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Steady‐state serum T levels were achieved within a few days, and these levels were maintained with once‐daily applications. Similar to the 2.5 mg/day and 5.0 mg/day systems, peak T levels occurred 8 h post‐application, mimicking diurnal variation when the patch is applied at night. This reduced dosing regimen was approved in 2011, and manufacturer data show that following 28 days of transdermal T application, 97% (34/35) men with TD were able to achieve Cavg within 10.4 to 35.7 nmol/L (300–1030 ng/dl).51 Mean Cmax values with 2.0 mg/day and 4.0 mg/day treatment were 22.5 ± 5.0 nmol/L (648 ± 145 ng/dl) and 24.1 ± 5.5 nmol/L (696 ± 158 ng/dl), respectively. The recommended dose of IM TU is an initial 750 mg injection, followed by 750 mg 4 weeks later, and 750 mg every 10 weeks thereafter, injected in the gluteus medius.40 Depending on the formulation and dosage, following IM injection of TE or TC, supraphysiologic levels occur within a week after administration, decreasing to sub‐therapeutic levels in between dosing intervals, resulting in large TT peak‐to‐trough ratios. The Cmax (27.4 ± 7.5 nmol/L, or 789.8 ± 215.4 ng/dl; Table 1) and Cmin (15.1 ± 3.8 nmol/L, or 435.6 ± 109.2 ng/dl) measured during the 7‐day period at week 12 yielded a peak‐to‐trough ratio of 1.8.
In a phase 3 study comparing the efficacy and safety of 237 mg oral TU given twice daily with once daily 60 mg topical T solution, 87% (145/166) of men with TD treated with oral TU were able to achieve a mean Cavg within 8.7 to 31.4 nmol/L (252–907 ng/dl), meeting the primary objective.89 At the final study visit on day 105, the mean Cavg was 14.0 nmol/L (403 ng/dl) and Cmax was 34.9 nmol/L (1008 ng/dl). Historically, oral TTh with non‐esterified T has been unsuccessful in delivering physiological T because of first‐pass hepatic metabolism; to overcome this, high doses were needed to achieve measurable serum T levels.86 A new, oral TU formulation delivered via a self‐emulsifying drug delivery system was developed to promote solubilization and absorption of the lipophilic TU in the gastrointestinal tract, and in March 2019, became the first oral TTh approved by the FDA. While men experience two Cmax peaks daily produced from two daily doses, there does not appear to be an accumulation of T over time.85 This product has since been discontinued. Following 12 weeks of applying TBS twice daily, the mean T Cavg increased to 20.1 to 24.9 nmol/L (580–718 ng/dl) at weeks 4, 8, and 12 from baseline levels of 5.2 ± 3.1 nmol/L (150 ± 89 ng/dl). Furthermore, an ongoing phase 4 clinical trial suggests that not only can T nasal gel increase serum T over time, but it can also maintain FSH, LH, and semen parameters.81 At day 90, the Cmax and Cmin were 32.4 nmol/L (934.9 ng/dl) and 7.0 nmol/L (200.9 ng/dl), respectively, with a peak‐to‐trough ratio of 4.7.
It’s worth noting that while testosterone levels may peak within a few days, the full effects of the treatment may not be noticeable for several weeks or even months. Men using nasal and oral T products are able to achieve mean serum T levels that are within the normal range, but they experience several T peaks and troughs throughout the day because of the multiple daily dosing regimens required (2 or 3 times/day). At week 12, steady‐state T concentrations within 20.1 to 24.9 nmol/L (580–718 ng/dl) were achieved by 87% (71/82) of patients, a slightly lower percentage than in another study where 92% of men achieved a Cavg within the normal range following TBS application.84 The time‐averaged steady‐state Cavg measured over the two consecutive 12‐h dosing intervals was 18.7 ± 5.9 nmol/L (540 ± 170 ng/dl), with a peak‐to‐trough ratio of 3.3 (Cmax of 34.3 ± 12.5 nmol/L, or 990 ± 360 ng/dl; Cmin of 10.4 ± 4.2 nmol/L, or 300 ± 120 ng/dl). In a phase 3 study evaluating the efficacy and safety of TESTAVAN® 2% gel over 90 days, 76.1% of men achieved average T concentration of 10.4–36.4 nmol/L (300–1050 ng/dl) on day 90.75 Depending on dose, T levels peaked approximately 2–4 h post‐application and decreased to pre‐application levels within 12 h, mirroring the natural diurnal rhythm of male T. After the first application of either 5 g or 10 g T gel, mean Cavg, Cmax, and Cmin T levels were within the normal physiological range (values ranged from 7.9 ± 0.5 to 25.9 ± 1.4 nmol/L; 228 ± 14 to 747 ± 40 ng/dl).64 The Cavg, Cmax, and Cmin following 90 days of 10 g T gel application were 27.5 nmol/L (793 ng/dl), 41.7 nmol/L (1203 ng/dl), and 17.4 nmol/L (502 ng/dl), respectively, compared with 19.2 nmol/L (554 ng/dl), 29.3 nmol/L (845 ng/dl), and 12.3 nmol/L (355 ng/dl) with 5 g T gel.64 At day 90, peak T levels were reached after 4 and 8 h with 5 g and 10 g T gel application, respectively. In a study of 11 men with hypogonadism, every‐other‐week administration of 200 mg IM TC caused a threefold rise in serum T, with peak values occurring between 2 to 3 days (38.4 ± 15.3 nmol/L; 1108 ± 440 ng/dl) and 4 to 5 days (38.6 ± 10.3 nmol/L, or 1112 ± 297 ng/dl) post‐injection.35 Similarly, E2 levels also increased almost threefold.
Measurement of serum testosterone level at various times after application of the gel is regarded as one of the ways of monitoring response to treatment. Longer‐lasting TU injections do not demonstrate the supratherapeutic peaks of other IM formulations, with trough levels occurring at later time points after each injection and a peak‐to‐trough ratio of approximately 2.6 to 2.8. The PK profile appears to mimic the flatter profile of older males’ endogenous T.95 IM T injections can cause both supratherapeutic T levels post‐injection and subtherapeutic levels during the dosing interval, and depending on the formulation and dosage, peak‐to‐trough ratios of IM TC and TE range between 2 and 5.3. Once‐weekly SC TE injections bring mean T levels into the physiologic range within 24 h after the first dose, with a total T Cmax/Cmin ratio of 1.8. In 1983, a study by Bremner et al. showed that there was a clear difference between serum T levels in normal young men (mean age 25.2 years) and older men (mean age 71.0 years).5 In young men, serum T levels were highest in the morning, falling to their lowest levels approximately 12 h later and gradually increasing again to peak levels the next morning.
With less frequent injections, levels tend to spike higher and drop lower, which can lead to noticeable ups and downs in how you feel. After an injection, testosterone levels typically rise within the first 24–72 hours, depending on the ester used. After an injection, testosterone levels don’t stay steady. This pattern has been documented in pharmacokinetic studies showing peak-and-decline profiles following intramuscular testosterone injections (Snyder et al., 1999) Longer gaps between injections can lead to more noticeable fluctuations, which is why some patients feel strong early on and less so later in the dosing cycle. Testosterone esters like cypionate and enanthate have a known release pattern in the body, where levels rise after injection and then decline over several days.
As someone who’s been in the field for over a decade, I’ve seen firsthand how life-changing this treatment can be. Testosterone replacement therapy has become increasingly popular among men seeking to address hormonal imbalances and improve their overall well-being. Because in hormone optimization, the difference between chaos and clarity is structure. • Be consistent every time • Whether weekly dose is excessive When in reality, you just caught the peak. "Probably the day after."
But what actually determines how you feel is how stable those levels are, and injection frequency plays a major role in that. If you feel great for a few days after your injection… then worse before your next one, that’s not random. Three Hone patients share a timeline of benefits and changes during the first year of TRT treatment. Changes in mood, energy levels, or cognition might signal low testosterone levels. In particular, resistance training, high-intensity interval training (HIIT), and walking have been shown to positively affect testosterone levels.
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