Treatment of Low Testosterone in Men Desiring Children:
Topical, injectable, and subcutaneous testosterone preparations will have very negative effects on sperm, semen quality (azoospermia is possible), and male fertility. These effects (often mentioned quickly and in small print at the end of the advertisements seen on TV and in magazines) can linger for months or even years after stopping testosterone. This problem is highlighted in the journal Fertility and Sterility in 2014 by Canadian researchers, who describe that over 1% of men seeking fertility treatment were taking testosterone, with 2/3 of men recovering sperm production after 6 months. However, the question remains about the remaining 1/3 and when and whether they recover sperm production.
For men interested in fertility, low testosterone should not be treated with testosterone. However there are several other options that do not harm fertility. Men desiring children may be treated with pulsatile gonadotropin releasing hormone (GnRH) or gonadotropin therapy using purified or recombinant luteinizing hormone (LH), human chorionic gonadotropin (hCG), follicle stimulating hormone (FSH), and/or human menopausal gonadotropin (hMG) preparations. The use of a selective estrogen receptor modulators (such as clomiphene citrate, tamoxifen, toremifene) and aromatase inhibitors for the treatment of men with primary hypogonadism is associated with variable outcomes. Since treatment may be required for up to 24 months for the induction of spermatogenesis in men with longstanding issues with the low testosterone due to an issue with the brain (pituitary or hypothalamus), it is recommended that these men initiate therapy long before immediate desire to have a child. The use of clomiphene citrate (weak estrogen receptor antagonist that competes with estradiol which normally reduces the fuel or gonadotropins that drive testosterone production) for treatment of subfertile men with low testosterone is common, with a typical dose of 25 mg every other day to 50 mg daily, adjusted to achieve ideal serum testosterone. Such treatment with clomiphene citrate in men with low testosterone has been demonstrated to be safe with up to 3 years of follow-up. For patients with primary hypogonadism who have elevated estradiol (E) levels (E >50 pg/mL or Testosterone:Estradiol (T:E) ratio less than 10) treatment with an aromatase inhibitor (anastrozole 1 mg daily, testolactone 100-200 mg daily, or letrazole 2.5 mg daily) may be helpful. Aromatase inhibitors increase serum testosterone by inhibiting the negative effects of estradiol on the brain (pituitary), in addition to directly decreasing the conversion of testosterone to estradiol. Aromatase inhibitors have been shown to improve the T:E ratio and semen parameters in subfertile men, and may be especially helpful in obese men. Unlike TRT, pulsatile GnRH and gonadotropin therapy increases testicular size as well as testosterone levels, which may have psychological benefit for the patient in addition to the effects on fertility.
The benefits of raising testosterone to normal levels includes improvement in energy, strength, sexual function, body composition (increased lean body mass, decreased fat mass), bone mineral density, decreased diabetes, cholesterol and heart issues, mood, and cognition in men of all ages. More trials are needed to establish benefits and adverse effects of raising testosterone with the medications discussed. Risks of treatment include acne, increased male pattern baldness, gynecomastia, decreased spermatogenesis, worsened prostatic enlargement and difficulty urinating (AUA symptom score). Stopping treatment typically reverses these side effects in most men. Serious risks of treatment to raise testosterone include development or acceleration of prostate or breast cancer, but the prostate cancer risk has not been supported by current available studies and low testosterone is being treated in some patients with a history of prostate cancer at certain centers. Men with elevated PSA or abnormal prostate exam, or recent heart issue in past 6 months such as heart attack or congestive heart failure require further evaluation before any consideration of treatment. Other risks include increased blood count, worsening of sleep apnea (abnormal breathing during sleep), worsening of heart failure, and decreased “good” HDL cholesterol in blood. Additional risks of clomiphene citrate are minimal with mild lower extremity edema and visual blurring both rarely reported in men. Of course, your physician in consultation with you will determine which treatment is best for you.
–Matthew Wosnitzer, M.D.
September 10, 2013