Low Testosterone / Hypogonadism and Male Infertility
Around 25 percent of men with fertility issues are found to have low testosterone (also called hypogonadism or “low T”) on hormone testing. Normal testosterone levels are necessary to provide an optimal environment within the testicles for normal sperm production. Testosterone levels also play a role in libido, erectile function, and ejaculatory function.
Causes of Low Testosterone
There are many different reasons—some reversible, others not—for a man of reproductive age to have low testosterone levels:
1) Aging. As men get older, they tend to have lower levels of total testosterone. They also have higher levels of SHBG (sex hormone binding globulin), which decreases free and bioavailable testosterone levels.
2) Idiopathic hypogonadism. In many cases, no specific cause can be found for the low testosterone level, though we can speculate that there is likely some genetic abnormality affecting either the hormonal process that stimulates the testicles to produce testosterone or the actual production of testosterone within the testicles. This is the most common scenario when we find hypogonadism in younger men seeking treatment for infertility issues.
3) Obesity. This is a known risk factor for hypogonadism, with studies showing that over 50 percent of obese males have low testosterone levels. Weight loss can boost testosterone levels in overweight men.
4) Elevated prolactin levels. See “Elevated Prolactin” section for more information.
5) Excessive alcohol intake. Reducing alcohol consumption to less than four drinks a week may help.
6) Chronic narcotic use. Studies have shown that up to 75 percent of men on long-term narcotics have low testosterone levels. Prolonged use of methadone carries an especially elevated risk of hypogonadism. Cessation or significant reductions in narcotic use can help to improve testosterone levels.
7) Varicoceles. Large varicoceles have been associated with lower levels of testosterone production. Small varicoceles are unlikely to have much impact on T levels. See the "Varicoceles" section for more information.
8) Malnutrition. Better nutrition may help increase testosterone.
9) Acute illness. Temporary decreases in testosterone levels may result from an acute illness or from significant trauma to the body.
10) LH deficiency. Congenital LH production problems are rare and can be treated with LH replacement (HCG injections). Lesions of the pituitary gland (such as a tumor or damage from trauma or radiation) can also result in decreased LH production.
Medications That Can Increase Testosterone Levels
There are two methods by which to increase testosterone levels in men:
1) Giving exogenous androgens. This involves providing androgens directly in the form of hormone replacement (injections, patches, gels, pellets), anabolic steroids, prohormones, or testosterone boosters. See “Exogenous Androgens/Anabolic Steroids" section for more detailed information.
2) Increased endogenous androgen production. These medications cause a man’s body to produce more testosterone.
Endogenous Androgens Only!!!
A key point in the management of male fertility is that increased endogenous production of testosterone in hypogonadal men can help to improve semen parameters and fertility, while exogenous testosterone administration causes significant drops in sperm counts and fertility.
The take-home point: never give exogenous androgens to a man who is trying to have a child.
Unfortunately, this seemingly basic concept is not as widely known as it should be within the medical community. I regularly see primary care physicians (and even some urologists) prescribing exogenous androgens to young male patients who are trying to have children. Hypogonadal men who are trying to have children (or who would like to have children in the future) should instead be treated with medications that increase their own endogenous testosterone production.
Increasing Endogenous Testosterone Production
There are three classes of medications that can increase endogenous T production:
1) Selective estrogen receptor modulators (SERMS)
2) Aromatase Inhibitors
3) HCG (human chorionic gonadotropins)
Selective estrogen receptor modulators (SERMs)
Estrogen normally sends a signal back to the pituitary gland telling it to make less LH and FSH. SERMs block this action of estrogen on the pituitary, and therefore increase the production of LH. This causes the testicles to make more testosterone. Examples of SERMs include:
1) Clomiphene (Clomid). This is the most commonly used SERM for male fertility-related hypogonadism. Its use is reviewed in detail
in the "Clomiphene" section of this website
2) Tamoxifen (Nolvadex). Sometimes used for the treatment of male hypogonadism, typically in dosages of 10–15 mg twice a day.
Efficacy and side effects are similar to those of clomiphene.
3) Raloxifene (Evista). Not generally used in the treatment of male hypogonadism.
4) Enclomiphene (Androxal). Similar to clomiphene but isolating only its biologically active isomer, enclomiphene was developed by
Repros Therapeutics. It is currently being investigated for use in hypogonadal men and undergoing FDA review.
Aromatase inhibitors
Aromatase is an enzyme located within the testicles, liver, and fat cells. Its role is to convert some of the body’s testosterone into estradiol. Aromatase inhibitors are oral medications that decrease the action of the enzyme aromatase, thereby lowering the levels of estradiol while increasing testosterone levels. (Aromatase inhibitors are also used in the treatment of breast cancer in women due to their estrogen-lowering effects.) Types of aromatase inhibitors include:
1) Anastrazole (Arimidex). Anastrazole is the most commonly used aromatase inhibitor for male fertility-related hypogonadism. It is a
non-steroidal drug and therefore does not impact adrenal function. Its use is reviewed in detail in the "Anastrazole" section of this
website.
2) Letrozole (Femara). This medication is commonly used in female infertility treatments but is not generally used for male infertility at
this time. Letrozole is also non-steroidal and therefore does not affect adrenal function.
3) Testolactone (Teslac). Testolactone is used by some urologists in the treatment of male hypogonadism, and it is thought to potentially
offer improved benefit for men with Klinefelter’s disease (though this remains controversial). The primary downside of testolactone
is that it has corticosteroidal activity and can affect adrenal gland function.
4) Exemestane (Aromasin). Another steroidal aromatase inhibitor. Exemestane is generally not used in the treatment of male
hypogonadism at this time.
Human chorionic gonadotropin (HCG)
HCG has a mechanism of action similar to that of luteinizing hormone (LH). Like LH, HCG directly stimulates the Leydig cells of the testicles to make more testosterone. HCG is generally considered to be stronger than clomiphene and anastrazole, but it is also more expensive and needs to be given by injection. The use of HCG is reviewed in detail in the "HCG" section of this website.
Can Exercise Increase Testosterone Levels?
While there may be some evidence that testosterone levels increase slightly with strength training, the evidence is controversial. Furthermore, the increases in blood testosterone levels are minimal and would not be expected to have any significant clinical impact on fertility.
Choosing Which Medication to Start With
For the treatment of low testosterone in men who wish to conceive children, clomiphene is usually the first choice due to its ease of use (it comes in pill form) and relatively low cost. If a man’s baseline estradiol is relatively high (greater than 45 pg/mL or so), then I consider starting with anastrazole, since clomiphene tends to increase estradiol levels in a significant percentage of men. Occasionally patients are immediately started on the stronger HCG injections without trying oral clomiphene or anastrazole first, such as in men who have been taking long-term exogenous testosterone replacement or anabolic steroids. These men often do not respond well to oral clomiphene or anastrazole, and going straight to HCG is sometimes the best choice.
There is some controversy among fellowship-trained experts regarding the use of medications to treat decreased sperm count in men with low testosterone levels. If FSH levels are normal or high, then some experts feel that increasing testosterone levels does not provide much fertility benefit unless testosterone levels are extremely low. Unfortunately, we don’t yet have good clinical data on this. Definitive double-blind studies are difficult to perform, since infertile couples are understandably not often eager to sign up for a trial in which they might wind up in the control group of patients being given a placebo (sugar pill) for a year instead of in the group receiving a medication that could increase their chances of having a baby. Despite the lack of definitive clinical data, I often opt for prescribing medication: we know that sperm are ideally made in a very high-testosterone environment, and if we can bump a man’s testosterone level up to roughly normal levels with safe and relatively inexpensive medications (like clomiphene and anastrazole), it makes sense to do so in the interest of optimizing the environment for sperm production.
Response to Therapy
Hormone values tend to respond within one to two weeks of starting a man on therapy. Generally, repeat blood levels are drawn about two weeks after starting any new medication (or after a change of medication dosage) in order to assess the response.
In general, I aim for the following goals for fertility patients:
1. Total testosterone above 300 ng/dL, and ideally between 500–1000 ng/dL
2. Free or bioavailable testosterone (only one of these needs to be checked, not all three):
a) Direct (analog) free T: over 15 ng/dL
b) Calculated free T: over 50 ng/dL
c) Bioavailable testosterone: over 156 ng/dL
3. Total estradiol: under 60 pg/mL
4) Total testosterone to estradiol (T/E) ratio: over 10:1
I also look for improvement in the symptoms of low testosterone (which include decreased energy, reduced libido, decreased sexual function, etc.). Some men see improvements in just a few days, while in others it may be three to twelve months before they see maximal improvement.
The spermatogenic cycle (the length of time for a sperm precursor cell to form into a fully mature sperm) is approximately ten weeks long, and so improvement in semen parameters generally occurs over the first one or two spermatogenic cycles (roughly two and a half to five months) after starting medications to enhance endogenous testosterone production. I generally check a semen analysis around ten weeks after starting or adjusting medications, as long as the hormone levels have normalized on this medication regimen, but I remind patients that a repeat semen analysis in another ten weeks may be necessary.
General Protocol for Using Medications That Increase Endogenous Testosterone Production
If a man with fertility problems is diagnosed with low testosterone and started on clomiphene, anastrazole, or HCG, the following is a general protocol that can be used (although individual fertility doctors may have variations of this protocol in terms of timing and tests ordered):
Step 1: Make initial diagnosis of hypogonadism.
Step 2: Start therapy with clomiphene, anastrazole, or HCG.
Step 3: After two weeks, do a blood test (between the hours of 7:00 and 10:00 in the morning).
The diagnosis code that can be used for this test is currently E29.1. The testing should include:
1) Total and free testosterone
2) Estradiol
3) Hematocrit
4) Prolactin (if total testosterone is found to be under 300 ng/dL)
Step 4: Adjust medication as needed (with repeat blood tests two weeks after every medication change) until hormone levels have
normalized.
Step 5: Have a semen analysis about ten weeks after hormone levels have normalized.
Modifications to this timeline will sometimes need to be made. An example would be a situation in which time is of the essence, such as when the woman is over forty years old, in which case repeat semen analysis testing may be moved up to an earlier date.
It is important to remember that it takes about ten weeks for a sperm precursor cell to develop into a fully mature sperm, and in order to optimize sperm numbers and quality, the proper environment is needed for this whole period. Taking hormonal medication for just one or two months is not going to have a significant long-term impact on sperm quality. Male hormonal treatments are intended to be taken over the long term, typically until a pregnancy has been established.
Combination Therapy with Clomiphene, Anastrazole, and HCG
Sometimes multiple medications to increase endogenous testosterone production are used in combination. Of course, any time you combine medications you have higher costs, as well as increased potential for side effects.
One combination that typically does not work very well to raise endogenous testosterone production is clomiphene plus HCG. The reason is that clomiphene works by increasing LH secretion from the pituitary, and HCG is already increasing the LH levels in the bloodstream directly. However, clomiphene can raise FSH levels, so if the FSH is inappropriately low in a man receiving HCG, then adding clomiphene to HCG might be of benefit.
A better combination in terms of T production is combining anastrazole with either clomiphene or HCG. Since anastrazole works in a completely different manner than clomiphene or HCG, it can complement their effect on testosterone production while also keeping estradiol levels from getting too high.
For example, let’s say a man who has been taking exogenous androgens for low T comes to my office for fertility treatment. After stopping the exogenous androgens, he has a baseline testosterone level of 168 ng/dL with a normal FSH. On clomiphene 50 mg daily his total testosterone increases to only 256 ng/dL, so he changes over to HCG 2,000 IU by injection three times per week. On this regimen, his total testosterone increases to 640 ng/dL with a normal free testosterone, but his estradiol has increased from 30 pg/mL to 85 pg/mL. He therefore decreases his HCG dosage to 1,500 IU three times per week and adds anastrazole 1 mg every other day to lower his elevated estradiol levels. On a repeat test, his lab values are now normalized, showing a total testosterone of 614 ng/dL with a normal free testosterone and estradiol of 48 pg/mL.
What If Testosterone Levels Will Not Increase Despite Therapy?
Every so often I have a patient who cannot get total testosterone levels above 300 ng/dL despite maximal therapy (HCG 4,000 IU three times a week combined with anastrazole 1 mg daily). In this situation, the Leydig cells that produce testosterone within the testicles are presumably not functioning properly and do not respond to LH stimulation. From a fertility standpoint, one can only maximize the hormonal environment as much as possible with the HCG and anastrazole and then, after the couple is done having children, change to exogenous testosterone replacement therapy. There have been some case reports of men who have developed antibodies against HCG, making it less effective. Antibodies would not be expected to be the problem in men who have little or no remaining testicular tissue because of previous surgical removal or trauma, but they may be suspected in men who have some response to clomiphene but no significant response to HCG. Some experimental treatments have been suggested in an attempt to circumvent the antibody activity (such as plasmapheresis), but no effective standard treatment has been identified. An option would be to try HCG therapy in the form of Ovidrel, since this medication is made through genetic manipulation of bacteria (as opposed to most of the other HCG formulations, in which the HCG is extracted from the urine of pregnant women), and therefore may have a chance of being more effective in the face of antibodies. Ovidrel comes in a single-use pre-filled syringe of 250 µg (essentially equivalent to 5,000 IU of HCG), and this dose can be given as a subcutaneous injection twice a week.
Contraindications to Endogenous Testosterone Therapy
The American Society of Andrology recommends that men with any of the following contraindications should not start testosterone replacement:
1) History of prostate cancer
2) History of (male) breast cancer
3) Untreated sleep apnea (though this is controversial)
4) Untreated or severe congestive heart failure
General Health Evaluation for Men on Medications That Increase Testosterone Levels
The American Society of Andrology (ASA) has published guidelines for labs and other evaluations for men who are on testosterone replacement therapy:
1) Prostate-specific antigen (PSA). PSA is a blood test that serves as a screening tool for prostate cancer. Testosterone makes prostate cancer grow, so men with prostate cancer would not want to increase their testosterone levels. Prostate cancer is rare in young men, and the new American Urologic Association guidelines do not recommend screening for prostate cancer in men less than forty years of age. Men between the ages of forty and fifty-four should be screened only if they have certain risk factors, such as a family history of prostate cancer or are of African American descent.
2) Digital rectal exam. In this screening test, the doctor places a gloved finger in the rectum to palpate the prostate gland for any nodules or other abnormalities. Along with a PSA test, the digital rectal exam is used by urologists and primary care physicians to screen for prostate cancer.
3) Hematocrit. This test measures the percentage of red blood cells in the bloodstream. Elevated levels of testosterone can increase the hematocrit in some men, which can increase their risk of developing clotting problems, such as stroke or heart attack. See “Erythrocytosis Polycythemia" section for more detailed information.
4) Prostate-related symptom assessment. Elevated testosterone levels can cause enlargement of the prostate in some men, especially as they get older. An enlarged prostate can block the flow of urine and cause symptoms such as a slow urinary stream and difficulty emptying the bladder. These symptoms are rare in young men but can occur in some circumstances. Assessment for symptoms of urinary obstruction can be performed in older men, or younger men with a history of benign prostatic hyperplasia (BPH, or enlarged prostate) or voiding problems. A simple review of voiding symptoms is fine in most men. Standardized evaluations, such as the AUASS (American Urologic Association Symptom Score), can also be utilized.
5) Osteoporosis prevention/DEXA scanning. All men with low testosterone levels are at an increased risk for developing osteoporosis, or weakening of the bones, and should receive counseling on osteoporosis prevention. Though it is not included in the ASA guidelines, I recommend obtaining a DEXA scan (which evaluates bone density) in men with a baseline total testosterone of less than 200 ng/dL. See the "Osteoporosis" section of this website for more information.
What I recommend for the fertility-age population
The ASA guidelines recommend that a baseline evaluation be performed before therapy is started. After treatment has begun, the guidelines recommend additional evaluations after three, six, and twelve months, and then yearly thereafter. However, these guidelines were designed primarily for older men using exogenous testosterone replacement therapy, and these men generally are at much higher risk for problems such as prostate cancer and BPH. I therefore use the following guidelines for my generally younger fertility patients, but I recommend that you can get your medical provider's opinion as well.
1) Baseline hematocrit should be performed at the time of repeat blood work after a medication for increased endogenous testosterone replacement has been started (such as clomiphene, anastrazole, or HCG). The hematocrit can then be repeated in about six months. If it is normal at that time, then it is rechecked every six to twelve months while the patient is on the medication.
2) PSA screening and digital rectal exam are recommended for the following groups: men over fifty-five, men over forty who have a family history of prostate cancer, and African American men over forty. These screening tests should be performed at the start of therapy, six months later, and then every six to twelve months, by either the urologist or the patient’s primary care physician.
3) Prostate-related symptom assessments can be done for men who have a history of BPH or urinary voiding problems to see if there are any adverse changes in their symptoms after the start of therapy.
4) A baseline DEXA scan should be done for men with a total testosterone of under 200 ng/dL. The scan should be repeated every one to two years thereafter.
(All of these recommendations assume that test results are normal; additional testing may need to be done more often if abnormal or borderline results are found.)
When to Stop Medications for Increased Endogenous Testosterone Production
Clomiphene and anastrazole are generally safe to take over the course of several years with proper monitoring. There are some concerns about taking these medications, especially anastrazole, for more than three to five years, as we still have questions about their impact on general medical issues, such as bone health. HCG should be safe to take indefinitely with proper monitoring since it basically just mimics LH, the body’s natural pituitary hormone.
All men taking medications to increase their endogenous testosterone production eventually come to a point when they consider stopping them, either because their partner is pregnant or because they have decided to put their fertility efforts on hold. The primary question that needs to be addressed at that time is whether they may want to conceive children again in the future.
Couples Who Want More Children
Couples in which the woman is currently pregnant or who are temporarily putting their fertility efforts on hold but who want to have more children in the future have several options:
1) Stop all of their hormonal medications
2) Continue their endogenous testosterone therapy
3) Switch to exogenous testosterone therapy (hormonal replacement)
For couples who would like to keep their fertility options open, I do not recommend switching to exogenous androgen replacement. There is evidence that sperm quality does not always rebound completely when men are on alternating cycles of exogenous and endogenous androgen replacement.
The decision about whether to stop the medications completely or to continue taking clomiphene, anastrazole, or HCG depends on several factors. If the patient had a significantly low total testosterone level (under 250 ng/dL) before therapy began, if a DEXA scan shows evidence of osteoporosis or osteopenia, or if the patient has seen significant improvement in symptoms (such as mood, energy, and sexual function) with increased testosterone levels, then therapy can be continued. However, if total testosterone was only borderline low (over 250 ng/dL) and the man did not notice any change in how he felt while on the medication or felt worse due to bothersome side effects, then he can stop the endogenous testosterone treatment. If the woman is pregnant, I would recommend that the man wait to stop the medication until she has entered the second trimester and everything seems to be going well with the pregnancy. The man can then restart the medications a few months prior to trying for more children in the future.
Couples Who Are Done Having Children
When a couple is 100 percent sure that they are done with their fertility efforts, men with a history of low testosterone should be assessed for the need for ongoing exogenous hormonal replacement therapy. In the United States, exogenous androgens do not come in a safe oral form (due to liver toxicity issues), so some men would prefer to stay on their oral clomiphene or anastrazole rather than switch over to a gel, patch, pellet, or injection. The problem with this approach is that the impact of taking clomiphene and anastrazole on a man’s general health over the course of decades is not known. Estradiol levels play an important role in bone health, so the decreased estradiol levels associated with long-term anastrazole use can have a potential negative impact on bone mineral density. Clomiphene does not decrease estradiol levels, but its different impact on estrogen receptors throughout the body could have unknown health consequences when used for decades. To date, studies looking at clomiphene and bone density have shown conflicting results. Further studies are being performed to see if these medications (especially clomiphene) are safe to take for indefinite periods of time, but we will not have the results of these studies for quite a while. On the other hand, exogenous testosterone replacement has been used for decades and is considered to be fairly safe if accompanied by proper periodic monitoring (including hematocrit and PSA). HCG can theoretically be used long-term since it really is just LH, which is a normal pituitary hormone produced by the body. However, the cost of HCG along with the need for injections three times a week has limited the enthusiasm for long-term maintenance usage.
Men who should strongly consider starting ongoing hormonal replacement therapy (if they do not have other intervening health risk factors) are those who have:
1) Baseline (pre-treatment) total testosterone of under 200 ng/dL
2) History of osteoporosis or osteopenia on DEXA scan
3) Significant improvement in symptoms from previous endogenous testosterone therapy (such as increased energy, mood, or sexual
function)
For men who do not fall into one of these categories, I generally recommend that they stop their clomiphene, anastrazole, or HCG, wait four weeks, and then get a new baseline total testosterone. I would then consider offering ongoing hormonal therapy to men who have a new baseline total testosterone of less than 250 ng/dL, in order to prevent potential health problems related to low testosterone. I would also consider it in men who developed new low-testosterone-related symptoms during the four weeks they were off the medications (such as negative changes in mood, energy, or sexual function).
Men who switch over to exogenous testosterone replacement should be followed with the same guidelines as for clomiphene, anastrazole, or HCG in terms of periodic hematocrit, testosterone levels, PSA, digital rectal exam, and prostate-related symptom scores (as per the ASA guidelines described earlier).