The influence of high doses of testosterone and anabolic steroids on testicular endocrine function and on circulating steroid-binding proteins, sex hormone-binding globulin (SHBG) and cortisol binding globulin (CBG), were investigated in power athletes for 26 weeks of steroid self-administration and for the following 16 weeks after drug withdrawal. [1]

The depressed circulating levels of dehydroepiandrosterone(DHEA) and its sulphate indicate that the androgenic-anabolic steroids suppress adrenal androgen production also. [1]

 

We all know that testosterone is a major male hormone and it is involved in more than 150 processes in our body. It has a direct effect not on muscle mass only, but also on sleep and mood, and bone density, and it has dozens of indirect effects, also.

Let's observe the cascade of steroidogenesis

 

In addition to testosterone, other hormones are also included in it, but they often remain completely unknown to athletes, because they do not have such a dramatic effect on muscle mass, but their importance remains significant.

Like their "big brother" testosterone, they are included in various processes, have their own receptors, and are also necessary for life, health, and well-being.

 

Let's consider in detail just a few of them.

Progesterone​

Progesterone is a neurosteroid and a neuroactive steroid; that is, it plays a role in the brain. It can cross the blood-brain barrier to go to the brain. Progesterone classically exerts its effects via the progesterone receptor. Unfortunately, it’s relatively understudied in males, particularly in a clinical and non-animal model.

Nonetheless, studies do demonstrate that it plays a significant role in maintaining a healthy brain in both women and men who are healthy or otherwise [2-4].

In animal models, progesterone demonstrates that it plays an important role in the recovery of Traumatic Brain Injury too [5]. Whether this translates to Humans or not will require additional studying.

What a lot of men also don’t realize is Progesterone functions as a precursor in our body to produce Testosterone while also acting as a balance to decrease estrogen impact, sleep improvement, and effects on tumors in the CNS (meningioma, fibroma), as well as effects on the immune system, cardiovascular system, kidney function, adipose tissue, behavior, and respiratory system.

DHEA​

Dehydroepiandrosterone (DHEA) is a hormone that your body naturally produces in the adrenal gland . It results in a shift of a catabolic state to an anabolic or protein building state.

ts role is not fully understood, but it plays an important part in the synthensizing estrogen and androgen.

It reduces cardiovascular risks by increasing lipolyses (decrease visceral fat), stimulates the immune system, restores sexual vitality, improves moods, decreases cholesterol and body fat, improves memory, increases energy, and has anti-cancer properties by enhancing the immune system. DHEA is an endocrine precursor to other hormones, prevents immuno-senescence, loss of sleep, osteoporosis and atherosclerosis also it reduces insulin requirement [7].

DHEA is a protective anabolic hormone. It has antioxidant activity and can help in neuronal preservation, thus is ergogenic to cognition. That is, it’s good for your brain. It may well be associated with executive function and memory [8]. Although, we can’t say this with a large degree of confidence in men as studies are a bit unclear; more studies are needed.

The World Anti-Doping Agency classes DHEA as a banned substance in sports – it’s the best evidence. They will never ban something useless.

Pregnenolone​

Naturally occurring pregnenolone is the precursor to all steroid hormones. But it acts itself also to improve memory and combat depression has powerful anti-inflammatory arthritis pain-relieving properties, and helps improve mood.

In well-designed studies using men with bipolar disorder, it has been shown to reduce and improve depressive symptoms [9].

It also reduces perceived pain, as shown in a randomized control trial with Army veterans who had lower back pain; pregnenolone reduced perceived pain in a clinically meaningful manner [10].

The hormone is well known to play important roles in cognition, improving mood and reducing pain.

In addition to stress and depression, pregnenolone supplementation also entered the antiaging arena to address mental decline and memory loss, and act as a memory enhancer.

Pregnenolone antagonizes the GABAB1 receptor and increases neurogenesis in the hippocampus and is a negative modulator of the endocannabinoid CB1 receptor.

Allopregnanolone​

​Allopregnanolone is neurosteroid, metabolite of allopregnanedione. It is synthesized both by the adrenal cortex and directly in the brain from the serum progesterone and it showed its importance in psychiatry and well-being. This steroid plays a multifaceted role in the development and maintain of the central nervous system, has antidepressant activity.

Allopregnanolone exerts neurogenetic, neuroprotective, antidepressant, and anxiolytic effects. Reduced levels of allopregnanolone are found to be associated with major depression, anxiety disorders, premenstrual dysphoric disorder, and Alzheimer’s disease.

Yes, there is a piece of evidence that your girlfriend’s PMS is induced by the lack of allopregnanolone:

Neurosteroid allopregnanolone has been implicated in perimenstrual seizure exacerbations in women with a normal menstrual cycle. It is hypothesized that withdrawal of progesterone-derived neurosteroids leads to enhanced excitability predisposing to seizures (Reddy et al., 2001, 2012; Reddy, 2013b)[11]

It modulates the activity of the GABA-A receptor.[ 12]

Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.[13]

Decreased levels of allopregnanolone have been noted in the serum and cerebrospinal fluid of patients with depression; successful antidepressant therapy is reported to be associated with an increase in allopregnanolone, as well as an antidepressant-like effect of allopregnanolone in animal models.[14,15]

One preliminary report from an unpublished study reported that allopregnanolone levels were inversely correlated with various manifestations of post-traumatic stress disorder and that a reduced allopregnanolone/progesterone ratio was found in depressed military veterans with PTSD and suicidal ideation.[16]

Allopregnanolone, is a fresh discovery, but it already prove it efficiency and used in psychiatry as brexanolone for the treatment of depression. In March 2019, brexanolone was approved in the United States by Food and Drug Administration (FDA)- as fast-acting antidepressant. It prove its efficiency and recommended for treating of resistant depressions.

In an open-label study, a single brexanolone IV administration showed rapid and long-lasting antidepressant effects in severe post-partum depression and other types of depressive disorders [17,18,19]

Allopregnanolone found safe, may slow brain atrophy from Alzheimer’s[20]

So what is the issue with this all?

We discussed that molecules that in a past were considered just as precursors of testosterone or just metabolites of testosterone synthesis, we found that they are important in and of themselves.

Ceasing HPTA by AAS will leave you with testosterone(or its derivates) only, while other elements of the cascade are important and each of them has its own unique function.

Now let's return to the research we discussed in the whole beginning of this article:

Self-administrated doses of testosterone and anabolic steroids lead to complete cessation of steroidogenesis cascade for the following 16 weeks after drug withdrawal.

This time needs to “restart” and the whole chain of reactions, and sometimes it is not so easy.

What should we do to escape it?

Beware of steroids and keep the sports clean?

weeeeell....

 

Ok, there is another way... To keep steroidogenesis cascade active and make your body produce all the steroid hormones needed use Human chorionic gonadotropin (HCG)!

HCG activates the p450 side chain cleavage (p450scc) enzyme which converts cholesterol to Pregnenelone – the father of all steroid hormones, to produce the precursors for DHEA, Pregnenelone, Allopregnenelone Estrogen, Cortisol, Testosterone and DHT…back filling the pathways.

Literally! Gonadotropins contribute to steroid hormone production along the classic Δ4 pathway and co-activate an alternative pathway of testosterone biosynthesis via androstenediol, so in males with CHH, serum steroid hormone profiles resemble those of healthy men, if hCG is used for substitution. [21]

As the net result you will keep the activity of your testicles, ease your PCT even after a super long cycles – HCG will make it possible, get the better sense of well-being and many, many more.

So brief conclusion is: during TRT or the 6+ weeks cycle HCG is mandatory, period.

Your testicles will appreciate it, gentlemen!

 

[1] https://www.sciencedirect.com/science/article/abs/pii/0022473185902572

Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man’ Ruokonen M.Alén N.Bolton R.Vihko1

[2] Singh M, Su C. Progesterone and neuroprotection. Horm Behav. 2013;63(2):284-290. doi:10.1016/j.yhbeh.2012.06.003

[3] Henderson VW. Progesterone and human cognition. Climacteric. 2018;21(4):333-340. doi:10.1080/13697137.2018.1476484

[4] Champagne J, Lakis N, Bourque J, Stip E, Lipp O, Mendrek A. Progesterone and Cerebral Function during Emotion Processing in Men and Women with Schizophrenia. Schizophr Res Treatment. 2012;2012:1-6. doi:10.1155/2012/917901

[5] Espinoza TR, Wright DW, Glenn MB. The role of progesterone in traumatic brain injury. J Head Trauma Rehabil. 2011;26(6):497-499. doi:10.1097/HTR.0b013e31823088fa

[6] de Menezes KJ, Peixoto C, Nardi AE, Carta MG, Machado S, Veras AB. Dehydroepiandrosterone, Its Sulfate and Cognitive Functions. Clin Pract Epidemiol Ment Heal. 2016;12(1):24-37. doi:10.2174/1745017901612010024

[7] Effect of Dehydroepiandrosterone Replacement on Insulin Sensitivity and Lipids in Hypoadrenal Women Ketan Dhatariya; Maureen L. Bigelow;K. Sreekumaran Nair

[8] "Effect of dehydroepiandrosterone (DHEA) on monoamine oxidase activity, lipid peroxidation and lipofuscin accumulation in aging rat brain regions" Pardeep Kumar 1, Asia Taha, Deepak Sharma, R K Kale, Najma Z Baquer • PMID: 18307051• DOI: 10.1007/s10522-008-9133-y

[9] Brown ES, Park J, Marx CE, et al. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014;39(12):2867-2873. doi:10.1038/npp.2014.138

[10] Naylor JC, Kilts JD, Shampine LJ, et al. Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial. JAMA Netw open. 2020;3(3):e200287. doi:10.1001/jamanetworkopen.2020.0287

[11] Allopregnanolone

[12] Pinna G, Uzunova V, Matsumoto K, Puia G, Mienville JM, Costa E, et al. (January 2000). "Brain allopregnanolone regulates the potency of the GABA(A) receptor agonist muscimol". Neuropharmacology. 39 (3): 440–8. doi:10.1016/S0028-3908(99)00149-5. PMID 10698010. S2CID 42753647.

[13] Reddy DS (2010). Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog. Brain Res. Progress in Brain Research. Vol. 186. pp. 113–37. doi:10.1016/B978-0-444-53630-3.00008-7. ISBN 9780444536303. PMC 3139029. PMID 21094889.

[14] Girdler S. S., Klatzkin R. Neurosteroids in the context of stress: implications for depressive disorders (англ.) // Pharmacology & Therapeutics : journal. — 2007. — October (vol. 116, no. 1). — P. 125—139. — doi:10.1016/j.pharmthera.2007.05.006. — PMID 17597217.

[15] Pinna G., Dong E., Matsumoto K., Costa E., Guidotti A. In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine (англ.) // Proceedings of the National Academy of Sciences : journal. — 2003. — February (vol. 100, no. 4). — P. 2035—2040. — doi:10.1073/pnas.0337642100. — PMID 12571361.

[16] Candidate Biomarkers for PTSD Symptoms Identified

[17] Zorumski CF, Paul SM, Covey DF, Mennerick S (November 2019). "Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond". Neurobiology of Stress. 11: 100196. doi:10.1016/j.ynstr.2019.100196. PMC 6804800. PMID 31649968.

[18] Kanes S, Colquhoun H, Gunduz-Bruce H, Epperson CN, Rubinow D, Paul S, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. (2017) 390:480–9. doi: 10.1016/S0140-6736(17)31264-3

[19]The role of allopregnanolone in depressive-like behaviors: Focus on neurotrophic proteins Felipe Borges Almeida 1, Maurício Schüler Nin 1 2 3, Helena Maria Tannhauser Barros 1 Affiliations expand PMID: 32435667 PMCID: PMC7231971 DOI: 10.1016/j.ynstr.2020.100218

[20] Frontiers in therapeutic development of allopregnanolone for Alzheimer’s disease and other neurological disorders

[21] Julia Rohayem , Michael Zitzmann , Sandra Laurentino , Sabine Kliesch, Eberhard Nieschlag , Paul-Martin Holterhus , Alexandra Kulle "The role of gonadotropins in testicular and adrenal androgen biosynthesis pathways-Insights from males with congenital hypogonadotropic hypogonadism on hCG/rFSH and on testosterone replacement" PMID: 32871622 DOI: 10.1111/cen.14324 DOI: 10.1111/cen.14324