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Does Patient‐Applied Testosterone Replacement Therapy Pose Risk for Blood Pressure Elevation? Circadian Medicine Perspectives

Michael H. Smolensky, Ramon C. Hermida, Linda Sackett‐Lundeen, Ramon G. Hermida‐Ayala, Yong‐Jian Geng

10.1002/cphy.c220014

Source: Volume 12, Issue 4, October 2022

Published online: August 2022

Full Article on Wiley Online Library



Abstract

We reviewed medication package inserts, US Food and Drug Administration (FDA) reports, and journal publications concerning the 10 nonbiosimilar patient‐applied (PA) testosterone (T) replacement therapies (TRTs) for intraday serum T patterning and blood pressure (BP) effects. Blood T concentration is circadian rhythmic in young adult eugonadal males, being highest around awakening and lowest before bedtime. T level and 24 h variation are blunted in primary and secondary hypogonadism. Utilized as recommended, most PA‐TRTs achieve nonphysiologic T 24 h patterning. Only Androderm®, an evening PA transdermal patch, closely replicates the normal T circadian rhythmicity. Accurate determination of risk for BP elevation and hypertension (HTN) by PA‐TRTs is difficult due to limitations of office BP measurements (OBPM) and suboptimal methods and endpoints of ambulatory BP monitoring (ABPM). OBPM is subject to “White Coat” pressor effect resulting in unrepresentative BP values plus masked normotension and masked HTN, causing misclassification of approximately 45% of trial participants, both before and during treatment. Change in guideline‐recommended diagnostic thresholds over time causes misclassification of an additional approximately 15% of participants. ABPM is improperly incorporated into TRT safety trials. It is done for 24 h rather than preferred 48 h; BP is oversampled during wakefulness, biasing derived 24 h mean values; 24 h mean systolic and diastolic BP (SBP, DBP) are inappropriate primary outcomes, because of not being best predictors of risk for major acute cardiovascular events (MACE); “daytime” and “nighttime” BP means referenced to clock time are reported rather than biologically relevant wake‐time and sleep‐time BP means; most importantly, asleep SBP mean and dipping, strongest predictors of MACE, are disregarded. © 2022 American Physiological Society. Compr Physiol 12: 4165–4184, 2022.

Figure 1. Figure 1. Circadian rhythm of: (A), serum TT; (B) serum sex hormone‐binding globulin (SHBG); (C) serum total proteins; (D) serum non‐SHBG bound T (method of Plymate et al. 125) of 10 young healthy men (closed square symbols with dispersion indices), mean age 27.3 years, and 10 elderly men (open circle symbols with dispersion indices), mean age 70.7 years—all nonsmokers, nonalcohol abusers, nonmedicated, and all within 10% ideal body weight. Black and white shading of horizontal bar shown at bottom of each graph represents, respectively, presumed sleep and wake spans of the cohorts of the young and elderly male participants. Time is indicated in military form; 06:00 h = 6 AM and 18:00 h = 6 PM. Adapted, with permission, from Plymate SR, et al., 1989 124.
Figure 2. Figure 2. Serum TT concentration 24 h pattern (with dispersion indices) under steady‐state pharmacological conditions of each of the six nonbiosimilar FDA‐approved gel and solution PA‐TRTs. Horizontal axis of each graph shows time in hours after the previous dose. (A) AndroGel® 1%, testosterone gel applied to the skin of shoulders, upper arms, or abdomen mornings as either a 5 (unknown N) or 10 mg (unknown N) T daily dose. AbbVie Inc. / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021015s036lbl.pdf. / last accessed May 2022. (B) AndroGel® 1.62%, testosterone gel applied to skin of upper arms and shoulders or rotational method of upper arms and shoulders plus abdomen mornings as an 81 mg T daily dose (N = 33). AbbVie Inc. / Adapted from https://www.rxabbvie.com/pdf/androgel1_62_pi.pdf. / last accessed May 2022. (C) Axiron®, testosterone solution applied to skin of axilla mornings (N = 135) as either a 30, 60, 90, or 120 mg T daily dose. Lilly USA, LLC / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022504s013lbl.pdf. / last accessed May 2022. (D) Fortesta®, testosterone gel applied in mornings to skin of thighs as a 40 mg T daily dose (N = 12). Endo. Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021463s020lbl.pdf. / last accessed May 2022. (E) Testim®, testosterone applied to shoulders and upper arms mornings (unknown N) as either a 50 mg or 100 mg T daily dose. Auxilium Pharmaceuticals, Inc. / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021454s008lbl.pdf. / last accessed May 2022. [Serum T concentration of the nondepicted biosimilar Vogelxo® is therapeutically equivalent to Testim® (https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204399s010lbl.pdf)]. (F) Natesto®, 5.5 mg of testosterone gel applied to each nostril at 6‐8 h intervals during waking for a total daily T dose of 33 mg (N = 69). Trimel BioPharma SRL / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205488s000lbl.pdf. / last accessed May 2022).
Figure 3. Figure 3. Serum TT concentration 24 h pattern (with dispersion indices) under steady‐state pharmacological conditions for the buccal, oral, subcutaneously injected, and transdermal patch PA‐TRTs. Horizontal axis of each graph shows time in hours after the first dose of the day for those PA‐TRTs administered more than once daily (A‐C). (A) Striant®, testosterone mucoadhesive buccal tablet (30 mg T/dose) inserted twice daily to upper gum above incisor tooth, on both sides of mouth, as a 60 mg T daily dose (N = 82). Actient Pharmaceuticals LLC. Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21543s002lbl.pdf. / last accessed May 2022. (B) Jatenzo®, soft gel oral capsules ingested twice daily with meals as a total daily dose ranging between 158 and 396 mg testosterone undecanoate (N = 166). Claus Therapeutics, Inc. / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/206089s000lbl.pdf. / last accessed May 2022. (C) Xyosted®, testosterone enanthate self‐administered by subcutaneous injection to the abdominal region at weekly intervals as a daily dose of ≥75 mg (N = 13). Antares Pharma, Inc. / Adapted from https://www.xyosted.com/PI.pdf. / last accessed May 2022. (D) Androderm®, testosterone patch applied nightly (∼22:00 h) in a dose either of 2.5 mg T daily (one 2.5 mg T patch; N = 29), 5 mg T daily (as two 2.5 mg patches; N = 27), and 7.5 mg T daily (as three 2.5 mg patches; N = 2). Watson Pharma, Inc. / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020489s025lbl.pdf. / last accessed May 2022. Designated high and low normal limits (dashed lines) of TT for Androderm®, the PA‐TRT that most closely approximates the circadian rhythm of healthy young males, are upper and lower circadian time‐qualified 95% confidence limits of the normal blood TT concentration of young healthy men.


Figure 1. Circadian rhythm of: (A), serum TT; (B) serum sex hormone‐binding globulin (SHBG); (C) serum total proteins; (D) serum non‐SHBG bound T (method of Plymate et al. 125) of 10 young healthy men (closed square symbols with dispersion indices), mean age 27.3 years, and 10 elderly men (open circle symbols with dispersion indices), mean age 70.7 years—all nonsmokers, nonalcohol abusers, nonmedicated, and all within 10% ideal body weight. Black and white shading of horizontal bar shown at bottom of each graph represents, respectively, presumed sleep and wake spans of the cohorts of the young and elderly male participants. Time is indicated in military form; 06:00 h = 6 AM and 18:00 h = 6 PM. Adapted, with permission, from Plymate SR, et al., 1989 124.


Figure 2. Serum TT concentration 24 h pattern (with dispersion indices) under steady‐state pharmacological conditions of each of the six nonbiosimilar FDA‐approved gel and solution PA‐TRTs. Horizontal axis of each graph shows time in hours after the previous dose. (A) AndroGel® 1%, testosterone gel applied to the skin of shoulders, upper arms, or abdomen mornings as either a 5 (unknown N) or 10 mg (unknown N) T daily dose. AbbVie Inc. / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021015s036lbl.pdf. / last accessed May 2022. (B) AndroGel® 1.62%, testosterone gel applied to skin of upper arms and shoulders or rotational method of upper arms and shoulders plus abdomen mornings as an 81 mg T daily dose (N = 33). AbbVie Inc. / Adapted from https://www.rxabbvie.com/pdf/androgel1_62_pi.pdf. / last accessed May 2022. (C) Axiron®, testosterone solution applied to skin of axilla mornings (N = 135) as either a 30, 60, 90, or 120 mg T daily dose. Lilly USA, LLC / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022504s013lbl.pdf. / last accessed May 2022. (D) Fortesta®, testosterone gel applied in mornings to skin of thighs as a 40 mg T daily dose (N = 12). Endo. Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021463s020lbl.pdf. / last accessed May 2022. (E) Testim®, testosterone applied to shoulders and upper arms mornings (unknown N) as either a 50 mg or 100 mg T daily dose. Auxilium Pharmaceuticals, Inc. / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021454s008lbl.pdf. / last accessed May 2022. [Serum T concentration of the nondepicted biosimilar Vogelxo® is therapeutically equivalent to Testim® (https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204399s010lbl.pdf)]. (F) Natesto®, 5.5 mg of testosterone gel applied to each nostril at 6‐8 h intervals during waking for a total daily T dose of 33 mg (N = 69). Trimel BioPharma SRL / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205488s000lbl.pdf. / last accessed May 2022).


Figure 3. Serum TT concentration 24 h pattern (with dispersion indices) under steady‐state pharmacological conditions for the buccal, oral, subcutaneously injected, and transdermal patch PA‐TRTs. Horizontal axis of each graph shows time in hours after the first dose of the day for those PA‐TRTs administered more than once daily (A‐C). (A) Striant®, testosterone mucoadhesive buccal tablet (30 mg T/dose) inserted twice daily to upper gum above incisor tooth, on both sides of mouth, as a 60 mg T daily dose (N = 82). Actient Pharmaceuticals LLC. Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21543s002lbl.pdf. / last accessed May 2022. (B) Jatenzo®, soft gel oral capsules ingested twice daily with meals as a total daily dose ranging between 158 and 396 mg testosterone undecanoate (N = 166). Claus Therapeutics, Inc. / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/206089s000lbl.pdf. / last accessed May 2022. (C) Xyosted®, testosterone enanthate self‐administered by subcutaneous injection to the abdominal region at weekly intervals as a daily dose of ≥75 mg (N = 13). Antares Pharma, Inc. / Adapted from https://www.xyosted.com/PI.pdf. / last accessed May 2022. (D) Androderm®, testosterone patch applied nightly (∼22:00 h) in a dose either of 2.5 mg T daily (one 2.5 mg T patch; N = 29), 5 mg T daily (as two 2.5 mg patches; N = 27), and 7.5 mg T daily (as three 2.5 mg patches; N = 2). Watson Pharma, Inc. / Adapted from https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020489s025lbl.pdf. / last accessed May 2022. Designated high and low normal limits (dashed lines) of TT for Androderm®, the PA‐TRT that most closely approximates the circadian rhythm of healthy young males, are upper and lower circadian time‐qualified 95% confidence limits of the normal blood TT concentration of young healthy men.
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Article Title: Does Patient‐Applied Testosterone Replacement Therapy Pose Risk for Blood Pressure Elevation? Circadian Medicine Perspectives
 

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Michael H. Smolensky, Ramon C. Hermida, Linda Sackett‐Lundeen, Ramon G. Hermida‐Ayala, Yong‐Jian Geng. Does Patient‐Applied Testosterone Replacement Therapy Pose Risk for Blood Pressure Elevation? Circadian Medicine Perspectives. Compr Physiol 2022, 12: 4165-4184. doi: 10.1002/cphy.c220014