Low testosterone can occur for a variety of medical reasons including obesity, sleep apnea, prolactinoma and more. Some men can have borderline testosterone or slightly below normal levels; sometimes this will occur without any symptoms and other times symptoms will be present. Symptoms of low testosterone include: low sex drive, loss of morning erection, decreased energy and increased fatigue throughout the day and craving sweets to maintain energy level. Some men also notice a lack of focus or “Brain fog.”
Almost all exogenous testosterone therapy will suppress the normal pituitary stimulation of the testes to make sperm and testosterone. Fortunately, there are a few therapies that can increase serum testosterone levels without impairing spermatogenesis. Two of these medications are clomiphene and Natesto.
Clomiphene is in the class of medications known as SERM or selective estrogen receptor modifier. Clomiphene will block estrogen receptors resulting in increased production of pituitary hormones FSH and LH which stimulate testosterone and sperm production by the testes. Treatment with clomid will almost always increase endogenous testosterone production but is less reliable with respect to increasing sperm production; however, it will almost never decrease sperm production. Clomid is FDA approved as a treatment for female infertility and its use for men is off label.
Natesto is a testosterone gel formulated to apply three times daily inside the nostril. Natesto causes short durations of increased testosterone levels in the blood. Somehow, because these increases are of short duration, FSH and LH production are not significantly changed and sperm production is maintained. Natesto is currently the only exogenous form of testosterone that does not suppress spermatogenesis.
An article by Kavoussi et al in the February 2021 issue of Urology focuses on converting men in this situation from clomiphene to Natesto and reports that Natesto maintained semen parameters and also improved libido and reduced Estradiol.
The study was retrospective chart review looking at 41 patients who switched from clomiphene to Natesto. Interestingly, even though semen parameters did not significantly change during the three month period of evaluation, there was a significant decrease in FSH levels, though levels did stay in the normal range.
MY EXPERIENCE: I agree with study findings regarding symptoms in that it is interesting how testosterone levels can sometimes double on clomiphene and yet the patient will sometimes not feel any different. The clomid dose in the study was either 25 mg or, if an insufficient testosterone level was achieved, the dose was increased to 50 mg. These are double the doses that I use and I find that the higher the dose, the more common it is to have side effects. Furthermore, even though there is discussion of estrogen increasing in these patients, there is no discussion of adding in a second medication such as an aromatase inhibitor like anastrozole to bring estrogen levels back down. Another consideration is that clomid can sometime improve sperm production, whereas Natesto, at best, maintains production at the same level. Finally, there is no discussion of the cost. If the patient pays out of pocket, in my experience Natesto can cost10 times (1000%) the cost of clomiphene.