High hematocrit prevalence with intranasal vs. intramuscular testosterone

madman

Member
A cross-sectional comparison of secondary polycythemia in testosterone-deficient men treated with nasal testosterone gel vs. intramuscular testosterone cypionate


Abstract

Introduction:
Secondary polycythemia is a known adverse effect of testosterone replacement therapy (TRT). Different testosterone formulations are available, with significantly different half-lives, which have varying influences on the development of secondary polycythemia. Herein, we compared the prevalence of secondary polycythemia in testosterone-deficient men treated with intranasal testosterone gel (Natesto) vs. intramuscular testosterone cypionate (TC) therapy.

Methods: We performed a cross-sectional analysis of secondary polycythemia (hematocrit [Hct] ≥54%) in men who received TRT. We included a total of 60 men: 30 men who received Natesto (4.5% testosterone gel [tid, 5.5 mg/nostril, 11 mg/dose, 33 mg/day]), and 30 who received TC (between 0.5 and 1.0 mL or 100–200 mg intramuscularly weekly). A univariable and multiple regression analysis was performed considering the last Hct measurement as the main outcome. The analyzed variables included were age, body mass index (BMI), smoking history, treatment group, and testosterone levels on followup.

Results: We identified polycythemia (Hct ≥54%) in 10% (3/30) of men who received TC. Additionally, in men treated with TC, 33.3% (10/30) had a Hct ≥50% during therapy. None of the men who received Natesto had a Hct ≥50% during therapy. On multivariable linear regression analysis, we demonstrated that the use of TC increased Hct by 3.24% (95% confidence interval [CI] 0.74–5.73%; p=0.012) compared to Natesto.

Conclusions:
The prevalence of polycythemia in men treated with Natesto was markedly lower compared to the men who received TC therapy.


Discussion

To the best of our knowledge, this is the only study comparing the prevalence of secondary polycythemia in testosterone deficient patients treated with either intranasal testosterone (Natesto) or IM TC therapy. There was a lower prevalence of secondary polycythemia (Hct ≥54%) in the cohort treated with Natesto (0%) compared to that on TC therapy (10%). In addition, using various cutoffs for Hct, significant differences were seen between treatment groups. In men treated with TC, 33.3% (10/30) had a Hct ≥50% and 20% (6/30) had a Hct ≥52% on follow-up, compared to men treated with Natesto, which had no one develop a Hct ≥50% during treatment. The prevalence of secondary polycythemia due to TC is comparable to previous studies that have evaluated this phenomenon.19

A study performed by Bachman et al. showed that supraphysiologic T levels suppressed hepcidin in a dose- and t age-dependent manner by > 50% and resulted in an increased hematocrit along with stable erythropoietin levels. His study also supported the hypothesis that older men respond to testosterone with a relatively greater level of hepcidin suppression than younger men. This mechanism may be responsible for the difference in the prevalence of polycythemia and change in Hct seen in TC patients, as the average age was 17.4 years older in our cohort. Since men interested in fertility preservation were treated with Natesto, this group was younger than the TC group, who were not interested in fertility preservation. Additionally, post-treatment levels of testosterone were significantly higher than Natesto (983.1 ± 394.1 ng/dL vs 640.3 ± 302.4 ng/dL), and this could have contributed to the observed difference. However, in an attempt to further analyze the effect of different independent variables on follow-up Hct, we performed a multivariable analysis that was adjusted by variables including age, BMI, smoking history, and testosterone on follow-up. Our findings indicate that the most influential factor contributing to an increase in Hct on follow-up was the use of TC.

Previous studies have demonstrated that different T formulations may have varying effects on erythropoiesis, and some have proposed that the troughs in serum T between doses are most predictive of developing polycythemia20,21 Importantly, the pharmacokinetic profile and TID dosing of Natesto allows T levels to return to baseline multiple times daily, whereas TC leads to steady-state levels over days. This property of Natesto was highlighted in our published clinical trial, in which the majority of men on Natesto maintained semen parameters during treatment. This was likely attributed to the maintenance of pulsatile secretion of GnRH that allowed the daily release of gonadotropins.22 Regardless of the proposed mechanisms for the erythrogenic effect of T,10-12 Natesto’s short half-life and frequent troughs in T during treatment would have less of an influence on these mechanisms. Of note, although Natesto can provide symptom relief similar to that of TC, the TID administration that Natesto requires can be cumbersome for patients when compared to a single injection that lasts for weeks.22


Our study had several limitations, including its retrospective nature, variability in dosages of TC taken and although adequately powered, a relatively small sample size and a non-age matched cohort. Strengths of the study are the novelty in the literature, adequate power, directly comparing the biochemical effects of TC and short-acting Natesto, multivariable regression analysis demonstrating the mode of therapy as an independent predictor of polycythemia. Further prospective randomized trials are needed, in which men are matched by age, serum testosterone, and hematocrit levels on baseline to confirm our findings.


Conclusions


The prevalence of polycythemia in men treated with Natesto were markedly lower compared to the men who received testosterone cypionate injections. Given that the most frequent adverse effect of TRT is the resulting polycythemia, Natesto could be a potential option if this is a concern, although larger prospective studies with age-matched cohorts are needed to validate the finding in our cross-sectional study.
 

Attachments

Last edited:

madman

Member
Fig. 1. Followup hematocrit (Hct) levels during therapy with Natesto or testosterone cypionate

(TC). Represents the number of patients reaching various Hct cutoffs during treatment with TC or Natesto.

Screenshot (1734).png
 

madman

Member
Table 1. Comparison between the clinical and demographic characteristics of men in the Natesto and TC group
Screenshot (1735).png
 

madman

Member
Table 2. Univariable and multivariable linear regression analysis used to predict follow-up hematocrit
Screenshot (1736).png
 

Eklutna

New Member
I quit TRT due to high HCT levels and a corresponding increase in blood pressure. This is really good news. I might have to give it a try.
 

Cataceous

Well-Known Member
I suspect that even on injections most guys could fix high hematocrit by switching to daily dosing and keeping peak testosterone physiological. A cypionate/propionate blend could be used to push average serum testosterone even lower while preserving TRT benefits, mimicking what happens naturally.
 

readalot

Member
I suspect that even on injections most guys could fix high hematocrit by switching to daily dosing and keeping peak testosterone physiological. A cypionate/propionate blend could be used to push average serum testosterone even lower while preserving TRT benefits, mimicking what happens naturally.
Thanks very much again @madman. You are a machine.

@Cataceous, I've thought quite a bit about this as once or twice weekly TC really does a number on my Hct.

From the paper above:



Reference 21:

Seems to me you'd need something with a very short half life like Natesto or even the creams with crystalline testosterone (half life of hours) to really get the benefit here on reduced Hct.

Let's say you are doing 80 mg per week either 1 weekly injection or breaking it up daily:

1596577899151.png


Either way your trough never drops below physiological. Although AUC invariant, seems like these papers indicate you need time under physiological test levels in order to reap the benefit on your Hct. If I remember correctly trying to trace back the kinetics of testosterone on hepcidin suppression and to EPO, it's first order and you'd reach saturation, so whether you do Test Ester once a day (weekly dosage / 7) or once weekly (weekly dosage / 1) you run into the same problem (trough never drops below physiologic range). To turn off hepcidin suppression and slow down erythropoiesis in an interval fashion, you have to drop test levels intermittently below where they activate the chemical cascade.

Thanks to you guys for bringing this up. Curious your thoughts.

There is seldom a free lunch, bummer.
 
Last edited:

Cataceous

Well-Known Member
...
Either way your trough never drops below physiological. Although AUC invariant, seems like these papers indicate you need time under physiological test levels in order to reap the benefit on your Hct. If I remember correctly trying to trace back the kinetics of testosterone on hepcidin suppression and to EPO, it's first order and you'd reach saturation, so whether you do Test Ester once a day (weekly dosage / 7) or once weekly (weekly dosage / 1) you run into the same problem (trough never drops below physiologic range). To turn off hepcidin suppression and slow down erythropoiesis in an interval fashion, you have to drop test levels intermittently below where they activate the chemical cascade.
...
This is why you need a blend that includes propionate with a longer ester. It can be tailored to provide an approximation of a natural diurnal rhythm when given daily. Normal men see a variation in serum testosterone of 20-25% about the mean. For me, pure propionate was too much, giving upwards of +/-50% variation about the mean. I now take an enanthate/propionate blend—4:3 by weight—which gives about 23% variation. In making the transition from EOD enathate I went from injecting 6.5 mg testosterone daily to 5 mg while maintaining the same peak serum testosterone, close to 800 ng/dL.
 

readalot

Member
Thanks very much for your response and sharing your experience. In this case it took you stating propionate twice before it sunk in. Sorry for my poor reading comprehension!

So if I read this correctly, you are injecting 5 mg daily of 4/3 by weight enanthate/propionate blend and hitting 800 ng/dL peak after how many hours?

23% variation about mean puts you at 500, 650, 800 ng/dL (trough, mean, peak)?

Interesting reading on the within patient variation documented in the literature.


1596656326210.png
 

Cataceous

Well-Known Member
...
So if I read this correctly, you are injecting 5 mg daily of 4/3 by weight enanthate/propionate blend and hitting 800 ng/dL peak after how many hours?

23% variation about mean puts you at 500, 650, 800 ng/dL (trough, mean, peak)?

Interesting reading on the within patient variation documented in the literature.

...
To further clarify the daily dosing: The 5 mg figure refers to pure testosterone. Total weight of the ester combination is more like 6.5 mg. With this combination peak testosterone is nearly 800 ng/dL, which I estimate occurs in the range of 1-3 hours post-injection. Those figures you cite for 23% variation are correct.

Thanks for the interesting reference. I'm actually pleased to see that natural men can have pretty long periods without GnRH and LH pulses. This means that the overnight breaks in my GnRH therapy are maybe less of a concern.
 

madman

Member
I suspect that even on injections most guys could fix high hematocrit by switching to daily dosing and keeping peak testosterone physiological. A cypionate/propionate blend could be used to push average serum testosterone even lower while preserving TRT benefits, mimicking what happens naturally.
Unfortunately, too many men on trt would not settle for such due to the more T is better mentality.

Let alone injecting daily is not common and many are injecting twice or even once weekly and the serum levels they tend to run are well above the physiological range as in absurd peaks or sky-high trough levels.

Daily low dose T (stable blood levels/minimizing peak--->trough) but even then one needs to keep serum levels in mind as some of these same individuals are running 1400+ ng/dL levels.
 

madman

Member
Thanks very much again @madman. You are a machine.

@Cataceous, I've thought quite a bit about this as once or twice weekly TC really does a number on my Hct.

From the paper above:



Reference 21:

Seems to me you'd need something with a very short half life like Natesto or even the creams with crystalline testosterone (half life of hours) to really get the benefit here on reduced Hct.

Let's say you are doing 80 mg per week either 1 weekly injection or breaking it up daily:

View attachment 10306

Either way your trough never drops below physiological. Although AUC invariant, seems like these papers indicate you need time under physiological test levels in order to reap the benefit on your Hct. If I remember correctly trying to trace back the kinetics of testosterone on hepcidin suppression and to EPO, it's first order and you'd reach saturation, so whether you do Test Ester once a day (weekly dosage / 7) or once weekly (weekly dosage / 1) you run into the same problem (trough never drops below physiologic range). To turn off hepcidin suppression and slow down erythropoiesis in an interval fashion, you have to drop test levels intermittently below where they activate the chemical cascade.

Thanks to you guys for bringing this up. Curious your thoughts.

There is seldom a free lunch, bummer.



This is key:

* the unique, ultradian, pulsatile nature of TNG
* limited impact on the HPG axis
with significant trough time






TNG 4.5% testosterone nasal gel (Natesto® ) is a thixotropic gel that is applied to the nasal cavity. Testosterone levels or symptoms are used to guide titration decisions between either twice daily or three times a day doses used to restore testosterone levels to the normal range. Surprisingly, patients report higher convenience with TNG than once-daily topical gels. The pharmacokinetic (PK) profile of TNG of different concentrations has been studied in a series of single and multidose PK studies, including in women, healthy volunteers with allergic rhinitis, and TDS men. The 24-hour pharmacokinetic profile of testosterone for patients on TNG treatment has two or three discrete peaks (“pulses”) of testosterone provoked by LH secretions that occur on average every 2 hours. A maximal peak of testosterone appears at about 1h (Tmax) followed by a return to endogenous, pre-dose levels, 4-6 hours later (t1/2 ~1h). The nadir (trough) between doses correlates well with pre-treatment endogenous levels at diagnosis.

The unique, pulsatile, pharmacokinetic profile is believed to have limited impact on the HPG axis with significant trough time preserving luteinizing hormone (LH), follicle stimulating hormone (FSH), endogenous testosterone production and sperm counts, while also limiting excess RBC production, estradiol, DHT and PSA in clinical trials. However, it was previously unclear whether TNG was sufficient to produce strong efficacy outcomes when baseline endogenous production was very low, thus the impetus to perform a post-hoc analysis of Phase 3 data with particular attention to pre-study baseline and its effects on the pharmacokinetics and symptomatic efficacy. Of particular interest was the subset of patients who presented with very low baseline endogenous testosterone (<100 ng/dL (3.5 nmol/L)) to determine if TNG is a suitable treatment option for this population.



Conclusions

Testosterone nasal gel treatment restores TT levels while preserving significant aspects of HPG function, including the continued release of gonadotropins and production of endogenous testosterone, which allows maintenance of baseline levels.
Both modest TDS (TT 250-300 ng/dL; (8.7 – 10.4 nmol/L)) and more severe TDS patients (TT 0-100 ng/dL (0 – 3.5 nmol/L), when treated with TNG, achieve max TT levels around 800 ng/dL (27.7 nmol/L). Efficacy, as measured by erectile function and mood were significantly improved to similar levels in both groups. The unique, ultradian, pulsatile nature of TNG, which does not depress endogenous testosterone production means that a wide range of testosterone deficient patients can effectively be treated with it.
 

readalot

Member
Unfortunately, too many men on trt would not settle for such due to the more T is better mentality.

Let alone injecting daily is not common and many are injecting twice or even once weekly and the serum levels they tend to run are well above the physiological range as in absurd peaks or sky-high trough levels.

Daily low dose T (stable blood levels/minimizing peak--->trough) but even then one needs to keep serum levels in mind as some of these same individuals are running 1400+ ng/dL levels.
Great points! Easy to run and rationalize >1500 ng/dL trough when you watch trusted medical providers dismiss long term risk of elevated Hct levels. Even without JAK2 mutation, I have very non-linear Hct response to even modest elevations of Test.
 

Nelson Vergel

Founder, ExcelMale.com
I could not tolerate Natesto. I had sinus congestion and my nostrils started hurting. My blood pressure would increase by 10 points a few minutes after the twice per day application. That was followed by throbbing in my head.

I am one of those guys whose hematocrit has stabilized at 49-50 after the first year on injectable 100-200 mg per week testosterone cypionate or enanthate injections.
 

Willyt

Member
I am currently experimenting with Natesto and am putting together a write-up. In short, the results have been encouraging, but the delivery method (gel up the nostril) and expense are major downsides.
 

readalot

Member
This is key:

* the unique, ultradian, pulsatile nature of TNG
* limited impact on the HPG axis
with significant trough time






TNG 4.5% testosterone nasal gel (Natesto® ) is a thixotropic gel that is applied to the nasal cavity. Testosterone levels or symptoms are used to guide titration decisions between either twice daily or three times a day doses used to restore testosterone levels to the normal range. Surprisingly, patients report higher convenience with TNG than once-daily topical gels. The pharmacokinetic (PK) profile of TNG of different concentrations has been studied in a series of single and multidose PK studies, including in women, healthy volunteers with allergic rhinitis, and TDS men. The 24-hour pharmacokinetic profile of testosterone for patients on TNG treatment has two or three discrete peaks (“pulses”) of testosterone provoked by LH secretions that occur on average every 2 hours. A maximal peak of testosterone appears at about 1h (Tmax) followed by a return to endogenous, pre-dose levels, 4-6 hours later (t1/2 ~1h). The nadir (trough) between doses correlates well with pre-treatment endogenous levels at diagnosis.

The unique, pulsatile, pharmacokinetic profile is believed to have limited impact on the HPG axis with significant trough time preserving luteinizing hormone (LH), follicle stimulating hormone (FSH), endogenous testosterone production and sperm counts, while also limiting excess RBC production, estradiol, DHT and PSA in clinical trials. However, it was previously unclear whether TNG was sufficient to produce strong efficacy outcomes when baseline endogenous production was very low, thus the impetus to perform a post-hoc analysis of Phase 3 data with particular attention to pre-study baseline and its effects on the pharmacokinetics and symptomatic efficacy. Of particular interest was the subset of patients who presented with very low baseline endogenous testosterone (<100 ng/dL (3.5 nmol/L)) to determine if TNG is a suitable treatment option for this population.



Conclusions

Testosterone nasal gel treatment restores TT levels while preserving significant aspects of HPG function, including the continued release of gonadotropins and production of endogenous testosterone, which allows maintenance of baseline levels.
Both modest TDS (TT 250-300 ng/dL; (8.7 – 10.4 nmol/L)) and more severe TDS patients (TT 0-100 ng/dL (0 – 3.5 nmol/L), when treated with TNG, achieve max TT levels around 800 ng/dL (27.7 nmol/L). Efficacy, as measured by erectile function and mood were significantly improved to similar levels in both groups. The unique, ultradian, pulsatile nature of TNG, which does not depress endogenous testosterone production means that a wide range of testosterone deficient patients can effectively be treated with it.
Very nice paper @madman, thank you.


For someone already shut down after esterified testosterone usage, would be interesting to see if they could restore HPG function (partial or complete LH recovery) while also providing symptom relief during the potential recovery period. This approach may be much more effective that the typical "PCT" methods used with a SERM? An eager expermentalist might vary the daily applications to spend more time below physiological to see if that provided more "driving force" for pituitary.

1597411487535.png


1597411522923.png


Also, I did pick up on this part of the discussion:

Thus, TNG’s ultradian profile is the means to maintain an active HPG. Despite modest Cavg, significant Cmax values may be sufficient for positive symptom outcomes. TNG has up to 12 hours of trough time at or below patients’ baseline (i.e., below the normal range), which is likely a factor in limiting unwanted anabolic effects on hematocrit [22].

Interesting proposition is whether you could use this tool to recover an active HPG as opposed to maintain using frequency modulation. Opens up a lot of potential options but I am probably down a rabbit hole here.

I appreciate it.
 
Last edited:

readalot

Member
Very nice paper @madman, thank you.


For someone already shut down after esterified testosterone usage, would be interesting to see if they could restore HPG function (partial or complete LH recovery) while also providing symptom relief during the potential recovery period. This approach may be much more effective that the typical "PCT" methods used with a SERM? An eager expermentalist might vary the daily applications to spend more time below physiological to see if that provided more "driving force" for pituitary.

View attachment 10387

View attachment 10388

Also, I did pick up on this part of the discussion:

Thus, TNG’s ultradian profile is the means to maintain an active HPG. Despite modest Cavg, significant Cmax values may be sufficient for positive symptom outcomes. TNG has up to 12 hours of trough time at or below patients’ baseline (i.e., below the normal range), which is likely a factor in limiting unwanted anabolic effects on hematocrit [22].

Interesting proposition is whether you could use this tool to recover an active HPG as opposed to maintain using frequency modulation. Opens up a lot of potential options but I am probably down a rabbit hole here.

I appreciate it.

1597416722634.png


Much better than my experience on 100 mg/wk (twice weekly sub-Q) of testosterone cypionate. RBC superfactory!
 

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