Help/Advice Interpreting My Labs? Fertility After Blast/Cruise

I like it. After my long screed, I figured I’d outsource this to you. I hit the character limit :-). So the hypothesis is the Doc blew out the Leydig cells with hCG (no dosage given) but then another 6 weeks with “reasonable” Clomid dosing came with reversing LH receptor sensitivity and improvement in Test levels. I can buy that. I like that graph, thank you. Maybe that’s why the doc didn’t mention the hCG dosage given.

To the OP, good example of why you should start low with hCG although Fertility doctors usually much more aggressive on hCG dosage so this example just another example of individual variation which is critical to the discussion.

I think he didn’t know but he knew instinctively it was too much.

One question came to mind as I read the article. Is the doc right about the E receptors in the hypothalamus being the only receptors for the feedback loop?
I did my own research months ago and read a few studies that suggested that there are T receptors responsible for the feedback, too.
Just wanted to get your opinion on this.

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Not my active area of research but I would agree with you. That diagram ain’t correct.

This human investigative model employing sex steroid ablation and selective physiological sex steroid add-back in healthy and GnRH-deficient men provides novel insights into the study of LH regulation in men. These data suggest a model of sex steroid feedback whereby 1) T and E2 have independent effects on LH secretion, 2) inhibition of LH by T requires aromatization for its pituitary but not its hypothalamic effects, and 3) E2 has dual sites of feedback, but its predominant effect is at the hypothalamus.

Typical med school diagrams circa 2019:

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This is nice! Thanks for the input, that’s what I came around to when I researched it but I read other studies so thanks for the support

Sure. Just for fun…these folks really exceeded expectations on their study:

https://academic.oup.com/jes/article/3/1/235/5198611

Although this study really belongs over in the TRT forum given the range on the dose response curve:

In summary, pulsatile T is less effective as a negative-feedback signal on LH secretion than continuous T administration, as demonstrated by two independent methods. This difference in feedback strength occurs, probably in part, at the pituitary level, but the data do not exclude hypothalamic involvement. Visceral and total abdominal fat by CT correlated negatively with basal and total LH secretion but not with pulsatile secretion. Feedback strength decreased with higher BMI, both without and with exogenous GnRH stimulation. These data could indicate that physiologically pulsatile and pharmacologically continuous T feedback has unequal, suppressive effects on the central gonadal axis in men.

Good demonstration of how Natesto can be used to control Hct and have minimal negative feedback on HPG axis.

https://cuaj.ca/index.php/journal/article/view/6651

Hat tip to at madman at the other forum.

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This natesto seems like it could be a revolutionary step in TRT practice! I’m stunned by the fact that the feedback doesn’t get inhibited (as strongly) by pulsatile administration but since GnRH receptors work the same it’s not that outlandish a thought.

(i) pulsatile T is less effective than continuous T delivery in suppression of LH secretion, (ii) T feedback is reduced by BMI, and (iii) basal and total, but not pulsatile, LH secretion, estimated by deconvolution analysis is negatively correlated to visceral fat and total abdominal fat area, calculated from a single CT slice at L3-L4.

That’s what the study found. I like it, but we always gotta keep statistics in mind. Deconvolution is not the best way of getting data.

What’s also interesting was that free T and LH secretion correlated negatively with BMI (I think we knew that) which shows us again that fat people are hormonally fucked.

This might be a compensatory mechanism to decreased LH secretion in severe obesity

I’m surprised they got this approved by an ethics committee cause I wouldn’t be excited about getting 800 mg of Ketoconazole orally haha!
The discussion in the end about glucocorticoids and emotions is definitely a topic for another day.

A major discovery recently is that the pulsatility of cortisol is required for normal emotional and cognitive responses in man [42]

To the OP: I think you got some really good input here, I wish you and your family the best and report back how your fertility and T levels are going!
Also OP, maybe your Willy grows on HCG:

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Interesting mechanistic study from a while back. Great conversation @lordgains, thanks for your time.

Credit to @cataceous at the other place.

Nice find. It seems to be way more difficult to apply HCG right than we thought. I saw studies where people are given 3000 IU (I recently saw one with 5000 IU ED) hCG for a few weeks which should definitely be enough to suppress T production but it didn’t happen (at least not in that limited time frame, think it was 3-4 weeks). As I stated above: the effect is highly individual which shows is again how important bloods are.

If we are on the topic of hCG, there’s one thing I want to point out/discuss.
I repeatedly saw the mantra “AIs won’t stop the aromatization induced by hCG” on this forum and I’d like to get a rationale for that as I couldn’t verify this and my understanding would suggest otherwise. I’ll give my opinion:

HCG increases E2 before it increases T. Several studies show that E2 is highest 24 h after HCG dosing and T 72 h. (Won’t link that) Here you can see an example of acute stimulation of aromatization by hCG in Leydig cells independent of T production:

This could mean that the LH receptor regulates aromatase expression and voila, it does:

With 50 ng/ml oLH, a large augmentation (twofold) of the P450arom mRNA level either without or with testosterone was observed.

With that in mind the only question becomes if AIs get into the Leydig cells (primary T and E2 producers in man) so they can inhibit the aromatase there.
Since the next study shows that non-steroidal AIs readily cross the blood brain barrier, it’s safe to assume they pass the blood testis barrier. They are lipophilic and only anastrozole gets actively transported out of the brain. (I couldn’t find studies about the concentration measured in the testis)

All this info leads me to believe that AIs do

  1. Get into the Testis and Leydig cells
  2. Inhibit the aromatase there
  3. Therefore inhibit aromatization by hCG

Finally this paper shows that AIs do prevent the increase of E2 caused by hCG

In the hCG group, the rate of testicular aromatase activity and testicular E2 level were higher and the diameter of seminiferous tubules was smaller than in the control group. However, these changes were not observed in the hCG+A.I. group

If some of you have evidence suggesting the contrary I’m open to change my opinion.

@readalot I learned a lot too, thanks!

I got a few things I’d like to discuss in the near future: Glucucorticoids (find them extremely interesting and complicated, also in combination with androgens) and then a smaller one would be thyroid hormones (here we could also discuss differences with synthetic and swine derived (I heard it’s a difference but I didn’t research yet, don’t know what it contains right now). I’ll open up new threads then and I’d appreciate your opinion there too.

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My understanding was that the increase of e2 by HCG wasn’t via aromatase, so an AI wouldn’t be able to control it. The studies you linked show that’s not the case, so very interested to learn more about this. I’m one of those guys that doesn’t take HCG regularly for fear of higher e2

I tried to find an answer to that question too but it was difficult. One study wrote “all E2 from the Testis gets created through the aromatase enzyme complex” and others just used the higher aromatase activity as a reason.

Im skeptical myself because a few studies showed an increase in E2 after 1 hour with the peak at 24 h which seems a bit fast for an up regulation of the expression (takes a day usually so 24h makes sense).
It was also difficult to find studies linking LH to an upregulation of aromatase but the one I found supports it.

So we’re left with this non conclusive area. But if my hypothesis is wrong there are many questions:

  1. What means a higher activity of aromatase if not an increase in expression? It could be that aromatase enzymes are inactive in the cell per example as vesicles because it is an ER associated enzyme.
  2. If the AIs don’t block the aromatization, it shouldn’t happen through aromatase so what way is there to synthesize E2 in the testis without aromatase? (I touched on it in another lengthy post but I don’t think these ways happen in the testis on a large scale)
  3. Why does an AI seem to suppress the increase in E2 caused by hCG in some studies?

The easiest thing would be if we guys on here reported their blood results and experiment next time they PCT or are on TRT+hCG. Our own independent, no conflict of interest, crossover study.

I think the evidence I provide is the best we have right now. Let’s see if somebody finds additional knowledge.

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Thanks for this post. Very nice points. This is THE if not one of THE main posts that drove this narrative:

I’ll make some comments in the following days. I think the concern expressed is the relative concentration of competitive AI like anastrozole inside the testicles vs the intratesticular concentration of testosterone caused by hCG. Since the inhibition is competitive, we have to look at the relative concentration of testosterone and competitive AI inside the testicles as well as the respective binding affinities. I don’t think there is any concern that non-steroidal AI can’t get into the Leydig cells. I can share multiple research papers that shows this happens easily.

I’ll get back on this later @lordgains. I’m impressed with your research and cognitive abilities.

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More to come with some discussion.

This paper supports everything we wrote about down regulation of LH receptors. It even hints at upregulation (indirectly through T administration).
I’m out for today and I’m excited to read your input tomorrow!

@readalot

I looked into the intratesticular T concentrations a bit and that’s what I came up with:

LH and FSH were profoundly suppressed to 5% and 3% of baseline, respectively, and ITT was suppressed by 94% (1234 to 72 nmol/liter) in the T enanthate/placebo group. ITT increased linearly with increasing hCG dose (P < 0.001). Posttreatment ITT was 25% less than baseline in the 125 IU hCG group, 7% less than baseline in the 250 IU hCG group [all every other day], and 26% greater than baseline in the 500 IU hCG group.

Which leads me to believe, if you inject 500 IU two times weekly your intratesticar T levels are most likely within normal range (if you’re shut down and you inject more, you should also not get crazy high levels otherwise why inject that much when you respond well?) which means even a competitive AI will do it’s job.

For more info on competitive AIs see my Independence Day post here:

Now, even if a competitive AI like anastrozol doesn’t work, you’d always have the option of Exemestane to inhibit Aromatase which has different kinetics (see post) and simply doesn’t care about T level that much.

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Very nice follow up and post from July 3. Here’s another small (small) case study by a very smart clinician showing the effect of 150 IU vs 500 IU injection:

Results
A relevant note for consideration in comparison of quantitative serum beta hCG concentrations with endogenous luteinizing hormone (LH) concentrations is that the typical “normal” range for endogenous LH is 1.7 – 8.6 mIU/mL. As noted, half-life differences (of large magnitude) are present, but this offers some perspective with the comparison.

Discussion

This data indicates that there is indeed a drastic difference in quantitative serum beta hCG concentrations achieved following a single hCG injection of 150iu vs 500iu. More interesting is the fact that this dose-response relationship does NOT appear to be linear based on this limited data. The serum beta hCG concentration following a single hCG injection of 150iu appears to peak at ~1mIU/mL at 8 hours and has retreated to baseline prior to 24 hours after the injection. On the contrary, the serum beta hCG concentration following a single hCG injection of 500iu attains a level of 2mIU/mL at 8 hours and subsequently INCREASES to 3mIU/mL at 24 hours and 48 hours, before retreating to 1mIU/mL at 72 hours (still has not declined to baseline

According to this data, it would appear that a hCG dosage of 150iu would have to be administered on AT LEAST a daily basis (if not more frequently) to allow continual stimulation of the leydig cells of the testes. Further, with an apparent maximal serum concentration from a hCG dosage of 150iu reaching a peak of ~1mIU/mL, this may prove to be insufficient stimulation for SOME patients to achieve consistent testicular activity and prevent the aforementioned side effects of testicular deactivation/dormancy. Certainly one could debate the relative need for continual stimulation of the testes, however this may offer a clue for dosage adjustments for patients that either experience poor results, poor fertility, or continued decrease in testicular volume at lower hCG dosages.

A single dosage of 500iu of hCG appears to exert a much more prolonged (and pronounced) increase in serum beta hCG concentrations, likely coinciding with a more prolonged and pronounced biological effect. Once again, whether this is beneficial or detrimental, can certainly be debated and will often hinge on many factors on an individualized case by case basis. It does appear obvious from the data that a dosage of 500iu of hCG will maintain levels >1mIU/mL for up to 3 days (72 hours) following a single injection. Thus, it would seem a direct conclusion to state that an hCG injection of 500iu every 3.5 days (twice weekly) would provide relatively continual stimulation of the leydig cells of the testes (concentration >1mIU/mL), and injections of this magnitude in dosage would NOT be needed any more frequently than that.

My clinical mind and instincts suggest that the “ideal” hCG dosage likely lies in between these two extremes (150iu vs 500iu) and ideal frequency will hinge upon ideal dosage (with 150iu or less dosages likely requiring daily or even more frequent injections) and larger dosages (500iu, possibly even slightly smaller) requiring no more frequent than twice weekly injections, but this conclusion simply cannot be made concretely from this limited data. Furthermore, dosage decisions and frequencies are always individualized case-by-case based on many variables specific to the individual (fertility considerations, injection compliance, complicating factors such as SHBG levels, current/prior response to hCG, estradiol levels, testicular health, etc). Without specific data on other dosages (which I would like to obtain), these patterns suggest that a dosage regimen of hCG 250iu-350iu on an every other day (QOD) schedule would likely offer an alternative regimen for relatively steady and consistent testicular stimulation, although these conclusions are only speculative and cannot be drawn definitively from this limited data.

The argument that competitive AI will not reduce estradiol levels is not based on the data or the theoretical and constitutive framework we have in hand. Futhermore, don’t go crazy with the hCG dosage and 500 IU 3x weekly seems like plenty (especially if you are using hCG proactively while using exogenous T). Your point on irreversible AI is spot on. Great job @lordgains for the detailed review. The forum needs more of this along with relevant anecdotal and clinical experiences instead of hand waving. Thank you.

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There is a blood barrier that prevents AI’s from passing to the testes, thus being unable to inhibit aromatase there. HCG stimulates production there, so AI’s cannot stop the aromatization effected by HCG. In short, it suppresses aromatisation everywhere except where it is happening. That being said, if Ksman wrote the post, you should assume it’s incorrect and work out from there. I would be interested in reading the studies he claims exist in that post, I haven’t found them and he doesn’t actually reference them. I am leaning towards the opnion that they have never existed at all and he is just making stuff up.

See my post above, I addressed this. My research and knowledge leads me to believe otherwise.
This also stands in stark contrast to @readalot ‘s comment.

I just saw you yourself (@hardartery) wrote you couldn’t find them and it’s probably incorrect. My point is: if non steroidal AIs pass the blood brain barrier which has a significantly higher integrity and more proteins which transport molecules out, then they should easily be able to pass through the blood testis barrier. I think it’s very unlikely they don’t get into the nuts. @readalot could you point us in the right direction?

I am happy to stand corrected. I am going on what I have read, which I have on my old laptop and not with me. It would change my understanding of some things if that info is incorrect - and I prefer to have a correct understanding than to be right.

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Me too! And I think it’s a lot of fun to learn new stuff especially when you put some effort into researching something and get presented with different findings, that way everybody can work on their research skills as well as their knowledge.

You meant intratesticular E2 Levels right? Just for clarification.

Yes we need some experience here. @iron_yuppie since you are using hCG with your TRT, what’s your experience?

@hardartery @lordgains

@lordgains shared good paper on Femara (letrozole) vs Arimidex (anastrozole) on blood brain barrier in mice:

https://jpharmsci.org/article/S0022-3549(15)30948-5/abstract
https://jpharmsci.org/action/showPdf?pii=S0022-3549(15)30948-5

Clearly not all competitive AIs are created equal wrt blood brain barrier.

Again pure conjecture on the Ksman angle, I guess someone could read this paper and conclude anastrozole is of limited effectiveness on the testes and therefore any competitive AI won’t work:

The aim of the present study was to evaluate the effects of the administration of a potent non-steroidal aromatase inhibitor, anastrozole, on male reproductive function in adult rats. As anastrozole was to be administered via the drinking water, a preliminary study was undertaken in female rats and showed that this route of administration was effective in causing a major decrease in uterine weight (P<0.02). In an initial study in male adult rats, anastrozole (100 mg/l or 400 mg/l) was administered via the drinking water for a period of 9 weeks.

On the basis of the present findings, oestrogen appears to be involved in the regulation of FSH secretion and testosterone production, and is also essential for normal mating behaviour in male rats. Furthermore, these data suggest that the brain and the hypothalamo-pituitary axis are considerably more susceptible than is the testis to the effects of an aromatase inhibitor. Anastrozole treatment has resulted in a model of brain oestrogen insufficiency.

But just like the blood brain barrier, you see letrozole very effective in crossing the blood-testis barrier in mice:

Pigs:

https://academic.oup.com/biolreprod/article/74/1/58/2666814

Abstract

Boars have high concentrations of plasma and testicular estrogens, but how this hormone is involved in feedback regulation of the gonadotropins and local regulation of testicular hormone production is unclear. The present study examined the effects of reducing endogenous estrogens by aromatase inhibition on concentrations of plasma LH and FSH and on testicular and plasma concentrations of testosterone (T) and immunoreactive inhibin (INH). Thirty-six littermate pairs of boars were used. One boar from each pair was assigned to the control group (vehicle); the other boar to the treatment group (aromatase enzyme inhibitor, Letrozole, 0.1 mg/kg body weight [BW]). Weekly oral treatment started at 1 wk of age and continued until castration at 2, 3, 4, 5, 6, 7, or 8 mo. Plasma concentrations of gonadotropins, INH, T, estradiol (E2), and estrogen conjugates (ECs) were determined. Testicular tissue was collected at castration for determination of INH and T and for confirmation of reduced aromatase activity. The acute effects of aromatase inhibition on gonadotropins were monitored in two adult boars treated once with Letrozole (0.1 mg/kg BW). Treatment with the aromatase inhibitor reduced testicular aromatase activity by 90% and decreased E2 and ECs without changing acute, long-term, or postcastration LH and FSH. Plasma T, testicular T, and circulating INH concentrations did not change. Testicular INH was elevated in treated boars compared with controls. In conclusion, estrogen does not appear to play a regulatory role on gonadotropin secretion in the developing boar. This is in direct contrast to findings in males of several other species.

Aromatase Activity and Protein Levels

Treatment with the aromatase enzyme-inhibitor Letrozole significantly reduced aromatase activity in testicular tissue of boars overall by 83% ([Fig. 5](javascript:;)A). A significant effect of the age by treatment interaction was detected for aromatase activity ( P = 0.004). Testes from Letrozole-treated boars before and at the onset of puberty (∼4–5 mo) had significantly reduced aromatase enzyme activity compared with that of control littermates ( P ≤ 0.05). This reduction was 92% at 2 mo (168.1 ± 16.5 pmol (mg protein)−1 h−1 in control boars vs. 13.7 ± 16.5 pmol (mg protein)−1 h−1 in Letrozole-treated littermates) and 80% at 5 mo of age (79.0 ± 16.5 pmol (mg protein)−1 h−1 in control boars vs. 15.5 ± 16.5 pmol (mg protein)−1 h−1 in treated littermates). Furthermore, an overall 90% decrease in aromatase activity was found from 2 to 8 mo of age ( P = 0.0004).

In contrast to the reduction in aromatase activity, aromatase protein levels were actually increased by Letrozole treatment as determined by Western blot analysis ([Fig. 5](javascript:;)B) and confirmed by densitometry ( P < 0.025).

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