TRT Effect on 5 Alpha Reductase and Upstream Hormones- Cause of Low Mood and Anxiety?

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Really?

hCG mimics LH which stimulates Leydig cells leading to an increase in both ITT (intratesticular testosterone) and circulating testosterone levels.

LH is critical as it stimulates cAMP production and cholesterol transport to and metabolism within mitochondria.



post#37


My reply:

The main purpose of adding hCG to trt is to preserve/maintain fertility and prevent/minimize testicular atrophy.

The use of exogenous testosterone results in the suppression of ITT (intra-testicular testosterone) which is critical for sperm production.

The main goal when using hCG is to restore physiological ITT levels and in order to achieve such a minimum effective dose would be needed (125-500IU) and 250-500IU would seem to be the sweet spot.

Anything less will have a minimal impact on increasing ITT!

Other than one experiencing possible side effects from such doses (250-500IU) using anything <125IU will have a minimal impact on increasing ITT.

My reply from a previous thread where the poster asked if hCG was needed.


Depends on the individual.....Is hCG needed?

*To preserve/maintain fertility then yes.

*To prevent/minimize testicular atrophy then yes.

*To enhance mood/libido than it is not a given as some may experience such effects whereas others may feel worse-off.


*To maintain upstream hormones and possibly prevent long-term consequences for health/well-being.....you be the judge!





*take-home point

A replacement regimen with combined hCG/rFSH mimics physiologic steroid hormone profiles better than a substitution with exogenous testosterone. The documented differences in steroid profiles on testosterone replacement in hypogonadal males with absent or severely reduced endogenous LH and FSH secretion may have long-term consequences for health and wellbeing. Specifically, body composition, bone health, glucose, and lipid metabolism, salt and water balance, cognition, mood, sleep, and sexual function could be affected.
The steroidogenic differences could also be relevant for gonadotropin-suppressive treatments with long-acting testosterone preparations in males with primary hypogonadism. To what extent this hypothesis is true, should be addressed in future clinical studies.








Testosterone synthesis in Leydig cells

Steroidogenesis is a multi-step process that converts cholesterol into final steroid hormone products.
As reviewed in Aghazadeh and coworkers (Aghazadeh et al. 2015), steroidogenesis consists of cholesterol mobilization from lipid droplets and/or the plasma membrane, cholesterol transport into mitochondria, pregnenolone formation in the mitochondria, and subsequent conversion of pregnenolone into the final steroid products by enzymes of the smooth endoplasmic reticulum (Fig. 1). In the adult testis, Leydig cell TS production depends upon the pulsatile secretion of LH by the pituitary gland into the peripheral circulation. LH plays two essential roles in Leydig cell steroidogenesis: (1) maintenance of optimal levels of steroidogenic enzymes (trophic regulation) and (2) mobilization and transport of cholesterol into the inner mitochondrial membrane (acute regulation).
View attachment 15215




Leydig cell steroidogenesis.

LH binds its receptor on the Leydig cell membrane. LH receptor/G protein coupling results in increased cAMP and arachidonic acid (AA) production. cAMP stimulates the mobilization and transport of cholesterol to and into the mitochondria in part by activating PKA and MAPK signaling.
At the same time, AA can be converted into prostaglandin by Cox2 to negatively regulate the transport of cholesterol across the mitochondrial membranes. At the inner mitochondrial membrane, cholesterol is converted to pregnenolone by CYP11A1, and pregnenolone is converted into testosterone by enzymes in the smooth endoplasmic reticulum (HSD3b, CYP17A1, and HSD17b). Aging and environmental factors may impact steroidogenesis by affecting the intracellular redox balance in part through increased ROS production. This has significant effects on the cAMP formation and/or cholesterol transport into the mitochondria, and thus on steroid formation. Steroidogenesis also might be affected by ROS-induced increases in Cox2 production and redox-sensitive MAPK activation.

Both the trophic and acute effects of LH are mediated by signaling pathways that begin with cAMP production (Fig. 1). LH binds to and activates G protein-coupled receptors, resulting in the activation of adenylyl cyclase, increased intracellular cAMP formation, and cAMP-dependent phosphorylation of proteins through protein kinase A (PKA). The acute stimulation of Leydig cells by LH results in cholesterol transfer into the mitochondria in part through the actions of steroidogenic acute regulatory protein (STAR), translocator protein (18 kDa; TSPO), and other proteins of the transduce some (Midzak et al. 2011). Cholesterol transport into the mitochondria, the rate-limiting step in steroid biosynthesis, is followed by the conversion of cholesterol to pregnenolone by the C27 cholesterol side-chain cleavage cytochrome P450 enzyme (CYP11A1) located on the matrix side of the inner mitochondrial membrane. Pregnenolone then is metabolized into TS by 3β-hydroxysteroid dehydrogenase (3b-HSD; HSD3B), 17α-hydroxylase/17,20 lyase (CYP17A1) and type 3 17β-hydroxysteroid dehydrogenase (17b-HSD3, HSD17B) in the smooth endoplasmic reticulum (Payne & Hales 2004, Aghazadeh et al. 2015, Beattie et al. 2015).

YES THERE IS NO NEED FOR HCG TO INCREASE PREGNENOLONE LEVEL, as you can see even form the recent Nelson report, Pregnenolone supplementation does a better job.
 
Defy Medical TRT clinic doctor
YES THERE IS NO NEED FOR HCG TO INCREASE PREGNENOLONE LEVEL, as you can see even form the recent Nelson report, Pregnenolone supplementation does a better job.
I stated hCG mimics LH which stimulates Leydig cells leading to an increase in both ITT (intratesticular testosterone) and circulating testosterone levels.

*LH is critical as it stimulates cAMP production and cholesterol transport to and metabolism within mitochondria.

*LH plays two essential roles in Leydig cell steroidogenesis: (1) maintenance of optimal levels of steroidogenic enzymes (trophic regulation) and (2) mobilization and transport of cholesterol into the inner mitochondrial membrane (acute regulation).



I was stressing the importance of LH/hCG/ITT especially when it comes to fertility/testicular atrophy!

*To preserve/maintain fertility then yes.

*To prevent/minimize testicular atrophy then yes.

*To enhance mood/libido than it is not a given as some may experience such effects whereas others may feel worse-off.


*To maintain upstream hormones and possibly prevent long-term consequences for health/well-being.....you be the judge!
 
I stated hCG mimics LH which stimulates Leydig cells leading to an increase in both ITT (intratesticular testosterone) and circulating testosterone levels.

*LH is critical as it stimulates cAMP production and cholesterol transport to and metabolism within mitochondria.

*LH plays two essential roles in Leydig cell steroidogenesis: (1) maintenance of optimal levels of steroidogenic enzymes (trophic regulation) and (2) mobilization and transport of cholesterol into the inner mitochondrial membrane (acute regulation).



I was stressing the importance of LH/hCG/ITT especially when it comes to fertility/testicular atrophy!

*To preserve/maintain fertility then yes.

*To prevent/minimize testicular atrophy then yes.

*To enhance mood/libido than it is not a given as some may experience such effects whereas others may feel worse-off.


*To maintain upstream hormones and possibly prevent long-term consequences for health/well-being.....you be the judge!

I see, forgive me I misunderstood your response
 
YES THERE IS NO NEED FOR HCG TO INCREASE PREGNENOLONE LEVEL, as you can see even form the recent Nelson report, Pregnenolone supplementation does a better job.
I have a lab report somewhere which I can get showing progesterone hitting high range with only 500 EOD. Not sure about pregnenolone though.
 
if DHEA makes you drowsy, simply take it before bed. My GF takes it at night and she sleeps deeper and wake up less during the night, if I take it at night it keeps my brain active. You have to try and see how things work for you, be patient and don't over think things, I have done this big mistake many times with HRT, and still do!

not sure what Xyosted is, but start by testing your Preogesterone/DHEA, if you have the extra $ include Pregnenolone, don't take hormones if you don't need to

I see a sedative effect from Progesterone capsule, Pregnenolone is calming for me, but not really sedative.

I used Nutricology brand in the past, the only OTC I used. The same brand was recommended by Dave Lee, but I have never checked any levels after supplementing with that. My concern with that brand, is that the capsule is in a lipid matrix, which should by pass the liver, you want the opposite especially if you are dealing with anxiety, as Pregnenolone when taken orally, because the actual first pass into the liver, will get converted into Progesterone and Allopregnanolone, all good things we need as calming/anxiolytic agent.

@Gianluca, Xyosted is just a version of testosterone enanthate in an auto injector pen. I like it for a variety of reasons.

Meanwhile, thank you for sharing your protocols. Do you mind also sharing what your testosterone protocol is? Are you injecting or using topical?
 
Nelson do you think it can help with libido ?
I have not felt any more libido on pregnenolone 100 mg per day plus hydrogel testosterone cream beyond what the cream already had done. The hydrogel testosterone cream applied to the scrotum boosted my libido during the first two weeks but it then stabilized. I want to remind everyone that I am not the "regular" TRT patient. I am 62 and on TRT for approximately 30 years. I also have history of long term nandrolone use.
 
@Gianluca, Xyosted is just a version of testosterone enanthate in an auto injector pen. I like it for a variety of reasons.

Meanwhile, thank you for sharing your protocols. Do you mind also sharing what your testosterone protocol is? Are you injecting or using topical?
26mg ED IM injection
 
I have a lab report somewhere which I can get showing progesterone hitting high range with only 500 EOD. Not sure about pregnenolone though.
Yes, I made that statement, because we can supplement Pregnenolone/Progest, therefore HCG is not needed for this purpose. If you search the forum there are studies in fact showing HCG increasing 17-OH Progesterone. With my own personal experience, and the one I see of many other men on line, supplementing downstream hormones works better in raising Pregnenolone levels, and alleviating anxiety and other symptoms.
 
Yes, I made that statement, because we can supplement Pregnenolone/Progest, therefore HCG is not needed for this purpose. If you search the forum there are studies in fact showing HCG increasing 17-OH Progesterone. With my own personal experience, and the one I see of many other men on line, supplementing downstream hormones works better in raising Pregnenolone levels, and alleviating anxiety and other symptoms.

Most definitely.

I would still like to see more men test upstream hormones (LC/MS-MS) after using high enough doses of hCG at least 250-500IU injected EOD as such doses are most likely needed to fully restore physiological ITT levels.






The goal should be to restore physiological ITT levels which may very well be needed to reap the full beneficial effects let alone to prevent disruption of upstream hormones!

Unfortunately, many may struggle with sides on such protocol (dose/injection frequency).

No point in stating/claiming that the addition of hCG has no impact on upstream hormones when you have never used high enough doses let alone tested using an accurate assay.



5.1 Effects on intratesticular testosterone

Exogenous testosterone administration suppresses intratesticular testosterone (ITT), which is crucial for the production of sperm [24]. IN SUCH PATIENTS, ITT HAS BEEN SHOWN TO BE SUPPRESSED BY 94%. However, with every other day injections of HCG at dosages of 125IU, ITT was only 25% LESS THAN BASELINE, with 250IU 7% LESS and with 500IU 26% GREATER THAN THE BASELINE [25].


*These studies indicate that HCG can significantly increase ITT in a dose-dependent manner and that dosages between 250 and 500 IU might be optimal to restore physiological ITT levels.
 
Last edited:
Most definitely.

I would still like to see more men test pregnenolone (LC/MS-MS) after using high enough doses of hCG at least 250-500IU injected EOD as such doses are most likely needed to fully restore physiological ITT levels.

The goal should be to restore physiological ITT levels which may very well be needed to reap the full beneficial effects let alone to prevent disruption of downstream hormones!

Unfortunately, many may struggle with sides on such protocol (dose/injection frequency).

No point in stating/claiming that the addition of hCG has no impact on downstream hormones when you have never used high enough doses let alone tested using an accurate assay.
I can attest to hCG seemingly having a critical threshold that needs to be achieved for full benefit. Although I did feel better taking 100-140iu’s daily than not taking it, and my new protocol’s still just a week in, taking 350-500iu’s close to EOD is a different ball game so far. Did 350 Monday and Wednesday and 500 on Friday since I’d be picking up again on Monday. Still injecting test daily.

Started Pregnenolone cream last night at 50mg as well. That had me feeling very calm and drowsy in a pleasant way, and I’m still very calm now the day after.

For full disclosure, I’m also usually on 250-333iu’s of BPC-157 once or twice a day, 2iu’s of HGH 4x a week, and 1 grain of NDT in the morning and 50mcg T4 daily at night. I have gut issues and BPC knocks those out within a week.
 


Treatment protocols

Subcutaneous hCG and rFSH injections were administered to CHH males for 2-4 years, according to a protocol as described previously 10, until testicular maturation was accomplished. Specifically, in pre-pubertal patients, a starting dose of 500 IU hCG was injected subcutaneously twice weekly. Incremental increases every 3-6 months to a maximum of 2-3 x 1500 IU hCG s.c./week were administered, if necessary, to achieve serum T levels in the mid-normal adult range (T>3.5 ng/ml, [12 nmol/l]) by one year after the start of hCG. In post-pubertal men who had previously received exogenous T, a starting dose of 2 x 1000-1500 IU hCG s.c./week was applied, aiming at adult serum T levels by 3 months. After 3(-6) months of hCG treatment, rFSH was added at a standard dose of 3x 150 IE s.c./week. This combined replacement was continued until gonadal maturation was achieved, as indicated by plateauing sperm concentrations in semen and achievement of maximal testicular volumes. Thereafter, males were switched to exogenous T substitution, either by application of T gel or by i.m. injections of T enanthate or T undecanoate. Doses were adjusted after 3 months of treatment, to achieve serum T levels in the mid-normal adult range.




Figure 4
-Serum steroid hormone concentrations of CHH males from alternative/backdoor pathways of androgen biosynthesis

-Serum androstenediol concentrations, representing the alternative pathway of testosterone formation, in CHH males on hCG/rFSH and T replacement, compared to those of healthy controls.

-Serum androstanediol concentrations, representing the backdoor pathway of DHT formation in CHH males, on gonadotropin and T replacement, and in healthy controls.

-Serum 11K T and 11 K DHT concentrations, representing the 11-oxygenated C19 androgen pathway in CHH males, on gonadotropin and T replacement, and in healthy controls.


Screenshot (5759).png

Screenshot (5760).png

Screenshot (5761).png

Screenshot (5762).png






Figure 3
-Serum steroid hormone concentrations from Δ5 and Δ4 pathways of CHH males (including testosterone metabolites) analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), once, while patients were undergoing hCG/rFSH treatment and again, while they were on T replacement, compared to those of healthy matched controls.

Screenshot (5763).png
 
Δ4 pathway
Progesterone, 17-OH-progesterone (17 OHP)


One major finding of this study is that hCG/rFSH replacement stimulates and thus normalizes some important steroid hormones belonging to the Δ4 pathway of steroidogenesis in hypogonadotropic hypogonadal males. 17-OHP levels were significantly decreased on treatment with testosterone, but not while the males were on gonadotropin replacement, indicating that a major proportion of this precursor steroid is produced in the gonads and requires gonadotropin stimulation for secretion, while a minor part of it stems from other sources. It is likely that ACTH- stimulated production in the adrenal gland contributes to it.

17-OHP is recognized to have anti-mineralocorticoid 15 and glucocorticoid potency 16,17, without direct androgenic properties.
Since cross-reactivity among steroids is a recognized phenomenon, due to the high degree of homology at the DNA-binding domains of nuclear receptors within the steroid hormone receptor superfamily 18, the measured differences in serum 17-OHP concentrations may have clinical implications. Surprisingly, progesterone serum levels in CHH males were decreased on both hCG+rFSH and testosterone substitution, when compared to controls, but the decrease was more pronounced on testosterone replacement. This indicates that the gonadotropins used for replacement do enhance progesterone serum production in males, albeit to a lower extent than in healthy subjects. The use of hCG instead of LH for CHH replacement may explain this phenomenon. Progesterone acts via intracellular progesterone receptors (PRs) A and B, thereby exerting classical genomic action. In addition, it has non-genomic effects. In males, progesterone is involved in sperm capacitation/acrosome reaction, it influences LH receptor expression and subsequent testosterone biosynthesis in Leydig cells; it interacts with the GABAA receptor complex in the CNS, thereby eliciting effects on sleep, mood, and cognition, and also exert effects in adipose tissue and kidneys 19. Progesterone is a high-affinity antagonist of the mineralocorticoid receptor (NR3C2; MR)15, thus eliciting anti-mineralocorticoid effects 20-23. Progesterone is able to transactivate the glucocorticoid receptor (NR3C1; GR) 16. A lack of progesterone and 17-OHP in men could therefore have an impact on water and electrolyte balance and systemic blood pressure regulation.





Figure 1

Pathways of human androgen biosynthesis


-The classic pathways, proceeding parallel for Δ5 and Δ4, convert steroidogenic precursors and lead to the formation of T, which can be further converted to DHT.

-The alternative pathway of T formation proceeds via androstenediol.

-The backdoor pathway proceeds via androstanediol to generate DHT.

-The 11-oxygenated C19 androgen pathway generates 11K T and 11 K DHT. The steroids measured in the present study are indicated in bold.

Screenshot (5764).png
 
Most definitely.

I would still like to see more men test upstream hormones (LC/MS-MS) after using high enough doses of hCG at least 250-500IU injected EOD as such doses are most likely needed to fully restore physiological ITT levels.






The goal should be to restore physiological ITT levels which may very well be needed to reap the full beneficial effects let alone to prevent disruption of upstream hormones!

Unfortunately, many may struggle with sides on such protocol (dose/injection frequency).

No point in stating/claiming that the addition of hCG has no impact on upstream hormones when you have never used high enough doses let alone tested using an accurate assay.



5.1 Effects on intratesticular testosterone

Exogenous testosterone administration suppresses intratesticular testosterone (ITT), which is crucial for the production of sperm [24]. IN SUCH PATIENTS, ITT HAS BEEN SHOWN TO BE SUPPRESSED BY 94%. However, with every other day injections of HCG at dosages of 125IU, ITT was only 25% LESS THAN BASELINE, with 250IU 7% LESS and with 500IU 26% GREATER THAN THE BASELINE [25].


*These studies indicate that HCG can significantly increase ITT in a dose-dependent manner and that dosages between 250 and 500 IU might be optimal to restore physiological ITT levels.
To add to this, I believe it is possible some of the men experiencing anxiety/sleepless after TRT, may already have some degree of undiagnosed adrenal insufficiency/fatigue, and that is why HCG alone may not restore fully Pregnenolone/Progesterone level. I think a clinician should include these hormones testing as pre TRT regiment
 
Progesterone increases allopregnanolone. This hormone has strong data on mood.


 
Progesterone increases allopregnanolone. This hormone has strong data on mood.



Just like we were guessing the other day. As the study shows, 5 alpha reductase is needed to convert Progesterone to Allopregnanolone, and that is why Finasteride is so bad!
 
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