While I'm skeptical of claims that 5ar1 inhibition-induced reduction of neurosteroids is disastrous, I don't know that this study provides evidence to the contrary. The observation that 0.5-mg/d dutasteride didn't decrease allopregnanolone in these women isn't generalizable because the PMDD-afflicted women have excessively high progesterone (and thus, allopregnanolone) during the luteal phase. This suggests that the 0.5-mg/d dosage was simply too weak to stave off the expected increase (which is why a mild increase was still observed), whereas the 2.5-mg/d dosage's greater inhibition of 5ar1 was sufficient (explaining the desired decrease in allop and concordant increase in prog). In a normal population whose progesterone levels aren't through the roof, I'd expect 0.5 mg/d dutasteride to be enough to put a dent into allopregnanolone.
This is from the other thread.
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To expand on the above, the increase in allopregnanolone levels during the luteal phase of the menstrual cycle is almost certainly due to the surge in the precursor to allopregnanolone, progesterone, that happens immediately prior to the luteal phase and not due to an increase in 5AR.
Menstrual Cycle and Women's Health Issues - Learn about from the Merck Manuals - Medical Consumer Version.
www.merckmanuals.com
The ovulatory phase begins with a surge in luteinizing hormone and follicle-stimulating hormone levels. Luteinizing hormone stimulates egg release (ovulation), which usually occurs 16 to 32 hours after the surge begins. The estrogen level decreases during the surge, and the progesterone level starts to increase.
During the luteal phase, luteinizing hormone and follicle-stimulating hormone levels decrease. The ruptured follicle closes after releasing the egg and forms a corpus luteum, which produces progesterone.
If there was a change in 5AR levels during the change from follicular to luteal phases then we could expect to also see a change in DHT levels yet that does not occur.
Measuring serum androgen levels in women has been challenging due to limitations in method accuracy, precision sensitivity and specificity at low hormone levels. The clinical significance of changes in sex steroids across the menstrual cycle and lifespan has remained controversial, in part due...
pubmed.ncbi.nlm.nih.gov
Samples were obtained in ovulatory women in the early follicular phase (EFP), midcycle and mid luteal phase (MLP). Overall, the levels of T, DHT, E2 and E1 in premenopausal women measured by LC-MS/MS were lower overall than previously reported with immunoassays. In premenopausal women, serum T, free T, E2, E1 and SHBG levels peaked at midcycle and remained higher in the MLP, whereas DHT did not change.
So with 5AR levels remaining seemingly constant, it takes 2.5 mg of dutasteride ED to stabilize allopregnanolone in women with PMDD. Also something to consider, due to the feed forward nature of DHT and 5AR, men will have more 5AR enzyme than women yet women will most likely have higher allopregnanolone due to having higher levels of progesterone, the precursor hormone to allopregnanolone.
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The point being that the reduction in 5AR1 was not a sufficient limiting factor with .5 mg ED and women with PMDD do not appear to have abnormal levels of 5AR1. In a normal population with lower progesterone, I would expect it to be a non issue. With lower progesterone, you are not going to have a bottleneck at the progesterone -> 5AR ->5alpha-DHP level. PMDD women who have high progesterone are actually the perfect group to test how effective inhibiting 5AR is at reducing allopregnanolone when substrate amount is not a limiting factor.
