Medications / Supplements and Their Potential Impact on Male Infertility
Introduction to Medications / Supplements and Their Potential Impact on Male Infertility
Sperm production is a complex process that lasts approximately ten weeks, during which time sperm precursor cells are transformed into fully mature sperm. At any time during this process, sperm production can be influenced by outside factors including medications or supplements that may be taken. In general, topical medications (such as creams or ointments) are going to have much less systemic absorption, and typically have little impact on male fertility potential. Also, it must be remembered that certain medications/supplements may have more or less of an impact on different people depending on individual factors such as genetics and other medical problems that they might have. For example, most men taking exogenous androgens (like testosterone injections) have profound decreases in sperm production, but a relatively small percentage (<10%) of men can maintain good sperm counts while taking these medications.
Prescription Medications and male infertility
The following categories of medications are known to potentially have a significant negative impact on male fertility:
1) Antibiotics
2) Anti-depressant/Anti-anxiety medications
3) Anti-fungal/Anti-parasitics
4) Anti-seizure medications
5) Anti-Psychotics
6) Cardiovascular medications
7) Chemotherapy agents
8) Erectile dysfunction medications
9) Gastrointestinal medications
10) Gout Medications
11) Hormonally active agents
12) Immunomodulators
13) Immunosuppressant agents
14) Narcotics/opiates
15) Prostate medications
16) Other Medications
This website does not contain a complete list of all medications that can potentially have a negative impact on sperm quality - studies are constantly being performed to identify additional medications that can affect fertility. However, we have tried to include as many as possible of the most common agents that are known to impact sperm numbers and quality. It must also be noted that certain medications are going to have more of an impact on sperm quality in some men as opposed to others.
It is important that you have a discussion with your health care provider before making any changes to your medications. This website aims to provide you with information for your own knowledge, and you can share it with your personal physician if you learn something that may be pertinent to your situation. Decisions about which medications are right for you depend heavily upon individual factors, and the potential risks or benefits to stopping or changing any of your medications need to be adequately weighed by a health care professional familiar with your medical history and circumstances.
Antibiotics and male infertility
There is not a large amount of data of the impact on male infertility associated with most antibiotics. Listed below is the data of what is known on some different antibiotics:
1) Nitrofurantoin- This is the exception in that there is pretty clear evidence that nitrofurantoin has the potential for direct gonadtoxic effects on the testicles. Human studies have shown decreases in sperm counts and motility, and this medication should be avoided if possible in men trying to conceive. [Semet M. Andrology 2017]
2) Aminoglycosides (Gentamycin, Neomycin, Streptomycin)- Human studies have shown disruption of sperm production and decreases in sperm counts and motility (with Streptomycin potentially having less of an impact). [Semet M. Andrology 2017]
3) Macrolides (Erythromycin)- Animals studies have shown testicular disruption of sperm production, while human studies have seen lower motility with their use. [Schlegal PN. FertSteril 1991]
4) Tetracycline- Decreases in sperm motility and fertilization capacity have been seen in sperm exposed to tetracycline in the lab, while studies in humans have shown decreases in sperm counts, motility, and morphology. [Semet M. Andrology 2017]
5) Sulfa Drugs (sulfamethoxazole)- Decreases in sperm counts, motility, and morphology have been seen with the use of these medications. [Schlegal PN. FertSteril 1991]
6) Penicillins- Some decreases in semen parameters have been seen in animal studies, but no human studies have found no negative impact. [Semet M. Andrology 2017]
Summary on Antibiotics
Multiple classes of antibiotic medications have been shown to have the potential for reversible decreases in semen parameters. However, infections can be dangerous and cause oxidative stress on the body which can be bad for sperm as well. Infection in the genital ducts can be especially damaging to sperm and antibiotics are recommended to be used for testicular and epididymal infections (though nitrofurantoin should likely be avoided if possible). [Semet M Andrology 2017]. Some of the more commonly used antibiotics in male infertility include cephalosporins, doxycycline, and ciprofloxacin which are not felt to be damaging to sperm in most patients.
ANTI-DEPRESSANT AND ANTI-ANXIETY MEDICATIONS and male infertility
Anti-depressant and anti-anxiety medications play an important role in many people’s lives but can also have an impact on the fertility potential of men. It is known that men with anxiety and depression can cause problems experience problems with ejaculation as well as sexual function prior to any treatment. [Norr L. Andrology 2016] Depression has also been found to potentially impact testosterone levels in some men as well. [Steiger A. JPsychiatRes 1991] Most classes of anti-depressants/anti-anxiety medications are known to be associated with an increased risk of sexual side effects which can impact erections, libido, and ejaculation. [Beeder LA. IntJUrol 2019]. Many also have been shown to have a negative impact on male fertility potential as well, though these effects appear to be reversible if the medication is stopped. We will now review the different classes of anti-depressant and anti-anxiety medications and their impact on male fertility.
Selective Serotonin Reupdate Inhibitors (SSRIs)
SSRIs are some of the most common medications used to treat problems like depression and anxiety, but unfortunately are also the most closely linked to problems with fertility potential in men. [Brezina PR. JReprodInfertil 2012] Examples of SSRIs include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). The negative impact of SSRIs is felt to be potentially due to oxidative stress, changes in the hormonal environment, as well as impaired ductal transport of sperm. [Beeder LA. IntJUrol 2019]. Studies of sperm in the lab show have shown that all SSRIs have some degree of spermicidal activity, with the most seen with sperm contact by fluoxetine. [Kumar VS. BioorgMedChemLett 2006].
Regarding testing in humans, a 2011 study of 25 men starting escitalopram found a decrease in sperm density, dropping from 68 million sperm/cc to 26.4 million/cc after 3 months of treatment, with a corresponding change in motility from 58.2% to 23.4%. [Koyuncu H. IntJImporRes 2011]. A trial of 60 men randomized to either sertraline or cognitive therapy for premature ejaculation showed lower sperm densities and morphology (but not motility) in the men treated with sertraline. [Akasheh G. Urology 2014]. A 2010 study of 35 men started on paroxetine did not show and changes in sperm counts, motility, or morphology, but there were significant elevations of sperm DNA fragmentation. [Tanrikut C. FertSteril 2010]. In contrast, a study of 74 men on various SSRIs for 6 or more months showed a decrease in sperm density from 184.1 million/cc at baseline to 61.4 million/cc with a drop in motility as well from 66% to 49%. [Safarinejad MR. JUrol 2008]. There appeared to be no significant differences in impact on semen parameters between citalopram, escitalopram, fluoxetine, paroxetine, and sertraline in this study. Several of the above studies (besides the previously mentioned 2010 Tanrikut) showed elevations in sperm DNA fragmentation as well with the use of SSRIs. [Akasheh G. Urology 2014][Safarinejad MR. JUrol 2008] For more information on sperm DNA fragmentation, please see the “Advanced Sperm Testing” section of this website.
Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
This class of medications include desvenlaxifine, duloxetine, levomilnacipran, and venlafaxine and have a high incidence (58-70%) of sexual-related side effects (in comparison to 25-73% for SSRIs). [Beeder LA. IntJUrol 2019]. According to the 2019 review, only 1 study had been performed on the effect of these medications and male fertility, and this was a mouse study which showed no significant changes in semen parameters with the use of venlaxafine. [Bandegi L IntJReprodBiomed 2018]
Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs)
These medications include bupropion, dexmethylphenidate, diphenylprolinol, ethylphenidate, methylenedioxypyrovalerone, methylphenidate, pipradrol, prolintane, and sibutramine. A single case study found significant improvements in semen parameters in a man (previously on an SSRI) when he stopped bupropion (sperm counts improved from 21 million/cc to 41 million/cc and motility rose from 10% to 75%). [Tanrikut C. FertSteril 2010]. No further human studies have confirmed these findings, but in rats, higher doses of bupropion cause a decrease in sperm motility (with no changes seen at lower medication dosage). [Cavariani MM. JApplToxicol 2015]. Animal studies on methyphenidate and sibutramine show potential negative impacts on aspects of fertility but no human studies are currently available. [Beeder LA. IntJUrol 2019].
Tricyclic Antidepressants (TCAs)
Medications in this class include amitriptyline, nortriptyline, amoxapine, desipramine, doxepin, imipramine, protriptyline, and trimipramine. Despite relatively low rates of sexual dysfunction (around 30%), these medications are no longer commonly used due to significantly higher rates of other adverse side effects. [Beeder LA. IntJUrol 2019]. Studies in rodents have found negative effects on semen parameters as well as increases in chromosomal abnormalities, but small human studies have not found significant changes in semen parameters. [Beeder LA. IntJUrol 2019].
Monoamine Oxidase Inhibitors (MOAs)
Medications in this class are commonly used only in patients who have not responded effectively to other antidepressants, and include selegiline, isocarboxazid, phenelzine, and tranylcypromine. Rates of sexual function with MOAs is around 40% but data on fertility impact is minimal. As per a 2019 review of the topic, only 2 rat studies (on Selegiline) have been performed, and both actually showed improvements in semen parameters. [Beeder LA. IntJUrol 2019].
Atypical Antidepressants
These medications include mirtazapine, trazodone, nefazodone, tianeptine, agomelatine, vilazadone, and vortioxetine. Once again, there is limited data on the impact of these medications on male fertility. [Beeder LA. IntJUrol 2019]. Trazadone in rats was found to decrease semen parameters as well as increased levels of sperm DNA fragmentation. [Ilgin S. OxidMetCellLongev 2018]. In contrast, a rat study of mirtazapine and single human case study of agomelatine did not suggest a negative impact on male fertility parameters. [Beeder LA. IntJUrol 2019].
Summary for Antidepressant Medications
The use of antidepressant medications clearly has the risk of sexual side effects on libido, erections and ejaculation. A negative impact on semen parameters and DNA fragmentation have been demonstrated by multiple studies on men taking SSRIs. The general recommendation has been made that men taking SSRIs and TCAs considering stopping the medication or changing to a different class when they want to conceive. [Semet M. Andrology 2017] However, changing these medications can be difficult and potentially risky, and should always be supervised by the patient’s medical provider who is managing their antidepressants (e.g. primary care provider or psychiatrist). Changing from an SSRI or TCA to another class of medications can be tricky, and the extremely sparse human data on the various classes of antidepressants make it extremely difficult to recommend particular alternatives. What is clearly needed is more research in the impacts of these medications on semen parameters and male fertility potential.
Antifungals and Antiparasitics and male infertility
Some antifungal and antiparasitic medications are known to have a potentially negative impact on sperm quality. The most common use of anti-fungal medications is with topical formulations, and these should not have a significant impact on a mans’s semen parameters. However, several systemic medications can potentially impact male fertility- these include:
1) Ketoconazole- This is an antifungal medication that has the ability to impact hormonal levels, causing decreases in intra-testicular testosterone levels. It is recommended to stop the use of ketoconazole in men trying to conceive. [Semet M. Andrology 2017]
2) Chloroquine- An antimalarial medication, it has been found to cause decreases in motility in animal studies and when tested on sperm in the lab. No definite recommendations have been made on the use of chloroquine in men trying to conceive due to a lack of data including human studies. [Semet M. Andrology 2017]
3) Niridazole- An antiparasitic medication, used to treat schistosomiasis which is called by flatworms. There is evidence that it can cause reversible abnormalities in semen parameters. [El-beheiry AH. ArchAndrol 1982]
Anti-seizure Medications and male infertility
Epilepsy has been shown to be a risk factor for male fertility problems, but it appears that the antiseizure medications that are used to treat it also have the potential to cause further problems with semen parameters. [Webber MP. Epilepsia 1986]. Lower sperm density, motility, and morphology have all been reported with medications such as carbamazepine, phenytoin, oxcarbazepine, and valproate. [Brezina PR. JReprodInfert 2012]. From a practical standpoint, these medications often cannot be safely stopped due to the health and safety risks involved with recurrent uncontrolled seizures. [Semet M. Andrology 2017] There is also not any data on “better” antiseizure medications to possibly switch to which could potentially decrease the impact on semen parameters. However, there is some evidence that the negative impact of male fertility may be related at least in part to imbalances in the normal testicular-pituitary axis function, so treatment with hormonal medications (such as clomiphene or HCG) may be able to mitigate some of the negative impact on fertility while men are taking anti-seizure medications. [Herzog AG. ArchNeurol 1986]
Anti-Psychotic Medications and male infertility
Antipsychotic medications can potentially impact male fertility indirectly. [Semet M. Andrology 2017] The “typical” anti-psychotics (phenothiazines: Haloperidol, Amisulpide) are known to have the ability to increase prolactin levels, which can lead to decreased levels of FSH, LH, and testosterone. This can potentially lead to abnormalities in sperm production and quality. These medications and their hormonal effects can also lead to decreased libido as well as erectile and ejaculatory problems (though the medication effects in these areas are sometimes difficult to distinguish from the impact of the underlying medical conditions themselves). [Semet M. Andrology 2017].
In contrast, the “atypical” anti-psychotics (e.g. Quetiapine, Ariprazole, Olanzapine, Clozapine) do not generally increase prolactin levels and therefore have less of a negative impact on hormone levels. Switching medication classes can be quite difficult but may offer a benefit to some men with fertility problems who are currently taking a “typical” class anti-psychotic medication. [Semet M. Andrology 2017]
Cardiovascular Medications and male infertility
There are many types of medications that are used to treat various cardiovascular problems. Some do not direct impact semen parameters but have the potential to affect fertility through an increased risk of erectile dysfunction, while other medications can potentially have a negative impact on sperm quality itself.
1) Spironolactone- This is a diuretic used to control hypertension. Unfortunately, this medication can also decrease testosterone levels and negatively impact sperm function. [Semet M. Andrology 2017]
2) Calcium channel blockers- Treatment of hypertension- examples: verapamil, nifedipine, diltiazem, amlodipine. Although the data in humans in sparse, there is quite a bit of laboratory data showing a negative effect of calcium channel blockers on sperm function. In the lab, when sperm are subjected to calcium channel blockers, there has been observed a decrease in both sperm motility and viability as well as changes in the structure of the head and tail regions. [Brezina PR. JReprodInfert 2012]. Lab studies have shown that sperm exposed to calcium channel blockers were unable to bind with sperm, but these findings have not been reproduced in small human studies which showed normal fertilization rates in men taking these medications who were undergoing standard IVF. [Katsoff D. HumReprod 1997]. Calcium channel blockers have also been related to ejaculatory abnormalities as well. [Semet M. Andrology 2017]
3) Beta blockers- Treatment of hypertension- examples: propranolol, metoprolol, carvedilol, atenolol, nebivolol. These medications have not been found to significantly impact sperm quality in men, but sperm exposed to beta-blockers in the lab have showed decreased motility. Animal studies have also shown lower testosterone levels. The only significant impact in humans so far appears to be a negative impact on erectile function in some men. [Semet M. Andrology 2017]
4) ACE-inhibitors- Treatment of hypertension- examples: captopril, enalapril. Some animal studies and tests on sperm in the lab have shown a negative impact on sperm motility [Semet M. Andrology 2017] while others have actually shown an improvement in sperm counts and motility in rats taking this class of medication. [Okeahialam BN. ArchAndrol 2006]. No negative impact on semen parameters have been observed in humans taking ACE-inhibitors.
5) Methyldopa- A central-acting medication used to treat hypertension. Has the potential to increase prolactin levels, thereby leading to hypogonadism. [Semet M. Andrology 2017]
6) Digoxin (Lanoxin)- Cardiovascular medication used to treat heart problems like atrial fibrillation, atrial flutter, and heart failure. It has been associated with decreased testosterone levels in some men as well as lower libido and erectile dysfunction. No recommendations have been made on this medication in men trying to conceive. [Semet M. Andrology 2017]
7) Lipid-lowering medications- These include the statins (pravastatin, simvastatin, atorvastatin) and gemfibrozil. In rats, pravastatin has been associated with decreases in semen parameters. [Semet M. Andrology 2017]. However, human studies have not found any negative impact of the use of statins on male fertility potential. [Keihani S. Andrologia 2018]. Simvastatin and pravastatin also have the potential to impact androgen synthesis, while this is not seen with atorvastatin. [Semet M. Andrology 2017] A reduction in the fertility of rats has been found with the use of gemfibrozil but there is no data showing any negative impact in humans. [Semet M. Andrology 2017]
Summary of Cardiovascular Medications
Men trying to conceive with a new diagnosis of hypertension may want to start with an ACE-inhibitor if possible. [Semet M. Andrology 2017]. Beta blockers likely have minimal impact on sperm quality as well, but an increased risk of erectile dysfunction. Changing from spironolactone and/or calcium channel blockers to another class of anti-hypertensive medication may provide some fertility benefit but should always be done under the close supervision of the man’s medical provider who is managing their hypertension (i.e. primary care provider or cardiologist).
Chemotherapeutic Agents and male infertility
See “Cancer Treatment” in the "Medical Conditions and Male Fertility" section of this website for more information regarding the impact of chemotherapy on male fertility.
Erectile Dysfunction Medications and male infertility
Type 5 Phosphodiesterase inhibitors are commonly used medications for erectile dysfunction, and include sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis). Studies have shown that the medications in this class do not impact semen parameters [Purvis K. BrJClinPharmacol 2002], and some studies have even shown an improvement in counts and motility with these agents. [Dimitradis F. AsianJAndrol 2008]
Alprostadil is a vasodilatory that either can be injected directly into the penis or absorbed through the urethra when placed as a small pill through the meatus (Muse). Alprostadil itself has not been found to negatively impact sperm motility and viability when tested in the lab. [Hellstrom WJG. JUrol 1998]. However, when medications are directly injected into the penis, some of the medication has been found to enter into the bloodstream. Alprostadil is often mixed with other medications whose impact on sperm have not been extensively studied, so penile injections should be used with caution in men trying to conceive. [Semet M. Andrology 2017]
Gastrointestinal Medications and male infertility
A number of drugs used to treat gastrointestinal problems may be problematic for men trying to conceive.
Medications for Inflammatory Bowel Disease (IBD). The following is a review of medications used to treat IBD [Shin T. WorldJGastrointPharTher 2016]. For more information on managing IBD, please see the “Medical Conditions and Male Infertility” section of this website.
1) Sulfasalazine- this medication is known to have a reversible negative impact on semen parameters in the majority of men who take it. A study of 21 patients on sulfasalazine showed that 18 of the men had abnormal semen parameters, with significant improvements seen after changing to mesalamine.
2) Mesalamine (5-ASA)- this medication is generally felt to be much safer for male fertility than sulfasalazine. There have been case reports of decreased semen parameters in men started on mesalamine, but the general recommendations are to only stop this medication in men with very stable IBD.
3) Corticosteroids- used to treat relapses of IBD but not generally used for maintenance therapy. Short term use of corticosteroids generally not negative impact semen parameters or health, though prolonged use in high doses can lead to significant general health problems.
4) Thiopurines- include azathioprine and its active metabolite (6-MP)- used and an adjunct treatment for IBD. Although no significant changes are generally seen in semen parameters, there seems to be a small increased risk of miscarriage and congenital abnormalities of offspring. It is therefore recommended to use contraception for men taking azathioprine and 6-MP. [Semet M. Andrology 2017].
5) Methotrexate- second line treatment for men not responding to thiopurines. Reversible decreases in semen parameters have been seen in men taking methotrexate so it is recommended to stop this medication 3 to 4 months prior to starting trying to conceive. At low doses there does not appear to be an increased risk of miscarriage or birth defects.
6) Cyclosporin A (CSA)- a calcineurin inhibitor (along with tacrolimus). In rats, the use of CSA has been associated with decreased testicular weight along with lower testosterone levels and semen parameters. To date, only small studies in humans have been performed, but these do not appear to show any significant decrease in male fertility potential.
7) Infliximib, adalimumab, certolizumab- these are biologic agents which are monoclonal antibodies against tumor necrosis factor alpha (anti-TNF). Not many studies have been performed in humans, but there does not appear to be any significant impact of these medications on semen parameters or rates of miscarriage and birth defects.
General recommendations for IBD medications: In men taking sulfasalazine, it is recommended to change to mesalamine at least 4 months prior to trying to conceive. In men taking mesalamine who have abnormal semen parameters, a trial of short periods off of mesalamine could be tried if the man’s IBD symptoms are stable. There is insufficient evidence to support the stopping of methotrexate in men who need this medication to control their symptoms. [Shin T. WorldJGastrointPharTher 2016].
A few other GI-related medications for which there is some evidence that they may have a negative effect on sperm quality include:
1) Cimetidine (Tagamet)- H2 blocker for the treatment of gastroesophageal reflux (GERD), heartburn, and stomach ulcers. This medication has been found to have anti-androgen properties, with the ability to cause reversible decreases in semen parameters. [Semet M. Andrology 2017]
-Potential other H2 blocker alternatives: ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid)
2) Lansoprazole (Prevacid)- Proton pump inhibitor for the treatment of gastroesophageal reflux (GERD), heartburn, and stomach ulcers. Some evidence exists of decrease testosterone production in rats, but no effects seen in humans. (Semet M. Andrology 2017]
-Potential other proton pump inhibitor alternatives: ranitidine omeprazole (Prilosec), pantoprazole (Protonix)
Gout Medications and male infertility
Medications which are used to treat gout have the potential to impact semen parameters. The most information is available on colchicine which has been shown to cause testicular dysfunction in rats and decreases in the semen parameters of some men taking the medication. [Haimov-Kochman R. HumReprod 1998]. Rare cases of azoospermia have also been linked to colchicine in humans. [Merlin HE. FertSteril 1972]. However, a larger study of 540 young patients taking colchicine for an average of approximately 20 years did not show decreases in fertility potential as well as no increase in the health problems of their offspring. [Yu TF. SemArthritisRheum 1982.
Allopurinol is another gout medication with much less data available on its impact on male fertility. There is some evidence that men taking allopurinol have normal semen parameters but possibly a potential for a decrease in the fertilizing capacity of their sperm. [Simsek M. ReprodToxicol 2018]
Potential alternatives for treating gout include probenecid, NSAIDs, corticosteroids, and dietary modification.
Hormonally Active Agents and male infertility
Medications that impact hormone levels can have a significant negative impact on sperm production and quality. Examples of these medications include:
1) Exogenous androgens. These are a very common source of male fertility problems, and are covered in their own section "Exogenous Androgens/Anabolic Steroids" in this website.
2) Treatments for advanced prostate cancer. Drugs such as cyproterone, leuprolide (Lupron), goserelin (Zoladex), and bicalutamide (Casodex) can decrease testosterone production.
3) Estrogen therapy. This may decrease sperm function and potentially increase the risk of testicular cancer.
Immunomodulators and male infertility
Monoclonal antibodies- trastuzumab, alemtuzumab, rituximab, cetuximab, bevacizumab, omalizumab, anakinra. These medications can be used in the treatment of certain types of cancer as well as rheumatoid arthritis. There is little to no evidence of a negative impact on fertility potential in humans and animal studies have not shown significant concerns as per a review of the literature in 2017. [Semet M. Andrology 2017] Current recommendation on its use in men are not possible due to a lack of data.
TNF-alpha inhibitors- infliximab, adalimumab, etanercept. These medications reduce inflammation and are used to treat problems such as rheumatoid arthritis, ulcerative colitis and Chrohns disease. There is very little data available on these medications and their impact on fertility. Infliximib has been correlated with an increase in ejaculate volume and decrease in motility, but no impact on overall infertility has been reported. [Semet M. Andrology 2017]. These medications are currently not recommended to be discontinued in men trying to conceive.
Dabrafenib (Tafinlar) is a medication which is used to treat melanoma, and vismodegib (Erivedge) is used to treat basal cell carcinomas of the skin. These medications have shown testicular toxicity seen in animal studies. Recommend freezing sperm if possible before treatment and stopping this medicine prior to conceiving. When the female partner is pregnant it is recommended to use safe sex (e.g. condom use) due to teratogenic concerns. [Semet M. Andrology 2017]
Ipilimumab (Yervoy)- monoclonal antibody used to treat cancer. Decreased testicular volume has been seen in animals as well as decreases in pituitary function. Recommended to freeze sperm prior to starting treatment. [Semet M. Andrology 2017]
Leflunomide (Arava)- Treatment of rheumatoid arthritis. Testicular toxicity seen in animal studies but effect in humans unknown. Recommendation to use contraception in men taking this medication. [Semet M. Andrology 2017]
Thalidomide (Thalomid)- Used to treat skin problems and multiple myeloma. Testicular atrophy in animal studies and the drug is found in the semen of men taking it. Recommended to stop this medication in men trying to conceive due to teratogenic concerns. [Semet M. Andrology 2017]
Interferon alpha- Used to treat certain cancers as well as chronic viral infections. Changes in semen parameters in animal studies but no known problems seen in humans. Recommendation that not need to freeze sperm or stop medication when trying to conceive. [Semet M. Andrology 2017]
Immunoglobulins- used to treat primary immunodeficiency. No animal or human studies and therefore no recommendations possible. [Semet M. Andrology 2017]
Sorafenib (Nexavar)- tyrosine kinase inhibitor used to treat certain types of cancer. Reversible decreases in semen parameters seen in animal studies. Reversible effect 10 weeks after finish treatment. [Semet M. Andrology 2017]
Immunosuppressant Agents and male infertility
1) Calcineurin inhibitors (CNIs)- these commonly used immunosuppressive medications include cyclosporin A (CSA) and tacrolimus. In rodent models, CSA has been found to have a negative impact on testicular function and semen parameters [Gawish AM. JBasApplZoo 2016], although human studies have not shown dramatic decreases in fertility potential of men taking these medications. [Semet M. Andrology 2017]. Animal studies on tacrolimus point to less of a negative impact on semen parameters, but data from human studies are limited. [Lundy SD. TranslAndrolUrol 2019]. The impact on hormone levels appear to be similar between men taking CSA and tacrolimus. [Kantarci G. TranplantProc 2004]. Recommendations are that CSA does not need to be discontinued in men who are trying to conceive, but no recommendations are currently available for tacrolimus due to a lack of data. [Semet M. Andrology 2017].
2) mTOR (rapamycin) inhibitors- these medications include sirolimus, everlimus, and temsirolimus. These medications have been associated with reversible negative changes in semen parameters, with potential teratogenic changes seen in animal models. [Semet M. Andrology 2017]. It is recommended to cryopreserve sperm in men to be started on sirolimus and use contraception while men are taking this medication.
3) Antimetabolites- mycophenalate is an an immunosuppressant agent which has been shown to decrease semen parameters in animals, though this has not been studied in human studies. [Lundy SD. TranslAndrolUrol 2019] Azathioprine is another mediation in this class which generally has not been associated with decreases in semen parameters. Both mycophenalate and azathioprine have been associated with mutagenic effects on sperm, so it is recommended that men use contraception when taking these medications. [Semet M. Andrology 2017]
4) Corticosteroids- Studies have not shown significant long-term negative effects on sperm production in men taking corticosteroids. Long-term corticosteroid use can lead to a number of other general health problems such as osteoporosis, thinning of the skin, weight gain, fluid retention, and an increased risk of infection and tumors. However, corticosteroids are not generally recommended to be stopped for fertility reasons in men who are trying to conceive. [Semet M. Andrology 2017]
PAIN MEDICATIONS and male infertility
NARCOTICS/OPIOIDS
The United States is in the midst of an opioid crisis with over 1.5 million people suffering from prescription opioid use problems. Commonly used opioids used in the U.S. include:
1) Codeine (Tylenol #3, Paramol, Nurofen Plus)
2) Hydrocodone (Vicodin, Norco, Lorcet, Lortab)
3) Oxycodone (OxyContin, Percocet, Roxicodone, Tylox)
4) Morphine (Duramorph, Avinza, Kadian)
5) Fentanyl (Durogesic, Actiq)
6) Methadone
Although short-term use of narcotics for acute pain does not appear to have any significant impact on male fertility potential, the long term use of these medications can be detrimental to sperm quality. Low testosterone levels are commonly seen with the prolonged use of narcotics which is felt to be due to an inhibitory impact on the pituitary gland. There is also evidence of a direct negative impact on testicular function with long term opioid use as well which can lead to decreases in sperm abnormalities as well as elevations of levels of sperm DNA fragmentation. [Drobnis EZ. AdvExpMedBiol 2017].
NON-OPIOD PAIN MANAGEMENT
Acetaminophen (Tylenol) is a commonly used over-the-counter (OTC) pain medication that is considered to be relatively safe (but can cause severe liver damage if taken in overdose quantities). Although there is no good data in humans, a study of rats taking acetaminophen daily for between 3 to 9 months showed decreases in semen parameters as well as increases in sperm DNA fragmentation. [Adebi N. MiddEastFertSocJ 2017].
Aspirin and non-steroidal anti-inflammatories (NSAIDs)
Studies on these medications suggest that long term (>6 months) use can lead to decreases in sperm counts and quality in some men. These were generally dose-related and reversible. [Semet M. Andrology 2017]. A study of 31 men in 2018 found that taking ibuprofen (Aleve/Motrin) at a dose of 600mg twice a day showed alterations in their testicular-pituitary axis function resulting in hypogonadism (low testosterone), though the direct impact on semen parameters was not evaluated. [Kristenen DM. PNAS 2018]
SUMMARY OF PAIN MEDICATION USE
There is ample evidence that long-term narcotic use is detrimental to sperm quality, though short-term use of these medications for an acute event (such as recovery after a surgical procedure) likely has no significant impact. The prolonged use of acetaminophen and ibuprofen may have some negative impact on fertility potential in men, though the data is extremely sparse. However, if these medications are needed for a man to avoid long-term narcotic use, these non-opioid alternatives appear to be a much better choice in terms of maintaining good sperm quality. The general recommendation for non-narcotic pain medications such as NSAIDs is that they generally do not need to be stopped in men trying to conceive, especially if semen parameters are normal. [Semet M. Andrology 2017].
Prostate Medications and male infertility
Benign enlargement of the prostate (BPH) can cause voiding symptoms (such as slow urinary flow and decreased bladder emptying) and has been associated with an increased risk of ejaculatory problems as well. [Avellino G. FertSteril 2017] However, many of the treatments for BPH can actually worsen male fertility potential further. There are 2 main classes of medications (as well as some non-prescription supplements) which are commonly used to treat BPH, and all have the potential to negatively impact male fertility.
1) Alpha-blockers
Alpha-blockers medication help to relax the smooth muscle in the prostatic urethra and bladder neck region, thereby opening up the channel to the flow of urine. Unfortunately, some alpha blockers cause ejaculatory problems, including retrograde ejaculation and even complete ejaculatory failure in some circumstances. Alpha blockers also have been shown to decrease the quality of semen parameters as well, including sperm counts and motility. [Hellstrom WJ. JAndrol 2009]. However, not all alpha blockers have the same impact on male fertility. Tamsulosin (Flomax) is a commonly used and effective oral medication for BPH. Unfortunately, up to 90% of men taking tamsulosin experience a decreased ejaculatory volume with complete ejaculation failure seen in about 35% of men. [Kusman AM. FertSteril 2020]. Relatively high rates of ejaculatory dysfunction have been seen with the use of silodosin (Rapaflo) as well. [Sakata K. BMCUrol 2012]. In contrast, alfuzosin (Uroxatral) does not appear to have a negative impact on sperm transport in most men. [Andersson KE. BJUInt 2003]
2) 5-alpha reductase inhibitors
These medications are used to shrink the size of enlarged prostates over time and include finasteride (Proscar), dutasteride (Avodart). Unfortunately, this class of medications can also decrease sperm quality even in low doses. [Overstreet JW. JUrol 1999] A 2013 study of 14 men being seen for infertility showed a 11.6 fold increase in sperm counts (from 1.48 million sperm/cc to 23.54 million/cc) when finasteride was discontinued, with a smaller increase in sperm motility (from 16.8% to 25.9%). [Samplaski MK. FertSteril 2013]. Though less well studied, dutasteride has also been shown to have the ability to decrease semen parameters. [Amory JK. JClinEndocrinolMet 2007]
3) Saw palmetto
Saw palmetto is an herbal supplement made from the berries of the Serenoa repens plant. It is a commonly used over-the-counter treatment for BPH and its mechanism of action is felt to be similar to that of 5-alpha reductase inhibitors. The impact of saw palmetto has not been extensively studied, but laboratory studies subjecting sperm to high levels of saw palmetto were noted to have a negative impact on sperm motility. [Ondrizek RR. Andrology 1998]
OTHER MEDICATIONS THAT CAN AFFECT SPERM PRODUCTION
A number of other drugs may cause fertility-related problems in men:
1) Ribavirin (Moderiba)- This is an anti-viral medication which is used to treat chronic hepatitis C as well as severe viral lung infections from respiratory syncytial virus (RSV). Reversible decreases in semen parameters as well as increased DNA fragmentation have been found in human studies, with DNA changes lasting up to 8 months after stopping the medication. It is recommended to freeze sperm prior to starting therapy and stopping the medication 7 months prior to starting to try to conceive. The use of contraception is also recommended in patients taking this medication. [Semet M. Andrology 2017]
2) Anti-retroviral medications- These medications are used to treat HIV infections have been shown to potentially decrease semen parameters in humans. However, they are generally not recommended to be discontinued as their impact is balanced by the positive role in controlling the chronic viral infection which itself often has a significant negative impact on male fertility potential. [Semet M. Andrology 2017]
3) Acyclovir (Zovirax)- used to treat herpes infections, chicken pox, and shingles. Animal studies have shown decreases in semen parameters, though no negative impact has been seen in humans. There are no current recommendations to stop the medication in men trying to conceive and any negative impact should resolve within 70 days of stopping the medication. [Semet M. Andrology 2017]
4) Danazol: A synthetic steroid with a structure similar to testosterone. Used to treat rare problems like idiopathic angioneurotic edema. Its androgenic effects are like exogenous androgens thereby causing decreases in FSH and LH secretion which can negatively impact sperm production. [Dmowski WP. FertSteril 1979]
5) Low dose finasteride (Propecia): used in the treatment of male pattern hair loss. Propecia is low dose finasteride which is known to have a negative impact on sperm quality and therefore should be discontinued in men trying to conceive. [Overstreet JW. JUrol 1999] An alternative that could be used is minoxidil (Rogaine).
6) Retinoic agents- isotretinoin, retinoic acid, acitretin- metabolites of vitamin A, these medications are used in the treatment of acne as well as certain types of leukemia. Although no human studies have shown a negative impact on male fertility, animal studies have shown damage to testicular sperm cells. It is recommended to stop these medications when a man is trying to conceive. When the female partner is pregnant, it is recommended to use safe sex (e.g. condoms) due to teratogenic concerns. [Semet M. Andrology 2017]
Herbal Medications / Supplements and male infertility
Herbal medications are widely used in the United States; many people believe that these “natural” remedies have a lower risk of adverse side effects than prescription medications. The use of herbal supplements in men with fertility problems is widespread. A 2004 study looked at 481 men evaluated in an infertility clinic and found that 31 percent of them were taking alternative medications, and that 17 percent of these supplements had clear hormonal activity that was potentially detrimental to sperm production. [Zini A. Urology 2004]
This is not to say that all herbal supplements are necessarily detrimental or provide no beneficial effects on sperm counts and quality. Rather, at this time there are multiple problems with the way that natural supplements are tested, manufactured, and marketed. You may think what you want about vast federal bureaucracies and their inevitable shortcomings and inefficiencies, but the FDA does provide a very powerful and beneficial service in terms of securing a degree of safety and fraud prevention in the manufacture, marketing, and distribution of prescription medications. The days of snake-oil salesmen peddling ineffective and sometimes dangerous homemade remedies are thankfully behind us, at least when it comes to medications requiring a prescription.
Unfortunately, natural supplements do not fall under the jurisdiction of the FDA, and therefore they do not undergo the same intense levels of scrutiny that prescription medications need to pass before being approved for use. The criteria for safety and efficacy testing are much less stringent with natural supplements. When it comes to male fertility, a huge number of alternative treatments, ranging from specific natural supplements to eating more avocados or oysters, have been found by small, uncontrolled studies to potentially be associated with an improvement in semen parameters. In the field of prescription medications, most medications that small uncontrolled studies have suggested may have some positive effects are later shown to not have significant positive outcomes after being tested in the much larger, more rigorous studies required to attain FDA approval. Natural supplements, however, do not have to undergo these larger studies, and therefore claims from these small initial studies are rarely proven or disproven. These small studies also do not produce the same kind of safety data seen with larger, more rigorous studies.
The other problem with a lack of FDA oversight is that the manufacturing process is much less stringently regulated for nonprescription substances. Therefore, purity and amounts of active ingredient can vary significantly between products from different manufacturers. Another alarming trend is the undisclosed addition of certain pharmaceutical agents into allegedly “natural” supplements. Sildenafil (Viagra) has been found in supposedly natural nonprescription supplements for erectile dysfunction, for example, and testosterone derivatives have been found in supposedly natural bodybuilding supplements.
In addition, many natural substances (such as root and bark extracts) have not been thoroughly studied and may in fact contain hormonally active chemicals that are actually detrimental to male fertility. The argument can be made that large scientific studies are expensive, and no company is going to spend the money to conduct these studies on natural supplements for which a patent cannot be obtained. I think that there may be a role for government financial support of such studies for particularly promising supplements. However, until larger controlled studies show measurable and reproducible improvements in fertility, I do not feel that these supplements are worth the money or the risk of potentially negative side effects.
A Review of Frequently Used Herbal Supplements for Male Infertility
1) Red ginseng (Panox or Korean)- This is the most commonly used ingredient in men’s sexual health and comes from root of the Panox plant. Studies have shown some positive impact on erectile dysfunction, possibly through its impact on nitric oxide levels. Though information is scarce, a review of the literature did show some improvements in sperm density, motility, and morphology in 2 small studies. [Kulchakulla M. JUrol 2019]. In terms of safety, concerns of hypoglycemia have been mentioned with the use of ginseng, so care should be taken in men with diabetes. [Cui T. JSexMed 2015]
2) Ashwagandha extract (Withania somnifera)- This is a traditional Indian treatment for infertility and erectile dysfunction. There is some evidence in rat studies of reductions in oxidative stress as well as improvements in the function of seminiferous tubules in rats. [Ambiye VR. EvidBasedComplAltMed 2013]. Two small studies have shown improvements in semen parameters with the use of Ashwagandha. [Kuchakulla M. JUrol 2019]
3) Pine bark (Pycnogenal)- This supplement is made from the French maritime pine tree bark extract and is felt to have antioxidant properties. One small study showed that taking 200mg daily showed some improvements in semen parameters. [Kuchakulla M. JUrol 2019]
4) Shuddha shilajit- Another traditional Indian medicine, this substance is found on the rocks of the Himalayan mountains and is derived from the slow breakdown of plant material. There are questions of antioxidant and anti-inflammatory effects as well as a possible increase in testosterone levels. There is one small study showing increases in sperm density with the use of this supplement. [Kuchakulla M. JUrol 2019]
5) Tribulus terrestris- This supplement is derived from a common low growing vine and is often marketed as a “testosterone booster”. Increased testosterone levels have been reported in animal studies. [Cui T. JSexMed 2015]. However, a randomized double-blind trial in men found no change in testosterone levels with its use. [Santos CA. ActasUrolEsp 2014]. Case reports of kidney and liver toxicity have been reported when used in high doses in young men. [Cui T. JSexMed 2015]
6) Horny goat weed- This supplement is made from an extract of the epimedium plant found in Asia and Southern Europe. Commonly used for erectile dysfunction, this supplement contains small amounts of icariin which is felt to have effects similar to PDE-5 inhibitors (like sildenafil). While improvement erectile function has been found in rats, no evidence of improvements in ED have been yet shown in studies on humans. [Cui T. JSexMed 2015]
7) Fenugreek (trigonella foenum graecum)- This supplement is felt to contain certain sex hormone precursors as well as impact estrogen receptors. [Cui T. JSexMed 2015]. A double-blind placebo controlled study showed improvements in libido while testosterone and prolactin levels stayed within the normal range. [Steels E. PhytotherRes 2011]
8) Maca- This supplement is derived from the root of the Maca plant found in the region of the Andes mountains. Although there is minimal evidence in humans, mice studies have shown improvements in sexual function and semen parameters. [Cui T. JSexMed 2015].
9) DHEA (dehyrdoepiandosterone)- DHEA is a weak prohormone produced by the adrenal gland. It is converted to testostosterone and estradiol in the peripheral tissues of the body. [Cui T. JSexMed 2015]. Since it is an exogenous androgen, it should not be used in men trying to conceive.
10) Ginkgo biloba- Derived from Ginkgo (or maidenhair) tree, this supplement has been used in the treatment of erectile dysfunction. It has been proposed to influence nitric oxide metabolism but there is not currently good evidence supporting its use. [Cui T. JSexMed 2015]. Associated toxicity includes potential headaches and bleeding problems. In the lab, high concentrations of this supplement have been associated with decreases in sperm motility. [Ondrizek RR. Andrology 1998]
11) Yohimbine- Derived from the yohimbe tree in Africa, Yohimbine is commonly used as a treatment for erectile dysfunction. There is some evidence that this supplement can impact nitric oxide metabolism and may be superior to placebo in the treatment of erection problems. [Cui T. JSexMed 2015]. Potential side effects include headaches, sweating, hypertension, insomnia, and agitation.
12) Saw palmetto- An herbal supplement made from the berries of the Serenoa repens plant, this supplement is commonly used for the treatment of BPH (benign prostatic hypertrophy). and its mechanism of action is felt to be similar to that of 5-alpha reductase inhibitors. Laboratory studies subjecting sperm to high levels of saw palmetto were noted to have a negative impact on sperm motility. [Ondrizek RR. Andrology 1998]
13) St John’s Wort- A supplement from the flowing plant Hypericum perforatum, St John’s wort is sometimes used for depression. Studies on sperm exposed to St John’s wort in the lab showed significant decreases in motility. [Ondrizek RR. JAssistReprodGenet 1999]
Summary of Herbal Supplements for Male Infertility
There is no solid evidence to date that any herbal supplement helps significantly with semen parameters and fertility potential in men. A few small studies show that Ashwagandha extra, red ginseng, pine bark extract, and Shuddha shilajit may have the potential to improve semen parameters, but the evidence is not strong enough to recommend their use at this time. Larger randomized trials are clearly needed to define the role of herbal supplements in the management of male infertility.