[Lotus]

Hi Sweets, 

Congrats on raising your Vit-levels. I've been researching Progesterone for years, the one thing I discovered was how taking progesterone lowers allopregnanolone which causes depression. I told myself I wasn't going to make this post into a TLR, well… It didn't work because there's so many side notes to explain. Tomorrow I'll add the Allopregnanolone supplement I've been taking. 

Finasteride inhibits allopregnanolone, which through its pathway causes depression by lowering allopregnanolone. Allopregnanolone is a modulator of GABA-A. 

Progesterone is a neurosteroid, meaning it crosses the blood/brain barrier and originates via cholesterol. The CNS (central nervous system)... progesterone is produced (synthesized) in the CNS and can cause many disorders (e.g. depression from pms, agitation, anxiety, etc) if allopregnanolone gets reduced by 5α-reductase. This happens in both sexes, but progesterone is produced elsewhere (like adrenals, ovaries, testes etc) Allopregnanolone doesn't appear to affect the breasts, I'm still trying to fact-check that though. 

I've been taking Allopregnanolone to ease the side-effects of taking progesterone rather than taking GABA (which is poorly metabolized in humans).

 

GABA decreases with age (Al-Sarraf, 2002). Perhaps more importantly, GABA’s half-life is about 17 min in mice (Kakee et al., 2001). If the half-life has a similar short duration in humans, direct administration of GABA is unsuitable as pharmacological treatment of epilepsy.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594160/

pregnenolone, progesterone, and their reduced metabolites are the most important steroids that can be formed de novo from cholesterol within the brain.
https://www.sciencedirect.com/science/ar...via%3Dihub

The Allopregnanolone to Progesterone Ratio Across the Menstrual Cycle and in Menopause
This preliminary study is the first to characterize the allopregnanolone to progesterone ratio, as a proxy for metabolism of progesterone to allopregnanolone, across the menstrual cycle and in non-depressed post-menopausal women using serum GC/MS measurements for both allopregnanolone and progesterone. As we hypothesized and now show, the ratio of allopregnanolone to progesterone decreases across the menstrual cycle; our data show that this decrease is 8-fold from the follicular to the luteal phase despite the increase in both progesterone and allopregnanolone across the cycle. Pineles et al. recently demonstrated by GC/MS that the ratio of ALLO (which includes allopregnanolone and its stereoisomer pregnanolone) to 5α-DHP – the immediate allopregnanolone precursor – increases from the follicular to the luteal phase (Pineles et al., 2018), which may be due to increased gene expression of 3α-HSD by estradiol (Mitev et al., 2003; Pineles et al., 2018). Despite these findings suggesting increased activity of 3α-HSD during the luteal phase, we show that levels of allopregnanolone do not increase proportionally to progesterone levels. We hypothesize that 5α-reductase may be saturated in the luteal phase from high progesterone levels, as it has been shown that 5α-reduction is the rate-limiting step in conversion of progesterone to allopregnanolone (Cai et al., 2018; Do Rego et al., 2009). Alternatively, it is possible that more progesterone is metabolized to pregnanolone through increased activity of 5α-reductase or 3α-HSD. Preclinical studies suggest that modulation of GABAA transmission by allopregnanolone plays a role in the pathogenesis of mood disorders. There are as yet few clinical data supporting a link between allopregnanolone and mood disorders, although, of note, a recently published placebo-controlled trial of an oral positive allosteric modulator of GABAA receptors (SAGE-217) demonstrated efficacy in major depressive disorder when administered for 14 days (Gunduz-Bruce et al., 2019). Our finding that the allopregnanolone/progesterone ratio decreases in the luteal phase suggests that relative allopregnanolone deficiency may be implicated in premenstrual syndrome or luteal phase mood disorders, although the cause of PMDD is likely multifactorial with hormonal, genetic, and psychiatric contributors. More studies investigating the role of allopregnanolone in the pathogenesis of mood disorders are needed.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935417/

Endocrinology of the Male Reproductive System and Spermatogenesis Https://www.ncbi.nlm.nih.gov/books/NBK279031/

I've put together some research on the effects of PM, sorry, it's complicated.

As estradiol did, induced expression of CYP2B9 mRNA whereas those of CYP1A2 were suppressed.

CY2B9 mRNA induced testosterone in women

CYP1A2 -aromatase (suppresses) 

HSD-17B2 suppressed (E2 and T pathway)

17β-HSD1 suppressed (E2 pathway)

3β-HSD suppressed (which catalyzes all steroids)

CYP17 (Human 17,20-lyase) activity is stimulated 10-fold by CYPB5 

CYP19 mRNA (aromatase) slightly decreased by 

____________________________

Posted research: 

The backdoor pathway proceeds from 17 OH-Prog to 17 OH-Prog, 17 OH-DHP, 17 OH-Allo, androsterone, androstanediol, and then to DHT, all in the testes.


Assessment of testicular enzymes involved in sex hormone synthesis pathway showed suppression of 3β-HSD, 17β-HSD1, and CYP17 expressions with those of CYP19 mRNA was slightly decreased by:

The pathways of androgen biosynthesis. The classic pathway and the alternative “backdoor pathway” are shown. The classic pathway proceeds from 17OH-Preg to DHEA, to androstenedione or androstenediol to testosterone in the testis, and thence to DHT in genital skin. The backdoor pathway proceeds from 17OH-Preg to 17OH-Prog, 17OH-DHP, 17OH-Allo, androsterone, androstanediol, and thence to DHT, all in the testis. The enzymes and cofactors shown in the classic pathway are: P450scc (cholesterol side-chain cleavage enzyme), StAR (steroidogenic acute regulatory protein), P450c17 (17α-hydroxylase/17,20-lyase), 3β-HSD (3β-hydroxysteroid dehydrogenase, type 2), cytochrome b5, 17β-HSD3 (17β-hydroxysteroid dehydrogenase, type 3), and 5αR2 (5α-reductase, type 2). The alternative pathway is characterized by the presence of three additional enzymes: 5αR1 (5α-reductase, type 1), reductive 3α-HSD (AKR1C2/4), and oxidative 3α-HSD (17β-HSD6, also known as RoDH and/or AKR1C4). Steroid names include: 17OH-Preg, 17-hydroxypregnenolone; 17OH-Prog, 17-hydroxyprogesterone; 17OH-DHP, 17-hydroxydihydroprogesterone (5α-pregnan-17α-ol-3,20-dione); 17OH-Allo, 17-hydroxy-allopregnanolone (5α-pregnan-3α,17α-diol-20-one); androstenediol, androsta-5-ene-3β,17β-diol; and androstanediol, 5α-androstane-3α,17β-diol.


Cytochrome P450 17A1 (zona reticularis) of the adrenal cortex suppressed steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.


Cytochrome P450 17A1, or steroid 17-alpha-monooxygenase, or 17α-hydroxylase/17,20 lyase/17,20 desmolase is an enzyme that in humans is encoded by the CYP17A1 gene. It is found in the zona reticularis of the adrenal cortex. This gene encodes a member of the cytochrome P450 Superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids. This protein localizes to the endoplasmic reticulum. It has both 17alpha-hydroxylase and 17,20-lyase activities, and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.

More specifically, CYP17A1 acts upon pregnenolone and progesterone to add a hydroxyl (-OH) group at carbon 17 of the steroid D ring (the hydroxylase activity), or acts upon 17-hydroxyprogesterone and 17-hydroxypregnenolone to split the side-chain off the steroid nucleus (the lyase activity).