Anastrazole / Arimidex for Male Infertility
Introduction to Anastrazole / Arimidex and Male Infertility
Anastrazole is a non-steroidal aromatase inhibitor- the brand name is called Arimidex. Aromatase is an enzyme located in the testicles, fat cells, and the liver that converts part of the testosterone in the bloodstream into estradiol. Anastrazole decreases the action of aromatase, which results in higher testosterone levels and lower estradiol levels. Anastrazole can also raise FSH and LH levels through an inhibition of the negative feedback that estradiol plays on the pituitary gland. [Naelitz BD. FertSteril 2023]
Elevated estradiol levels and abnormal testosterone-to-estradiol (T/E) ratios have been correlated with decreased semen parameters. [Schlegal P. FertSteril 2012]. Therefore for male fertility, anastrazole is commonly used in men with elevated estradiol levels (>60 pg/mL) or abnormal testosterone-to-estradiol ratios (<10:1). For these men with these hormone abnormalities, anastrazole has proven effective in improving abnormal semen parameters. [Raman J. JUrol 2002]
A meta-analysis of studies in 2022 confirmed the ability of anastrazole to increase testosterone, FSH and LH levels while decreasing estradiol levels. Improvements in semen parameters of infertile men with hypogonadism were also confirmed. [Guo B. Andrology 2022]. Because of their different mechanisms of action, anastrazole is commonly used in conjunction with SERMs with studies showing improvements in total motile sperm counts. [Osadchiy V. TranslAndrolUrol 2024]
Libido, Sexual function, and Bone Health
A common misconception is that a man will have decreased libido if his estradiol levels are elevated, implying that estradiol has a negative impact on male sexual desire. Actually the opposite is true. Studies have shown that estradiol actually plays a positive role in promoting male sexual interest as well as erectile function. [Schulster M. AsianJAndrol 2016]. Studies have shown that libido is optimized in men with normal testosterone and estradiol levels that are not too low (in one study that cut-off was 5 ng/dL). [Ramasamy R. EurUrol 2014]
Long term very low levels of estradiol also can increase the risk of osteopenia and osteoporosis. Studies have shown that estradiol has a clear role to play in maintaining good bone health in men. [Vandeput L. NatRevEndocrin 2009]. In contrast, elevated levels of estradiol can increase the risk for gynecomastia in men.
HOW ANASTRAZOLE IS USED
Anastrazole comes in 1 mg tablets. The typical starting dosage in men is 1 mg every other day (although some clinicians have begun to use smaller doses, such as 0.25 mg daily; the smaller-dose tablets must be made by specialty compounding pharmacies). The maximum dose is 1mg daily because of the potential risk of liver toxicity with dosages above this.
When properly used in male fertility, baseline hormones (usually total testosterone, estradiol, LH and FSH) are checked prior to starting anastrazole. Anastrazole can be used for the treatment of hypogonadism either by itself or in combination with a SERM. Usually the use of anastrazole is considered when the estradiol is higher (approaching 60 ng/dL) and/or the T/E ratio is near or less then 10:1.
After starting anastrazole it is always important to check repeat hormone testing 2-4 weeks after starting a SERM. Labs to always check include total testosterone (goal 500-1000 ng/dL), estradiol (goal <60 pg/mL and T/E ratio ³ 10:1) and hematocrit (goal <54%). Possible additional labs include a prolactin (if baseline testosterone was <300 ng/dL) and FSH (if it was inappropriately low at baseline to make sure it increases as expected). Once hormonal levels are normal, I typically repeat labs (testosterone, estradiol, hematocrit) 6 months later, and then every 12 months while the man is taking the medications. Any change in hormone medication or dosage should generally have repeat labs 2-4 weeks later to make sure that there was the appropriate change in the corresponding hormones.
In contrast to SERMs, anastrazole can be effective in men with LH levels >20 IU/L.
COST OF ANASTRAZOLE
The current 2024 cheapest listed price on GoodRx.Com for a month of brand name anastrazole (1 mg every other day) is $11.78.
Side Effects of Anastrazole
Similar to clomiphene, the majority of men taking anastrazole generally do not experience significant adverse side effects and some feel better because of the higher testosterone level.
A review of men taking anastrazole showed that <5% showed decreased libido and another 7.4% had mild elevations of their liver enzymes which was not felt to be clinically significant. [Raman JD JUrol 2002]
A meta-analysis of studies of men on aromatase inhibitors found that 15.2% experienced side effects, but they were mild and reversible upon stopping the medication. The most common side effect seen was again decreased libido in 6.2% of men. Other side effects included subclinical liver dysfunction (2.1%), skin rash (1.2%), headaches (1.2%) and nausea (1.2%). [Guo B. Andrology 2022]
Other rare potential side effects with the use of anastrazole that have been reported include increased blood pressure, rash, paresthesia (sensations of skin tingling, pricking, or burning), malaise, peripheral edema, glossitis (inflammation or swelling of the tongue), anorexia (lack of appetite), alopecia (hair loss; usually resolves spontaneously when the medication is discontinued), erectile dysfunction, and acne (due to increased skin gland oil production; usually subsides after a few months of treatment).
When combined with SERMs, the side effects were still infrequent and mild, though rates are slightly higher. A study of 51 men taking anastrazole along with clomiphene reported the following side effects:
1) Anxiety/irritability 9.8%
2) Decreased libido 7.8%
3) Increased hematocrit 3.9%
[Alder NJ. BJUI 2018]
Osteoporosis
As mentioned above, decreased estradiol levels and the use of aromatase inhibitors have been associated with lower bone mineral densities in men. [Burnett-Bowie SM. JClinEndocrinMet 2009]. Studies in elderly men have shown that men with long term estradiol levels below 20-26 pg/mL are at an increased risk of developing osteoporosis. [Doran PM. JBoneMinRes 2001][Amin S. JBoneMinRes 2000]. It is unclear whether these reference cut-offs are relevant in the young fertility-aged male population.
Short-term use of anastrazole (up to a few years) with proper monitoring and prevention strategies is typically fine in most men, but prolonged use may increase the risk of fractures. If men are going to be taking anastrazole for more than 1-2 years, baseline DEXA scanning may be indicated if estradiol levels are significantly decreased. For more information, see the “Osteoporosis” section of this website.
letrozole (Femara)
Letrozole is another non-steroidal aromatase inhibitor that is commonly used in female fertility. [Guo B. Andrology 2022] It is actually a more potent inhibitor of the aromatase enzyme than anastrazole, but not necessarily more clinically beneficial. Multiple studies have confirmed improvements in sperm counts and motility in hypogonadal men being treated for infertility. [Basar MM. TurkJMedSci 2009][Cavallini G. AsianJAndrol 2013] Though much less commonly used in men, it can be an alternative for men who are allergic to or have significant negative side effects from anastrazole.
Dosing of letrozole in men is 2.5mg once daily.
Cost of letrozole
The current 2024 cheapest listed price on GoodRx.Com for a month of brand name anastrozole (1 mg every other day) is $10.84.
Side effects of letrozole
Letrozole appears to have a similar side effects profile in men as anastrazole with a 2013 study showing that 15% of men dropped out due to side effects which included: decreased libido (7.7%), hair loss (3.8%), and skin rash (1.8%). Some studies have suggested an increased risk of side effects such as nervousness and headaches. [Schlegal PN. FertSteril 2012]. However, it can be used as a possible alternative in men who are either allergic to anastrazole or cannot tolerate that medication for some reason. [Schlegal PN. FertSteril 2012].
testolactone
Testolactone is a steroidal aromatase inhibitor that is currently not available in the United States. Although similar outcomes to anastrazole had been noted in terms of hormonal and semen parameter responses, the steroidal activity of testolactone increased the risk of adrenal suppression with the need to replace corticosteroids and mineralocorticoids. [Schlegal PN. FertSteril 2012]