Currently, there is a controversy on whether to treat patients on exogenous testosterone with high estrogens. One of our goals was to find out
if treatment was given, what the preferred drug might be. In our population, anastrazole (Arimidex) was the most prescribed AI. It does not appear that the preference is based on pricing alone. Of the AIs, the most expensive is Femara (letrozole), followed by Arimidex (anastrozole) and then Novaldex (tamoxifen), which is a SERM. A separate study would be needed to investigate further provider and patient preference.
Do We Need to Treat High E2 After TRT? Anastrozole
This study was not designed specifically to answer this question. A prospective, randomized controlled study would be needed over several years to understand if indeed high E2 after TRT may be beneficial or harmful. Currently, there are no national guidelines that are evidence based for treatment of high E2 after TRT. However, there was a high treatment rate for our group of patients at 30%. Based on interviews with select practitioners, we found that the reasons for the high rates of prescribing AI and SERM are partly patient pressure, practitioner confusion, and fear of the harmful effects of high E2 in long term. Some studies have indicated an association of high estrogens to higher rates of heart attacks, strokes, and prostate cancer (
Basaria et al., 2013;
Kristal et al., 2012;
Lerchbaum et al., 2011). In one such study, higher estradiol levels in men were significantly associated with prevalent strokes, peripheral vascular disease, and carotid artery stenosis compared to lower estradiol levels. High levels of estradiol were also associated with all-cause and noncardiovascular mortality in a large cohort of older men referred to coronary angiography (
Lerchbaum et al., 2011). These studies of association do not infer causality and as such should not be used for the basis for treatment of high estrogen. AI and SERM use may be justified for breast tenderness or gynecomastia. However, gynecomastia is rarely documented in problem list; this is an area of improvement for the practice.
In our study, high estradiol levels did not correlate with higher rates of low libido. On the other hand, low levels of E2 were associated with higher rates of low libido. The explanation could be that low E2 usually results from low testosterone levels, as E2 is aromatized from testosterone. Our study results parallel that of others (
Finkelstein et al., 2013) suggesting a positive role of estradiol in human male libido functioning. There are limitations to our present study and we do declare that our results cannot be generalized. This is based on our methodology of assigning low libido as captured in the problem list. Providers may have not uniformly entered the ICD-9 diagnoses, and hence it may be possible that results may be overstated. The other limitation is that although 34,016 patients who presented to the Centers were screened, only 50% were eligible for treatment, based on inclusion and exclusion factors. The analysis was done on patients who presented to the Centers and were screened and not limited to those on treatment. The correlation of libido is definitely an area for further study.
The effects of estradiol on the human brain are unclear. Currently, there are no hormone markers within the brain to determine the association of levels of sex hormones with libido. In this study a presumption was made that serum estradiol reflects brain estradiol levels or activity. It may be possible that if serum estradiol level is low more estradiol is available for the brain, as it is shifted from the rest of the body to the brain. This hypothesis is given to support the results of our study, of not associating low libido to higher estradiol levels. In a previous study, positive emission tomography was used in an attempt to map areas of the brain involved in glucose metabolism after administration of testosterone. The brain stem and parietal lobes were highly metabolic, suggesting that these areas are involved in sexual processing (
Tan, 2013). There are current arguments for an optimal T:E2 ratio for sexuality (
Shabsigh et al., 2005), rather than the actual amounts, but studies are weakly powered.
Conclusion
Not much work has been done to understand better the role of estrogens in men. There has also been a distinction between work done on endogenous estrogens and also exogenous estrogens, be it given as estrogen itself or converted from testosterone. Our work in a large database of 34,016 patients represents one of the first attempts to understand the characteristics of exogenous estrogens, which in this case are aromatized from exogenous testosterone given to treat hypogonadism. From our study, it appears that age may be a determinant of the conversion of testosterone to estrogens, except for later years in life after 65 years. The clinical importance of high estrogen after TRT continues to be debated. In our study, high estrogen after TRT does not necessarily associate with low libido. However, AI and SERM were prescribed frequently (30% of cases). There are challenges in setting up a guideline for the threshold beyond which AI and SERM are to be used, as there are no evidence-based studies at this time to guide the practice. Normality based on standard deviation can be used, but our study reports that age in itself may cause variations in normal values. Although our study did not associate low libido with high E2 levels; there may be foreseeable dangers to exposure to high estrogen over a longer period of time (
Lerchbaum et al., 2011). The use of AI and SERM should be individualized and carefully monitored. The common side effects of AIs include constipation, diarrhea, nausea, vomiting, upset stomach, loss of appetite, body aches and pains, breast swelling/tenderness/pain, headache, dry mouth, scratchy throat, increased cough, dizziness, trouble sleeping, tiredness/weakness, flushing and sweating (hot flashes/hot flushes), hair thinning, and weight change and should be communicated to the patent. Changes in diet such as eating several small meals may help lessen the chance of nausea and vomiting. More work such as a longitudinal, controlled study is needed to assess the role of exogenous estrogens from TRT and the need to treat this condition.