Androgen Receptor Gene CAG Repeat Length and Body Mass Index Modulate the Safety of Long-Term Intramuscular Testosterone Undecanoate Therapy in Hypogonadal Men
Abstract
CONTEXT: A reliable form of androgen substitution therapy regarding kinetics, tolerance, and restoration of androgenicity is paramount in hypogonadal men. Intramuscular injection of the long-acting ester testosterone undecanoate (TU) offers a new modality. OBJECTIVE: The objective of the study was to assess the safety of TU regarding metabolic and pharmacogenetic confounders. DESIGN: This was a longitudinal one-arm open observation trial. A minimum of five individual assessments was a prerequisite. Putative modulators of safety parameters entering regression models were nadir and/or delta total testosterone concentrations, body mass index, androgen receptor (AR) gene CAG repeat length, and age. SETTING: The study was conducted at an andrological outpatient clinic. PATIENTS: Patients included 66 hypogonadal men (mean age 38 +/- 9.9 yr). MAIN OUTCOME MEASURES: A total of 515 data time points each related to prostate, erythropoiesis, lipoproteins, and circulation during 118 treatment-years with 1000 mg TU at 10- to 14-wk intervals. RESULTS: Testosterone substitution resulted in significant decrements of serum levels of low-density lipoprotein-cholesterol, resting diastolic and systolic blood pressure, and heart rate. Erythropoiesis was stimulated and concentrations of high-density lipoproteincholesterol increased. Parameters remained stable after four injections. No adverse effects regarding the prostate were observed. Significantly increased hematocrit greater than 50% was predicted by enhanced androgen action (shorter AR CAG repeats per higher testosterone levels). However, insufficient androgen action (longer AR CAG repeats per lower testosterone levels) caused pathological safety parameters (high blood pressure, adverse lipid profiles). In addition, a body mass index 30 kg/m(2) or greater represents a clinically relevant factor for the occurrence of all pathological safety parameters. Risk calculations for obese patients and nonlinear pharmacogenetic models to tailor androgen substitution are presented. CONCLUSIONS: Testosterone substitution with im TU is generally well tolerated. Modifications of androgen action are due to both AR CAG repeats and testosterone levels. Adverse observations are mostly seen in obese patients.
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Prostate-specific antigen and prostate volume rise marginally and plateau at 12 months during testosterone treatment.
“Prostate-specific antigen and volume rise, marginally, plateauing at 12 months; further increase should be related to aging rather than therapy.”
From Onset of effects of testosterone treatment and time span until maximum effects are achieved (2011) · cites this paper as [44]
Low-density lipoprotein cholesterol decreases after 3 months, after 40-44 weeks, or after 12 months of testosterone treatment, with a maximum observed after 24 months.
“The decrease in low-density lipoprotein cholesterol seems somewhat slower: after 3 months (35), after 40–44 weeks, (44) or after 12 months (42) with a maximum observed after 24 months (32).”
From Onset of effects of testosterone treatment and time span until maximum effects are achieved (2011) · cites this paper as [44]
High-density lipoprotein cholesterol increases after 3 months, increasing further during 12 months, after 6 months, or close to 1 year, with continuous increase over 24 months.
“An increase was found to occur after 3 months increasing further during 12 months (43), after 6 months, (35) or close to 1 year (44). Continuous increase was observed over 24 months (32).”
From Onset of effects of testosterone treatment and time span until maximum effects are achieved (2011) · cites this paper as [44]
Resting heart rate decreases after 40-44 weeks of testosterone treatment.
“A decrease in the resting heart rate occurred after 40–44 weeks (44).”
From Onset of effects of testosterone treatment and time span until maximum effects are achieved (2011) · cites this paper as [44]
Higher age is a factor in the effects of testosterone on red blood cell formation.
“The effects of testosterone on red blood cell formation (hemoglobin and hematocrit) are dose dependent (14, 82, 83) while higher age is also a factor (44).”
From Onset of effects of testosterone treatment and time span until maximum effects are achieved (2011) · cites this paper as [44]
Prostate volume increases after 3 months and after 12 months of testosterone treatment.
“An increase in prostate volume was noted after 3 months (86) and after 12 months (44).”
From Onset of effects of testosterone treatment and time span until maximum effects are achieved (2011) · cites this paper as [44]
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- Authors
- Zitzmann, M., & Nieschlag, E.
- Affiliations
- University Hospital Münster (DE)
- Corresponding author
- Nieschlag, Eberhard
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2007-10-01
- Volume
- 92
- Issue
- 10
- Pages
- 3844-3853
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2127886125
- Cited by
- 216
- References
- 60
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 9 · 2023: 12 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 8 · 2018: 4 · 2017: 10 · 2016: 9 · 2015: 17 · 2014: 19 · 2013: 15 · 2012: 10
- FWCI
- 16.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- testosterone undecanoate, androgen receptor gene, CAG repeat length, hypogonadism, testosterone replacement therapy, body mass index, obesity, pharmacogenetics, lipid profile, blood pressure, erythropoiesis, hematocrit, prostate
- MeSH terms
- Adult, Humans, Hypogonadism, Injections, Intramuscular, Male, Middle Aged, Obesity, Pharmacogenetics, Receptors, Androgen, Regression Analysis, Testosterone, Body Mass Index, Nonlinear Dynamics, Trinucleotide Repeats, Testosterone Congeners
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