a consensus opinion on treatments.
