Advice on low dose daily testosterone

[Beken]

I might have to try the enan Ester as well since no matter what I've tried on cyp, there's issues. But, I remember all those years of test E cycles and felt awesome.

I was drinking one cup of tea every morning.... I didn't have my tea this morning and I don't have my usual late morning anxiety. I think TRT made me sensitive to caffeine. I know my relationship with sugar and my insulin resistance has gotten way better. I don't crave sugar in the same way anymore....

 

[Cataceous]

...
What is your current protocol and are you happy with it? Where do you get your esters blended? Thanks for the help!

The heart of my protocol is daily injections of 3.2 mg testosterone enanthate and 2.4 mg testosterone propionate. I blend the esters myself, creating a month's worth at a time. I also use enclomiphene and peptides to maintain HPTA activity. This obviates any need for hCG.

 

[Fortunate]

@Beken, are you taking any other supplements (even simple vitamins)? hCG? Lots of things can trigger anxiety.

I alluded above that I am not a stable, content TRT user, but for what it's worth I tend to notice minimal side effects with Natesto (a nasal form of TRT). I have used it for treatment for a long time in the past and currently use it periodically if I am trying to "wash out" between trying various protocols. You might consider a trial on it. There are a few reasons I don't use it long term, but it's a really solid option to consider.

I have also had issues with daily microdosing. Logic and the feedback of others would suggest its the most user-friendly form of TRT, but I tend to feel better with more periodic, larger doses. I have used Xyosted 50mg with decent success and am getting ready to re-try a protocol with this dose around every 4-5 days.

I have all kinds of theories about why I have struggled with daily dosing, but have not figured it out yet. As I troubleshoot and subsequently rule out a theory, the remaining theories become more and more kooky. For example, my current theory has to do with threshold levels. If I inject small amounts of enanthate, I tend to get a headache and feel a bit anxious later in the day. But, if I inject 50mg of Xyosted, I tend to feel ok to good for a few days. Maybe the carrier oil is causing and inflammatory reaction, but with a sufficient amount of testosterone, the inflammatory reaction is muted.

I can't remember if you posted this, but have you had estrogen levels checked? Too high or too low can cause problems.

In any case, my point is that:

1. Consider all possibilities for the anxiety episodes (including benign - seeming supplements)
2. Understand that TRT should be highly individualized and trial and error is common
3. You are not alone

 

[tareload]

Although TS is unesterified the crystals of T may very well behave like small implants being more slowly absorbed from the tissues which would have an impact on the half-life.

Depending on the source the half-life given was 2 – 4 hours and some studies (animal) stating 24-39 hours.

Daily injections let alone multiple would most likely result in the shutdown HPG axis.


Andronaq (testosterone suspension)

Description:

Testosterone suspension is an injectable preparation containing testosterone (no ester), usually in a water base.


History:

Testosterone suspension is one of the oldest anabolic/androgenic steroids, dating all the way back to the 1930’s. Used generically to describe any injectable form of free testosterone, testosterone suspension predates the development of slow-acting (depot) injections of esterified testosterone by several years. Even after the development of esterified derivates, testosterone suspension remained on The U.S. and other select drug markets. For example, testosterone propionate and testosterone enanthate were both commercially available by the 1950s, yet testosterone suspension remained a regularly produced item in the U.S. for decades more. Previous American trade names for the drug have include Sterotate (Ulmer), Andronaq (Central), Aquaspension Testosterone (Pitman-Moore), Injectable Aqueous Testosterone (Arlington-Funk), Virosterone (Endo), and Testosterone Aqueous (National Drug). A full accounting of the former generic manufacturers and brand names for this drug would be too numerous to list.


Structural Characteristics:

Testosterone suspension contains (free) testosterone in a water-based suspension, although oils are sometimes also used as carriers. Without esterification, testosterone has a short half-life in the body. Testosterone suspension may require a minimum of 2-3 injections per week to maintain consistent hormone elevations. When calculating dose, especially when moving from one testosterone preparation to another, it is also important to remember that testosterone suspension contains more active testosterone per milligram than its esterified derivatives. For example, when the weight of the ester is taken into account, 100 mg of testosterone enanthate actually only provides 72 mg of raw testosterone.


*Testosterone suspension contains undissolved testosterone particles, which form a short-acting repository in the muscle following injection. Depending on the size of the particles and other agents present, injections of testosterone suspension may result in local irritation, pain, and redness. Veterinary testosterone suspensions may use large particles that require a needle as large as 21 gauge for injection, for example, and can be very uncomfortable to use. Modern testosterone suspension preparations made for human use often contain microcrystalline steroid particles. These crystals are highly refined and are too small to see with the naked eye. This design provides significantly more patient comfort than less refined products and is generally well tolerated.





Injectable Aqueous Suspensions of Sex Hormones and How Depot Injectables Work

Introduction

Depot injectable sex steroids are administered by intramuscular injection (into the muscle) or subcutaneous injection (into fat) and are formulated in two main ways: 1) as oil solutions, and 2) as crystalline aqueous suspensions. What most transfeminine people are familiar with when it comes to injectable steroid preparations are oil solutions. This is how most common preparations like injectable estradiol valerate (Delestrogen, Progynon-Depot), estradiol cypionate (Depo-Estradiol), testosterone esters, progesterone, and hydroxyprogesterone caproate are formulated. However, injectable aqueous suspensions of sex steroids also exist and are used medically. The most major and well-known formulations include depot medroxyprogesterone acetate (Depo-Provera) and combined injectable contraceptives containing estradiol cypionate/medroxyprogesterone acetate (Cyclofem, Lunelle). Additionally, there exist more obscure preparations of aqueous suspensions such as estradiol benzoate (Agofollin Depot) and progesterone (Agolutin Depot) among others which are marketed in addition to the more common oil solutions of these steroids. These preparations may remain commercially available, including online from sites like EU Aibolit (Reddit). Many transfeminine people are unaware of what aqueous suspensions are or their medical availability. It is notable in this regard that aqueous suspensions are very different from oil solutions in their properties but can have much longer durations in comparison. This is potential of therapeutic value especially in the case of otherwise shorter-acting injectables like progesterone. The purpose of this article is to shed light on injectable aqueous suspensions, describe how injectable oil solutions and aqueous suspensions work to achieve their depot effect and how they are different, and discuss how relevant aqueous suspensions can be obtained for medical use.


How Depot Injectables Work

Sex steroids are typically lipophilic (fat-soluble or “lipid-loving”) and hydrophobic (water-insoluble or “water-hating”). In other words, they dissolve in and are “attracted to” lipids (e.g., fats), and they are poorly solubility in and repelled by water. From chemistry, this is because sex steroids are very non-polar, whereas water is a quite polar molecule. As a result of their lipophilicity, sex steroids readily form clear homogenous solutions when mixed into oil—that is, they form oil solutions. In contrast, because sex steroids are hydrophobic, they do not easily form solutions when mixed into the water—that is, they do not easily form aqueous solutions (like, e.g., salt and water). Instead of aqueous solutions, solid “clumps” or crystal particles of sex steroids can be mixed into and thereby suspended in water—that is, aqueous suspensions of sex steroid crystals can be made. Depot injectables are formulated as oil solutions or aqueous suspensions and these preparations have very different properties.


Injectable Oil Solutions

When an oil solution of a sex steroid is administered by intramuscular or subcutaneous injection, the solution is trapped within the tissue compartment it is injected into and remains there. As the tissue fluid is a water mixture, the oil solution stays together inside the tissue compartment and does not easily separate or distribute. This is because the lipophilic fats and sex steroids within the solution are attracted to each other and are repelled by water. Instead of rapidly dissolving, the fats and sex steroids at the edges of the oil solution are very slowly absorbed into the surrounding water. Once they have escaped the oil depot into the surrounding tissue fluid, they can be distributed into the bloodstream and then into other tissues to exert their biological effects. Eventually, the whole oil solution will be absorbed.

Oftentimes sex steroids that are used by intramuscular or subcutaneous injection are esterified with one or more lipophilic hydrocarbon esters. These esters include fatty acids like propanoic acid (propionate), pentanoic acid (valerate), hexanoic acid (caproate), heptanoic acid (enanthate), decanoic acid (decanoate or decylate), and undecanoic acid (undecylate or undecanoate) as well as cyclic compounds like benzoic acid (benzoate), cyclopentyl propanoic acid (cypionate), and phenylpropanoic acid (phenylpropionate), among many others. Examples of these sex steroid esters include the well-known estradiol valerate, estradiol cypionate, estradiol benzoate, hydroxyprogesterone caproate, and numerous others. The attachment of a lipophilic ester (e.g., valeric acid) to a sex steroid (e.g., estradiol) will increase the lipophilicity of the sex steroid compared to merely injecting the unesterified sex steroid in an oil solution. The longer the carbon atom chain in the case of the simple fatty acid esters (e.g., propionate, valerate, enanthate, undecylate), the more lipophilic the resulting esterified sex steroid will be. As a result, the injected sex steroid ester will escape the oil tissue depot more slowly, lengthening the amount of time it takes for the sex steroid ester to be absorbed and therefore its duration in the body. The tables here and here show the lengthening duration of estradiol with longer or bulkier and more lipophilic esters. Whereas an intramuscular injection of estradiol or progesterone in an oil solution has a duration of only around 2 days, an intramuscular injection of an oil solution of estradiol undecylate, an ester of estradiol with a long fatty acid chain, has a duration measured in months. And an intramuscular injection of an oil solution of hydroxyprogesterone caproate, an ester of a derivative of progesterone that has a medium-length fatty acid chain, has a duration measured in weeks.

Most sex steroid esters themselves are biologically inactive. Once they have left the oil tissue depot, they are rapidly cleaved by esterase enzymes into free unesterified steroid (e.g., estradiol, testosterone) and the previously connected ester moiety (e.g., valeric acid). Hence, most sex steroid esters are prodrugs and are otherwise identical to their parent sex steroids in their biological actions. In the case of esters of estradiol and testosterone, this means that they are bioidentical just like the unesterified steroids. Certain synthetic progesterone derivatives like hydroxyprogesterone caproate and medroxyprogesterone acetate are however not prodrugs and are not meaningfully cleaved into the unesterified parent compound. Instead, they have intrinsic hormonal activity of their own and act without bioactivation.


Injectable Aqueous Suspensions

Aqueous suspensions of sex steroids also form an injection-site depot and achieve a long-lasting depot effect when administered by subcutaneous or intramuscular injection. However, they work in a completely different way than oil solutions. Aqueous suspensions of sex steroids consist of tiny crystal particles of pure sex steroids that are suspended in water. These sex steroid particles are highly lipophilic and hydrophobic. When injected, the hydrophilic water vehicle is rapidly mixed into the fluid of the tissue compartment and absorbed by the body. But the hydrophobic sex steroid crystals are not, and instead float about in the fluid of the tissue compartment. As with oil solutions, the sex steroids at the edges of the crystals very slowly dissolve off the surface of the crystals into the surrounding water and are then distributed into the circulation and tissues. Eventually, the crystal will be fully absorbed into the body, but only after a long period of time. Since the rate of absorption is dependent on lipophilicity and hydrophobicity, lipophilic esters lengthen the durations of aqueous suspensions of sex steroids by intramuscular or subcutaneous injection similarly to the case of oil solutions of sex steroids.

In the case of aqueous suspensions, the duration of the sex steroid is additionally highly dependent on particle size. These particle sizes have ranged from nanocrystalline to microcrystalline to macrocrystalline in their range. Almost always however it is microcrystalline particle sizes that have been used in injectable aqueous suspensions of sex steroids. (The present author has seen macrocrystalline preparations described a few times, specifically in research on combined injectable contraceptives (Garza-Flores, Del, & Perez-Palacios, 1992; Newton, d’Arcangues, & Hall, 1994; Sang, 1994), and is fairly sure that no such preparations have ever been marketed. On the other hand, nanocrystalline aqueous suspensions have been used with depot antipsychotics (Spanarello & Ferla, 2014; Correll et al., 2021).) Typically, there is a given particle size range for the formulation, such as 0.01 to 0.1 mm in diameter. The larger the particle sizes, the slower the absorption into the body, and the longer the duration of the preparation; the smaller the particle sizes, the faster the absorption, and the shorter the duration. When microcrystalline aqueous suspensions of sex steroids are manufactured nowadays, the particle sizes are defined and carefully controlled. Particle sizes influence the duration of injectable aqueous suspensions because they result in different surface areas from which sex steroid ester can escape particles. A single large particle has a smaller total surface area and hence dissolution rate than the same particle divided up into many smaller particles.

Particle sizes are manipulated during manufacturing via micronization—the process of decreasing the diameter of larger particles, such as via milling or grinding. Whereas more micronization improves the absorption and bioavailability of estradiol and progesterone with oral administration by increasing the surface area available for absorption into the body (Wiki; Wiki), less micronization decreases the rate of absorption of crystalline aqueous suspensions via depot injection and thereby extends the durations of these preparations by decreasing the total surface area for absorption.

There is a notable similarity of injectable aqueous suspensions of sex steroids to implantable sex steroid pellets, for instance of estradiol, testosterone, and progesterone (Wiki; Wiki; Wiki). Pellet implants are basically just pure crystalline sex steroids compressed into the shape of a small cylinder (Photo; Photo). They are inserted into subcutaneous fat in the body through a small incision using a large needle-like instrument called a trocar (Diagram). Once implanted, pellets slowly dissolve and absorb into the body over time, eventually disappearing completely. As they are nothing but pure crystalline hormones, there is no need for them to be removed or retrieved later on. In other words, implantation of a pellet is in a way the same thing as a subcutaneous injection of an aqueous suspension of sex steroid crystals—a single pellet is just one massive crystal instead of many tiny crystals suspended in water. And with very large crystals comes a very long duration—typically 6 months or more for each subcutaneous pellet of estradiol or testosterone (Kuhl, 2005; Wiki; Wiki). However, though injectable aqueous suspensions are typically much less prolonged than pellet implants, they have the advantages over pellets of being less expensive and not requiring a surgical incision. Due to the similarity between aqueous suspensions and pellet implants, aqueous suspensions have been described and marketed as “micropellets” in the past.

Would be helpful to include bibliographical reference information or DOI with your posts.

 

[Bigben]

Thank you for this trove of information, madman.

What was your dosage? Since it was only for a week, daily, E3.5D or EOD? Thanks.

10 mg daily or EOD when not training.