Exogenous Androgens / Anabolic Steroids and Male Infertility
Introduction to the Impact of Exogenous Androgens / Anabolic Steroids on Sperm Numbers and Quality
Hypogonadism (low testosterone, or “low T”) is a common problem that is being increasingly diagnosed by the medical community, primarily due to an increased awareness of the problem. Some studies have shown that as many as 20 percent of men being treated for fertility issues have hormone problems such as low testosterone. Normalization of testosterone levels can potentially result in improvements in energy, libido, sexual function, and fertility. However, the types of hormonal treatment that a man chooses to use can have a dramatic impact on his fertility.
Terminology note: the word “androgen” refers to any substance or compound which has male hormonal activity. Testosterone is a common androgen.
When a man has low testosterone levels, there are two ways in which they can be increased:
1 )Exogenous androgen replacement
Exogenous replacement in when androgens are given through pills, patches, gels, injections, or pellets
2) Increased endogenous production
Increased endogenous production involves giving a medication that causes the man’s own testicles to increase their production of testosterone. Medications such as SERMs, anastrazole, and HCG cause increased endogenous production of testosterone. See the "Low Testosterone" section of this website for more information on these medications.
Both of these approaches effectively increase blood testosterone levels. However, sperm production is dependent upon high testosterone levels within the testicles, not just in the bloodstream. Therefore, if a man is trying to have a child, medications that increase endogenous testosterone production should be used. Exogenous androgens, on the other hand, cause the pituitary gland to decrease the release of FSH and LH. Without sufficient FSH and LH, testicular production of testosterone and sperm dramatically decreases, with significant negative implications for male fertility.
Exogenous androgens come in four basic types:
1) Prescription testosterone replacement therapy
2) Anabolic steroids
3) Prohormones
4) T boosters.
Prescription Testosterone Replacement
Over the last decade, there has been a significant increase in awareness and treatment of low T in men. Many people are now aware that certain aging-related problems in men, such as decreased libido, erectile dysfunction, decreased lean body mass, and osteoporosis, are associated with decreased testosterone levels and are at least partially reversible with testosterone replacement therapy. Between 2008 and 2013, there was a 170 percent increase in testosterone prescriptions written in the United States, with this trend continuing as shown by a 2023 study which found the number of prescribers of TRT increasing by 8.8% per year. [Sellke N. IntJImpotRes 2023] Most of these prescriptions were for older men in whom fertility is not a concern. However, as part of this trend of increasing usage, more young men are being prescribed exogenous T replacement as well, typically without the doctor knowing of its significant negative impact on male fertility. Due to its suppression of the HPG axis, the majority of men have dramatic reductions in sperm production while taking testosterone replacement therapy (TRT). Studies performed in China looking at the use of TRT as a form of birth control found that between 93-98% of men had sperm concentrations of <1 million sperm/cc at 6 months. [Gu Y. JClEndMet 2009][Yiu PY. JClEndMet 2008]. By 6 months after starting TRT 64-75% of men are completely azoospermic on TRT. [Patel A. WJMenHealth 2018]. Clearly, men who are interested in pregnancy should avoid the use of exogenous androgens.
Types of Androgen Replacement
I. Injectable androgens
a. Testosterone cypionate (Depo-testosterone)- administered IM or SQ- available since the 1950s, with FDA recommended dosing of 50-400mg every 2-4 weeks. Commonly given weekly or twice-weekly in split doses. Average dosing is 200mg every other week.
b. IM Testosterone enanthate (Delatestryl)- usually administered IM- shorter acting than cypionate. Average dosing is 200mg every other week.
[Note: both IM testosterone enanthate and cypionate have highest risks (40%) of developing secondary erythrocytosis]
c. SQ Testosterone enanthate (Xyosted)- comes in dosing of 50mg, 75mg, and 100mg with disposable self-injector. Lower risk of secondary erythryocytosis than IM formulation.
d. IM Testostrone undecanoate (Aveed)- longer acting- average dose 750mg to start, repeat 4 weeks later and then every 10 weeks thereafter. Dose not require dose titration. Small risk of pulmonary microembolism so patients must wait in the office for 30 minutes following injection.
II. Topical Androgen Gels/Solutions
a. Androgel 1%- 25mg and 50mg packets (pump no longer available)- applied once daily to the shoulders, uppers arms, or abdominal area- dose titration up to 100mg daily
b. Androgel 1.62%- packets or pump available- to shoulder or upper arm region- dosages between 20.25mg to 81mg.
c. Fortesta 2%- comes as pump and applied to inner thigh regions- dose range 10-70mg daily
d. Testim 1%/Vogelxo 1%- topical testosterone gels that come as tubes, packets and pump (Testim is tube only) applied to shoulders and upper arms- dosing between 50-100mg daily
e. Axiron- pump dispenses into applicator which is applied to the armpit area. Dosing between 30-120mg daily.
III. Transdermal Patches
a. Androderm- 2mg and 4mg patches- applied to the back, abdomen, upper arms or thigh regions- sites should be rotated daily. Dosing between 2mg-6mg daily. If there is skin irritation then application of triamcinolone acetonide 0.1% cream may be used (do not use ointment as reduces testosterone absorption).
IV. Nasal Gel
a. Natesto- 5.5mg/pump- starting dose 11mg (1 pump each nostril) three times a day at least 6-8 hours apart. Should be avoided in men with chronic nasal conditions. Short acting so appears to have less impact on gonadotropins and therefore sperm production at least short term. See below for more information on Natesto.
V. Oral Testosterone undecanoate- designed to bypass the liver (unlike earlier versions of oral methylated testosterone). Very low rates (<5% of erythrocytosis).
a. Jatenzo- 158mg, 198mg, and 237mg capsules with dosing range of 158mg to 396mg twice daily (starting dose 237mg twice daily).
b. Kyzatrex- 100mg, 140mg, and 200mg capsules- starting dose 200mg twice daily- dosing range 100mg once daily to 400mg twice daily.
c. Tlando- 112.5mg capsules- recommended starting dose is 225mg twice daily with no dose adjustment.
V. Injectable pellets
a. Testopel- 75mg pellets- applied under skin (usually in hip) as in-office procedure- common starting dose is 10 pellets every 3-4 months (range 6-12 pellets). To discontinue therapy the pellets must be removed.
[Sun AY. Reviews in Urology 2024][Bookwalter C. US Pharm 2023]
Side effects of prescription testosterone include:
1) Acne
2) Gynecomastia (breast enlargement)
3) Fluid retention
4) Sleep apnea (though not all experts agree on this)
5) Testicular atrophy
6) Erythrocytosis (increase in red blood cells as a percentage of total blood volume; can make the blood more viscous and lead to
heart attack or stroke)- see "Erythrocytosis/Polycythemia" section for more detailed information.
Natesto
Natesto has generated some interest in the male fertility community for its potential ability to preserve sperm production in men unlike most every other androgen. Due to its low dose and three times daily dosing, studies have found significantly decreased gonadotropin suppression with Natesto. [Kavoussi PK. JUrol 2021]. A small study of 60 men taking Natesto found that at 6 months, 81.2% of men still had normal FSH levels and 72.7% normal LH levels. In this study total motile sperm counts dropped (from 45.9 million to 33.9 million) but were maintained at fairly high levels. [Ramasamy R. JUrol 2020]. Further data will be needed to assess whether this slow drift downward continues with time. It is unclear whether men taking Natesto eventually reach similar levels of sperm production suppression as with other androgens but just over a longer period of time. Further studies will be needed to answer these questions.
Anabolic Steroids
Anabolic steroids are androgens that are particularly effective at increasing muscle and bone mass. They accomplish this by promoting protein metabolism and storage.
There are some legitimate medical uses for anabolic steroids, including the treatment of anemia and to reverse protein loss in patients who have prolonged immobilization following severe illness, trauma, or surgery. Anabolic steroids are also used for appetite stimulation and maintenance of muscle mass in patients with diseases such as cancer and AIDS.
Most commonly, however, anabolic steroids are used illicitly by bodybuilders and athletes to increase muscle mass and strength, and also by athletes to help speed their recovery following sports-related injuries. Some take oral forms, such as oxymetholone (Anadrol), oxandrolone (Anavar, Oxandrin), stanozolol (Winstrol), or methandrostenolone (Dianabol, also called “Dbol”). Others use injections of nadrolone decanoate (Deca-Durabolin, also called “Deca”), nandrolone phenpropionate (Durabolin), or Boldenone undecylenate (Equipoise). There’s also an ointment form, tetrahydrogestrinone (known as THG, “the cream,” or “the clear”).
All anabolic steroids, however, still have androgenic hormonal activity as well. Men who abuse anabolic steroids for bodybuilding purposes often take the equivalent of as much as 5,000 mg of testosterone per week, an amount far greater than the body naturally produces. The result is blood testosterone levels than can be many times higher than what is considered normal. As discussed above, high blood levels of testosterone cause the pituitary gland to decrease the release of FSH and LH, which causes testicular production of testosterone and sperm to drop significantly.
The use of anabolic steroids is banned by all major sports leagues because of the unfair competitive advantage these substances provide. Anabolic steroids are listed as controlled substances, which means that it is technically illegal to possess these substances without a prescription. Production and distribution by non-physicians is also illegal, and therefore most anabolic steroids used for non-medical reasons are manufactured in other countries and smuggled into the United States. This makes quality control and safe manufacturing supervision by such agencies as the FDA not possible.
Anabolic steroid users commonly believe that warnings about the risk of anabolic steroid use are overblown and exaggerated. However, the use of anabolic steroids is associated with many potential side effects, including:
1) High blood pressure
2) Erythrocytosis (increase in red blood cells as a percentage of total blood volume; can make the blood more viscous and lead to
heart attack or stroke)- see the "Erythrocytosis/Polycthemia" link above for more information.
3) Gynecomastia (breast enlargement)
4) Abnormal cholesterol levels
5) Blood sugar control problems
6) Acne
7) Increased male-pattern baldness
8) Increased risk of low testosterone levels later in life
Anabolic steroids have also been linked to an increased risk of coronary artery disease as well as potential direct damage to left ventricular heart function. Liver damage and failure are other serious conditions seen with oral anabolic steroid use. Mood disorders have also been found to be more common in users of anabolic steroids.
It’s estimated that more than a million men in the United States have used anabolic steroids for non-medical reasons at some point. True rates of usage are difficult to determine, as studies have shown that over half of men who use anabolic steroids for non-medical reasons do not tell their physicians that they are using these substances. However, the impact of anabolic steroid use on male fertility is quite clear, with the vast majority of men suffering a significant negative impact on sperm production and quality. It is therefore very important for all men using anabolic steroids to report their use to their fertility doctor if they are trying to conceive.
Prohormones
Prohormones are precursors to androgens. Prohormones have minimal hormone activity themselves, but they are converted by the body’s metabolic processes into active androgens. Interest in prohormones increased following the Anabolic Steroid Control Act of 1990, which made anabolic steroids controlled substances in the United States. Through the use of prohormones such as androstenedione, 4-androstenediol, 1-androstenediol, and 19-norandrostenedione, bodybuilders and athletes found a way to use androgenic compounds legally. In an attempt to close this loophole, the Anabolic Steroid Act of 2004 included prohormones on the list of illegal anabolic steroids.
Since 2004, producers of prohormones have taken several different strategies to keep their products on the market. One (illegal) strategy is to use estrogen derivatives (which are not particularly effective at increasing muscle mass) and illicitly add other undeclared anabolic steroids to these. A second approach is the use of plant-based phytoandrogens (plant substances with androgenic actions), which are currently available over the counter in the United States. Examples of phytoandrogens include triterpenoids and pine pollen. A third approach is through the use of “designer steroids” that are specifically produced to bypass the legal restrictions on anabolic steroids and prohormones, while maintaining androgenic and anabolic actions. Some examples of these designer steroids include Helladrol or H-Drol (4-chloro-17a-methyl-androsta-1,4-diene-3,17-diol), Methastadrol or M-Drol (2a, 17a-dimethyl-etiocholan-3-one, 17b-ol), Epi-MAX (2a, 3a-epithio-17a-methyl-17b-hydroxy-5a-androstane), and 11-OXO (adrenosterone).
Controversy continues to surround prohormones in regard to their legality and effectiveness. From a fertility perspective, however, little controversy exists. The goal of prohormones is to mimic the effects of other exogenous androgens, which have a known significantly negative impact on male fertility.
DHEA
Dehydroepiandrosterone, or DHEA, is a hormone precursor to testosterone that is naturally produced by the body. It was exempted from the Anabolic Steroid Control Act of 2004 due to its designation as an “old dietary ingredient.” It is therefore legal to sell in the United States as a dietary supplement, but its use is banned in organized sports competitions. DHEA has some degree of direct exogenous androgenic activity, and therefore should be avoided in men trying to conceive a child.
T Boosters
T boosters are substances that are supposed to increase the natural production of testosterone by the body. The most common use of T boosters is in men using anabolic steroids who want to promote the return of natural testosterone production between anabolic cycles. Commonly used T boosters include Tribulus terrestris (also known as puncture vine), ginseng (from the Panax genus), and D-aspartic acid (DAA), an amino acid. Examples of commercially available T boosters include Perform, T-Force, Testogen XR, and Testopro, among many others.
T boosters are not regulated by the FDA, and questions remain as to their efficacy and potential mechanisms of action, as most have not been closely studied. The few available controlled studies failed to find an increase in testosterone levels associated with their use, or any improvement in strength. From a fertility standpoint, if they really did enhance endogenous testosterone production, then there should be no detrimental impact on sperm production. However, I recommend that men who are trying to optimize their fertility stop taking T boosters, for two reasons: (1) their production is not regulated by the FDA, so quality control and review of actual ingredients are not under any supervision, and (2) their mechanism of action has not been carefully studied, and therefore certain T boosters may actually have negative hormonal effects on male fertility. For example, ginseng has been shown to contain phytoestrogens, which have female hormonal activity.
Fertility Management of Men Taking Exogenous Androgens
As mentioned earlier, most men taking stronger exogenous androgens—prescription testosterone, anabolic steroids, and some prohormones—see their sperm count drop significantly (oligospermia), and often go to zero (azoospermia), after taking these substances for only three to six months. When they stop taking exogenous androgens, most men will have sperm production return. In some men this may happen as little as three months after the exogenous androgens, but normally it takes four to six months before sperm production resumes, and it can even take two years or longer in some circumstances. Some men never regain their prior sperm production capacity, and a minority (<5 percent) can remain permanently azoospermic. Men who retain even small numbers of sperm in their ejaculate while taking androgens have higher rates of sperm returning to the ejaculate 6 months after starting hormonal therapy [Ledesma BR FertSteril 2023]
Other factors that affect the speed and degree of sperm production recovery include the type and strength of exogenous androgens used, the length of time they were used, age of the male, and each person’s individual physiologic response. [Kohn TP. FertSteril 2017][Alhaman A. FertSteril 2023] For example, men using transdermal testosterone preparations (patches, gel) tend to require a longer sperm recovery time than men taking testosterone injections. The strength of androgens also plays a role in how quickly sperm usually returns to the ejaculate. In men taking normal dose TRT, about 67% have return of sperm at 6 months, 90% at 12 months, 96% at 16 months, and 100% at 24 months. [Liu PY. Lancet 2006]. In contrast, men who are taking supraphysiologic doses (such as high dose anabolic steroids often take longer to recover, with the average time for sperm returning at 10.4 months. [Shankara-Naraynana N. JClEndoMetab 2020]
Men who stop taking exogenous androgens typically experience subsequent low testosterone levels. This can be because their baseline T levels are low (which is why they started taking the androgens in the first place), because their body’s endogenous T production remains suppressed even after going off the exogenous androgens, or both. Men who have taken exogenous androgens in the past are also predisposed to having low T in the future, even if the use of the androgens was many years prior. These men therefore generally need to be started on medications that increase endogenous testosterone production (such as SERMs, anastrazole, or HCG), both to improve the hormonal environment for sperm production as well as to decrease the adverse symptoms of low testosterone, such as low energy levels and low libido.
I personally recommend hormonal treatment in all men coming off exogenous androgens for fertility reasons for two reasons. One, I have found that if we can get the man’s testosterone levels back to a good level, then he is less likely to experience bothersome low T symptoms and therefore go back on TRT before he has succeeded in having a child. The other reason is that the return of sperm production is usually faster when hormonal medications are started.
There are two basic options for hormonal treatments in men coming off exogenous androgens.
1. Oral medications (SERMs and anastrazole)- this route if much cheaper and easier (no injections involved). This may be a good choice if the man stopped his exogenous androgens at least a few months prior. However, if the androgens have just been stopped, then the man’s pituitary is not likely going to respond well to the SERM stimulation which typicalled increases LH and FSH release. An example of this approach would be a SERM (e.g. clomiphene 100mg every other day or tamoxifen 20mg twice a day) and anastrazole 1mg every other day.
2. HCG and a SERM- this approach is more expensive but for testosterone production it does not rely on the pituitary gland responding with increased LH production. The HCG directly stimulates the testicles to make more testosterone while the SERM tries to speed up the process of FSH production by the pituitary. Typical regimens would include HCG 3000 IU SQ three times a week in addition to a SERM (e.g. clomiphene 50mg every other day or tamoxifen 10mg twice a day).
After each of these regimens are started, hormone testing (testosterone, estradiol, FSH, and hematocrit) are usually checked 3-4 weeks later and medication doses adjusted accordingly (with repeat blood work 2-3 weeks after each medication change). Hormones are then typically repeated 6 months later and then yearly. Semen analysis testing is usually performed 3 months after initially starting the hormonal treatments (though it can take 6-12+ months for sperm to return).
For detailed information on endogenous testosterone replacement therapy, see the "Low Testosterone" section of this website.
Can Men Who Want to Have Children Ever Take Exogenous Androgens?
In couples where the man has stopped taking exogenous androgens and the wife becomes pregnant, a common question is whether he can restart taking exogenous androgens if they want to have more children in the future. Emerging scientific evidence suggests that ideally he should stay off all exogenous androgens while he is still interested in conceiving children. When men use exogenous androgens intermittently, their sperm production typically rebounds each time they are “off cycle”—but often sperm numbers and quality do not recover to the same baseline levels that they had prior to restarting the exogenous androgens. [Ledesma BR. FertSteril 2023] This progressive decrease in sperm quality can impair a couple’s future fertility chances, so it is best to stick with increased endogenous production alone until the couple’s fertility efforts are complete.
Some men are very reluctant to stop exogenous testosterone therapy (for example, professional bodybuilders). I think that if the couple really wants the best chance of conceiving a child, then the man should stop taking exogenous androgens and switch over to medications that increase endogenous T production. However, for men who refuse to stop taking anabolic steroids or other exogenous androgens, there have been some studies that show that being on low-dose HCG at the same time as exogenous androgens may somewhat protect sperm production.
In one study, men were given exogenous testosterone by injection or gel, as well as low-dose HCG injections (500 IU three times per week). The study found that these men were able to maintain elevated intra-testicular testosterone levels on this regimen. With short term follow-up, semen parameters were decreased, but no men experienced azoospermia. [Hsieh TC. JUrol 2013] Eventually one would expect sperm production to eventually fall without any FSH stimulation of the testicles. However, the potential advantages of adding low dose HCG to TRT is to slow the progression to azoospermia and also potentially speed up return of sperm with hormonal treatments in the future in couples who want to have more children.