5-alpha androstanediol goes by many names: 5-Androstane-3,17-diol,3α-androstanediol, and simply 5A-AD – but what is its clinical significance?
Dihydrotestosterone (or DHT), produced via 5-alpha reductase conversion of testosterone, is one of the most potent androgens driving symptoms of androgen excess. Yet patients with androgenic symptoms don’t always have elevated DHT in serum. Read on to understand why.
Free testosterone is converted into DHT intracellularly in certain tissues (skin cells, pilosebaceous glands, prostate cells) where it binds androgen receptors and exerts local effects. DHT binds to androgen receptors with 3 times the potency of testosterone, causing a host of symptoms and conditions depending on the tissues affected including scalp hair loss and prostate hypertrophy in males; PCOS, unwanted facial and body hair growth, oligomenorrhea, acne, and visceral fat accumulation in females.
Intracellularly, DHT is rapidly metabolized to 5-alpha-androstanediol (5A-AD). The vast majority of intracellular DHT will not return to the bloodstream, however once metabolized, 5A-AD is released from the cell into circulation where it can be measured in both serum and urine. While 5A-AD is less androgenic than DHT, elevated levels can indicate increased intracellular DHT utilization. Intracellular DHT does not usually result in elevated serum DHT, as it is primarily converted to 5A-AD within the cell; the 5A-AD then enters the circulation and is ultimately excreted in urine. Consequently, higher urinary 5A-AD may not correlate with serum DHT concentrations. Similarly, females with androgen excess symptoms may not always show elevated serum testosterone or DHEA, but instead demonstrate increased 5A-AD, reflecting local tissue utilization, conversion and metabolism of these hormones.
Urine testing provides an important advantage for assessing androgen status as it not only captures elevations but also captures patterns of hormone metabolism by measuring metabolites at the endpoint of their metabolic pathways. Another benefit: a single void reflects hormone excretion and metabolism over the entire period since the last urination, whereas serum measures hormone levels only at the moment of blood draw.
The ability for urine to reveal 5A-AD as a marker for intracellular DHT activity is particularly clinically relevant in conditions associated with androgen- excess symptoms in both females and males.
PCOS:
In a pilot study using 24-hour urine steroid hormone profiling of 40 analytes, 5A-AD emerged as the single best discriminating metabolite for identifying PCOS. Notably, the observed metabolic pattern was distinct from that of congenital adrenal hyperplasia, raising the possibility that in the future PCOS diagnosis could be based on urinary hormone metabolites rather than solely as a diagnosis of exclusion after ruling out congenital adrenal hyperplasia.
Hirsutism:
5A-AD is strongly associated with hirsutism. In idiopathic hirsutism, serum androgens remain within range despite androgenic symptoms; however, research has shown that urinary 5A-AD may be elevated in these patients, offering both an explanation of symptoms, as well as a means to select therapeutics and monitor treatment response. One study found that higher serum 5A-AD correlates positively with hirsutism, including PCOS-related hirsutism. Interestingly, females diagnosed with PCOS but without hirsutism didn’t show the same magnitude of elevation, though their levels remained significantly higher than the non-PCOS control group.
ACNE:
Among females with acne but without menstrual irregularities, one study found ~60% to have elevated androgens, while half of the remaining cases showed elevated 5A-AD. So, in total at least 80% of females with acne demonstrated some form of excess androgen activity, suggesting that therapies aimed at lowering androgenic actions or reducing 5-alpha reductase activity may be appropriate in most cases.
Men’s health:
In men, particularly those with benign prostatic hyperplasia (BPH) or prostate cancer, 5A-AD serves as a marker of DHT activity within the prostate gland. Similarly, in male pattern baldness, 5A-AD testing can help elucidate DHT utilization at the hair follicle.
Neurosteroid effects:
On the plus side, similarly to allopregnanolone (a 5-alpha reductase metabolite of progesterone), 5A-AD acts as a positive allosteric modulator of GABA-A receptors. Testosterone has been shown to modulate seizure susceptibility via its conversion to neurosteroids such as 5A-AD. Animal studies have demonstrated that 5A-AD has anxiolytic and sedative effects. Conversely, insomnia has been reported with 5-alpha reductase inhibitors, likely due to suppression of anxiolytic neurosteroids such as 5A-AD and allopregnanolone.
Conclusion:
For patients with acne, hirsutism, oligomenorrhea, PCOS, or prostate concerns, the HuMap™ offers a more comprehensive assessment of androgen excess and 5-alpha reductase metabolism that may be driving these symptoms and conditions.
When urine testing reveals increased 5A-AD or other 5-alpha reduced metabolites, potential contributing factors include inflammation, insulin resistance, sleep deprivation, hypertension, obesity, high carbohydrate intake, and sodium restriction. Addressing these underlying causes along with therapeutics that decrease 5-alpha reductase activity may be clinically appropriate in such cases. The Androgens and Progesterones Profile is a more abbreviated option that can be used to follow up on the effectiveness of any protocols aimed at reducing androgens or 5-alpha reductase activity.
