Understanding Anastrozole: Benefits and Risk of Off-Label Prescribing with Male HRT

Testosterone replacement has become increasingly more common over the last decade, as many male patients are seeking hormonal optimization to improve long term metabolic health outcomes and day to day well-being. Increased testosterone prescribing has also resulted in increased use of anti-estrogenic medications, primarily in off-label prescribing for male patients utilizing testosterone.

Estrogen Synthesis in Men:

While the testicles are largely responsible for endogenous testosterone production, only a small percentage of male estrogen is produced by the testes. The vast majority of male estrogen is produced in peripheral tissue, e.g., adipose tissue, bone, via the aromatase enzyme. The aromatase enzyme converts testosterone to estrogen, primarily estradiol, in the male body. For this reason, substantial and abrupt increases in serum testosterone values like those experienced with testosterone replacement therapy will often result in a significant increase of serum estrogen values. Often times, additional pharmacologic intervention is required to mitigate potential estrogenic side effects, e.g., weight gain, gynecomastia, clot risk and mood disturbance.

Common Anti-Estrogen Medication(s): SERMS vs Aromatase Inhibitors

There are two common classes of drugs used in HRT practices to mitigate the potential negative effects of significantly increased estrogen levels in male patients: SERMs (Selective Estrogen Receptor Modulators) and AI’s (Aromatase Inhibitors).  SERMs, like Clomiphene and Tamoxifen do not mitigate estrogen conversion from testosterone, instead, they bind to estrogen receptors sites on target cells to reduce estrogen uptake at the cellular level. While SERMs may mitigate some estrogenic symptoms, they can be difficult for doctors to titrate, as quantitative estrogen values do not change on laboratory results, leaving dose adjustment based solely on subjective data (symptoms). Aromatase Inhibitors reduce the creation of estrogen from testosterone by binding to the aromatase enzyme’s heme ion. For this reason, aromatase inhibitors give medical providers more concrete quantitative data to assess safety and efficacy of care, as they will result in changes in serum estrogen concentrations. Both classes of drugs have been used “on-label” for the treatment of estrogen receptor positive breast cancer for many years. When used in combination with testosterone for men, these drugs are used in an “off-label” manner, meaning they are being used for purposes beyond their traditionally intended use as identified by the manufacturer and FDA.  

Concerns with Aromatase Inhibitors:

The use of aromatase inhibitors has come under great scrutiny as of recent due to growing concern for potential side effects of these drugs for male patients. Unfortunately, much of this concern is a result of incomplete information or misinterpretation of clinical literature. To understand the benefits and potential side effects of aromatase inhibitors, we must also understand the systemic effects of estrogen and data published on the drugs themselves.

Estrogen plays many essentials roles in the female and male body, including, but not limited to: regulation of osteoblasts for healthy bone formation, maintenance of vascular endothelial tissue, and neural cell protection. For this reason, the over-suppression of estrogen can become problematic. Many patients researching aromatase inhibitors online may see potential side effects such as bone density loss (Osteopenia/Osteoporosis), joint pain, cognitive decline, and reduced cardiovascular health. However, it is important to understand that the associated potential side effects are under conditions of “on-label” prescribing. In instances of estrogen receptor positive breast cancer, aromatase inhibitors are used as a means of complete estrogen suppression, often times resulting in patients’ estrogen being consistently maintained below detectable serum levels. It is the complete suppression of estrogen that results in the aforementioned side effects or complications from aromatase inhibition.  However, in a testosterone replacement setting, the dosing of aromatase inhibitors is typically much lower and non-suppressive in nature. Appropriate “off-label” use of aromatase inhibitors allows HRT doctors to mitigate potential excess accumulation of estrogen, while still maintaining levels in a healthy, physiologic range that is proportionally balanced relative to serum total and free testosterone values.

Factors that Influence Aromatization:

The aromatization of testosterone to estrogen is a naturally occurring process for all men and provides the bulk of endogenous estrogen. While testosterone and estrogen generally have a substrate to product relationship, several factors may influence the rate of aromatization in regards to testosterone replacement, including body composition, dose volume and frequency of administration. Adipose tissue is one of the body’s primary sites of aromatization, therefore, maintaining an appropriate body weight with lower body fat percentage can reduce the likelihood of excessive aromatization with testosterone replacement. Administration of a patient’s weekly dose, split into multiple, smaller doses may also help reduce estrogen creation. Patient’s will generally aromatize testosterone the most during the transient post-injection peak, therefore, administration of smaller, more frequent doses that reduce the magnitude of transient post-injection peak, may help control the aromatization profile relative to larger, once weekly bolus doses.

It’s important that testosterone replacement and aromatase inhibitors are managed by an experienced and knowledgeable clinic with routine blood work monitoring and follow-up to ensure the safety and efficacy of care.

Author: Joseph Matovich