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Review
. 2022 Feb;10(2):209-222.
doi: 10.1111/andr.13108. Epub 2021 Oct 8.

Pharmacokinetics of testosterone therapies in relation to diurnal variation of serum testosterone levels as men age

Alexander W Pastuszak  1 , Marc Gittelman  2 , James P Tursi  3 , Jonathan S Jaffe  3 , David Schofield  3 , Martin M Miner  4
Affiliations
Review

Pharmacokinetics of testosterone therapies in relation to diurnal variation of serum testosterone levels as men age

Alexander W Pastuszak et al. Andrology. 2022 Feb.

Abstract

Background: To improve symptoms associated with testosterone deficiency, many testosterone therapies are available that aim to restore serum testosterone (T) levels to the normal physiologic range. The magnitude, frequency, and duration between peak and trough T concentrations vary with route of administration, and none reflect normal endogenous daily diurnal T variations.

Objective: To compare pharmacokinetic profiles of serum T from approved T formulations with endogenous diurnal T variations in young and older men, and to consider whether there may be value in mimicking the diurnal T rhythmicity with exogenous testosterone therapies as men age.

Materials and methods: A literature search of studies examining the diurnal variation of endogenous T in healthy men and men with testosterone deficiency was performed using PubMed in January 2020. Additional searches for serum T pharmacokinetic profiles of various testosterone therapy formulations were also conducted. Prescribing information for various T formulations was also reviewed.

Discussion and conclusion: Endogenous diurnal T variation is well described and appears to be blunted naturally as men age. Men with testosterone deficiency lack diurnal T variation and exhibit a flatter T profile compared with eugonadal men. Some T replacement options provide intraday T level variations similar to normal circadian secretion, and others provide a flatter exposure profile reflective of depot release. Others provide profiles that exceed the frequency and physiologic range of the natural diurnal variation of T. All exogenous T replacement dosing targets an increase in average T levels to within the normal physiologic range and improves symptoms associated with low T, but no single testosterone therapy can exactly mimic the normal diurnal T patterns seen in younger men and the blunted circadian T secretion of older men.

Keywords: diurnal variation; testosterone deficiency; testosterone therapy.

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Conflict of interest statement

Alexander W. Pastuszak: consultant, speaker, research support, Endo Pharmaceuticals; founder and leadership role, Woven Health; leadership role, Vault Health; speaker, Bayer AG; advisor, Allotrope Medical, Inherent Biosciences. Marc Gittelman: consultant, speaker, research support, Clarus. James P. Tursi: former employee, Antares Pharma, Inc. Jonathan S. Jaffe: employee, Antares Pharma, Inc. David Schofield: employee, Antares Pharma, Inc. Martin M. Miner: leadership role, Vault Health; research support, Acerus Pharmaceuticals.

Figures

FIGURE 1
FIGURE 1
Extrapolateda mean steady‐state serum total testosterone concentrations. Estimated diurnal T in young men (blue, range: 23–28 years) and older men (age range 58–82 years). Red arrows indicate time of T administration. Dotted lines indicate C avg over a dosing interval of 168 h. Black lines in each panel represent mean steady‐state T profiles of: (A) weekly SC TE administration; (B) average mean T profiles for IM TC, TE, and TU over 2 weeks; (C) 900 mg subdermal T pellets; (D) 4.0 mg daily transdermal patch; (E) average mean T profiles of 100 mg TESTIM®/VOGELXO®, 40 mg FORTESTA®, 1.62% AndroGel®, and 2% AXIRON®; (F) nasal gel T at day 90 three times daily; (G) 30 mg buccal mucoadhesives applied twice daily; and (H) twice daily 200 mg oral TU capsules. aFor products with ≥1 daily dose, we extrapolated data over 1 week to compare all PK profiles consistently. For products with dosing regimens of longer than a week (eg, IM injections and T pellet implantation), only the PK profile in the first week following dosing is presented; these data do not reflect average concentrations throughout the entire dosing interval. IM, intramuscular; SC, subcutaneous; T, testosterone; TC, testosterone cypionate; TE, testosterone enanthate; TU, testosterone undecanoate
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References

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