What is the best dose of HCG? Dr Saya presents two case studies.

[Dr Justin Saya MD]

Community - I am sharing and have attached the write-up of a recent small case study I have conducted on quantitative serum beta hCG concentrations relating to hCG injections. This study is limited to dosages of 150iu and 500iu, although I hope to obtain more data in the near future.

P.S. Attempted to copy/paste plain text for those that may have a challenge viewing the pdf on mobile, but formatting wouldn't cooperate.

 

[Vince]

Dr. Saya, thanks for posting this Study.

 

[Vince Carter]

Read this...best way to spend 5-10 minutes with some many questions of how to use HCG and how long it acts in the body and it's influence of serum LH levels.

 

[ERO]

Terrific study Dr. Saya - Very informative!

 

[torrential]

I hope I didn't miss this in the document, but were the injections IM or SQ?

 

[MG123]

It states subq.

 

[Dr Justin Saya MD]

SQ as is the most common method with hCG, I would suspect IM would be similar...but never know!

 

[Nelson Vergel]

Dr Saya:

You know how much I like data even if it is from a small pilot or case study. Thanks for this!

I was able to paste the text here to make it easier for people to read:





Serum Beta hCG Concentrations Resulting from Single hCG Injection

Dr Justin Saya, M.D. Defy Medical, LLC


Prior to delving into discussion, I wanted to take time to express a special thank you to Defy Medical management and staff for following through with the logistics of the following case study, the study participants for their willingness to volunteer, and also my colleagues, Jill Dillenburg, RN and Dr John Crisler, D.O. for their support of the case study.


Introduction



The human endocrine system comprises a complex network of organs, glands, hormones, receptors, binding globulins, enzymes, and mRNA/DNA transcription cascades that result in a multitude of vital end-products and processes throughout the body. Furthermore, this network is, for the most part, self-regulating via intricate control processes involving both positive and negative feedback loops.

One such negative feedback loop is particularly relevant for male patients prescribed treatment for hypogonadism with testosterone replacement therapy. The introduction of exogenous testosterone into the endocrine system initiates a negative feedback loop whereby endogenous testosterone production is suppressed/halted via suppression of the hypothalamus-pituitary signaling resulting in a steep decline (and eventual cessation) of luteinizing hormone (LH) production. Of note, introduction of exogenous testosterone also suppresses the pituitary production of another gonadotropin, follicle stimulating hormone (FSH), however we will focus on luteinizing hormone for this discussion as it relates to human chorionic gonadotropin (hCG). The physiologic action of luteinizing hormone in the male body is to stimulate the leydig cells of the testes (for testosterone production). Thus, with the introduction of exogenous testosterone for a male on testosterone replacement therapy, and the resultant suppression of endogenous luteinizing hormone (LH) and follicle stimulating hormone (FSH), the testes go without stimulation and will become inactive (dormant). The consequence of this inactivity of the testes is a significant decline in fertility/spermatogenesis, decline in endogenous testicular testosterone production, and often atrophy (shrinkage) of the testes.

Human chorionic gonadotropin (hCG) has been shown to be an analog of endogenous luteinizing hormone. Human chorionic gonadotropin is so similar in structure to endogenous luteinizing hormone, in fact, that hCG interacts with the luteinizing hormone receptors on the testicular leydig cells and will stimulate their activity. Thus, hCG has been shown both clinically and scientifically to reverse signs and symptoms of testicular suppression for males on testosterone replacement.



Indeed, introduction of hCG for a male on testosterone replacement therapy whom has experienced suppression of the testes, will often improve spermatogenesis, testicular fullness/volume, and endogenous testicular testosterone production.

Given the growing awareness of the benefits of hCG treatment as an adjunct to TRT for male patients, the use of hCG has been increasing significantly. However, despite the increase in use, there has been no consensus reached regarding the ideal or optimal dosing. This article will not attempt to establish concrete recommendations for ideal dosing regimens, but, rather, will outline a case study of serum hCG concentrations achieved during a 72 hour period immediately following a single hCG injection of 150iu and 500iu in two test subjects. As the goal of adjunctive hCG treatment is to mimic the action (and amplitude) of the lost luteinizing hormone stimulation, it is my position that hCG dosing guidelines should be designed for exactly this purpose. In other words, dosing guidelines should aim to, as closely as possible, mimic the endogenous action and amplitude of luteinizing hormone stimulation, with care taken to avoid both under-stimulating or over-stimulating in comparison to endogenous luteinizing hormone levels.

Laboratory studies for both luteinizing hormone and beta hCG concentrations are reported in the same units (mIU/mL), making comparison, at least in this regard, fairly straightforward. However, discussion will be made regarding the varying half-life and pattern of secretion of endogenous luteinizing hormone and injected human chorionic gonadotropin. Luteinizing hormone is secreted in a pulsatile nature from the pituitary gland with a half-life estimated at approximately 20 minutes. On the contrary, hCG is injected, not secreted in pulses, and has a much longer half-life estimated at approximately 24-30 hours. As a consequence, the “area under the curve” (AUC) and resultant biological potency for these two differs distinctly.



Methods



This small case study is comprised of two test subjects, a 34 year-old male and a 47 year-old male, both of which have been on testosterone replacement therapy for greater than a five year duration, and both of which were verified and documented to have suppressed endogenous luteinizing hormone levels (0.1) prior to commencement of the study. This is significant as the laboratory methodology for serum beta hCG quantitative testing is Roche ECLIA, with possible cross- reactivity for the serum hCG test via endogenous luteinizing hormone. However, verifying absent endogenous luteinizing hormone levels (0.1 &#8211; lowest value for lab result) for the test subjects eliminates the possibility of this cross-reactivity skewing the study results. Both patients were previously on hCG treatment as an adjunct to their TRT, however their hCG treatment was ceased 7 days prior to study commencement as a wash-out period, and baseline serum hCG levels were confirmed to be <1 (lowest threshold for lab results, in effect 0) immediately prior to the single hCG injection to commence the study.


The 34 year-old subject (subject “A”) had serum luteinizing hormone and quantitative serum beta hCG concentrations tested at hour 0 (prior to single hCG injection), then a single hCG injection of 150iu subcutaneously was administered, with subsequent quantitative serum beta hCG concentrations drawn at hour 8, hour 24, hour 48, and hour 72 following the 150iu injection. The 47 year-old subject (subject “B”) had serum luteinizing hormone and quantitative serum beta hCG concentrations tested at hour 0 (prior to single hCG injection), then a single hCG injection of 500iu subcutaneously was administered, with subsequent quantitative serum beta hCG concentrations drawn at hour 8, hour 24, hour 48, and hour 72 following the 500iu injection. Each subject was injected from a vial of freshly reconstituted hCG, kept under favorable conditions and refrigerated throughout duration of study, and both subjects were injected with hCG from the same vial to avoid possible vial-to-vial variability.



Results



Results for both subject A and subject B for the serum tests at hour 0 (after 7 day wash-out with no hCG and before the single test hCG injection) demonstrated serum luteinizing hormone level 0.1 mIU/mL (lower threshold for results, in effect 0) for both test subjects, and quantitative serum beta hCG level <1 mIU/mL (lower threshold for results, in effect 0) for both test subjects. Results of the quantitative serum beta hCG concentration tests administered at hour 0, hour 8, hour 24, hour 48, and hour 72 are summarized in Table 1 below.



Table 1
Quantitative serum beta hCG concentration - hour 0, hour 8, hour 24, hour 48, hour 72

Hours after hCG Injection	Serum hCG Concentration (mIU/mL) 150iu Injection	Serum hCG Concentration (mIU/mL) 500iu Injection
0	0	0
8	1	2
24	0	3
48	0	3
72	0	1

A graphical representation of the resultant quantitative serum beta hCG concentrations is depicted below in Graph 1.



Graph 1
Quantitative serum beta hCG concentration - hour 0, hour 8, hour 24, hour 48, hour 72





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 &#8211; 8.6 mIU/mL. As noted, half-life differences (of large magnitude) are present, but this offers some perspective with the comparison.


A graphical representation of the resultant quantitative serum beta hCG concentrations with shading to demonstrate area under curve is depicted below in Graph 2.


Graph 2
Shading of Area Under Curve
Quantitative serum beta hCG concentration - hour 0, hour 8, hour 24, hour 48, hour 72









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 <1 by the 72 hour mark following injection). Taking into account the physiologic range of luteinizing hormone (LH) of 1.7 &#8211; 8.6mIU/mL (and once again the differences in half-life) can enable some interesting debate on the physiologic/biological effects of these resultant levels. Further, the apparent time to retreat to baseline levels can offer some guidance on dosing frequency/timing for these varying dosages of hCG.

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.



Conclusions



The clinical use of human chorionic gonadotropin (hCG) as an adjunctive treatment to testosterone replacement therapy (TRT) in males is an important, and often overlooked and misunderstood, aspect of successful treatment of hypogonadism. However, a consensus on use and dosing/frequency has not been reached among practitioners and the situation is complicated by the degree of bio-hormonal individuality present across the population and the varying effects and goals of hCG treatment in different clinical scenarios (low SHBG levels, high estradiol levels, fertility concerns, etc). The data in this limited case study suggest that a dosage of 150iu hCG appears to attain minimal to moderate stimulation (serum concentration of 1mIU/mL) of the testicular leydig cells for a duration less than 24 hours and would likely be insufficient to attain continuous stimulation of the testicular leydig cells, UNLESS given on a daily basis, perhaps more frequently. Whereas, an injection of hCG 500iu appears to attain moderate stimulation (serum concentration 2mIU/mL -> 3mIU/mL -> 3mIU/mL -> 1mIU/mL) for a period slightly longer than
3 days (72 hours), likely enabling twice weekly, evenly spread, injections to attain continuous stimulation. As noted previously, I believe these patterns also suggest that a dosage regimen of hCG 250iu-350iu on an every other day (QOD) schedule would likely offer an alternative regimen for moderate, relatively steady and consistent testicular stimulation, although more data would be needed to confirm this conclusion.

As a future consideration, and to offer more insight, I would like to obtain data on dosages between 150iu and 500iu, specifically 250iu and 350iu dosages. Further, the apparent non-linear dose response relationship in this data is intriguing and would warrant further study. Due to the interesting serum results within the first 24 hour period from the smaller 150iu hCG dosage and the logistical limitations in this study of obtaining results at 8 hours and then 24 hours, it would be useful to obtain data on serum hCG concentrations at several time points WITHIN the first 24 hour period, especially following smaller hCG dosages (150iu or less). Indeed, further study would assist in shedding more light onto the preferred dosage and frequency suggestions for hCG use as an adjunct to TRT in male patients and continue the advancement of this treatment into mainstream usage.

 

[Nelson Vergel]

More on HCG here:

The Use of HCG to Prevent / Reverse Testicular Shrinkage and Preserve Fertility

 

[Re-Ride]

IIRC earlier studies showed a second peak ( 72 hrs? ) of serum T. Worthy to note this is serum b hCG. Thank you this study Dr.Saya!

 

[mike7]

Thanks Doc! Great info.

 

[Jon H]

Dr. Saya - Thanks so much for this post. These results seem to mirror my results when changing hCG dose. I initially used 500iu twice per week. However, by day three I noticed a definite diminished effect on how I felt, and testicular volume. I tried changing to daily injections of 150iu, thinking that would work much better, but that quickly lost its effect. I might feel a little effect for a few hours, but after a couple weeks my testicles steadily got smaller, and the effects were almost nonexistent. I changed a few months ago to 350iu every M/W/F, which seemed to get better, but then I still felt very diminished effects by Monday morning. I recently switched to 350iu every M/W/F, with an additional 200iu "bump" on Sunday morning, which seems to be working much better for me at the moment.

I am a Defy patient, and am extremely primary. Before starting TRT my FSH/LH were very high, with a testosterone level of only 180. I'm starting to believe that the level of being primary hypogonadal plays a very big role in the effectiveness of hCG dosing amounts and injection schedule. To be honest, I would probably feel a lot better if my hCG dosing levels would mirror my pre-TRT LH levels (pretty high), but I try to stay pretty close to what I'm being prescribed.

 

[Dr Justin Saya MD]

Dr. Saya - Thanks so much for this post. These results seem to mirror my results when changing hCG dose. I initially used 500iu twice per week. However, by day three I noticed a definite diminished effect on how I felt, and testicular volume. I tried changing to daily injections of 150iu, thinking that would work much better, but that quickly lost its effect. I might feel a little effect for a few hours, but after a couple weeks my testicles steadily got smaller, and the effects were almost nonexistent. I changed a few months ago to 350iu every M/W/F, which seemed to get better, but then I still felt very diminished effects by Monday morning. I recently switched to 350iu every M/W/F, with an additional 200iu "bump" on Sunday morning, which seems to be working much better for me at the moment.

I am a Defy patient, and am extremely primary. Before starting TRT my FSH/LH were very high, with a testosterone level of only 180. I'm starting to believe that the level of being primary hypogonadal plays a very big role in the effectiveness of hCG dosing amounts and injection schedule. To be honest, I would probably feel a lot better if my hCG dosing levels would mirror my pre-TRT LH levels (pretty high), but I try to stay pretty close to what I'm being prescribed.

Everyone - you're welcome! It is a pleasure sharing with you all.

Jon H - very astute observation and I would have to say that I currently lean in that direction as well based on patterns I've seen over the years. In fact, I'm pasting below a separate forum post that I submitted a few weeks back while conducting the above study stating the same:

"I personally use the degree of suspected PRIMARY HYPOGONADISM in my dosage decisions for hCG. In other words, the degree of suspected testicular failure. If I suspect a patient has a stronger primary hypogonadal component (less responsive or less capable testes), I dose slightly higher hCG for more stimulation of the "less capable" testes. If I suspect a patient has less of a primary hypogonadal component, I typically will dose hCG somewhat lower as the testes are more responsive/capable. This is why my hCG dosages often vary from patient to patient. I believe with hCG, as with all other areas of HRT that we have found, a cookie-cutter/one-size-fits-all approach is not ideal as some factors vary amongst patients.

The REAL question is how much is needed to keep the Leydig cells in the testes stimulated and to reap the other benefits of the hCG. Again, this is not fully known (we have some data on this for fertility - i.e. Lipshultz study, but not for other areas). I believe the goal should be to attempt to approximate hCG's endogenous equivalent LH. Now this is difficult as they have much different half-lifes (with LH being very short) and endogenous LH is only secreted in a pulsatile nature. I am currently working on a few case studies of patients to determine the quantitative beta hCG serum levels achieved at various times following various hCG dosages. I currently have two patients enrolled, after a 7 day washout to ensure all hCG is out of the body (and these are longtime TRT patients so endogenous LH is suppressed) one patient will inject a single hCG 150iu injection, the second patient will inject a single hCG 500iu injection (I'm trying to arrange another patient for a single 350iu injection as well). I will then measure quantitative serum hCG levels at various times - hour 0 ( before injection) -> hour 12 -> hour 24 -> hour 48 -> hour 72. This data will be very interesting especially in the sense that I want to try to compare the resultant levels of hCG at various times to the normal physiologic levels of its equivalent, LH. This may give a little more insight into what the "best" dose of hCG may be. I'll share once complete, likely 6-8 weeks...maybe sooner."

As promised in that post a few weeks ago, this is the data. Hope to work on more, possibly chart reviews, coming up...free time with the busy practice and 4 kiddos running around at home is the limiting factor! Hope this benefits some...

 

[Henry]

Wow, this is very interesting.

I have a question though. I started at 250iu's every Tues and Thurs. My testicles started getting soft so I moved to 250iu's every M,W,F. I then went to 350 every M,W,F and that was my best result. I eventually moved to Androgel and read that it's best to take a daily shot of hGC with my daily application of Androgel so I went to 150iu's every day.

After reading this, it seems like the best course of action would be to go back to 350iu's every M,W,F. I would get more stimulation and use less needles.

Am I reading this correctly?

Thanks

 

[Henry]

Also, why not just inject 500iu's every other day? It seems like that would produce the best results? Are there any side effects of too much hCG?

 

[Vince Carter]

Also, why not just inject 500iu's every other day? It seems like that would produce the best results? Are there any side effects of too much hCG?

I think me personally I have a hard time managing the aromatization in the testes, the Estrogen that is produced with too much HCG. I use 500 2XW, I've used as much as 750 and had some night sweats and and had an sensitive E2 test @ 58. I did that for I think two weeks before I tested and returned to 500iu.

 

[Dr Justin Saya MD]

I then went to 350 every M,W,F and that was my best result.

Then that is the dosage I suggest you should stay at.

In fact, in my write-up I even mentioned that the data SUGGESTS that a dosage in that range (~250 - 350iu) on a QOD basis (slightly different than MWF as you won't have the Friday to Monday gap with the QOD) may be an effective regimen. If 350iu TIW did well for you, I wouldn't have changed it...don't fix it if it isn't broken.

 

[Henry]

Thank you Dr. Saya

 

[midlifealpha]

I look forward to this and personally might experiment beyond my current 150IU daily. I'm liking the idea of the 350IU every other day with a bump although it would seem a 150 bump on Sunday would suffice.

 

[1Draw]

Dr. Saya - Thanks for a very interesting study that so far no other MD has covered in such detail. When are you writing your book? Great Stuff!