Risk-reward profile for progesterone/allopregnanolone supplementation

[Type-IIx]

Risk-reward profile for progesterone/allopregnanolone supplementation
Author: Type-IIx

It has come to my attention that there is a growing number of bodybuilders and AAS users subscribing to the practice of administering exogenous progesterone or allopregnanolone (or both) as supplemental neurosteroids. I want to put this information out there for them, so that they may balance the tradeoffs of this risky endeavour with appropriate information from different sources.

This article purposely discusses progestins (synthetic) and progesterone receptor agonists, including "bioidentical" progesterone (which is not inherently safe due to its being "bioidentical...") as a singular class of agents that are classic female hormonal agents. A later "article" will be forthcoming that distinguishes between progestins, progesterone, and prolactin (as there is widespread confusion, understandably).

Neurosteroids: steroids that are synthesized in the CNS from cholesterol or sterol precursors [1].


Biosynthesis of allopregnanolone [5].

Allopregnanolone

The recent FDA approval of the neurosteroid, brexanolone (allopregnanolone), as a treatment for women with postpartum depression, and successful trials of a related neuroactive steroid, SGE-217, for men and women with major depressive disorder offer the hope of a new era in treating mood and anxiety disorders based on the potential of neurosteroids as modulators of brain function... contributing to antidepressant and anxiolytic effects of allopregnanolone and other GABAergic neurosteroids ... as positive allosteric modulators of GABA-A receptors. We also consider their roles as endogenous "stress" modulators and possible additional mechanisms contributing to their therapeutic effects. We argue that further understanding of the molecular, cellular, network and psychiatric effects of neurosteroids offers the hope of further advances in the treatment of mood and anxiety disorders.

[1]

Allopregnanolone: potent and positive allosteric modulator (PAM) of GABA-A receptors [1], regulates stress, mood, and female sexual behavior [3].

Allopregnanolone exhibits benzodiazepine and antidepressant qualities by modulating GABA-A receptors. Allopregnanolone and progesterone, as steroids, are broad spectrum in their actions, meaning that they affect multiple systems in unpredictable ways.

Progesterone
The "mother molecule"

Progesterone is a steroid hormone, and, like prolactin, it seems to largely play an irrelevant role in male physiology. Again, don't misunderstand my statement. I'm not saying it does nothing. It's an important precursor to the endogenous production of some other steroid hormones (aldosterone and cortisol). Additionally, it affects the brain [5].

[4]

Progesterone and its metabolites are neurosteroids that also play an important role in myelination. Consequently, blocking the production of the metabolites of progesterone has been found to have an adverse effect on the myelination process. In rodent and in vitro models, there is evidence of therapeutic benefits for certain types of injury (ischemic stroke, ALS, MS, carpal tunnel syndrome) (22) [6]. Progesterone is upregulated in TBI and stroke patients.
Thus, exogenous progesterone likely has some efficacy in recovery from TBI and stroke, and perhaps for demyelinating disorders. It also has demonstrable efficacy in the treatment of postpartum depression.

Micronized progesterone
Micronised P4 (but not synthetic progestins) and one of its major metabolites, allopregnanolone, have been shown to modulate GABAergic transmission with a similar potency or even greater efficacy, than those of alcohol, benzodiazepines, or barbiturates (4) [6].
P4 is a weak agonist for the GR and AR, has no significant activity via the estrogen receptor (ER), and is a full antagonist for the MR which is beneficial during pregnancy; counteracting possibly excess water retention induced by estrogens (29,30,31) [6].
P4 is slightly anti-androgenic because it also binds to 5-α reductase enzyme and will therefore interact with the conversion of testosterone in dihydrotestosterone, its active metabolite (2) [6]. This is analogous to dutasteride and finasteride.

Safety and Pharmacodynamics in men
There are no established safety profiles for progesterone in men [6]. Safety profiles in women differ depending on when these hormones are used during the menstrual cycle, in early and late pregnancy and in the alleviation of peri- or postmenopausal symptoms [6].

Trying to divine the pharmacodynamics of these exogenous classical female hormones in men should likely focus on the activity on the CNS and on activity in binding the classical nuclear steroid family, chiefly the progesterone receptor (PR), androgen receptor (AR), and mineralocorticoid receptor (MR). Generally, progestagens and (synthetic) progestins agonize the PR, antagonize the AR, agonize the GR, and antagonize the MR.

These classical female hormones regulate the menstrual cycle and pregnancy, and thus certainly have myriad unquantifiable effects in the male organism. Progesterone produced in the luteal phase of the menstrual cycle has several physiological effects regulating menses, and in the pregnant uterus, controlling the development of endometrial receptivity preparing the endometrium for implantation [6].

It is difficult to assess the full spectrum of genomic and nongenomic action of these hormones in men given the paucity of research on these hormones in this population.

Progesterone and its metabolites (allopregnanolone and 4α,5α-tetrahydrodeoxycorticosterone) are potent activators of the PR. Extra-nuclear, non-classical (nongenomic) effects mechanisms include interactions with membrane receptors from the oxytocin (the "bonding" hormone) and GABA-A receptors, and the induction of a direct relaxing effect on uterine contractility by blocking calcium influx [6].

Activation of the PR regulates mammalian female sexual behavior (heat, behavioral estrus), and concurrent treatment with E2 (estradiol) treatment with E2 maximizes the probability that the female will display “lordosis” response, a primary reflexive component of female reproductive behavior, upon mounting by a con-specific male [11].

The extent of activity of progesterone on the CNS is modulated by the route of administration: oral P4 is affected by the presence of bacteria and gut enzymes, the intestinal wall, and liver, wheras intramuscular P4 is not [6].

Micronized progesterone (P4) and allopregnanolone, its chief metabolite, modulate GABAergic transmission with a similar potency or even greater efficacy than alcohol, benzodiazepines, or barbiturates [6]. Thus, similar to mesterolone (Proviron), this hormone is likely to be accompanied by withdrawal symptoms and there is no reason to believe that it is not reinforcing (add
ictive), as a class effect of GABAergic agents.

Oral route
Orally administered P4 undergoes several successive metabolic steps in the gut (5β-reductase), in the intestinal wall (5α-reductase), and the liver (5β-reductase, 3α- & 20α- hydroxylase). The resulting metabolites, 5α-pregnanolone (allopregnanolne; AlloP) and 5β-pregnanolone, bind the GABA-A-R, whilst 5α-pregnanedione & 5β-pregnanedione exert anti-mitotic (suppressing growth) and tocolytic (anti-contraction/relaxation) effects [6]. Oral P4 increases bone formation and is attended by estrogen-related improvements in bone mineral density (BMD), likely via production of new osteoblasts from mesenchymal stem cells and stimulation of osteoblasts to generate bone matrix (8),,[6],,. Oral P4 results in rapid absorption, a maximal plasma concentration within 4 hr with a 8.6% bioavailability versus intramuscular administration, and twice that when administered before food (5) [6].

Intramuscular route
Analogous to the most common (vaginal) route of administration, the intramuscular (IM) route of P4 results in only a small increase in allopregnanolone and no change in 5β-pregnanolone. Thus, men seeking the most relevant function (GABA-A-R modulation) of this hormone would be advised to use via the oral route (and, this is likely to modulate serum levels within the endogenous male range.

Reduced HPG Axis Functioning
"HPTA suppression"
Progesterone and its derivatives dysregulate hypothalamic regulation of T and gonadotropins via KNDy dendron signalling, disrupting GnRH pulsatility, and inhibiting pituitary LH secretion [8] [9]. Synthetic progestins used in male contraception derive efficacy from this feature. Bebb, et al. randomized healthy men to receive either testosterone enanthate (100 mg weekly), or the same dosage of testosterone in combination with the progestin levonorgestrel, the addition of which virtually abolished LH and FSH secretion [10].

The effects of progestins relate to their interactions with receptors: AR (e.g., acnea, lipid effects); glucocorticoid receptors (GR) (eg., salt and water retention, bloating); or mineralocorticoid receptors (e.g., decreased water retention and weight). Anti-androgenic progestins may act in several ways. They can exert competitive inhibition of the AR, or bind to the enzyme 5-alpha reductase and hence interact with the conversion of testosterone into dihydrotestosterone (its active metabolite). When combined with estrogen the non-androgenic progestins do not oppose the estrogen-dependent increase in SHBG. The latter effect results in more binding of the circulating androgens and less free T available for action at the receptor level. Thus, anti-androgenic progestins may have beneficial effects (e.g., controlling endogenous androgen and decreasing acnea or hirsutism) [7].

Circulating levels in healthy adult men
AlloP serum:
- 0.75 nmol/L
- 0.24 ng/mL
Prog serum:
- 1.9 nmol/L
- 0.60 ng/mL
DHEA serum:
- 16.33 nmol/L
- 4.71 ng/mL [3]

DHEA is primarily an adrenal steroid; AlloP and Prog, as active neurosteroids, are primarily synthesized in the brain.

If one does embark on the use of exogenous neuroactive steroids, it would be prudent to "dial in" bloodwork to healthy endogenous male serum levels.
Whether the adult male's interest in
- allopregnanolone and/or
- exogenous (e.g., micronized) progesterone (P4)
- to treat:
+ anxiety (with drug-like efficacy; on par or greater than benzodiazepines or barbiturates, alcohol)
+ depression (with drug-like efficacy)
+ bones/joints (potential bone formation; augmented BMD)
+ adverse sexual effects of the rare (up to 4% prevalence) post-finasteride syndrome (the efficacy for which these agents have never been rigorously examined scientifically)
- outweighs:
- negative impact on HPG axis functioning (HPTA)
- anti-androgenic action (indeed, progesterone functions analogously to dutasteride/finasteride)
- potential for habituation (addiction) as GABAergic agents
- off-target hormonal effects (particularly egregious with progesterone)
- in consideration of:
+ exogenous T supplanting the role of DHT (but not allopregnanolone, progesterone [whose function in male physiology is markedly limited]) in prostate, scalp, etc.
+ exogenous T potently stimulating osteoblast activity (bone formation; augmented BMD)
+ availability of clinically indicated treatments, including TRT which demonstrably improves its patients' mental health, sexual function, QoL, and bone mineral density, administered by medical professionals, and
- the absence of any demonstrable clinical relevance of supplemental neurosteroids for healthy men
_______________________________
References:
[1] Zorumski, C. F., Paul, S. M., Covey, D. F., & Mennerick, S. (2019). Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. Neurobiology of Stress, 11, 100196. doi:10.1016/j.ynstr.2019.100196
[2] Irwig, M. S. (2014). Persistent Sexual and Nonsexual Adverse Effects of Finasteride in Younger Men. Sexual Medicine Reviews, 2(1), 24–35. doi:10.1002/smrj.19
[3] Genazzani, A. R., Petraglia, F., Bernardi, F., Casarosa, E., Salvestroni, C., Tonetti, A., … Luisi, M. (1998). Circulating Levels of Allopregnanolone in Humans: Gender, Age, and Endocrine Influences. The Journal of Clinical Endocrinology & Metabolism, 83(6), 2099–2103. doi:10.1210/jcem.83.6.4905
[4] Bond, P. (2020). On Steroids.
[5] Schumacher, M., Mattern, C., Ghoumari, A., Oudinet, J. P., Liere, P., Labombarda, F., … Guennoun, R. (2014). Revisiting the roles of progesterone and allopregnanolone in the nervous system: Resurgence of the progesterone receptors. Progress in Neurobiology, 113, 6–39. doi:10.1016/j.pneurobio.2013.09.004
[6] Piette, P. C. (2020). The Pharmacodynamics and Safety of Progesterone. Best Practice & Research Clinical Obstetrics & Gynaecology. doi:10.1016/j.bpobgyn.2020.06.002
[7] Sitruk-Ware, R. (2004). Pharmacological profile of progestins. Maturitas, 47(4), 277–283. doi:10.1016/j.maturitas.2004.01.001
[8] Navarro, V. M., Gottsch, M. L., Chavkin, C., Okamura, H., Clifton, D. K., & Steiner, R. A. (2009). Regulation of Gonadotropin-Releasing Hormone Secretion by Kisspeptin/Dynorphin/Neurokinin B Neurons in the Arcuate Nucleus of the Mouse. Journal of Neuroscience, 29(38), 11859–11866. doi:10.1523/jneurosci.1569-09.2009
[9] Girmus, R. L., & Wise, M. E. (1992). Progesterone Directly Inhibits Pituitary Luteinizing Hormone Secretion in an Estradiol-dependent Manner1. Biology of Reproduction, 46(4), 710–714. doi:10.1095/biolreprod46.4.710
[10] Bebb, R. A., Anawalt, B. D., Christensen, R. B., Paulsen, C. A., Bremner, W. J., & Matsumoto, A. M. (1996). Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. The Journal of Clinical Endocrinology & Metabolism, 81(2), 757–762. doi:10.1210/jcem.81.2.8636300
[11] Mani S, Portillo W. Activation of progestin receptors in female reproductive behavior: Interactions with neurotransmitters. Front Neuroendocrinol. 2010;31(2):157-171. doi:10.1016/j.yfrne.2010.01.002

 

[Dr JIM]

Risk-reward profile for progesterone/allopregnanolone supplementation
Author: Type-IIx

It has come to my attention that there is a growing number of bodybuilders and AAS users subscribing to the practice of administering exogenous progesterone or allopregnanolone (or both) as supplemental neurosteroids. I want to put this information out there for them, so that they may balance the tradeoffs of this risky endeavour with appropriate information from different sources.

This article purposely discusses progestins (synthetic) and progesterone receptor agonists, including "bioidentical" progesterone (which is not inherently safe due to its being "bioidentical...") as a singular class of agents that are classic female hormonal agents. A later "article" will be forthcoming that distinguishes between progestins, progesterone, and prolactin (as there is widespread confusion, understandably).

Neurosteroids: steroids that are synthesized in the CNS from cholesterol or sterol precursors [1].

View attachment 158812
Biosynthesis of allopregnanolone [5].

Allopregnanolone

[1]

Allopregnanolone: potent and positive allosteric modulator (PAM) of GABA-A receptors [1], regulates stress, mood, and female sexual behavior [3].

Allopregnanolone exhibits benzodiazepine and antidepressant qualities by modulating GABA-A receptors. Allopregnanolone and progesterone, as steroids, are broad spectrum in their actions, meaning that they affect multiple systems in unpredictable ways.

Progesterone
The "mother molecule"

[4]

Progesterone and its metabolites are neurosteroids that also play an important role in myelination. Consequently, blocking the production of the metabolites of progesterone has been found to have an adverse effect on the myelination process. In rodent and in vitro models, there is evidence of therapeutic benefits for certain types of injury (ischemic stroke, ALS, MS, carpal tunnel syndrome) (22) [6]. Progesterone is upregulated in TBI and stroke patients.
Thus, exogenous progesterone likely has some efficacy in recovery from TBI and stroke, and perhaps for demyelinating disorders. It also has demonstrable efficacy in the treatment of postpartum depression.

Micronized progesterone
Micronised P4 (but not synthetic progestins) and one of its major metabolites, allopregnanolone, have been shown to modulate GABAergic transmission with a similar potency or even greater efficacy, than those of alcohol, benzodiazepines, or barbiturates (4) [6].
P4 is a weak agonist for the GR and AR, has no significant activity via the estrogen receptor (ER), and is a full antagonist for the MR which is beneficial during pregnancy; counteracting possibly excess water retention induced by estrogens (29,30,31) [6].
P4 is slightly anti-androgenic because it also binds to 5-α reductase enzyme and will therefore interact with the conversion of testosterone in dihydrotestosterone, its active metabolite (2) [6]. This is analogous to dutasteride and finasteride.

Safety and Pharmacodynamics in men
There are no established safety profiles for progesterone in men [6]. Safety profiles in women differ depending on when these hormones are used during the menstrual cycle, in early and late pregnancy and in the alleviation of peri- or postmenopausal symptoms [6].

Trying to divine the pharmacodynamics of these exogenous classical female hormones in men should likely focus on the activity on the CNS and on activity in binding the classical nuclear steroid family, chiefly the progesterone receptor (PR), androgen receptor (AR), and mineralocorticoid receptor (MR). Generally, progestagens and (synthetic) progestins agonize the PR, antagonize the AR, agonize the GR, and antagonize the MR.

These classical female hormones regulate the menstrual cycle and pregnancy, and thus certainly have myriad unquantifiable effects in the male organism. Progesterone produced in the luteal phase of the menstrual cycle has several physiological effects regulating menses, and in the pregnant uterus, controlling the development of endometrial receptivity preparing the endometrium for implantation [6].

It is difficult to assess the full spectrum of genomic and nongenomic action of these hormones in men given the paucity of research on these hormones in this population.

Progesterone and its metabolites (allopregnanolone and 4α,5α-tetrahydrodeoxycorticosterone) are potent activators of the PR. Extra-nuclear, non-classical (nongenomic) effects mechanisms include interactions with membrane receptors from the oxytocin (the "bonding" hormone) and GABA-A receptors, and the induction of a direct relaxing effect on uterine contractility by blocking calcium influx [6].

Activation of the PR regulates mammalian female sexual behavior (heat, behavioral estrus), and concurrent treatment with E2 (estradiol) treatment with E2 maximizes the probability that the female will display “lordosis” response, a primary reflexive component of female reproductive behavior, upon mounting by a con-specific male [11].

The extent of activity of progesterone on the CNS is modulated by the route of administration: oral P4 is affected by the presence of bacteria and gut enzymes, the intestinal wall, and liver, wheras intramuscular P4 is not [6].

Micronized progesterone (P4) and allopregnanolone, its chief metabolite, modulate GABAergic transmission with a similar potency or even greater efficacy than alcohol, benzodiazepines, or barbiturates [6]. Thus, similar to mesterolone (Proviron), this hormone is likely to be accompanied by withdrawal symptoms and there is no reason to believe that it is not reinforcing (add
ictive), as a class effect of GABAergic agents.

Oral route
Orally administered P4 undergoes several successive metabolic steps in the gut (5β-reductase), in the intestinal wall (5α-reductase), and the liver (5β-reductase, 3α- & 20α- hydroxylase). The resulting metabolites, 5α-pregnanolone (allopregnanolne; AlloP) and 5β-pregnanolone, bind the GABA-A-R, whilst 5α-pregnanedione & 5β-pregnanedione exert anti-mitotic (suppressing growth) and tocolytic (anti-contraction/relaxation) effects [6]. Oral P4 increases bone formation and is attended by estrogen-related improvements in bone mineral density (BMD), likely via production of new osteoblasts from mesenchymal stem cells and stimulation of osteoblasts to generate bone matrix (8),,[6],,. Oral P4 results in rapid absorption, a maximal plasma concentration within 4 hr with a 8.6% bioavailability versus intramuscular administration, and twice that when administered before food (5) [6].

Intramuscular route
Analogous to the most common (vaginal) route of administration, the intramuscular (IM) route of P4 results in only a small increase in allopregnanolone and no change in 5β-pregnanolone. Thus, men seeking the most relevant function (GABA-A-R modulation) of this hormone would be advised to use via the oral route (and, this is likely to modulate serum levels within the endogenous male range.

Reduced HPG Axis Functioning
"HPTA suppression"
Progesterone and its derivatives dysregulate hypothalamic regulation of T and gonadotropins via KNDy dendron signalling, disrupting GnRH pulsatility, and inhibiting pituitary LH secretion [8] [9]. Synthetic progestins used in male contraception derive efficacy from this feature. Bebb, et al. randomized healthy men to receive either testosterone enanthate (100 mg weekly), or the same dosage of testosterone in combination with the progestin levonorgestrel, the addition of which virtually abolished LH and FSH secretion [10].



Circulating levels in healthy adult men
AlloP serum:
- 0.75 nmol/L
- 0.24 ng/mL
Prog serum:
- 1.9 nmol/L
- 0.60 ng/mL
DHEA serum:
- 16.33 nmol/L
- 4.71 ng/mL [3]

DHEA is primarily an adrenal steroid; AlloP and Prog, as active neurosteroids, are primarily synthesized in the brain.

If one does embark on the use of exogenous neuroactive steroids, it would be prudent to "dial in" bloodwork to healthy endogenous male serum levels.
Whether the adult male's interest in
- allopregnanolone and/or
- exogenous (e.g., micronized) progesterone (P4)
- to treat:
+ anxiety (with drug-like efficacy; on par or greater than benzodiazepines or barbiturates, alcohol)
+ depression (with drug-like efficacy)
+ bones/joints (potential bone formation; augmented BMD)
+ adverse sexual effects of the rare (up to 4% prevalence) post-finasteride syndrome (the efficacy for which these agents have never been rigorously examined scientifically)
- outweighs:
- negative impact on HPG axis functioning (HPTA)
- anti-androgenic action (indeed, progesterone functions analogously to dutasteride/finasteride)
- potential for habituation (addiction) as GABAergic agents
- off-target hormonal effects (particularly egregious with progesterone)
- in consideration of:
+ exogenous T supplanting the role of DHT (but not allopregnanolone, progesterone [whose function in male physiology is markedly limited]) in prostate, scalp, etc.
+ exogenous T potently stimulating osteoblast activity (bone formation; augmented BMD)
+ availability of clinically indicated treatments, including TRT which demonstrably improves its patients' mental health, sexual function, QoL, and bone mineral density, administered by medical professionals, and
- the absence of any demonstrable clinical relevance of supplemental neurosteroids for healthy men
_______________________________
References:
[1] Zorumski, C. F., Paul, S. M., Covey, D. F., & Mennerick, S. (2019). Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. Neurobiology of Stress, 11, 100196. doi:10.1016/j.ynstr.2019.100196
[2] Irwig, M. S. (2014). Persistent Sexual and Nonsexual Adverse Effects of Finasteride in Younger Men. Sexual Medicine Reviews, 2(1), 24–35. doi:10.1002/smrj.19
[3] Genazzani, A. R., Petraglia, F., Bernardi, F., Casarosa, E., Salvestroni, C., Tonetti, A., … Luisi, M. (1998). Circulating Levels of Allopregnanolone in Humans: Gender, Age, and Endocrine Influences. The Journal of Clinical Endocrinology & Metabolism, 83(6), 2099–2103. doi:10.1210/jcem.83.6.4905
[4] Bond, P. (2020). On Steroids.
[5] Schumacher, M., Mattern, C., Ghoumari, A., Oudinet, J. P., Liere, P., Labombarda, F., … Guennoun, R. (2014). Revisiting the roles of progesterone and allopregnanolone in the nervous system: Resurgence of the progesterone receptors. Progress in Neurobiology, 113, 6–39. doi:10.1016/j.pneurobio.2013.09.004
[6] Piette, P. C. (2020). The Pharmacodynamics and Safety of Progesterone. Best Practice & Research Clinical Obstetrics & Gynaecology. doi:10.1016/j.bpobgyn.2020.06.002
[7] Sitruk-Ware, R. (2004). Pharmacological profile of progestins. Maturitas, 47(4), 277–283. doi:10.1016/j.maturitas.2004.01.001
[8] Navarro, V. M., Gottsch, M. L., Chavkin, C., Okamura, H., Clifton, D. K., & Steiner, R. A. (2009). Regulation of Gonadotropin-Releasing Hormone Secretion by Kisspeptin/Dynorphin/Neurokinin B Neurons in the Arcuate Nucleus of the Mouse. Journal of Neuroscience, 29(38), 11859–11866. doi:10.1523/jneurosci.1569-09.2009
[9] Girmus, R. L., & Wise, M. E. (1992). Progesterone Directly Inhibits Pituitary Luteinizing Hormone Secretion in an Estradiol-dependent Manner1. Biology of Reproduction, 46(4), 710–714. doi:10.1095/biolreprod46.4.710
[10] Bebb, R. A., Anawalt, B. D., Christensen, R. B., Paulsen, C. A., Bremner, W. J., & Matsumoto, A. M. (1996). Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. The Journal of Clinical Endocrinology & Metabolism, 81(2), 757–762. doi:10.1210/jcem.81.2.8636300
[11] Mani S, Portillo W. Activation of progestin receptors in female reproductive behavior: Interactions with neurotransmitters. Front Neuroendocrinol. 2010;31(2):157-171. doi:10.1016/j.yfrne.2010.01.002

I don't know of a single male BODYBUILDER, that supplement progestins or estrogens, NUTS!

 

[Jin23]

While progesterone isn't really something one would need to supplement, as there are better options, deficiency in allopregnanolone is associated with anxiety and depression. Actually, most SSRI's upregulate allopreg production and some studies have shown a positive correlation between remission from depression and the elevation of allopreg while on treatment with an ssri, ie. those who had a bigger improvement in depressive symptoms also had higher elevations in allopregnanolone levels. Agents like etifoxine, also directly upregulate allopregnanolone and they have been shown to be effective, with little rebound anxiety simpotms upon discontinuation. So your worries in regards to downregulation of gaba receptors might be worth a reconsideration?

While I have never heard of exogenous allopregnanolone supplementation, I do think that elevating endogenous allopregnanolone synthesis is a novel and promising treatment option. It's effects are purportedly not as strong, they are effective. I just ordered some etifoxine in oral form and will soon see for myself how effective it really is for somebody with GAD.

Also, seeing how aas upregulate the HPA axis, subsequently leading to anxiety and then to something that is neurologically very similar to depression, an anxiolytic agent makes a lot of sense. Most aas users that I see in reall life are really struggling with an inclination towards negative emotions, aggression, anxiety, ... ie. they are not really happy, light mood,. brisk people. And most family doctors that I've spoken to, that have aas user in their care, all say the same thing; anxiety and subsequently aggression towards their closest family members. So, what I'm reaffirming, again, is a more positive outlook to allopregnanolone "supplementation" - agents that modulate 3α-HSD and thus lead to a higher conversion rate of allopreg from 5α-dihydroprogesterone ...

 

[Klimmzugernie]

Would it make more sense to micro dose DHEA instead of pregnenolone or pregnenolone + dhea?
I take 10mg of dhea during cycle and feel great. Better libido and brain focus.
If I take more than 20mg I start to have water retention.
This effect is increased if I take 10mg pregnenolone... I feel weird and look soft.. but my libido is sky high.
So I figure out what could be the best compromise. I ended up at 10mg if DHEA

 

[Inspired]

The original post is severely lacking.

When it comes to hormones, especially thyroid, progesterone, and pregnenolone, Ray Peat is the guy to read.

5mg DHEA per day, or even twice a day, is good.

Pregnenolone should be taken in one larger dose (example, 300mg) every few days or even once a week. The body recycles Pregnenolone.

Progesterone: is a male hormone as much as it is a female hormone, despite what we've been made to believe. It has a wide range of uses. It's only effective topically, as a cream. Progesterone completely opposes and combats estrogen in the body.

All of these are useful.

 

[Type-IIx]

The original post is severely lacking.

When it comes to hormones, especially thyroid, progesterone, and pregnenolone, Ray Peat is the guy to read.

5mg DHEA per day, or even twice a day, is good.

Pregnenolone should be taken in one larger dose (example, 300mg) every few days or even once a week. The body recycles Pregnenolone.

Progesterone: is a male hormone as much as it is a female hormone, despite what we've been made to believe. It has a wide range of uses. It's only effective topically, as a cream. Progesterone completely opposes and combats estrogen in the body.

All of these are useful.

"The original post is severely lacking" is, naturally, YouTube dipshit speak for "The original post does not comport with my idiotic beliefs."

If you quasi-hermaphrodites want to inject, pop, or swallow female hormones, please, be my guest.

DHEA as DHEA sulfate is a potent estrogen (at ERα, its log EC50 is -6.01 & its relative transcriptional activity was 162% versus E2). While in women it has anabolic/androgenic activity (this makes sense given its endogenous adrenal cortex origin and involvement in T synthesis in women), in men it merely serves to dose-dependently increase E2.

While DHEA replacement to raise its serum concentrations to 4.71 ng/mL may be worthwhile, TRT increases serum DHEA; in contravention of the YouTube geniuses that argue for all of these hormones because AAS deplete them (bullshit).

Nah mate, what we've been led to believe about the hormones, the mother molecule/hormone, and that which controls female estrus and sex behavior (regulating lordosis, or raising the ass for penetration) is, in fact, correct.

 

[Inspired]

"The original post is severely lacking" is, naturally, YouTube dipshit speak for "The original post does not comport with my idiotic beliefs."

If you quasi-hermaphrodites want to inject, pop, or swallow female hormones, please, be my guest.

DHEA as DHEA sulfate is a potent estrogen (at ERα, its log EC50 is -6.01 & its relative transcriptional activity was 162% versus E2). While in women it has anabolic/androgenic activity (this makes sense given its endogenous adrenal cortex origin and involvement in T synthesis in women), in men it merely serves to dose-dependently increase E2.

While DHEA replacement to raise its serum concentrations to 4.71 ng/mL may be worthwhile, TRT increases serum DHEA; in contravention of the YouTube geniuses that argue for all of these hormones because AAS deplete them (bullshit).

Nah mate, what we've been led to believe about the hormones, the mother molecule/hormone, and that which controls female estrus and sex behavior (regulating lordosis, or raising the ass for penetration) is, in fact, correct.

Go read Ray Peat. I'm not going to do your homework.

To anyone else reading this: go read Ray Peat and his articles.

Ray Peat

Ray Peat

raypeat.com

And search on that forum for these hormones. The studies are there.

Low-Toxin Lifestyle, Toxic Bile Theory, Ray Peat's Research

Ray Peat Forum: Interweaving Low-Toxin Lifestyle Approaches, Toxic Bile Theory Insights, and Ray Peat's Research.

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[Jin23]

TRT increases serum DHEA;

Are you implying that people don't need to use hcg or supplement with oral dhea/pregnenolone in order to fulfill their neurosteroid cascade?

From what i've seen, most people retain some neurosteroid production, but it remains really on the low end, which is not optimal. But it varies from person to person and I don't quite understand why. Is it just the difference in enzymatic variance between individuals?

 

[jtmarlin]

Are you implying that people don't need to use hcg or supplement with oral dhea/pregnenolone in order to fulfill their neurosteroid cascade?

From what i've seen, most people retain some neurosteroid production, but it remains really on the low end, which is not optimal. But it varies from person to person and I don't quite understand why. Is it just the difference in enzymatic variance between individuals?

I will tell you as a subject of 1 on TRT who gets bloodwork done for these markers.

My DHEA-S is mid range. Always is the same 270s.

My pregnenlone is practically non-existent. Bottom end of reference range. I'm not actually sure that we really need any of this if we are supplementing Testosterone as it is a master hormone that gets us to good T levels to begin with. The body may shut this off bc it doesn't need it.

I use actavis test cyp and pregnyl HCG that I get from a local American pharmacy.

300iu of HCG 2X per week. Seemingly does nothing for my DHEA/Preg numbers and I even went completely sterile while on TRT while using HCG.

I have begun to supplement with 25mg DHEA + 10mg Preg daily and will get my bloodwork again in a few months.

 

[Type-IIx]

Are you implying that people don't need to use hcg or supplement with oral dhea/pregnenolone in order to fulfill their neurosteroid cascade?

From what i've seen, most people retain some neurosteroid production, but it remains really on the low end, which is not optimal. But it varies from person to person and I don't quite understand why. Is it just the difference in enzymatic variance between individuals?

I'm not implying it, I'm saying it in plain English (with respect to supplemental neurosteroids). HCG is in a different class altogether, its use is rational for maintaining spermatogenesis/fertility/HPG axis functioning.

Consider these facts:
* brain concentrations of these exogenous hormones are not reflected by serum concentration

* the role of DHEA, allopregnanolone, progesterone is markedly limited in male physiology

* Exogenous T (TRT) increases DHEA; there is evidence in orchidectomized (OCX) rats of
increased hippocampal, hypothalamic, and anterior pituitary levels of allopregnanolone by T


Rather, it is the 5α-reductase inhibitors and not TRT/AAS that cause problems (some instances of depression and perhaps sexual dysfunction as in the post-finasteride syndrome), with an association with depleted neurosteroids.

 

[Jin23]

Consider these facts:
* brain concentrations of these exogenous hormones are not reflected by serum concentration

Interesting, never considered that blood serum markers would be of little relevance ... This I guess, is the most important factor to consider. But also one, that would be really hard to measure, if possible at all on a living subject ...?

Congratulations on your English.

 

[Klimmzugernie]

http://biochemical-pathways.com/#/map/1

 

[Klimmzugernie]

That means DHEA can just converted in estriol... Guess it is E1.
Or is being built in testosterone and then aromatized in Estradiol E2.
There is no way back to pregnenolone or progesterone.

....if this map is correct and complete.
Idk, but in fact 3a HSD at dht is missing.

 

[Type-IIx]

That means DHEA can just converted in estriol... Guess it is E1.
Or is being built in testosterone and then aromatized in Estradiol E2.
There is no way back to pregnenolone or progesterone.

....if this map is correct and complete.
Idk, but in fact 3a HSD at dht is missing.

In men, DHEA sulfate just dose-dependently increases E2 & is itself a potent ERα agonist. It aromatizes at 67% the rate of T, ⇒ E₁ (estrone) & E₂ (estradiol). Its aromatization to E1 occurs via 3β-HSD ⇒ Δ⁴-3-keto (E1) from 3β-HSD modification at the Δ⁵-3β-OH group. E₂ always via Aromatase.

 

[Type-IIx]

I will tell you as a subject of 1 on TRT who gets bloodwork done for these markers.

My DHEA-S is mid range. Always is the same 270s.

My pregnenlone is practically non-existent. Bottom end of reference range. I'm not actually sure that we really need any of this if we are supplementing Testosterone as it is a master hormone that gets us to good T levels to begin with. The body may shut this off bc it doesn't need it.

I use actavis test cyp and pregnyl HCG that I get from a local American pharmacy.

300iu of HCG 2X per week. Seemingly does nothing for my DHEA/Preg numbers and I even went completely sterile while on TRT while using HCG.

I have begun to supplement with 25mg DHEA + 10mg Preg daily and will get my bloodwork again in a few months.

This was all perfectly sensible, until you said you begun to supplement with DHEA & Preg.

The problems with routine bloodwork for these things is that they elicit a false sense of control and they lead to playing whack-a-mole with hitting values that, rather than based on symptomology, are based on perceptions surrounding arbitrary normal reference values (remember, you're on exogenous T).

DHEA is an adrenal steroid that in women confers some basal androgen function. Men don't need it, plain and simple. Besides, T/TRT increases its levels in blood, and you already said you're dead-on in the middle of the normal range. Your bloodwork values showing low pregnenolone does not reflect brain activity, where best evidence shows T/TRT increases this local (brain) activity (of AlloP). Moreover, T (in brain, it is aromatization to E2 that provides for male behaviors including sexual; that is, Aromatase in brain raises brain estradiol, so that E2 and not T confers male behavior) & DHT supplant the role of weak adrenal steroids like DHEA.

T/TRT consistently improves QoL metrics and promotes feelings of well-being (coming up from hypogonadal ranges). This is not consistent with bullshit beliefs surrounding depletion of important neurosteroids.

 

[jtmarlin]

T/TRT consistently improves QoL metrics and promotes feelings of well-being (coming up from hypogonadal ranges). This is not consistent with bullshit beliefs surrounding depletion of important neurosteroids.

You should spend some time at a TRT board... 3/4 of the guys are in absolute misery since being on TRT yet they soldier on tweaking things by 4mg here, 8 hours there, hoping to find some magic solution where they are horny 24/7, sleep 8 straight hours, and are happy as fuck 24/7. They are chasing a myth... rubbing cream on the left nut but not the right at 12 hour intervals. It's nuts. I think most of them are crazy TBH.

I started supplementing with DHEA/Preg to see if it helped my cognition. This is hard to measure obviously and quite subjective. Many of the more successful guys on TRT have DHEA at the top of reference range (400s), so I'd like to see how it goes with a higher level. As for pregnenolone, I think we are still learning. My personal hunch is that TRT reduces it and we don't need much of it, but I don't think there is really any downside supplementing with 10mg in the AM.

The body is pretty good at figuring things out I mean hell guys live on Deca alone for years and are fine.

 

[Inspired]

You should spend some time at a TRT board... 3/4 of the guys are in absolute misery since being on TRT yet they soldier on tweaking things by 4mg here, 8 hours there, hoping to find some magic solution where they are horny 24/7, sleep 8 straight hours, and are happy as fuck 24/7. They are chasing a myth... rubbing cream on the left nut but not the right at 12 hour intervals. It's nuts. I think most of them are crazy TBH.

I started supplementing with DHEA/Preg to see if it helped my cognition. This is hard to measure obviously and quite subjective. Many of the more successful guys on TRT have DHEA at the top of reference range (400s), so I'd like to see how it goes with a higher level. As for pregnenolone, I think we are still learning. My personal hunch is that TRT reduces it and we don't need much of it, but I don't think there is really any downside supplementing with 10mg in the AM.

The body is pretty good at figuring things out I mean hell guys live on Deca alone for years and are fine.

How old are you? Stick to 5mg DHEA daily or maybe twice per day. No more than that.

 

[jtmarlin]

How old are you? Stick to 5mg DHEA daily or maybe twice per day. No more than that.

Early 40s

 

[Type-IIx]

You should spend some time at a TRT board... 3/4 of the guys are in absolute misery since being on TRT yet they soldier on tweaking things by 4mg here, 8 hours there, hoping to find some magic solution where they are horny 24/7, sleep 8 straight hours, and are happy as fuck 24/7. They are chasing a myth... rubbing cream on the left nut but not the right at 12 hour intervals. It's nuts. I think most of them are crazy TBH.

I started supplementing with DHEA/Preg to see if it helped my cognition. This is hard to measure obviously and quite subjective. Many of the more successful guys on TRT have DHEA at the top of reference range (400s), so I'd like to see how it goes with a higher level. As for pregnenolone, I think we are still learning. My personal hunch is that TRT reduces it and we don't need much of it, but I don't think there is really any downside supplementing with 10mg in the AM.

The body is pretty good at figuring things out I mean hell guys live on Deca alone for years and are fine.

I've seen it bro, it was one of those boards that drove me to post this thread. Good post, I think we are of a similar mind also.

It may well be that DHEA confers this effect. By corollary, some people that use Proviron, which increases DHEA in these users by apparently blocking the Δ⁵ pathway of T synthesis, thereby ↑DHEA supply from [the adrenal] DHEA pool, report feelings of well-being, improved cognition and such; but also withdrawal symptoms upon cessation.

 

[jtmarlin]

I've seen it bro, it was one of those boards that drove me to post this thread. Good post, I think we are of a similar mind also.

It may well be that DHEA confers this effect. By corollary, some people that use Proviron, which increases DHEA in these users by apparently blocking the Δ⁵ pathway of T synthesis, thereby ↑DHEA supply from [the adrenal] DHEA pool, report feelings of well-being, improved cognition and such; but also withdrawal symptoms upon cessation.

We shall see what happens. I was finding myself literally forgetting words and not being able to remember shit. Felt slow witted. To the point my wife asked wtf was wrong with me. Been noticing it for awhile. I was a straight A student, so I don't have learning issues. I've always avoided Proviron for the most part. Always wonder why anyone needed more DHT while on supra physical levels of test. I understand the reduction in SHBG part, but mine is always low so I'm getting plenty of free T conversion already. My guess is I'd get acne as well. Primobolan alongside my TRT gave me back and shoulder acne whereas test doesn't.

As for the TRT crew who is constantly adjusting things I'm getting pretty close to shooting a cc of test cyp every Thursday and throwing everything else in the trash and moving on with it.