Risk-reward profile for progesterone/allopregnanolone supplementation

[Type-IIx]

Risk-reward profile for progesterone/allopregnanolone supplementation​

Author: Type-IIx​

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

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 effect 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 endgenous 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. 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, this hormone is likely to be accompanied by withdrawal symptoms and there is no reason to believe that it is not reinforcing (addictive), 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​

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 suppresion
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]

 

[Type-IIx]

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

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.

Risk-balancing considerations​

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

 

[maldorf]

No mention of effects on clotting. I know progesterone only birth control pills are prescribed to those with clotting disorders.

 

[Type-IIx]

No mention of effects on clotting. I know progesterone only birth control pills are prescribed to those with clotting disorders.

Yes, but this is intended for the ProM audience (healthy men and men on T). I tried to narrow the focus to relevant use cases. Do you think this is accurate within this context?

 

[maldorf]

Yes, but this is intended for the ProM audience (healthy men and men on T). I tried to narrow the focus to relevant use cases. Do you think this is accurate within this context?

Well, with guys taking a lot of hormones already and then adding in more, this probably introduces more risk.

In a healthy male just looking to do hrt, the risk is a lot lower.

I'm not familiar at all with the other hormone allopregnanolone.

 

[Type-IIx]

Well, with guys taking a lot of hormones already and then adding in more, this probably introduces more risk.

In a healthy male just looking to do hrt, the risk is a lot lower.

I'm not familiar at all with the other hormone allopregnanolone.

Epidemiological studies suggest that estrogens may have opposite effects on vessels: estrogens used for contraception are known to increase both arterial and venous risk, while hormone replacement therapy could reduce the risk of cardiovascular disease. In both situations, estrogens are associated with progestogens. Progestogens are rarely used alone, thus the effect of progestogens on haemostasis or vessel wall is unclear. Data can be obtained from studies using progestogens alone or from studies comparing unopposed estrogens to combined estrogen-progestogen therapy. Progestogens alone have few effect on the haemostatic system. In combined therapy used for contraception, progestogens modify the effects of estrogens on haemostasis and endothelium: the overall effect, including modifications of coagulation factors and inhibitors could a prothrombogen trend, mainly for third generation progestogens. Unopposed estrogens are also rarely used for post menopausal hormone replacement therapy (HRT). Experimental studies have shown that progestogens are able to inhibit the beneficial effect of estrogens. Two mechanisms have been suggested: first, progestogens may reduce the endothelium-dependent vasodilatator action of estrogens. Another explanation concerns the neointimal proliferation leading to atherosclerosis: Estradiol are known to reduce this proliferation. Progestogens could reduce the protective effect of estrogens. These pharmacological effect of progestogens must be taken in account to interpret the negative results of HERS study that failed to demonstrate a cardiovascular benefit of estrogens plus progestin therapy in postmenopausal women.

[Progestogens, progesterone, coagulation and vascular tone] - PubMed

Epidemiological studies suggest that estrogens may have opposite effects on vessels: estrogens used for contraception are known to increase both arterial and venous risk, while hormone replacement therapy could reduce the risk of cardiovascular disease. In both situations, estrogens are...

pubmed.ncbi.nlm.nih.gov

So, progestogens, combined with FEMALE HRT (contraceptives) modifies coagulation factors, and may inhibit the beneficial effect of estrogens by several mechanisms. This likely explains the progesterone only contraceptive use (lowering CV and clotting risk by not coadministering progesterone and estrogens).

Do you have any evidence that supplemental progesterone is beneficial for men on T in regards to clotting/CV risk?

 

[maldorf]

[Progestogens, progesterone, coagulation and vascular tone] - PubMed

Epidemiological studies suggest that estrogens may have opposite effects on vessels: estrogens used for contraception are known to increase both arterial and venous risk, while hormone replacement therapy could reduce the risk of cardiovascular disease. In both situations, estrogens are...

pubmed.ncbi.nlm.nih.gov

So, progestogens, combined with FEMALE HRT (contraceptives) modifies coagulation factors, and may inhibit the beneficial effect of estrogens by several mechanisms. This likely explains the progesterone only contraceptive use (lowering CV and clotting risk by not coadministering progesterone and estrogens).

Do you have any evidence that supplemental progesterone is beneficial for men on T in regards to clotting/CV risk?

No, don't know a thing about progesterone exogenous use in men on testosterone, but it's a very good question.

 

[Kaladryn]

No mention of effects on clotting. I know progesterone only birth control pills are prescribed to those with clotting disorders.

This is only because estrogen-based ones cause clots not because progesterone-based ones reduce clots.

 

[buck]

No mention of effects on clotting. I know progesterone only birth control pills are prescribed to those with clotting disorders.

Most birth control pills i have seen have use progestin Progestin is a synthetic, lab created hormone meant to mimic progesterone. Not sure how many pills if any use real estrogen and progesterone. And progestin seems to raise the chance of clots. As pharma can't patent naturally occurring substance so there would be no profit from the research. When they do use them they patent the delivery process from what i have seen.

 

[maldorf]

This is only because estrogen-based ones cause clots not because progesterone-based ones reduce clots.

thats what I figured.

 

[OuchThatHurts]

Doesn't estrogen actually have a positive effect on lipids in both men and women? Provided the levels aren't extremely high (eg while on birth control in women or high levels of aromatization in males)?

I get a periodical from the AHA and I'm sure I just read that. The article I read went on to say that it is for that exact reason than women lag 10 years behind males in age of MI, stroke, and CVD.

 

[Type-IIx]

Doesn't estrogen actually have a positive effect on lipids in both men and women? Provided the levels aren't extremely high (eg while on birth control in women or high levels of aromatization in males)?

I get a periodical from the AHA and I'm sure I just read that. The article I read went on to say that it is for that exact reason than women lag 10 years behind males in age of MI, stroke, and CVD.

Yes, estrogen does positively impact lipids. It's the sole justification for wanting to increase E2 into the normal range in low aromatizers. Still, there are other means to improve lipids.

The chief concern, with exogenous estradiol if that's what you're thinking of, is that it increases IGFBP-1, thus reducing free IGF-I availability. It's the reason women are so resistant to rhGH treatment (see https://www.professionalmuscle.com/...-dosages-effects-of-estradiol-igfbp-1.169919/)

What we really want is aromatization itself from aromatizing androgen (test, nand, dbol, MENT, etc). The aromatic products, however, do pose a net negative beyond, in the case of E2, arbitrarily, 60-75 pg/m?L. Given the known unknowns with respect to the aromatic products of MENT (see https://www.professionalmuscle.com/forums/index.php?threads/ment-profile.170059/) and Dbol, it's more difficult to ascribe even an arbitrary value to a "theoretical upper limit."

Note that the exogenous use of estradiol + progesterone would be highly detrimental due to the increased prothrombotic/increased cardiovascular risk (https://www.professionalmuscle.com/...gnanolone-supplementation.170204/post-3049757)

 

[Type-IIx]

@OuchThatHurts another important deleterious impact of estradiol (and especially oral estrogens) is that they dramatically increase SHBG.

 

[Love_to_Bodybuild]

Pregnenolone is different from allo. One is a Precursor, prohormone or converts to, is this correct?

Also I mentioned 10 mgs of pregnenolone because typical oral dose is 30 mgs however this smaller dose is being on the safe side. Just like 25 mgs dhea, as oral dhea converts to testosterone at like 3%.

I prefer transdermal as it absorbs much more efficient than oral, esp on the testes. I prefer daytime dosing however with oral 10mgs this dose is so small and doesn't absorb well so it's more than likely fine before bed, as too much pregnenolone, allo, or progesterone can cause anxiety and less ness, even though it's says it's for anti anxiety.

 

[blackjack]

@OuchThatHurts another important deleterious impact of estradiol (and especially oral estrogens) is that they dramatically increase SHBG.

I've recently started taking HCG at a very low dose every other day. It has been a total game changer in terms of how I feel in almost every way(long time TRT). It's my understanding there are a lot of similarities between HCG and Progesterone/Pregnenolone. Would the above apply here?

 

[BYBON]

I wanted to give a shout out to an alternative. No biggy if no one cares. I won't get into too much nerdy detail.

Given that GABA-A activity is the desired effect in those studies, focusing on the use of safer GABA-A agonists would be a far safer method.

Did the studies show differences in activity with GABAA Receptor subunits A1, A2, A3, and/or A5? That is a very important distinction, especially since GABAA Receptor α1 is widely seen abuse of gabaergic drugs. Table 1 for your viewing pleasure:

Everyone gets excited to see "hormone", which is perfectly fine. Yet, there are far safer avenues to manipulate the GABAA receptor and its subunits, like taking Imidazenil.

Also, make sure you intake plenty of serine, threonine, and glycine.

 

[Type-IIx]

Pregnenolone is different from allo. One is a Precursor, prohormone or converts to, is this correct?

Also I mentioned 10 mgs of pregnenolone because typical oral dose is 30 mgs however this smaller dose is being on the safe side. Just like 25 mgs dhea, as oral dhea converts to testosterone at like 3%.

I prefer transdermal as it absorbs much more efficient than oral, esp on the testes. I prefer daytime dosing however with oral 10mgs this dose is so small and doesn't absorb well so it's more than likely fine before bed, as too much pregnenolone, allo, or progesterone can cause anxiety and less ness, even though it's says it's for anti anxiety.

Here's the biosynthetic pathway.

Transdermal application pharmacokinetics and -dynamics hints at chronic progesterone exposure. From Footnote [5], "...both chronic exposure to progesterone or allopregnanolone or withdrawal from these steroids increase [GABA subunit] α4 expression, resulting in decreased benzodiazepine sensitivity and neuronal hyperexcitability...related to premenstrual and post-partum symptoms: increased anxiety, seizure susceptibility, depression and insensitivity to benzo. sedatives."

 

[Type-IIx]

I wanted to give a shout out to an alternative. No biggy if no one cares. I won't get into too much nerdy detail.

Given that GABA-A activity is the desired effect in those studies, focusing on the use of safer GABA-A agonists would be a far safer method.

Did the studies show differences in activity with GABAA Receptor subunits A1, A2, A3, and/or A5? That is a very important distinction, especially since GABAA Receptor α1 is widely seen abuse of gabaergic drugs. Table 1 for your viewing pleasure:

Everyone gets excited to see "hormone", which is perfectly fine. Yet, there are far safer avenues to manipulate the GABAA receptor and its subunits, like taking Imidazenil.

Also, make sure you intake plenty of serine, threonine, and glycine.

Allopregnanolone acts primarily at subunits α4, δ, and γ2.

 

[Type-IIx]

I've recently started taking HCG at a very low dose every other day. It has been a total game changer in terms of how I feel in almost every way(long time TRT). It's my understanding there are a lot of similarities between HCG and Progesterone/Pregnenolone. Would the above apply here?

There are not many similarities between hCG and progesterone/pregnanolone. Completely different hormones and uses. They act in opposition in important ways.

 

[Zarati]

I love progesterone, bloodwork came back at 0, taking 1mg a night. I feel better on it.


Good write up by Phil Hernon.

The progesterone biosynthesis chain somewhat......cholesterol to pregnenolone to progesterone to mineralcorticoids to glucocorticoids to androgens.........from there to estrogens......on to specific proteins

or cholesterol to pregnenolone to progesterone to 17-OH-prog to androstenedione to
androgens.........from there to estrogens....... to specific proteins

progesterone can't do its job if the progesterone receptor is not activated by......ESTROGEN......but too much progesterone in relation to estrogen can raise insulin levels, decreasing sensitivity, weight gain, reducing sex drive.......

You dont need progesterone for DHEA, you would need cholesterol to pregnenolone, to 17-OH-prog, then DHEA then to androstenedione then to androgens........you need progesterone for cortisol and aldosterone yes