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Why do you need Testosterone Replacement Therapy?

Testosterone is associated with some of the most crucial body functions like bone density and muscle mass maintenance, fat distribution, facial and body hair distribution, red blood cell production, sex drive and mood swings. Although an increase in age naturally causes testosterone levels to fall, some men may experience lower testosterone levels (hypogonadism or “low-T” conditions) than normal, due to multiple medical reasons. (1) Testosterone replacement therapy (TRT) is prescribed only to such individuals to restore testosterone levels in the body. This is done predominantly through testosterone gels, skin patches and injections.(2) Testosterone is also recommended for post-menopausal women, as per the physician’s examination.

Testosterone injections are administered as oil-soluble ester-based formulations. An ester is an organic compound where the hydrogen in the compound’s carboxyl group is replaced with a hydrocarbon group. Choosing an appropriate ester is crucial to determining treatment efficacy for low-T conditions. The formulation, frequency, and dosage are then tailored to suit individual needs.​ Previously, testosterone in the form of a powder was mixed in water to form a testosterone suspension and injected, which was extremely painful.

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Chemically synthesised testosterone was discovered in the 1930s, and later in the 1970s, more effective testosterone formulations were introduced. (3)Testosterone Enanthate and Testosterone Cypionate are two of the most prevalent ester-based formulations used in the present day to treat low-T conditions.​(4) Other esters are Undeconate, Propionate, Sustenol, and Nebido. (5) (6)

Also read: Testosterone Propionate vs Cypionate and Enanthate

Is there a one-size-fits-all TRT protocol?

There is no cookie-cutter protocol that everyone is put on. It is only after a thorough assessment of a patient’s blood work and medical history that the practising physician or specialist will recommend a dosing of synthetic testosterone to eligible patients. That’s exactly the process we follow at Science and Humans for our testosterone replacement therapy program.

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The holy grail of TRT therapy is to avoid peaks and valleys in testosterone concentration (suprapsychological levels of testosterone, which is an issue with frequent testosterone injections) and enable a steady testosterone boost to counter symptoms of low-T, to ensure minimal side-effects. A system where the injected testosterone injected will get metabolised and absorbed as per the natural (endogenous) testosterone is the ideal system for TRT.

However, given the chemical nature of synthetic testosterone, achieving the near-natural pattern becomes difficult owing to the short half-life of some formulations like testosterone propionate due to its chemical structure which is less polar in nature. However, testosterone enanthate & testosterone cypionate have a comparatively higher half-life, with very similar chemical structure, and are preferred for injectable low-T treatment options.

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Testosterone enanthate works wonders in achieving stable levels while keeping potential side effects manageable. Although it has a higher half-life (4.5 days) in comparison to propionate, it is still not as much as cypionate (8-9 days). (6) (7) (5) However, the main advantage comes in the form of dosing modalities and frequencies which can be altered. This keeps side-effects minimal.

Testosterone Cypionate vs Enanthate: The Key Differences

Both enanthate and cypionate are similar in chemical nature. Enanthate is a heptanoate, sterol ester while cypionate is an oil-soluble 17 (beta)-cyclopentylpropionate ester. In simple terms, testosterone cypionate has an additional carbon atom which makes its half-life longer, about 8-10 days, as it takes greater time to be metabolized and absorbed by the system. (8) (9). This makes the compound release free testosterone for a longer period, reduces aromatization of testosterone and production of DHT and estrogen as metabolites. This in turn reduces risks of side effects like gynecomastia and fluid retention.(6) (7) (10) Testosterone enanthate has a half-life of 5-7 days.(11)

The physiochemical nature of the carrier oil also causes a major difference. A more viscous sesame oil makes testosterone enanthate painful for subcutaneous (SC) injections. Long term patient compliance with this formulation is also an issue since preparing the injection takes time. Painful lumps due to the high viscosity can be a problem for a few from testosterone enanthate. Enanthate uses 5% Chlorobutanol as a preservative in which irritates the skin. This is because it exceeds the available limit of .5% by 10X. ​(10)

Olive oil or cottonseed oil is a lighter solvent used in testosterone cypionate. Hence it is easier to inject subcutaneously. SC injections are less painful than intramuscular (IM) injections and ensure a more stable release of the compound (testosterone). (10)

Clinical Considerations – Intramuscular or Subcutaneous?

The route and mode of administration also make a significant difference in the efficacy of both formulations. The high viscosity of T-enanthate makes it harder to formulate SC injections which is a superior way to achieve stable levels of serum testosterone, avoiding peaks and troughs and minimizing side effects.

IM injections make absorption quicker due to increased vascular exposure which causes the released testosterone get absorbed into the system faster. This results in unwanted suprapsychological levels of testosterone and higher amounts of unwanted estrogen and DHT as metabolites due to the action of 5 alpha-reductase, an enzyme breaking down testosterone. This unwanted DHT and estrogen can cause irritation, mood swings, hair loss, acne, and an enlarged prostate, among others. (12)

The impact of the mode of dosing have been discussed in multiple clinical studies as well. SC formulations have shown to cause a more sustained release of the product, irrespective of the ester used. SC testosterone enanthate was found to be associated with significantly lower levels of HCT and estrogen, as compared to IM testosterone cypionate, despite cypionate having a higher half-life.(13) (14)

Clinical Considerations: Timing And Dosage

The general dosing for both IM testosterone enanthate and cypionate are 50-400 mg every 2-4 weeks, and need to be monitored for adverse effects every week. Alternately, testosterone enanthate can be administered 100 mg once weekly or 200 mg every 2 weeks.(4)

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However, the time taken for testosterone enanthate to reach supratherapeutic levels is 36-48 hours post-dose and that for subtherapeutic levels is 3-4 weeks. The same for testosterone cypionate is 4-5 days after dose for the supratherapeutic levels and 14 for subtherapeutic levels.(4)

For testosterone cypionate, an alternative dosing of either 75 to 100 mg IM weekly or 150 to 200 mg IM every 2 weeks is also recommended. The use of cottonseed oil makes it necessary to prevent cypionate doses in people allergic to soy. (4)

Testosterone enanthate needs to be administered every 5-7 days while testosterone cypionate needs to be administered every 7-10 days, depending on the after-effects and patient profiles.

Keep In Mind That

SC testosterone cypionate injected subcutaneously leads to fewer side-effects due to a higher half-life and lower metabolite concentration. However, if subcutaneous injection is not a choice for patients, they will be prescribed for a different IM route owing to their lifestyle and medical histories. Different modes of injection and chemical composition of esters are the major determining factors for a choice of TRT, but this is only defined in a patient population undergoing treatment for hypogonadism, and not for any lifestyle or recreational purpose. The examining specialist has the final say, depending on patient history.

FAQ:

Testosterone Cypionate vs Enanthate – which is the best injectable testosterone?

Only your doctor can tell you that. It is up to the patient’s medical history, especially if they have been diagnosed for male breast cancer, prostate cancer or have cardiovascular issues or risk of strokes. There are too many parameters to keep in mind while prescribing an appropriate treatment regimen and it depends on individual patients and their doctors. However, all therapies are prescribed on clinical grounds and not recreational or athletic purposes.

Test enanthate vs. cypionate – what is the difference?

The key difference between testosterone cypionate and enanthate is the duration that each ester lasts in your body. Cypionate lasts longer than Enanthate, but undecanoate outlasts the other two. Both cypionate and enanthate can be self-administered at home after consulting a medical professional. It totally depends on the practitioner’s knowledge of your medical history and your habits.

References:

1. Kumar P, Kumar N, Thakur DS, Patidar A. Male hypogonadism: Symptoms and treatment. J Adv Pharm Technol Res. 2010;1(3):297-301.
2. Mayo Clinic [Internet]. [cited 2023 Dec 29]. Male hypogonadism-Male hypogonadism – Diagnosis & treatment. Available from: https://www.mayoclinic.org/diseases-conditions/male-hypogonadism/diagnosis-treatment/drc-20354886
3. Nieschlag E, Nieschlag S. Testosterone deficiency: a historical perspective. Asian J Androl. 2014;16(2):161-8.
4. Shoskes JJ, Wilson MK, Spinner ML. Pharmacology of testosterone replacement therapy preparations. Transl Androl Urol. 2016 Dec;5(6):834-43.
5. Testosterone Propionate – an overview | ScienceDirect Topics [Internet]. [cited 2023 Dec 27]. Available from: https://www.sciencedirect.com/topics/nursing-and-health-professions/testosterone-propionate
6. Testosterone Cipionate – an overview | ScienceDirect Topics [Internet]. [cited 2023 Dec 29]. Available from: https://www.sciencedirect.com/topics/nursing-and-health-professions/testosterone-cipionate
7. Testosterone Enantate – an overview | ScienceDirect Topics [Internet]. [cited 2023 Dec 28]. Available from: https://www.sciencedirect.com/topics/medicine-and-dentistry/testosterone-enantate
8. PubChem. Testosterone Cypionate [Internet]. [cited 2023 Dec 30]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/441404
9. PubChem. Testosterone Enanthate [Internet]. [cited 2023 Dec 30]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/9416
10. Dip.FIPT DRSMbcM. Testosterone Cypionate in the UK [Internet]. The Men’s Health Clinic. 2019 [cited 2023 Dec 30]. Available from: https://themenshealthclinic.co.uk/testosterone-cypionate-in-the-uk/
11. Weinbauer GF, Jackwerth B, Yoon YD, Behre HM, Yeung CH, Nieschlag E. Pharmacokinetics and pharmacodynamics of testosterone enanthate and dihydrotestosterone enanthate in non-human primates. Acta Endocrinol (Copenh). 1990 Apr;122(4):432-42.
12. Randall VA. Role of 5 alpha-reductase in health and disease. Baillieres Clin Endocrinol Metab. 1994 Apr;8(2):405-31.
13. Choi EJ, Xu P, Barham D, El-Khatib FM, Yafi FA, Kavoussi PK. Comparison of Outcomes for Hypogonadal Men Treated with Intramuscular Testosterone Cypionate versus Subcutaneous Testosterone Enanthate. J Urol. 2022 Mar;207(3):677-83.
14. Choi E, Xu P, Loeb C, El-Khatib F, Yafi F, Kavoussi P. Intramuscular testosterone cypionate vs subcutaneous testosterone enanthate: Comparing the outcomes in hypogonadal men. J Sex Med. 2022 May 1;19(5, Supplement 2):S148-9.

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