Elevated Estradiol and Male Infertility
Introduction to Elevated Estradiol Levels and Male Infertility Problems
Elevated levels of the female hormone estradiol can potentially have a negative impact on sperm production and quality. Elevated estradiol levels can also lead to gynecomastia (enlargement of breast tissue in men).
There are 2 ways that estradiol levels can be assess:
1) Elevated estradiol level itself
2) The ratio between the testosterone and estradiol levels- this is called the T/E ratio.
Abnormal Estradiol Levels
Abnormal estradiol levels can come in two forms: an elevated estradiol level (I consider over 59 pg/mL to be elevated, though some people use 50 pg/mL as the cutoff for normal), and an abnormal testosterone-to-estradiol (T/E) ratio of over 10:1.
Clinical Effect of Elevated Estradiol
The clinical impact of elevated estradiol levels on male fertility is controversial, as is the impact of an abnormally low testosterone-to-estradiol ratio. However, studies have shown improved fertility and semen parameters in men taking aromatase inhibitors which increase testosterone levels while keeping estradiol levels in balance. [Guo B. Andrology 2022]. In the treatment of male fertility issues, I personally try to normalize estradiol levels in order to obtain a fully optimized hormonal environment for sperm production.
Potential Reversible causes of elevated estradiol levels
Obesity and Drugs
Potentially reversible reasons for an elevated estradiol level include obesity. A large portion of the conversion of testosterone to estradiol by the aromatase enzyme occurs in fat cells, and so obese men are at an increased risk for having elevated levels of estradiol. Other reversible risk factors include excessive alcohol intake, and use of illicit drugs such as amphetamines, heroin, or marijuana.
Medications that Can Increase Estradiol Levels
Certain medications can increase estradiol levels, including:
1) Any medication that increases testosterone levels (SERMs, HCG, T replacement,
anabolic steroids, etc.), as elevated blood testosterone levels promote increased
conversion by aromatase into estradiol
2) H2 blockers, such as cimetidine (Tagamet) or ranitidine (Zantac)
3) Benzodiazepines, such as diazepam (Valium)
4) Tricyclic antidepressants, such as amitriptyline (Elavil), clomipramine (Anafranil), and others
5) Certain cardiovascular medications, including digoxin (Lanoxin), amlodipine (Norvasc), and
spironolactone (Aldactone)
6) The antifungal ketoconazole (Nizoral)
7) The antibiotic metronidazole (Flagyl)
8) Finasteride, whether at doses used to treat prostatic enlargement (Proscar) or at the low
doses used to prevent hair loss (Propecia)
General Health Problems that Can Increase Estradiol Levels
1) Hyperthyroidism
2) Kidney failure
3) Liver failure or cirrhosis
4) Malnutrition
5) Estrogen-secreting tumors (see below)
Estrogen Secreting Tumors
Tumors of the adrenal glands, testicles, pituitary, or breast can produce large amounts of estradiol. These are very rare, but the possibility must be kept in mind, especially if estradiol levels are very high (over 80 pg/mL) and no other reason can be found (such as a medication that can increase estradiol).
Idiopathic elevated estradiol
In some men, no cause for an elevated estradiol level can be found. These men probably have a naturally elevated level of aromatase activity as the cause of their increased estradiol levels. This is a presumptive diagnosis, as there is no commercially available way to directly measure aromatase activity.
Assessment of High Estradiol Levels
When estradiol is elevated, I recommend evaluation for potentially reversible causes, including an assessment of medications being taken as well as a review of alcohol and illicit drug use. A more extensive evaluation is indicated in some men where there is some concern about an estradiol-secreting tumor, though these tumors are very rare. Indications for more extensive evaluation include:
1) Significantly elevated baseline estradiol levels (over 80 pg/mL)
2) Elevated estradiol levels that do not respond to therapy (by, e.g., anastrazole)
3) Estradiol levels that continue to progressively increase over time
Men who fit these criteria should have an evaluation by an endocrinologist, as well as have consideration of undergoing some or all of the following imaging studies:
1) Scrotal ultrasound (looking for testicular tumors)
2) MRI or CT scan of the abdomen and pelvis with contrast (looking for adrenal tumors)
3) Breast exam
4) Pituitary MRI (if pituitary hormone levels are abnormal)
5) Mammogram (if scrotal ultrasound and CT scans are normal)
Any imaging findings consistent with a tumor should be immediately evaluated by an appropriate cancer specialist.
Treatment of Elevated Estradiol Levels
Any risk factors that are discovered should be addressed. Such actions could include:
1) Weight loss in overweight men
2) Decreasing alcohol intake to no more than four drinks per week
3) Stopping marijuana use
4) Stopping medications that can increase estradiol levels, such as changing from ranitidine (Zantac) to omeprazole (Prilosec)
Aromatase Inhibitors
Aromatase inihibitors, such as anastrazole (Arimidex), provides effective medical treatment of elevated estradiol levels. This medication works by blocking the action of the aromatase enzyme, thereby decreasing estradiol levels while increasing testosterone levels. This medication is discussed in more detail in the "Anastrazole" section of this website.
The goal of anastrazole therapy is to normalize estradiol levels to under 59 pg/mL and normalize the testosterone-to-estradiol (T/E) ratio to 10:1 or above. Men taking anastrazole need to be followed with ongoing testing, as described in “Management of Low Testosterone,” earlier in this chapter.
Follow-Up for men with elevated estradiol levels
Men with a history of an elevated estradiol level should be followed with repeat estradiol levels every six months for a year, and then yearly thereafter while on therapy.
For couples who will want more children in the future, the man can stop taking anastrazole after the woman is pregnant or after they have decided to put their fertility efforts on hold, and then restart the medication three months before beginning to try for subsequent children. Men who are done with their fertility efforts can stop anastrazole therapy and have a new baseline estradiol level checked a few months later. Mild persistently elevated estradiol levels (60–80 pg/mL) can be followed with estradiol testing every six to twelve months; if the levels remain stable after two to three years, the testing can be discontinued. There is no good evidence that mildly elevated estradiol levels have a negative impact on health or testosterone-related symptoms, but there is some evidence showing that low estradiol levels in men may have a negative impact on mood, sex drive, or sexual function. Men with very high, persistently elevated estradiol levels (over 80 pg/mL) should consult with their endocrinologist for decisions regarding ongoing monitoring and management. There is some emerging evidence that very high estradiol levels might somewhat increase the risk of cardiovascular events, but prolonged anastrazole use can also potentially increase the risk of osteoporosis and bone fracture.