In this study, we demonstrated that testosterone has potent anti-obesogenic effects. Dutasteride treatment significantly reduced seminal vesicle weight (Supp. Fig. 2H), indicating an effective reduction of DHT levels. To test this hypothesis, we treated wildtype male mice with dutasteride, a pan 5a-reductase inhibitor that blocks the conversion of testosterone to DHT. If DHT was the major agonist of AR responsible for blocking adipogenesis, we would predict that reducing DHT levels in male mice would exacerbate HFD-induced adipogenesis. Notably, treating castrated mice with either testosterone or DHT rescues the hyperproliferative response of APs to the HFD in castrated mice (Figure 4B,C).
The four-point salivary cortisol test, taken at waking, midday, late afternoon (4 PM), and before bed (10 to 11 PM), maps the actual diurnal cortisol curve. It tells you almost nothing about functional cortisol dysregulation, because it captures only one point on a 24-hour rhythm. Standard practice for cortisol testing is a single serum cortisol drawn in the morning, typically between 8 and 9 AM. This is biologically indistinguishable from depression at the symptom level, which is why cortisol testing is essential before initiating antidepressant therapy in men presenting with anhedonia and reduced motivation. Chronic cortisol elevation downregulates dopamine receptor density in the nucleus accumbens, reducing the reward response to activities that previously felt satisfying. Low motivation and anhedonia are the psychological symptoms that most often lead to a depression diagnosis rather than a cortisol investigation. The mechanism is related to DHT pathways involved in androgenetic alopecia, but it is amplified and accelerated by cortisol.
It treats free testosterone as the primary outcome variable and everything else as secondary. All of these factors can produce the symptom profile above, and none of them are fixed by adjusting testosterone dose. The men who land in this metabolic trap often describe a recognizable pattern. No amount of free testosterone compensates for chronic sleep debt.
First, high cortisol acts directly on the hypothalamus to reduce GnRH (gonadotropin-releasing hormone) pulsatility. The problem with diagnosing high cortisol in men is that most physicians do not test for it unless they suspect Cushing’s syndrome, a rare tumor-driven condition. Determining the individual contributions of sex hormones to the regulation of total adiposity and fat distribution at different life stages will be an important area of further investigation. However, the cellular mechanisms and adipose depot-specific effects of testosterone and its metabolites have been poorly described in vivo. Thus, the major physiologic ligand of AR that negatively regulates adipogenesis in vivo is probably testosterone, not DHT.
Cortisol also raises SHBG (binding and inactivating free testosterone) and increases aromatase activity in visceral fat, converting more testosterone to estradiol. Higher aromatase activity in visceral fat means more testosterone is being converted to estrogen, compounding the testosterone deficit. A man can have cortisol levels high enough to suppress his HPG axis, shrink his hippocampus, and accumulate visceral fat at a rate that no diet will touch, while every standard lab panel comes back normal. But chronic cortisol elevation from psychological stress, poor sleep, overtraining, and metabolic dysfunction is far more common than Cushing’s and has measurable effects on testosterone, body composition, and brain function. Treating castrated mice with either testosterone or DHT completely rescued this effect (Figure 4B,C), which was surprising due to the inability of DHT to reduce total fat mass gain on an HFD (Figure 3B).
Estrogen replacement has been shown to suppress binge eating behaviors in female mice. Hormone replacement therapy using estrogen may be a possible treatment for binge eating behaviors in females. Contrarily, local application of estrogen has been shown to block the ability of fluvoxamine to slow serotonin clearance, suggesting that the same pathways which are involved in SSRI efficacy may also be affected by components of local estrogen signaling pathways. Local application of estrogen in the rat hippocampus has been shown to inhibit the re-uptake of serotonin. Aromatase deficiency is ultimately suspected which is involved in the synthesis of estrogen in humans and has therapeutic implications in humans having obsessive-compulsive disorder. Researchers have urged for further research to illuminate the role of estrogen and its potential for improvement on cognitive function. Studies have also shown that the Met allele gene and level of estrogen mediates the efficiency of prefrontal cortex dependent working memory tasks.

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