Research Report: Testosterone vs. aromatase inhibitor in older men with low testosterone: Effects on cardiometabolic parameters

This new study (Oct 28, 2016) assessed the effects of long-term testosterone replacement (TT) and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers in older non-diabetic men with low testosterone levels (≥65 years, mean age 71 ± 3 years, serum total T < 350 ng/dL).

Researchers from the National Institute on Aging and Harvard Medical School examined the effects of testosterone replacement (5 g transdermal testosterone gel) versus an aromatase inhibitor (1 mg Anastrozole), taken daily for one year. There were ten men randomly assigned to each group and the study was double-blinded and placebo-controlled. There nine age- and testosterone level-matched men in the placebo group (age=72 ± 3; serum total T = 302.6 ± 95.1 ng/dL).

Aromatase Inhibitors

Aromatase inhibitors (AI) stop the conversion of testosterone into estradiol by inhibiting aromatase, (CYP19A1, a member of the cytochrome P450 superfamily), the enzyme that synthesizes estrogens from androgens. Estradiol is a strong inhibitor of the pituitary/gonadal axis in men, which makes inhibition of its synthesis through AI a pathway to increase circulating gonadotropins (testosterone precursors).

The same researches reported (Dias, et al, 2015) that a 12-month AI intervention in older men with low testosterone raised serum testosterone levels into the normal range and resulted in improved lean body mass and muscle strength. That study, however, did not examine the long-term effects of AI on glucose homeostasis, insulin sensitivity and cardiovascular risk markers.

Using AIs rather than testosterone replacement in older men is thought to be a way to avoid possible complications with prostate enlargement due to androgen stimulation (higher T levels often result in increased PSA scores). The prostate is less likely to be impacted by endogenous T (produced by reduced estradiol, from AI intervention) than by exogenous T (from T replacement therapy).

The researchers in this study did not mention the prostate issues but, rather, possible cardiometabolic issues of increased androgen (decreased HDL cholesterol and increased triglycerides), both of which can be ameliorated with high DHA-fish oil supplementation and a healthy, low-sugar diet (as well as regular exercise).

The primary outcome in the study was the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), which marks for both the presence and extent of any insulin resistance.

Secondary outcomes included:

• OGIS (oral glucose insulin sensitivity) in response to OGTT (oral glucose tolerance test), essentially a test of insulin sensitivity, which is a good prognostic for metabolic syndrome and diabetes
• fasting lipids, a "lipid panel" that includes cholesterol, triglycerides, and high-density lipoproteins (HDLs) as primary markers, but generally will include low-density lipoproteins (LDLs) and very-low-density lipoproteins (VLDLs)--Type 2 diabetes tends to have high triglycerides levels and low HDL levels
• C-reactive protein (CRP), a marker for inflammation, especially as an indicator of heart disease 
• adipokines, which are cytokines (cell-signaling proteins) secreted by adipose tissue (fat), the most well-known of which are leptin, adiponectin, and interleukin-6 (but there are hundreds)--in obesity, leptin sensitivity is decreased (results in lowered awareness of fullness); adiponectin is reduced in diabetics compared to non-diabetics and weight reduction significantly increases circulating concentrations (so high adiponectin = lower body weight)
• abdominal and mid-thigh fat by computed tomography, as indicators of lowered insulin effectiveness (sensitivity) that causes increased body fat storage

All outcomes were assessed at baseline and 12 months.

TAKEAWAYS

Insulin Function

• At the end of 12 months, neither insulin resistance nor insulin sensitivity were improved.
• Likewise for fasting glucose and insulin levels. 
• Further, the AI group experienced decreased insulin sensitivity in muscle.

Gonadal Hormones

• Testosterone levels in both groups significantly increased from baseline into the target range. 
• Serum estradiol levels significantly increased in the TT group. 
• A reduction in estradiol was seen in the AI group. 
• Serum sex-horomone binding globulin (SHBG) levels did not change in any group. 
• Gonadotropin levels were suppressed in the TT group.
• Gonadotropin levels increased in the AI group. 

The decreased insulin sensitivity in the AI group more than offsets the reduced estradiol and increased gonadotropin levels in the AI group.

My suggestion, based on this study (and remember, I am NOT a doctor): Traditional TT models are sufficient and might be improved with a 2x weekly dose of an AI.

Further, the most common methods of TT are somewhat erratic--both intramuscular injections and topical applications are unreliable in terms of providing stable levels of testosterone. On the other hand, newer research suggests subcutaneous injection of testosterone enanthate or cypionate may provide more stable and sustained T levels.

IN DEPTH

Testosterone vs. aromatase inhibitor in older men with low testosterone: effects on cardiometabolic parameters

Dias JP, Shardell MD, Carlson OD, Melvin D, Caturegli G, Ferrucci L, Chia CW, Egan JM, Basaria S.

Andrology. 2016 Oct 28. DOI: 10.1111/andr.12284. [Epub ahead of print]

Abstract

Testosterone (T) replacement is being increasingly offered to older men with age-related decline in testosterone levels. The effects of long-term testosterone replacement and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers were determine in older non-diabetic men with low testosterone levels. Men ≥65 years, mean age 71 ± 3 years with serum total T < 350 ng/dL were randomized in a double-blind, placebo-controlled, parallel-group, proof-of-concept trial evaluating the effects of 5 g transdermal testosterone gel (TT) (n = 10), 1 mg anastrozole (n = 10) or placebo (n = 9) daily for 12 months. Homeostatic Model Assessment of insulin resistance (HOMAIR ) was the primary outcome. Secondary outcomes included OGIS in response to OGTT, fasting lipids, C-reactive protein (CRP), adipokines, and abdominal and mid-thigh fat by computed tomography. All outcomes were assessed at baseline and 12 months. After 12 months, absolute changes in HOMA-IR in both treatment arms (TT group: -0.05 ± 0.21); (AI group: 0.15 ± 0.10) were similar to placebo (-0.11 ± 0.26), as were CRP and fasting lipid levels. Adiponectin levels significantly decreased in the TT group (-1.8 ± 0.9 mg/L, p = 0.02) and abdominal subcutaneous fat (-60.34 ± 3.19 cm2 , p = 0.003) and leptin levels (-1.5 ± 1.2 ng/mL, p = 0.04) were significantly lower with AI. Mid-thigh subcutaneous fat was reduced in both treatment arms (TT group: -4.88 ± 1.24 cm2 , p = 0.008); (AI group: -6.05 ± 0.87 cm2 , p = 0.0002). In summary, in this proof-of-concept trial, changes in HOMA-IR AI were similar in all three groups while the effects of intervention on subcutaneous fat distribution and adipokines were variable. Larger efficacy and safety trials are needed before AI pharmacotherapy can be considered as a treatment option for low T levels in older men.

The primary purpose of the study (in layman's terms) was to determine if aromatase inhibition (AI) therapy can be as effective as testosterone replacement therapy in controlling diabetes in older men.

The results are interesting but do not seem to support use of AI over TT in men from this age cohort, while also not ruling it out either.

RESULTS

Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and other glucose homeostasis measures

• At the end of the 12-month intervention, HOMA-IR levels were not significantly altered in any of the three group.
• Oral glucose insulin sensitivity (OGIS) was also not statistically altered by any of the treatment regimens.
• The fasting glucose and insulin levels remained unchanged. 
• The total AUC _{0–120 min} for plasma glucose for the three groups was similar.

[AUC = area under the curve = the shape of the plasma glucose course measured at 0, 30, 60, 90, and 120 min during an oral glucose tolerance test (OGTT), based on consuming 75 grams of glucose.]

• However, on analyzing the total insulin response to the glucose challenge, the total AUC _{0–120 min} for plasma insulin was significantly increased in the AI group at 12 months, compared to baseline (p = 0.04) and was not significantly different in the other groups (p > 0.05). 
• Upon further analysis, this increase was evident in the late post-glucose period, which is the muscle glucose uptake phase of insulin action (AUC Insulin _{40–120 min} = 8707.08 ± 2399.11 post-treatment, compared to pre-treatment: 6390.12 ± 1579.27, p = 0.04). 
• No increase was seen in the early post-glucose phase (AUC insulin _{0–20 min}).

These later results (in bold) are interesting because they suggest that additional insulin was needed at the muscle-uptake stage of glucose metabolism in the AI group, but not in the TT group. The authors:

However, and interestingly, an increase in insulin secretion was observed during the muscle glucose uptake phase (40–120 min) of the OGTT in the AI group, pointing to reduced insulin action and illustrating the importance of studying the whole body response to a metabolic challenge. These findings suggest that estradiol is a modulator of muscle insulin sensitivity and are consistent with some animal studies showing that estrogen receptor-α is important for insulin action (Ribas, et al, 2010). These findings should be confirmed in future trials.

For those men who use AIs in place of TT to maintain normal androgen levels, this might be of concern. At the very least, men taking AIs should be doing due diligence to maintain high peripheral insulin sensitivity. Weight training is the easiest way to do this, as well as maintaining a healthy body fat level. A healthy diet low in fructose (1-2 pieces of whole fruit a day) can support good insulin sensitivity (cut out high-fructose corn syrup, fructose sweeteners, table sugar, fruit juice, fruit smoothies, and dried fruit). Supplemental interventions might include curcumin, resveratrol, and cinnamon.

Additional Results

* Changes in gonadal hormones

In both the intervention groups, testosterone levels significantly increased from baseline into the target range. Serum estradiol levels significantly increased in the TT group while a reduction was seen in the AI group. Serum sex-horomone binding globulin (SHBG) levels did not change during intervention in any of the groups. As expected, gonadotropin levels were suppressed in the TT group, whereas they increased in the AI group.

* Adipocytokines

At 12 months, circulating C-reactive protein (CRP) level was not significantly altered in any of the groups. Circulating leptin levels, however, were significantly decreased in the AI group only compared to baseline (me: possibly suggesting impact of decreased insulin resistance?). In contrast, circulating adiponectin levels significantly decreased only in the TT group (me: paradoxical result?).

* Abdominal and mid-thigh fat

Abdominal subcutaneous fat was significantly decreased in the AI group after 12 months while no changes in abdominal visceral fat was seen in any of the groups (me: the failure of either treatment to reduce visceral fat does not seem to promote heart-healthy outcomes, considering the correlation of visceral fat with diabetes and heart disease--the mechanisms would be interesting to know). Mid-thigh subcutaneous fat significantly decreased in both TT group and AI group compared to placebo.

* Fasting lipid profile and BMI

At 12 months, BMI and waist circumference were not significantly different in any of the groups from baseline measurements. Furthermore, no significant changes were seen in fasting lipids after 12 months.