Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis

In SHBG transgenic mice, free testosterone concentrations measured by LC-MS/MS following equilibrium dialysis were not different compared to controls, despite raised androgen levels.

“Curiously, although androgen levels were raised in SHBG transgenic mice, free T concentrations, measured directly by liquid chromatography with tandem mass spectrometry (LC–MS/MS) following equilibrium dialysis (ED), were not different compared to controls.”

Following orchiectomy and implantation of a continuous-release testosterone implant, free testosterone was lower in transgenic compared to wildtype mice.

“Moreover, following orchiectomy and implantation of a continuous-release T implant, free T was lower in transgenic compared to wildtype mice [45].”

In SHBG transgenic mice, luteinizing hormone levels were significantly higher than in controls despite similar free testosterone levels.

“However, despite similar free T levels in SHBG transgenic mice, luteinizing hormone (LH) levels were significantly higher than in controls.”

SHBG has the capacity to bind and lengthen the half-life of its ligands.

“This confirms that SHBG has the capacity to bind and lengthen half-life of its ligands.”

Phenotyping of SHBG transgenic mice identified a partially compensated hypogonadism reflected in increased luteinizing hormone together with a minor but significant weight reduction of the seminal vesicles and pelvic bulbus cavernosus and levator ani muscles.

“Phenotyping of the SHBG transgenic mice identified a partially compensated hypogonadism reflected in an increased LH together with a minor, but significant, weight reduction of the seminal vesicles and pelvic bulbus cavernosus and levator ani muscles.”

Administration of anabolic doses of testosterone or DHT led to seminal vesicle hypertrophy in wildtype mice that is prevented by SHBG in transgenic mice.

“More profound, administration of anabolic doses of T or DHT led to seminal vesicle hypertrophy in wildtype mice that is, however, prevented by SHBG in transgenic mice.”

Despite extremely high total testosterone in SHBG transgenic mice, weight reduction of the most androgen-sensitive organs provides in vivo evidence of androgen deficiency attributed to the inhibitory effects of high levels of SHBG.

“Despite an extremely high amount of total T in these animals, weight reduction of the most androgen-sensitive organs provides in vivo evidence of androgen deficiency attributed to the inhibitory effects of high levels of SHBG [45].”

In SHBG transgenic mice, SHBG concentration increases with age and is higher in males; total serum testosterone and DHT are increased approximately 200-fold compared to wildtype, and multiple testosterone precursors are also increased.

“In more recent work from our research group, SHBG concentration in SHBG transgenic mice has been shown to increase with age and is remarkedly higher in males. In addition, total serum T and DHT are increased approximately 200-fold as opposed to wildtype and multiple T precursors (e.g., pregnenolone, androstenedione) were also found to be increased [45].”

Injection of castrated mice with testosterone, DHT or mibolerone revealed that SHBG prolonged the circulating half-life of testosterone and DHT, but not of mibolerone.

“Next to the androgen suppressing effect of SHBG, injection of castrated mice with T, DHT or mibolerone (a synthetic androgen with negligible binding affinity for SHBG) revealed that SHBG prolonged the circulating half-life of T and DHT, but not of mibolerone [45].”

SHBG may protect against HFD induced obesity through the induction of lipolysis in white adipose tissue, though this finding is contradicted elsewhere.

“may protect against HFD induced obesity through the induction of lipolysis in white adipose tissue, 229 though this finding is contradicted elsewhere.”