The effect of testosterone replacement therapy on erythropoiesis in middle aged and aged men: a systematic review protocol
Authors: Lowrance Kenneth , Sapp Alysha 
Published: December 2014

Review question/objective
The quantitative objective is to identify the effect of testosterone replacement therapy on erythropoiesis in middle aged and aged men due to potential complications that could result.
More specifically, the review question deals with the red blood cell volume as measured by hematocrit, hemoglobin, and/or red blood cell count in the selected population receiving testosterone replacement therapy.

Background
Throughout history, men have been concerned with strategies to preserve and enhance their virility. Many creative approaches have been utilized. Testes were viewed as being the source of vigor and longevity for men. For Greek and Roman men, consumption of a substance called "satyricon" was a popular treatment. This substance was a combination of goat and wolf testicular extracts. The 19th and 20th centuries brought an emergence of treatment derived from organs: thyroid extract and animal testicular extract were thought to be effective in maintaining virility. Technology progressed, and in the 1930s, it became possible to isolate various androgens from animal tissue. At this time, these substances were applied in clinical situations.2

Testosterone deficiency in men, oftentimes referred to as "Low T", has become a common concern for men globally. Testosterone is a hormone responsible for the secondary characteristics that appear at puberty. It has a potent effect on stimulating libido, sexual desire, and arousal. Testosterone is also an anabolic hormone that enhances metabolic processes in muscles, bones, bone marrow, the immune system, and the brain.3,4

A low testosterone level is a universal finding in hypogonadism in older men. Hypogonadism is a common syndrome among aging men over 60 years of age characterized by symptoms of decreased libido, erectile dysfunction, decreased vitality, decreased muscle mass, increased adiposity, depressed mood, osteopenia, and osteoporosis. In many instances, a significant percentage of men over 60 have testosterone levels below the lower limits of young male adults.1

In some countries, notably the USA which represents about 90% of the market for testosterone products, treatment is becoming more widely implemented due to increased public awareness of testosterone replacement promoted by such factors as internet information, safer and more convenient products, and easier access through private physicians and clinics rather than state-funded systems in some countries.5 In the USA, the market for testosterone therapies has increased from $49 million to almost $400 million between 1997 and 2003, with the majority of prescribing being for men 40 years or older.6

In contrast, European statistics indicate that 1% or less of men with symptoms of testosterone deficiency are treated.5 The exception is Germany where hypogonadism is better recognized and more accepted.5 In Russia, the testosterone market demonstrates doubling of spending on all testosterone preparations between 2001 and 2007.5 An issue of concern in Russia that may contribute to a lack of increased utilization of testosterone replacement deals with a most commonly prescribed form of replacement, methyl testosterone, which is low cost, yet toxic.5

A study by Harman et al.7 in the United States suggested that approximately 20% of men in their 60s and approximately 50% of men in their 80s have total serum testosterone levels below those of normal young men. The European Male Aging Study (EMAS)8 estimated a much lower prevalence of 2.1% for hypogonadism in this population. Even though several longitudinal and cross-sectional studies have been carried out to determine the prevalence of hypogonadism in men, the actual prevalence of low serum testosterone is not known with certainty, but it is projected to be up to 25% of middle aged and aged men.1

Heavy direct marketing activities related to testosterone replacement products to consumers in the USA may have increased awareness and interest in the concept of low testosterone and its effects.9 Identified symptoms of low testosterone are highlighted in marketing campaigns noted on television as well as in the print media, thereby triggering consumers to self-diagnose and to request testing from healthcare providers. Clinics specializing solely in low testosterone have appeared throughout the world.
In the minds of many consumers, testosterone replacement is viewed as a potential "fountain of youth". Even though advertisements for testosterone replacement products touch on potential adverse effects of this therapy, many consumers fail to comprehend the potential seriousness of potential adverse effects. Their focus is on a treatment perceived by them as simple which on the surface appears to possess the capability to restore vitality and enhance quality of life.
While testosterone deficiency can be diagnosed with sensitive laboratory testing, testosterone replacement should not automatically be instituted without taking a comprehensive medical history and performing a detailed physical examination to rule out other potential causes of testosterone deficiency and to identify any contraindications to therapy. The Endocrine Society published clinical guidelines in 2010 entitled Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes.10 These guidelines recommended diagnosing hypogonadism only in men with consistent symptoms and unequivocally low serum testosterone levels. The Society recommended the measurement of morning total testosterone levels by a reliable assay as the initial diagnostic test validated by a second measurement of morning total testosterone level on a separate day.10

The syndrome of hypogonadism with accompanying low testosterone levels can be classified as primary, secondary, and mixed. Primary hypogonadism results from disorders of the testes that lead to decreased testosterone levels and infertility. Laboratory values for individuals with primary hypogonadism show low testosterone and elevated leutenizing hormone (LH) and follicle stimulating hormone (FSH) levels. Secondary hypogonadism results from disorders of the hypothalamus and the pituitary gland. Laboratory values for men with this disorder demonstrate low testosterone and low or inappropriately normal LH and FSH levels. Mixed hypogonadism can result from dual defects in the testes and the pituitary-hypothalamic axis. The laboratory values found in mixed hypogonadism can be varied including cases with low testosterone with mild increases in LH and FSH levels.1

Many times in older men, the type of hypogonadism found is either secondary or mixed. Decline in testosterone levels can be due to several factors including: decline in Leydig cell function, decline in pituitary hypothalamic axis function with loss of circadian variation, increase in levels of sex hormone binding globulin (SHBG), changes in testosterone receptor sensitivity, and effects of altered cardiometabolic and inflammatory markers.11,12,13 Appropriate diagnosis of hypogonadism must be achieved via symptom analysis, quality of life assessment, physical findings, and appropriate and correctly performed laboratory testing techniques.
One source claims that on a significant number of occasions, prescriptions for testosterone replacement products have not been based in clinical practice and testosterone testing standards.14 Testosterone replacement therapy is not without significant risk. Consideration of these risks is essential for patient safety. Possible adverse effects related to testosterone therapy include cardiovascular disease, sleep apnea, erythrocytosis, prostate issues, softer testes, gynecomastia, and increased visceral obesity.1 Erythrocytosis, the focus of this systematic review, is defined as an increase in the number of circulating red blood cells, especially resulting from a stimulus. This situation of increased red blood cell volume is also known as polycythemia.15

In terms of red blood cell volume, men with hypogonadism have lower volumes.1 The anemia in aging hypogonadal men has been suggested to be partly due to the declining testosterone levels and partly due to effects of erythropoietin and erythroid progenitor cells.1 Testosterone replacement therapy can restore the anemia levels of older men to the normal range.17,18 Multiple routes of administration of testosterone replacement products exist: oral, injectable, scrotal and nonscrotal transdermal, buccal testosterone, and testosterone gel.1 Testosterone can act directly on bone marrow, increasing the number of burst forming units and erythropoietin-responsive cells which can increase red blood cell volume. It has also been reported that enhanced intestinal iron absorption which can contribute to increased red cell production is an effect of testosterone replacement therapy.19 An early study in 1968 posited that testosterone induces erythropoietin production.19 This has since been refuted as the assay used in the referenced study is now considered inaccurate because it is indirect and depends on red blood cell turnover. A recent randomized controlled trial of 96 subjects to study the effect of testosterone on erythropoietin production concluded that the hematopoietic effect of testosterone does not appear to be mediated by stimulation of erythropoietin production.19 Regardless of the mechanism by which there is an association of red blood cell volume increase in patients receiving testosterone replacement, potential consequences of increased volume must be taken into account for patient safety.
Although an increase in red blood cell volume as measured by hemoglobin, hematocrit, and/or red blood cell count is generally beneficial for hypogonadal men with anemia, an increase of blood volume as measured by these parameters can lead to increased blood viscosity and an array of associated problems. This increased viscosity can exacerbate vascular disease. While all potential adverse effects of testosterone replacement therapy are of concern, those associated with increased blood volume pose significant potential risks such as stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism.1 As a result, the importance of appropriate clinical monitoring of adverse effects is essential to assure patient safety.
The performance of this proposed systematic review will focus on men age 45 and older receiving testosterone replacement therapy and its effect on red blood cell production and volume increase. No other systematic reviews on this topic have been discovered during the review of literature. This information will be important for healthcare providers who prescribe testosterone replacement therapy or manage individuals receiving this intervention. A review of studies will assess the potential significance and prevalence of increased blood volume in men aged 45 and over as measured by hemoglobin, hematocrit, and/or red blood cell count.