How long for HCG to restore testicular size?

[Buffbanker]

I am making another run of HCG. I previously ran up to 500 iu twice weekly with no real benefits for the first year of TRT. Discontinued after the first year and atrophied within a couple months where I have been for the last 4 years. Dr Saya has me at 400 iu twice weekly and after 4 weeks I am still atrophied. Since it can take up to 90 days for sperm production I am wondering if I still have some time to go?

Due to the excess atomization I am wanting to drop to 250-350 iu twice weekly but want to see if I can even regain some testicular size first before I do.

 

[DorianGray]

Give it 3 months.

 

[Nelson Vergel]

You need higher doses during the first two weeks, then go back down.

If you did not see improvements at 500 IU twice per week, you won’t see improvement at 250 or 300.

Start with 1000 IU twice per week for two weeks to jump start your Leydig cells. Then move down to 500 twice per week.

What “aromatization” symptoms are you seeing ? Water retention ? Have you measured your T/E2 ratio ?

 

[Buffbanker]

You need higher doses during the first two weeks, then go back down.

If you did not see improvements at 500 IU twice per week, you won’t see improvement at 250 or 300.

Start with 1000 IU twice per week for two weeks to jump start your Leydig cells. Then move down to 500 twice per week.

What “aromatization” symptoms are you seeing ? Water retention ? Have you measured your T/E2 ratio ?

Mostly mood like irritability which I haven’t experienced since I last gave HCG a go. No other elevated E2 symptoms. E2 is around 40 with TT around 1300. I would like my E2 a little higher to bring my T/E2 ratio down but it seems HCG causes issues with mood for me. I’m afraid to run any higher.

 

[Buffbanker]

Could I run lower around 250 iu twice per week knowing it will take even longer to restore my ITT?

 

[bixt]

No. You need a large boost for 2 weeks to jump start them after being dormant for so long. Seen fertility clinics go as high as 1500 x 3 per week, even multiple 5000iu shots initially before dropping down.

After a long dormancy its not a question of low and slow, but hard and fast.

Its like how some Li-ion batteries refuse to charge after being left at 0% for long. It requires a special charge once off to wake up the battery, after which the regular charger will work.

Oh, and don't bother using an AI in those two weeks it wont work.

 

[Buffbanker]

No. You need a large boost for 2 weeks to jump start them after being dormant for so long. Seen fertility clinics go as high as 1500 x 3 per week, even multiple 5000iu shots initially before dropping down.

After a long dormancy its not a question of low and slow, but hard and fast.

Its like how some Li-ion batteries refuse to charge after being left at 0% for long. It requires a special charge once off to wake up the battery, after which the regular charger will work.

Oh, and don't bother using an AI in those two weeks it wont work.

That’s my concern as I am aware an AI won’t help. And if I am already irritable at my current dose, I know going any higher will not serve me well.

I am hesitant to supplement with DHEA and Preg as that seems like a wild goose chase as well. I have never tested my preg levels but my DHEA could be a little higher at 175 mcg/dL but I also guess I don’t know what I should feel with optimized DHEA and Preg levels. Is it noticeable?

 

[Systemlord]

That’s my concern as I am aware an AI won’t help.

AI’s won’t affect E2 produced inside the testicles.

 

[tmaxey1]

AI’s won’t affect E2 produced inside the testicles.

Is E2 actually produced inside the testicles? I thought the testicles are only capable of producing testosterone and the conversion that happens is in other parts of the body and not in the testicles?

I'm just not sure the testicles are producing E2. I believe E2 in men is all through the conversion of Test?

 

[Systemlord]

Is E2 actually produced inside the testicles?

Naturally and while on hCG, in men estrogen is mainly produced by the testes, adrenal and pituitary gland.

 

[madman]

Is E2 actually produced inside the testicles? I thought the testicles are only capable of producing testosterone and the conversion that happens is in other parts of the body and not in the testicles?

I'm just not sure the testicles are producing E2. I believe E2 in men is all through the conversion of Test?

Yes.


*About 20% of estradiol is secreted by the Leydig cells1–4 , whereas 80% is formed in peripheral tissues from androgens, in man, mainly from testosterone5

*Leydig cells, can also directly produce and release into the bloodstream small amounts of estrogens, with a daily production rate of 5-10 μg (up to 20% of circulating estrogens) [41]

*another derivative from testosterone, 17-estradiol, is produced by Leydig cells. The testicular contribution to total estrogen production, however, is small (in the order of 20%) as compared to peripheral aromatization. The local production of 17-estradiol may be of great importance for regulating Leydig cell functions




Estradiol in elderly men (2002)
A. Vermeulen, J. M. Kaufman, S. Goemaere & I. Van Pottelberg

Whereas testosterone is the major sex hormone in males, recently, several authors have emphasized the role of estrogens in male physiology. Indeed, remarkable progress in our understanding of the role of estrogen physiology has been made, as a consequence of the discovery of human models of estrogen deficiency such as estrogen resistance and aromatase deficiency. Estradiol, the major biologically active estrogen, is a metabolite of testosterone. Hence, the biological effects of testosterone are the result of the combined action of testosterone (and dihydrotestosterone) and of estradiol.




ORIGIN OF ESTROGENS IN THE MALE

About 20% of estradiol is secreted by the Leydig cells1–4 , whereas 80% is formed in peripheral tissues from androgens, in man, mainly from testosterone5 . Estrone, on the other hand, originates from aromatization of (mainly adrenal) androstenedione, with 20% being secreted directly by the adrenals.

The blood transfer constant of plasma testosterone to plasma estradiol, i.e. the fraction of the blood production rate of testosterone that is converted to estradiol is approximately 0.3–0.4% and of androstenedione to estrone approximately 1.4%, approximately 5% of the latter is then converted to estradiol6 . As the mean estradiol concentration in men is about 2–3 ng/dl, whereas the metabolic clearance rate is approximately 1600 l/24 h, it follows that the blood production rate of estradiol is about 30–40 mg/24 h. This includes a secretion rate of approximately 5–10 mg/day from the Leydig cells, 20 mg/day originating from peripheral conversion of plasma testosterone and about 5 mg/day from androstenedione. In patients with aromatase deficiency a daily dose of 25 mg of estradiol, administered transdermally, appeared to suffice for effective mineralization7 . The mean concentration of estrone in males is 3–6 ng/dl8 , and its blood production rate approximately 50–70 mg/24

These conversions occur, under the influence of an aromatase, mainly in fat and muscle tissue, although many other tissues, for example, the brain, liver, Sertoli and Leydig cells, and osteo- blasts9–11 , show aromatase activity. The aromatase activity increases with age12 and obesity.

The total quantity of estradiol which is formed in the organism may, however, be significantly higher than the blood production rate, as part of the peripherally formed estradiol is further metabolized in situ (to estrone, estriol or 2-hydroxyestradiol) and, hence, does not enter the peripheral circulation. This locally formed estradiol may be only locally active and, hence, plasma estradiol levels do not necessarily reflect the activity at tissue level




Testosterone: an overview of biosynthesis, transport, metabolism and non-genomic actions (2004)
F.F.G. Rommerts

1.5.2 Trafficking between the testicular compartments

Steroids such as pregnenolone, progesterone and testosterone not only rapidly pass the Leydig cell membranes but they can also equilibrate rapidly between different testicular compartments (van Doorn et al. 1974). The secretion pattern in the testis is thus most likely determined by amounts that are produced inside the tissue, the permeability characteristics of the membranes and the binding proteins in various testicular fluids. The Leydig cells in the testis are surrounded by an interstitial fluid that is rich in plasma proteins and the cells are also in close contact with blood vessels. The preferential direction of secretion in the testis is mainly determined by the concentration gradient andflowrates of the various fluids. Since the bloodflowis much higher than the flowof the interstitial fluid, most of the unconjugated steroids diffuse from the interstitial space to the blood and leave the testis via the venous blood (Maddocks and Sharpe 1989). The porcine testis is an exception that supports this view. In this species steroid sulphates, which cannot readily diffuse through the walls surrounding the interstitial space, were 13 to 35 fold more concentrated in interstitial fluid than in venous blood (Setchell et al. 1983). During the passage of venous blood through the pampiniform plexus the primary venous blood is diluted approximately 2 fold by incoming arterial blood. This occurs through anastomoses present in this network of interacting blood vessels (Noordhuizen-Stassen et al. 1985). The presence of relatively high levels of dihydrotestosterone in human spermatic venous blood has been taken as evidence that dihydrotestosterone is produced in the testis (Hammond et al. 1977). However, other studies have shown virtually no 5-reductase in human testis (Miautani et al. 1977). Although these data are contradictory, dihydrotestosterone is most likely an epididymal steroid and it is conceivable that dihydrotestosterone produced in the epididymis is transported to testicular venous blood during the dilution process that occurs in the pampiniform plexus. Although dihydrotestosterone is not produced in the testis from testosterone, another derivative from testosterone, 17-estradiol, is produced by Leydig cells. The testicular contribution to total estrogen production, however, is small (in the order of 20%) as compared to peripheral aromatisation. The local production of 17-estradiol may be of great importance for regulating Leydig cell functions, for instance in the previously mentioned development of steroidogenic lesions.




Testosterone: biosynthesis, transport, metabolism and (non-genomic) actions (2012)
C. Marc Luetjens and Gerhard F. Weinbauer

2.2 Leydig cells

The Leydig cells are located in the testicular interstitium. These cells are the main source of testosterone, and produce approximately 95% of circulating testosterone in men. Approximately 10–20% of the interstitial area is occupied by Leydig cells, and the human testes contain approximately 200 106 Leydig cells. Daily testosterone production from the testis is estimated to be around 6–7 mg. Since most of the peripheral testosterone is derived locally from the testicular Leydig cells, it is not surprising that testicular testosterone concentrations exceed those of sex hormone-binding globulin (SHBG)/androgen binding protein (ABP) by about 200-fold (Jarow et al. 2001), indicating a substantial surplus of (free) testosterone in the testis. Relative to concentrations in peripheral blood, testicular testosterone concentrations are indeed approximately 80-fold higher (Coviello et al. 2005). The Leydig cell is the only cell expressing all enzymes essential for converting cholesterol into testosterone (Payne 2007). In the Leydig cell, testosterone can also be further metabolized into dihydrotestosterone (DHT) or estradiol.




Steroids such as pregnenolone, progesterone and testosterone not only rapidly pass the Leydig cell membranes, but they can also equilibrate rapidly between different testicular compartments, and the testicular secretion pattern is most likely determined by amounts that are produced inside the tissue, the permeability characteristics of the membranes and the binding proteins in various testicular fluids (Rommerts 2004). As the blood flow is much higher than the flow of interstitial fluid, most of the unconjugated steroids diffuse from the interstitial space to the blood and leave the testis via venous blood. Estradiol is produced by Leydig cells, but the amount is small, with about 20% of peripheral aromatization (Rommerts 2004)





EAU Guidelines on Sexual and Reproductive Health 2023


3.2 Physiology of testosterone production

The pituitary gland regulates testicular activity through secretion of luteinising hormone (LH), which regulates testosterone production in Leydig cells and follicle-stimulating hormone (FSH), which mainly controls sperm production in seminiferous tubules [36, 37]. The production and secretion of gonadotropins is stimulated by hypothalamic gonadotropin releasing hormone (GnRH) and inhibited by negative feedback mediated by the central action of sex steroids and inhibin B (Figure 1) [36, 37]. Gonadotropin releasing hormone is secreted in a pulsatile manner and negatively controlled by the activity of hypothalamic neurons, including corticotrophin-releasing hormone (CRH) and β endorphin neurons [36, 37]. Conversely, kisspeptin-1 (Kiss-1) neurons, neurokinin-B and tachykinin-3 are involved in GnRH stimulation. Leptin is involved in activation of Kiss-1 signalling [38]. About 25 mg of testosterone is present in the normal testes, and, on average, 5-10 mg of testosterone are secreted daily [36, 37]. The testes also produce lesser amounts of other androgens, such as androstenedione and dihydrotestosterone (DHT). A small amount of extra-gonadal testosterone is derived from the circulating weak adrenal androgen precursor dehydroepiandrosterone (DHEA), although its specific contribution to daily testosterone production is limited in men [39, 40]. In physiological terms, DHT formation accounts for 6-8% of testosterone metabolism, and the ratio of plasma testosterone/DHT is approximately 1:20 [36, 37]. Finally, testosterone and its precursor, Δ4 androstenedione, can be aromatised through P450 aromatase to other bioactive metabolites, such as estrone (E1) and 17-β-oestradiol (E2), with a daily production of ~45 μg [36, 37]. Leydig cells, can also directly produce and release into the bloodstream small amounts of oestrogens, with a daily production rate of 5-10 μg (up to 20% of circulating estrogens) [41].

 

[madman]