Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels

Abstract

Benefits associated with lowered serum DHT levels after 5α-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate). Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels. To assess the clinical significance of modest elevations in serum DHT and the DHT/testosterone (T) ratio observed in response to common T replacement therapy, a comprehensive review of the published literature was performed to identify relevant data. Although the primary focus of this review is about DHT in men, we also provide a brief overview of DHT in women. The available published data are limited by the lack of large, well-controlled studies of long duration that are sufficiently powered to expose subtle safety signals. Nonetheless, the preponderance of available clinical data indicates that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice. Elevated DHT has not been associated with increased risk of prostate disease (e.g., cancer or benign hyperplasia) nor does it appear to have any systemic effects on cardiovascular disease safety parameters (including increased risk of polycythemia) beyond those commonly observed with available T preparations. Well-controlled, long-term studies of transdermal DHT preparations have failed to identify safety signals unique to markedly elevated circulating DHT concentrations or signals materially different from T.

Assessment of Simplified Methods for Quantification of 18F-FDHT Uptake in Patients with Metastatic Castration-Resistant Prostate Cancer

“…In mCRPC patients, both with and without prior treatment with docetaxel, these drugs have been shown to result in improved survival and quality of life (4,5). 18 F-fluorodihydrotestosterone ( 18 F-FDHT) is a positron-emitting tracer that provides a means to image the AR in vivo in mCRPC patients (6,7). Therefore, 18 F-FDHT PET/CT could potentially be used as an imaging biomarker to evaluate AR status and pharmacologic targeting on a lesion-by-lesion level.…”

“…18 F-fluorodihydrotestosterone ( 18 F-FDHT) is a positron-emitting tracer that provides a means to image the AR in vivo in mCRPC patients (6,7). Therefore, 18 F-FDHT PET/CT could potentially be used as an imaging biomarker to evaluate AR status and pharmacologic targeting on a lesion-by-lesion level. This potential is of particular significance because mechanisms of persistent AR signaling can differ between metastatic lesions (8,9).…”

“…This potential is of particular significance because mechanisms of persistent AR signaling can differ between metastatic lesions (8,9). In mCRPC, direct assessment of AR using 18 F-FDHT might aid AR-targeted drug development, and more personalized treatment planning, thereby potentially preventing unnecessary toxicities and costs.…”

“…Accurate quantification is required for objective evaluation of 18 F-FDHT uptake in mCRPC lesions. The gold standard for quantification of tracer uptake is pharmacokinetic modeling using nonlinear regression (NLR) in combination with a metabolite-corrected arterial plasma input function (10).…”

“…Full understanding of 18 F-FDHT kinetics is essential for developing simplified methods to quantify 18 F-FDHT uptake in clinical practice. Therefore, the objectives of this study were, first, to identify the optimal pharmacokinetic model for quantifying 18 F-FDHT kinetics in mCRPC patients using individually measured arterial input function; second, to comprehensively investigate whether simplified methods can be used for accurate quantification of 18 F-FDHT uptake; third, to measure the repeatability of 18 F-FDHT uptake metrics; and fourth, to assess potentially confounding effects of perfusion on these simplified 18 F-FDHT uptake metrics.…”