When to Treat Low Testosterone in Diabetes and Obesity

Ute Eppinger

July 15, 2022

Men with type 2 diabetes are at higher risk for testosterone deficiency. And in turn, hypogonadism is commonly associated with metabolic syndrome or type 2 diabetes. However, this does not imply a specific need for action, as Stephan Petersenn, MD, media spokesperson for the German Society of Endocrinology (Deutschen Gesellschaft für Endokrinologie, or DGE), clarified at the joint conference of the DGE and the German Diabetes Society (Deutscher Diabetes Gesellschaft).

"Even for patients with diabetes or obesity, a screening is in line with the general recommendations for diagnosing hypogonadism," said Petersenn, referring to the current guideline from the Endocrine Society. According to the guideline, obesity or diabetes alone does not constitute a reason for screening for a testosterone deficiency.

But because pronounced obesity can contribute to functional hypogonadism, the specific symptoms of testosterone deficiency should be searched for.

Typical symptoms are reduced libido, erectile dysfunction, lack of morning erections, feeling of tightness in the chest area, gynecomastia, reduced secondary hair growth and a decrease in shaving frequency, testicular involution, infertility, hot flashes, excessive sweating, and signs of osteoporosis.

Nonspecifically, testosterone deficiency can express itself as decreased energy, reduced endurance and muscular strength, depression, lack of ability to concentrate, decrease in memory capacity, fatigue, and increased fat mass.

Incorporate SHBG

To determine testosterone levels, Petersenn recommended that the sex hormone–binding globulin (SHBG) level be incorporated during interpretation or that BMI-dependent testosterone threshold values be considered. The basis for this is that free testosterone only accounts for about 0.5%-3% of the total testosterone; the predominant share is bound to albumin and SHBG.

Reduced SHBG levels are an observed symptom in obesity, diabetes, nephrotic syndrome, hypothyroidism, and acromegaly, as well as during glucocorticoid therapy. Increased SHBG levels are detected in later life, with hepatitis and HIV, with hyperthyroidism, and during therapy with certain anticonvulsants.

If the total level of testosterone is reduced, free testosterone should be calculated, considering the SHBG. After determining total testosterone, albumin, and SHBG, free testosterone can be estimated using approximation formulae such as the Vermeulen formula. If the total testosterone is in the normal range, then treatment-dependent hypogonadism should not be assumed.

For obesity and diabetes, the goal of substitution is to improve the specific symptoms and not primarily to support weight loss or to achieve better glycemic control.

Multiple Morning Measurements

When estimating the testosterone level, it should be considered that the level in men older than 40 years decreases by 1%-2% each year. The circadian rhythm of testosterone should also be considered, with maximum levels in serum occurring in the early hours of the morning and up to 24% lower levels over the course of the day, a drop in testosterone by up to 25% in a nonfasting blood sampling, and the influence of acute diseases and certain drugs (opiates, glucocorticoids).

In this regard, Petersenn indicated that the threshold value at which typical symptoms of testosterone deficiency occur and that may be improved through substitution has not yet been established for certain, and it differs for the individual clinical symptoms.

For most men, this corresponds to the lower threshold limit of the normal range for young men of approximately 10.4 nmol/L (3 mg/mL). Therefore, current guidelines suggest that hypogonadism should then be diagnosed if morning testosterone levels are repeatedly measured as below this threshold value.

In this regard, Petersenn provided a reminder that individual measurements should be analyzed critically, because 30% of men with slightly reduced testosterone values at the initial measurement later exhibit normal values at the repeat measurement. "Testosterone exhibits a significant variability from day to day, such that two independent testosterone measurements are required when diagnosing hypogonadism," said Petersenn.

The measured values should be interpreted while considering age and BMI, and determining the testosterone level during an acute disease is not sensible.

The aim of substitution in men is to achieve a stable normalization of the level in serum. Increases in sexual fantasies, sexual activity, and nocturnal erections should be expected. An increase in hair growth, an increase in muscle strength with simultaneous loss of fat mass, and an increase in bone density are all observed. Energy levels and endurance commonly increase as well.

Because prostate cancer largely depends on hormonal stimuli, it is a relative contraindication for testosterone substitution. Therefore, before starting substitution, a urologic examination, including ultrasound of the prostate and a PSA determination, is always necessary, whereby low PSA values do not rule out occult prostate cancer with low testosterone levels.

Further contraindications include a hematocrit > 50%, therapy-resistant urinary tract infections associated with prostatic hyperplasia, and therapy-refractive heart failure.

Biased Discussions of Cholesterol

Although in the current guidelines, the low-density lipoprotein (LDL) cholesterol target values for very high-risk patients have been lowered again (from 70 mg/dL to < 55 mg/dL), the media sometimes features heated discussions about the so-called "cholesterol lie."

"The causal role of LDL cholesterol in the development of cardiovascular diseases has been proven for a long time and without scientific challenge. The higher the LDL cholesterol, the higher the risk of suffering from cardiovascular disease," said W. Alexander Mann, MD, medical director at the Endocrinology Center in Frankfurt am Main, Germany.

The biased discussion about the meaning of cholesterol is, according to Mann, "not conducive to the necessary acceptance of a therapy," especially considering that most patients are still not receiving target value–adjusted therapy. The results of the EUROASPIRE V study show that in Germany, LDL cholesterol is below the previous target value of 70 mg/dL in fewer than 30% of those afflicted.

Cholesterol-reducing therapy is a core component of reducing the risk for cardiovascular events. In the event of high or very high risk in secondary prevention, pharmacologic therapy is essential to achieve the target values, emphasized Mann.

The study results from FOURIER and ODYSSEY showed that there was no lower LDL cholesterol threshold value when reducing cardiovascular risk, according to Mann. The negative consequences of a very low LDL cholesterol level were also not detected. Unlike for blood sugar and blood pressure, there is no so-called "J curve." A high HDL cholesterol level is also not enough to balance out the cardiovascular risk of elevated LDL cholesterol.

Excellently Equipped Toolbox

For target value–adjusted therapy of elevated LDL cholesterol, there are various therapeutic options that are administered in the form of an incremental regimen. Therapy is first administered using statins. The highly effective atorvastatin and rosuvastatin are useful above all. "Five million people are being treated with statins in Germany," said Mann. In Germany, the therapy is usually uptitrated in line with the target values. For most patients, even 5 mg of rosuvastatin can lead to significant reductions in LDL cholesterol.

Should the target value not be reached under 40 (80) mg of atorvastatin or 20 (40) mg of rosuvastatin, the cholesterol absorption inhibitor ezetimibe is also administered. This combination therapy decreases the LDL cholesterol level by more than 60%.

The most important side effect of statin therapy to note is muscle pain. "This is reported by 10% of patients," said Mann. He asked that the potential side effects be openly discussed with patients and that information about them be provided. "This ensures that the patient also takes their medication."

If the side effects are too radical, a switch to a different, potentially weaker, statin is possible, as is a dose reduction or the use of alternative preparations, such as bempedoic acid in combination with ezetimibe or ezetimibe alone.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are used in patients with serious familial hypercholesterolemia and a highly positive family history, as well as in secondary prevention. With these antibodies, which are intended to be administered subcutaneously, an additional LDL cholesterol reduction of 50%-60% can be achieved with a favorable side effect profile.

Inclisiran, another therapeutic option, is an antisense oligonucleotide against PCSK9. The last resort then is LDL apheresis.

An antisense oligonucleotide against lipoprotein is highly anticipated. "We have an excellently equipped toolbox on hand to reduce cholesterol, but it is being used too little," said Mann.

This article was translated from the Medscape German edition .

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