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Opioid-induced androgen deficiency (OPIAD) was initially recognized as a possible consequence of opioid use roughly four decades ago. Long-acting opioid use carries risks of addiction, tolerance, and systemic side effects including hypogonadotropic hypogonadism with consequent testosterone depletion leading to multiple central and peripheral effects. Hypogonadism is induced through direct inhibitory action of opioids on receptors within the hypothalamic-pituitarygonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes as well as testosterone production within the testes. Few studies have systematically investigated hormonal changes induced by long-term opioid administration or the effects of testosterone replacement therapy (TRT) in patients with OPIAD. Clomiphene citrate, a selective estrogen receptor modulator (SERM), is a testosterone enhancement treatment which upregulates endogenous hypothalamic function. This review will focus on the pathophysiology, diagnosis, and management of OPIAD, including summary of literature evaluating OPIAD treatment with TRT, and areas of future investigation. [ABSTRACT FROM AUTHOR]

Serum testosterone does not correlate with androgen tissue activity, and it is critical to optimize tools to evaluate such activity in males. Ultrasound measurement of bulbocavernosus muscle (BCM) was used to assess the relationship between the number of CAG repeats (CAGn) in the androgen receptor (AR) and the BCM size; the changes in the number of CAGn over age were also evaluated. Transperineal ultrasound measurement of the BCM was also performed. AR CAGn were determined by high performance liquid chromatography, and morning hormone levels were determined using immunoassays. Forty-eight men had CAG repeat analysis. Twenty-ive were <30 years of age, mean 23.7 years (s.d. = 3.24) and 23 were >45 years of age, mean 53 years (s.d. = 5.58). The median CAGn was 21 (13-29). BCM area was greater when the number of CAGn were <18 as compared to the number of CAGn >24 (P = 0.04). There was a linear correlation between the number of CAGn and the BCM area R² = 16% (P = 0.01). In the 45 to 65-years-old group, a much stronger negative correlation (R² = 29%, P = 0.01) was noticed. In the 19 to 29-years-old group, no such correlation was found (R² = 4%, P = 0.36). In older men, the number of CAGn increased with age (R² = 32%, P = 0.01). The number of CAGn in the AR correlates with the area of the BCM. Ultrasound assessment of the BCM is an effective surrogate to evaluate end-organ activity of androgens. The number of CAGn may increase with age. [ABSTRACT FROM AUTHOR]

Ubiquitin specific protease 26 (USP26), a deubiquitinating enzyme, is highly expressed early during murine spermatogenesis, in round spermatids, and at the blood-testis barrier. USP26 has also been recognized as a regulator of androgen receptor (AR) hormone-induced action involved in spermatogenesis and steroid production in in vitro studies. Prior mutation screening of USP26 demonstrated an association with human male infertility and low testosterone production, but protein localization and expression in the human testis has not been characterized previously. USP26 expression analysis of mRNA and protein was completed using murine and human testis tissue and human tissue arrays. USP26 and AR mRNA levels in human testis were quantitated using multiplex qRT-PCR. Immunofluorescence colocalization studies were performed with formalin-fixed/paraffin-embedded and frozen tissues using primary and secondary antibodies to detect USP26 and AR protein expression. Human microarray dot blots were used to identify protein expression in extra-gonadal tissues. For the first time, expression of USP26 and colocalization of USP26 with androgen receptor in human testis has been confirmed predominantly in Leydig cell nuclei, with less in Leydig cell cytoplasm, spermatogonia, primary spermatocytes, round spermatids, and Sertoli cells. USP26 likely affects regulatory proteins of early spermatogenesis, including androgen receptor with additional activity in round spermatids. This X-linked gene is not testis-specific, with USP26 mRNA and protein expression identified in multiple other human organ tissues (benign and malignant) including androgen-dependent tissues such as breast (myoepithelial cells and secretory luminal cells) and thyroid tissue (follicular cells). USP26/AR expression and interaction in spermatogenesis and androgen-dependent cancer warrants additional study and may prove useful in diagnosis and management of male infertility. [ABSTRACT FROM AUTHOR]