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Does Patient-Applied Testosterone Replacement Therapy Pose Risk for Blood Pressure Elevation? Circadian Medicine Perspectives (2022)
Michael H. Smolensky, Ramon C. Hermida, Linda Sackett-Lundeen, *Ramon G. Hermida-Ayala, and Yong-Jian Geng
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 the “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 the misclassification of an additional approximately 15% of participants. ABPM is improperly incorporated into TRT safety trials. It is done for 24 h rather than the 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.
Introduction
Testosterone (T), the principal male androgen hormone, exerts both anabolic effects—linear growth and maturation plus development, maintenance, and strength of muscle mass and bone structure—and androgenic effects—maturation and maintenance of sex organs and secondary sex characteristics. Male hypogonadism is a clinical syndrome of T deficiency due to inadequacy or absence of T synthesis by the Leydig cells of the testis. Its clinical diagnosis is based on a fasting morning T concentration <300 ng/dL on two separate occasions, typically in association with characteristic signs and symptoms (11, 103, 166). The usual signs of T deficiency in prepubertal boys are eunuchoidism, delayed and under-developed secondary male sex characteristics, and high-pitched voices. In adult males, they are diminished libido, infertility, low bone mineral density, reduced muscle mass, muted secondary sex characteristics, and small (<5 mL) testes. Male hypogonadism has two main etiologies: (i) defects of the testis (primary hypogonadism) and (ii) defects of the hypothalamus or pituitary (secondary hypogonadism, also termed hypogonadotropic hypogonadism). Primary hypogonadism, whether congenital or acquired, may be the consequence of Klinefelter syndrome, Leydig cell aplasia, hemochromatosis, cryptorchidism, abnormalities of testes, for example, bilateral torsion, mumps orchitis, vanishing testis syndrome, orchiectomy, and alcohol, drug, chemotherapy, or heavy metal toxicity (11, 84). Secondary hypogonadism, a condition in which the testicles are normal but fail to produce adequate T, entails pathology of the pituitary or hypothalamus that results in follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) insufficiency. Common causes of secondary hypogonadism are Kallmann and Prader-Willi syndrome, tumor, trauma, radiotherapy, infection, and inflammation of the hypothalamic-pituitary axis, for example, as the consequence of sarcoidosis, histiocytosis, tuberculosis, or other medical conditions, like obesity, type-2-diabetes, end-stage renal disease, human immunodeficiency virus, and acquired immunodeficiency syndrome (11, 84).
Clinical practice guidelines of the American Endocrine Society (11) and Urological Association (103) recommend the prescription of testosterone replacement therapy (TRT) to manage symptomatic androgen deficiency, that is, induce and maintain secondary sexual characteristics and improve bone mineral density, muscle mass, physical strength, sexual function, and overall wellbeing. While guidelines do not now officially endorse the prescription of TRT to manage age-related T deficiency, the 2020 guidelines of the American College of Physicians that are endorsed by the American Academy of Family Physicians (128) advocate discussion of this option between clinicians and older adult male patients. The US Food and Drug Administration (FDA), since the 1950s, has approved several physician-administered injectables and implantable pellets plus 10 unique (nonbiologically similar) patient-applied (PA) transdermal gel, intranasal gel, transdermal solutions, skin patches, buccal tablet, oral capsule, and subcutaneously injected TRTs. Intramuscularly injected and surgically implanted TRTs are administered by healthcare professionals at intervals of several weeks or months, whereas PA transdermal gel and solutions are dosed once daily at the commencement of the activity period, buccal tablet and oral soft gel capsule two times daily at approximately 12 h intervals, intranasal gel three-times daily at approximately 6 to 8 h intervals, and transdermal patch once daily before bedtime. As subsequently discussed, there is a substantial difference in the pharmacokinetics (PK) and attained T 24 h patterning between the 10 different PA-TRTs.
The FDA encourages each company sponsor of a PA-TRT to conduct clinical trials to assess specific features of its PK for use as surrogate endpoints of clinical efficacy. They are the 24 h average (Cavg), maximum (Cmax), and minimum (Cmin) serum concentrations of total testosterone (TT), protein-bound T, and/or nonbound, that is, free testosterone (FT), and proportion of treated participants who exhibit a serum TT (or another T variable) concentration within and beyond the respective surrogate endpoints under steady-state pharmacological conditions (166). The selection of these endpoints is based largely on the biological principle of homeostasis that assumes constancy during the 24 h of serum T concentration, thereby inferring an important goal of TRT is the attainment of constant or near-constant androgen hormone level. This perspective ignores the potential relevance of the circadian biology of patients, particularly the normative T circadian rhythm characteristic of healthy young adult males that may affect not only the efficacy but safety of a given TRT, for example, the risk for blood pressure (BP) elevation, new onset and worsened hypertension (HTN), and major acute cardiovascular events (MACE). Thus, in most instances, the goal of TRT is the normalization of the T level, without the complementary goal of normalization of T circadian patterning, which in both primary and secondary hypogonadism is blunted or absent. The aims of this article, with respect to the perspectives of circadian medicine, are to determine the (i) extent to which the T 24 h pattern achieved by each PA-TRT mimics the normal T circadian rhythm, (ii) current knowledge of the risk posed by each PA-TRT for elevated BP and new-onset and worsened HTN, and (iii) limitations of office blood pressure measurement (OBPM) and deficiencies of the methods and selected outcome variables of ambulatory blood pressure monitoring (ABPM) of past TRT safety trials conducted to assess BP effects and risk for MACE.
Human Biological Time Structure: Basis for Circadian Medicine
Human processes and functions are highly organized in time as (i) short-period ultradian and pulsatile rhythms that exhibit oscillations in the range of seconds to hours, (ii) medium-period circadian rhythms that show oscillations of approximately or exactly 24.0 h, and (iii) long period infradian rhythms that display oscillations in the range of about a week, month (mainly in reproductively aged women), and year (56).
Normal Adult Male Testosterone Circadian Rhythm
T synthesis takes place in the Leydig cells of the testes through LH stimulation. LH is secreted by the pituitary gland into the peripheral circulation in pulses in response to pulses of gonadotropin-releasing hormone (GnRH) emanating from the hypothalamus. LH pulses exhibit 24 h temporal patterning; they occur in greater number and higher amplitude during the sleep than wake span, suggesting the involvement of sleep-facilitating or sleep-dependent processes (10, 17, 57, 164, 175–177). Consequently, T production occurs in the greatest amount during sleep as recurring pulses at approximately 90 min intervals in healthy young males and approximately 140 min in healthy middle-aged males (91). T and its aromatized product estradiol, through negative feedback to the hypothalamus-pituitary axis, induce acute LH suppression and thus reduced T production. In response to the subsequently attenuated serum T concentration, GnRH and LH are again expressed in a pulsatile manner to induce pulsatile androgen hormone synthesis (28, 41, 123, 144).
Testosterone Replacement Therapy
US clinical practice guidelines recommend the prescribed dose of TRT attain a T level in the mid-range of normal, between 300 and 1050 ng/dL, to manage primary and secondary hypogonadism of adult males greater than 18 years of age (11, 103). The major goals of therapy are induction and maintenance of virilization, augmentation of bone density/prevention of osteoporosis, restoration of sexual libido/function, and enhancement of well-being. Typically, the decision of the type of TRT to prescribe is based upon patient preference in terms of treatment burden/compliance, affordability, and risk for adverse effects, which as a medication class can include: (i) azoospermia, (ii) gynecomastia, (iii) benign prostatic hyperplasia, (iv) elevated PSA/prostate cancer, (v) hypercalcemia in cancer patients, (vi) edema in patients with preexisting cardiac, renal, or hepatic disease, (vii) sleep apnea, particularly in obese and lung disease patients, (viii) venous thromboembolism, including deep vein thrombosis and pulmonary embolism, (ix) moodiness and depression, (x) altered lipid profile, (xi) elevated hemoglobin and hematocrit, (xii) new-onset or worsened HTN, and (xiii) MACE (5, 22, 111, 138, 167, 171, 172, 179). Additional concerns of specific TRTs, for example, testosterone undecanoate therapy (Aveed®), administered as an oily solution injected into the gluteal medius, is the risk for pulmonary oil microembolism and anaphylaxis (https://www.accessdata .fda.gov/drugsatfda_docs/label/2014/022219s000lbl.pdf)
Currently, 13 different (nonbiologically similar) TRTs are FDA approved to treat primary and secondary male hypogonadism (What are the brands of testosterone?). Three of them, that is, Aveed®, Depo-Testosterone®, and Testopel®, require administration by health professionals, while the other 10, the focus of this article, are patient administered. Table 2, guided by the format established by Shoskes et al. (148) and Barbonetti et al. (5), summarizes the dosing strategy, key PK features, advantages, disadvantages, major adverse effects, and dose monitoring based on information provided by the package insert of the respective 10 PA-TRTs. Major disadvantages of dermally applied gel and solution systems are a risk for T transfer to family members, potentially deleterious effects on children and women, and localized skin reactions. For the nasal gel medication, disadvantages include rhinorrhea, nasal discomfort, nasal scab, epistaxis, and parosmia, and for the buccal tablet system, they include bitter taste and localized gum tenderness, irritation, inflammation, and gingivitis. Drawbacks of the transdermal patch system are localized skin irritation, blistering, and pruritus, and for the subcutaneously injected one, they are injection-site bruising, inflammation, and pain.
Figures 2A-2F depict the TT 24 h pattern achieved by the 6 different solution and gel PA-TRTs, and Figures 3A-3D depict the TT 24 h pattern achieved by the buccal tablet, oral capsule, transdermal patch, and subcutaneously injected PATRTs. There are substantial differences between the therapies in the derived TT 24 h pattern; moreover, all but one of them differs either somewhat or greatly from the normative one of diurnally active young adult males, which is defined by: (i) elevated and near peak TT level during nighttime sleep, (ii) peak TT level around the time of morning awakening, (iii) moderately elevated TT level during the initial hours of wakefulness, (iv) reduced TT level in the late afternoon, and (v) lowest TT level in the evening. Based upon these criteria, only the Androderm® transdermal patch (Figure 3D), when applied in the evening (∼22:00 h) as recommended, closely mimics the TT circadian rhythm of normal young adult males.
AndroGel® 1%, AndroGel® 1.62%, Axiron®, Fortesta®, and Testim® (and its biosimilar Vogelxo®) gel and solution preparations are recommended for application once daily in the morning to attain the highest serum hormone level 2 to 6 h following dosing and lowest, instead of highest, hormone level during sleep, that is, final hours of the 24 h dosing interval (Figure 2A-2E).
The Natesto® gel product applied to each nostril three times daily at approximately equal intervals results in highly variable serum TT concentration during the 24 h, showing three prominent peaks (Cmax), each occurring approximately 40 min after the administrations, and three prominent nadirs (Cmin) of 2 to 4 h duration, each occurring midway through the dosing intervals (Figure 2F).
The serum TT concentration generated by the Striant® mucoadhesive buccal tablet system applied to the upper gum above the incisor of either side of the mouth twice daily at equal intervals displays 12 h-like patterning, with the Cmax following closely after each application and the overall 24 h Cmin occurring during sleep (Figure 3A).
The Jatenzo® oral soft gel capsule formulation ingested twice daily at equal intervals also gives rise to variable TT levels of distinct 12 h patterning, with prominent Cmax following 2 to 4 h after each ingestion and rapidly declining levels thereafter (Figure 3B).
Xyosted®, a patient subcutaneously injected TRT at weekly intervals, has yet to be rigorously evaluated for its TT day-night pattern. Available data based upon rather infrequent blood sampling indicate Cmax occurs approximately 12 h following each weekly administration and that TT is maintained within the therapeutic range in a relatively stable manner, at least throughout the initial days of the 7-day dosing period (Figure 3C).
*The TT concentration produced by the Androderm® transdermal patch applied to the skin of the back, stomach, upper arms, or thighs nightly before retiring to sleep more closely reproduces the normative TT circadian pattern of young adult males than any of the other marketed PA-TRTs. Following application, TT concentration progressively rises during sleep and peaks around the time of morning awakening; it progressively declines during late morning and afternoon, reaching its nadir (Cmin) in the evening before the next scheduled patch application (Figure 3D).
Testosterone Replacement Therapy and Blood Pressure
Elevation of BP and new-onset and worsened HTN are adverse effects of TRTs; they are of major concern because they are predisposing to MACE, especially when accompanied by a treatment-induced increase of low-density lipoprotein cholesterol, a decrease of high-density lipoprotein cholesterol, and polycythemia. The package insert of each PA-TRT reports by type and frequency of the likely medication-caused adverse effects recorded in company-sponsored safety trials. There is a great disparity between the 10 unique PA-TRTs in the reported effects upon BP. BP safety trials conducted prior to 2018 entailed only daytime OBPM; nonetheless, in most package inserts the actual mean numerical change in diastolic (D) and systolic (S) BP (DBP, SBP) from baseline and scheduled clinical patient visits during treatment is not specified. Furthermore, the exact incidence of new-onset and progressed HTN is not always conveyed; instead, their incidence is categorized along with other adverse effects as proportions, for example, less than 1% or less than 3%, of trialed participants so affected. With these limitations in mind, the incidence based on OBPM of new-onset HTN of five of the six gel and solution PA-TRTs, that is, of Axiron® (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/ 022504s013lbl.pdf),Fortesta®(https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021463s020lbl.pdf), Natesto® (https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2014/205488s000lbl.pdf), Testim® (https://www.accessdata .fda.gov/drug/satfda_docs/label/2009/021454s008lbl.pdf) [and its biosimilar Vogelxo® (https://www.accessdata.fda .gov/drugsatfda_docs/label/2019/204399s010lbl.pdf)], and Striant® (https://www.accessdata.fda.gov/drugsatfda_docs/ label/2004/21543s002lbl.pdf), is reported to be less than 1%. Even though the package insert of the other PA-TRTs warns of BP elevation and HTN as adverse effects, as later discussed few list specific incidences.
Accurate determination of the actual effect of the individual PA-TRTs on BP and induced incidence of HTN in hypogonadal men is difficult because of the inherent limitations of OBPM to ascertain representative DBP and SBP values, even though it is the recommended method of assessing BP and diagnosing HTN.
Discussion
Reports of animal model and human studies concerning the mechanisms mediating T-induced effects on BP are inconsistent (30, 37, 58, 72, 80, 82, 83, 90, 121, 157, 158, 178). According to Dubey et al. (37), T acts as a pro-hypertension hormone by stimulating catecholamine synthesis, modulating the renin-angiotensin-aldosterone system, altering endothelin-1 level, inducing endothelial damage to further atherosclerosis, and injuring glomerular endothelial cells to negatively affect renal function. Although some of the cited reports assert T constricts blood vessels and raises BP, some others assert T dilates blood vessels and lessens arterial stiffness and thus reduces BP.
The major focus of this article has been to compare the PK and achieved 24 h patterning of T concentration in relation to the adverse effects of BP elevation and HTN, known risk factors for MACE, of the different FDA-approved nonbiosimilar PA-TRTs. Serum TT, FT, and DHT concentrations in young adult men exhibit pronounced predictable-in-time 24 h variation. However, in men with an androgen hormone deficiency, these T concentrations are not only abnormally low but lack prominent circadian patterning. Accordingly, we characterized each PA-TRT according to its ability to simulate the normal TT circadian rhythm (Figure 1A). We developed five criteria for this purpose: (i) elevated and near peak TT level during nighttime sleep, (ii) peak TT level around the time of morning awakening, (iii) moderately elevated TT level during the initial hours of wakefulness, (iv) reduced TT level in the late afternoon, and (v) lowest TT level in the evening. Because at this time it is unknown whether any one of these criteria, for example, circadian time of highest or lowest TT level, is of greater biological importance than the others, we weighted each one of them equally.
*As shown in the graphs of Figures 2 and 3, the PK of most FDA-approved PA-TRTs gives rise to TT 24 h patterns that deviate greatly from the normative one thereby failing to satisfy one or more of the five specified criteria.
*AndroGel® 1%, AndroGel® 1.62%, Xyosted®, and Striant®, which achieve relatively constant serum hormone concentration throughout the 24 h, seem to have been incorrectly conceptualized, perhaps because of the presumed necessity to maintain nonvarying, that is, homeostatic, TT concentration to achieve consistency of biological effects.
*The FDA-approved gel and solution PA-TRTs when applied as directed, that is, morning after awakening from nighttime sleep, while achieving TT levels within the normal range to remedy androgen hormone deficiency, fail to restore the normal physiologic TT circadian variation.
*The temporal patterns of these PA-TRTs differ from normal, either in the timing of the peak and/or nadir TT concentrations, by achieving the highest hormone levels generally between midmorning and noon and lowest (rather than near peak) ones during sleep (Figure 2A-2F).
*The TT level produced by the Androderm® transdermal patch system when applied as recommended in the evening before bedtime most closely simulates the normal physiologic pattern. In this regard, the high and low limits of normal TT in the graph of this PA-TRT found in the package insert are unique (Figure 3D); they are depicted in a time-varying cyclic, rather than a time invariable constant, manner that takes into consideration the normal high-amplitude TT circadian variation of diurnally active healthy young men (https://www.accessdata.fda.gov/ drugsatfda_docs/label/2011/020489s025lbl.pdf). This is in distinct contrast to the manner in which the high and low limits of normal are depicted in the package insert of all the other PA-TRTs (Figure 2A-2F and Figure 3A-3C), that is, as constant values consistent with the presumed homeostatic perspective of human biology and endocrinology. Such a homeostatic perspective drives the recommended procedures of dose assessment and titration, although with inconsistencies between the different PA-TRTs in the recommended time of day when to conduct them (Table 2).
The package insert of AndroGel® 1.62%, Testim® 1% (and its biosimilar Vogelxo®), and Striant® specifies blood sampling be done in the morning before the next scheduled dose, the likely time of achieved TT Cmin; that of Axiron® and Fortesta® specifies blood sampling be done 2 h or more after morning administration, the likely time of achieved TT Cmax; that of Jatenzo® 6 h after morning ingestion of the first dose of its twice-daily administration, the likely time of achieved TT Cavg; and that of Androderm® approximately 8 h following application the previous evening, the likely time of TT Cmax.
In summary, the basis—TT Cmax, Cmin, or Cavg—for the timing of blood sampling, that is, immediately before the next, immediately after the last, or much later after the previous TRT administration, to assess the suitability and safety of the prescribed dose varies to a great extent between the various FDA-approved PA-TRTs. Moreover, the advocated procedure for identifying whether or not the prescribed dose is appropriate at the commencement of the daily activity span provides no information about its suitability some hours later, especially during sleep, in accordance with perspectives of circadian medicine, that is, the normal circadian patterning of TT in healthy young adult men and preservation of normal circadian time structure
The foregoing discussion regarding the circadian-rhythm-based treatment of adrenal insufficiency (Addison’s disease) seems of relevance to PA-TRT and raises several pertinent questions in need of answers. For example, would before bedtime, as opposed to the now recommended morning time, application of solution and gel formulations result in a closer simulation of the normative TT circadian rhythm and improved safety and efficacy of treatment, perhaps even in a reduced dose? Would unequal dosing of the oral soft gel capsule Jatenzo® TRT, for example, a higher dose in the evening before bedtime and a lower dose in the morning upon arising from slumber, better simulate the normative T circadian rhythm of day-active young men and lead to improved therapeutic outcomes and reduced risk for BP elevation, HTN, and MACE? The Phase 3 OBPM-based safety trials of the evening-applied Androderm® transdermal patch system that most closely approximates the normative 24 h hormone pattern of healthy young adult males, based on thus far reported trial findings, presents a very low risk for BP elevation and new-onset HTN (https://www.accessdata.fda.gov/drugsatfda_ docs/label/2011/020489s025lbl.pdf). Hopefully, findings of the recently concluded ABPM-based postmarketing Androderm® transdermal patch (Efficacy and Safety of a 'Graft/Prosthesis, Biomaterial (DKM410)' in the Treatment of Both Nasolabial Folds - Full Text View - ClinicalTrials.gov NCT04320745) plus ongoing ABPM-based AndroGel® 1.62% (A Study of the Effect of Topical Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism - Full Text View - ClinicalTrials.gov) safety trails, even if ABPM is conducted only for a duration of 24 h and the primary outcome variable is the 24 h SBP, DBP, or MAP mean, from our perspective all suboptimal choices, will lead to a better understanding of the relevance of the substituted TT 24 h pattern on the risk for BP elevation and MACE. The issues raised herein are not only pertinent to the proper management of T deficiency of primary and secondary hypogonadism but that to senior men and women. Moreover, the issues raised herein concerning the methods used to assess the pressor effects of TRT through ABPM are additionally pertinent to the conduct of safety trials to assess the potential for such effects of other classes of medications, such as nonsteroidal anti-inflammatory drugs (12, 78, 102, 141, 156, 170).
Michael H. Smolensky, Ramon C. Hermida, Linda Sackett-Lundeen, *Ramon G. Hermida-Ayala, and Yong-Jian Geng
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 the “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 the misclassification of an additional approximately 15% of participants. ABPM is improperly incorporated into TRT safety trials. It is done for 24 h rather than the 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.
Introduction
Testosterone (T), the principal male androgen hormone, exerts both anabolic effects—linear growth and maturation plus development, maintenance, and strength of muscle mass and bone structure—and androgenic effects—maturation and maintenance of sex organs and secondary sex characteristics. Male hypogonadism is a clinical syndrome of T deficiency due to inadequacy or absence of T synthesis by the Leydig cells of the testis. Its clinical diagnosis is based on a fasting morning T concentration <300 ng/dL on two separate occasions, typically in association with characteristic signs and symptoms (11, 103, 166). The usual signs of T deficiency in prepubertal boys are eunuchoidism, delayed and under-developed secondary male sex characteristics, and high-pitched voices. In adult males, they are diminished libido, infertility, low bone mineral density, reduced muscle mass, muted secondary sex characteristics, and small (<5 mL) testes. Male hypogonadism has two main etiologies: (i) defects of the testis (primary hypogonadism) and (ii) defects of the hypothalamus or pituitary (secondary hypogonadism, also termed hypogonadotropic hypogonadism). Primary hypogonadism, whether congenital or acquired, may be the consequence of Klinefelter syndrome, Leydig cell aplasia, hemochromatosis, cryptorchidism, abnormalities of testes, for example, bilateral torsion, mumps orchitis, vanishing testis syndrome, orchiectomy, and alcohol, drug, chemotherapy, or heavy metal toxicity (11, 84). Secondary hypogonadism, a condition in which the testicles are normal but fail to produce adequate T, entails pathology of the pituitary or hypothalamus that results in follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) insufficiency. Common causes of secondary hypogonadism are Kallmann and Prader-Willi syndrome, tumor, trauma, radiotherapy, infection, and inflammation of the hypothalamic-pituitary axis, for example, as the consequence of sarcoidosis, histiocytosis, tuberculosis, or other medical conditions, like obesity, type-2-diabetes, end-stage renal disease, human immunodeficiency virus, and acquired immunodeficiency syndrome (11, 84).
Clinical practice guidelines of the American Endocrine Society (11) and Urological Association (103) recommend the prescription of testosterone replacement therapy (TRT) to manage symptomatic androgen deficiency, that is, induce and maintain secondary sexual characteristics and improve bone mineral density, muscle mass, physical strength, sexual function, and overall wellbeing. While guidelines do not now officially endorse the prescription of TRT to manage age-related T deficiency, the 2020 guidelines of the American College of Physicians that are endorsed by the American Academy of Family Physicians (128) advocate discussion of this option between clinicians and older adult male patients. The US Food and Drug Administration (FDA), since the 1950s, has approved several physician-administered injectables and implantable pellets plus 10 unique (nonbiologically similar) patient-applied (PA) transdermal gel, intranasal gel, transdermal solutions, skin patches, buccal tablet, oral capsule, and subcutaneously injected TRTs. Intramuscularly injected and surgically implanted TRTs are administered by healthcare professionals at intervals of several weeks or months, whereas PA transdermal gel and solutions are dosed once daily at the commencement of the activity period, buccal tablet and oral soft gel capsule two times daily at approximately 12 h intervals, intranasal gel three-times daily at approximately 6 to 8 h intervals, and transdermal patch once daily before bedtime. As subsequently discussed, there is a substantial difference in the pharmacokinetics (PK) and attained T 24 h patterning between the 10 different PA-TRTs.
The FDA encourages each company sponsor of a PA-TRT to conduct clinical trials to assess specific features of its PK for use as surrogate endpoints of clinical efficacy. They are the 24 h average (Cavg), maximum (Cmax), and minimum (Cmin) serum concentrations of total testosterone (TT), protein-bound T, and/or nonbound, that is, free testosterone (FT), and proportion of treated participants who exhibit a serum TT (or another T variable) concentration within and beyond the respective surrogate endpoints under steady-state pharmacological conditions (166). The selection of these endpoints is based largely on the biological principle of homeostasis that assumes constancy during the 24 h of serum T concentration, thereby inferring an important goal of TRT is the attainment of constant or near-constant androgen hormone level. This perspective ignores the potential relevance of the circadian biology of patients, particularly the normative T circadian rhythm characteristic of healthy young adult males that may affect not only the efficacy but safety of a given TRT, for example, the risk for blood pressure (BP) elevation, new onset and worsened hypertension (HTN), and major acute cardiovascular events (MACE). Thus, in most instances, the goal of TRT is the normalization of the T level, without the complementary goal of normalization of T circadian patterning, which in both primary and secondary hypogonadism is blunted or absent. The aims of this article, with respect to the perspectives of circadian medicine, are to determine the (i) extent to which the T 24 h pattern achieved by each PA-TRT mimics the normal T circadian rhythm, (ii) current knowledge of the risk posed by each PA-TRT for elevated BP and new-onset and worsened HTN, and (iii) limitations of office blood pressure measurement (OBPM) and deficiencies of the methods and selected outcome variables of ambulatory blood pressure monitoring (ABPM) of past TRT safety trials conducted to assess BP effects and risk for MACE.
Human Biological Time Structure: Basis for Circadian Medicine
Human processes and functions are highly organized in time as (i) short-period ultradian and pulsatile rhythms that exhibit oscillations in the range of seconds to hours, (ii) medium-period circadian rhythms that show oscillations of approximately or exactly 24.0 h, and (iii) long period infradian rhythms that display oscillations in the range of about a week, month (mainly in reproductively aged women), and year (56).
Normal Adult Male Testosterone Circadian Rhythm
T synthesis takes place in the Leydig cells of the testes through LH stimulation. LH is secreted by the pituitary gland into the peripheral circulation in pulses in response to pulses of gonadotropin-releasing hormone (GnRH) emanating from the hypothalamus. LH pulses exhibit 24 h temporal patterning; they occur in greater number and higher amplitude during the sleep than wake span, suggesting the involvement of sleep-facilitating or sleep-dependent processes (10, 17, 57, 164, 175–177). Consequently, T production occurs in the greatest amount during sleep as recurring pulses at approximately 90 min intervals in healthy young males and approximately 140 min in healthy middle-aged males (91). T and its aromatized product estradiol, through negative feedback to the hypothalamus-pituitary axis, induce acute LH suppression and thus reduced T production. In response to the subsequently attenuated serum T concentration, GnRH and LH are again expressed in a pulsatile manner to induce pulsatile androgen hormone synthesis (28, 41, 123, 144).
Testosterone Replacement Therapy
US clinical practice guidelines recommend the prescribed dose of TRT attain a T level in the mid-range of normal, between 300 and 1050 ng/dL, to manage primary and secondary hypogonadism of adult males greater than 18 years of age (11, 103). The major goals of therapy are induction and maintenance of virilization, augmentation of bone density/prevention of osteoporosis, restoration of sexual libido/function, and enhancement of well-being. Typically, the decision of the type of TRT to prescribe is based upon patient preference in terms of treatment burden/compliance, affordability, and risk for adverse effects, which as a medication class can include: (i) azoospermia, (ii) gynecomastia, (iii) benign prostatic hyperplasia, (iv) elevated PSA/prostate cancer, (v) hypercalcemia in cancer patients, (vi) edema in patients with preexisting cardiac, renal, or hepatic disease, (vii) sleep apnea, particularly in obese and lung disease patients, (viii) venous thromboembolism, including deep vein thrombosis and pulmonary embolism, (ix) moodiness and depression, (x) altered lipid profile, (xi) elevated hemoglobin and hematocrit, (xii) new-onset or worsened HTN, and (xiii) MACE (5, 22, 111, 138, 167, 171, 172, 179). Additional concerns of specific TRTs, for example, testosterone undecanoate therapy (Aveed®), administered as an oily solution injected into the gluteal medius, is the risk for pulmonary oil microembolism and anaphylaxis (https://www.accessdata .fda.gov/drugsatfda_docs/label/2014/022219s000lbl.pdf)
Currently, 13 different (nonbiologically similar) TRTs are FDA approved to treat primary and secondary male hypogonadism (What are the brands of testosterone?). Three of them, that is, Aveed®, Depo-Testosterone®, and Testopel®, require administration by health professionals, while the other 10, the focus of this article, are patient administered. Table 2, guided by the format established by Shoskes et al. (148) and Barbonetti et al. (5), summarizes the dosing strategy, key PK features, advantages, disadvantages, major adverse effects, and dose monitoring based on information provided by the package insert of the respective 10 PA-TRTs. Major disadvantages of dermally applied gel and solution systems are a risk for T transfer to family members, potentially deleterious effects on children and women, and localized skin reactions. For the nasal gel medication, disadvantages include rhinorrhea, nasal discomfort, nasal scab, epistaxis, and parosmia, and for the buccal tablet system, they include bitter taste and localized gum tenderness, irritation, inflammation, and gingivitis. Drawbacks of the transdermal patch system are localized skin irritation, blistering, and pruritus, and for the subcutaneously injected one, they are injection-site bruising, inflammation, and pain.
Figures 2A-2F depict the TT 24 h pattern achieved by the 6 different solution and gel PA-TRTs, and Figures 3A-3D depict the TT 24 h pattern achieved by the buccal tablet, oral capsule, transdermal patch, and subcutaneously injected PATRTs. There are substantial differences between the therapies in the derived TT 24 h pattern; moreover, all but one of them differs either somewhat or greatly from the normative one of diurnally active young adult males, which is defined by: (i) elevated and near peak TT level during nighttime sleep, (ii) peak TT level around the time of morning awakening, (iii) moderately elevated TT level during the initial hours of wakefulness, (iv) reduced TT level in the late afternoon, and (v) lowest TT level in the evening. Based upon these criteria, only the Androderm® transdermal patch (Figure 3D), when applied in the evening (∼22:00 h) as recommended, closely mimics the TT circadian rhythm of normal young adult males.
AndroGel® 1%, AndroGel® 1.62%, Axiron®, Fortesta®, and Testim® (and its biosimilar Vogelxo®) gel and solution preparations are recommended for application once daily in the morning to attain the highest serum hormone level 2 to 6 h following dosing and lowest, instead of highest, hormone level during sleep, that is, final hours of the 24 h dosing interval (Figure 2A-2E).
The Natesto® gel product applied to each nostril three times daily at approximately equal intervals results in highly variable serum TT concentration during the 24 h, showing three prominent peaks (Cmax), each occurring approximately 40 min after the administrations, and three prominent nadirs (Cmin) of 2 to 4 h duration, each occurring midway through the dosing intervals (Figure 2F).
The serum TT concentration generated by the Striant® mucoadhesive buccal tablet system applied to the upper gum above the incisor of either side of the mouth twice daily at equal intervals displays 12 h-like patterning, with the Cmax following closely after each application and the overall 24 h Cmin occurring during sleep (Figure 3A).
The Jatenzo® oral soft gel capsule formulation ingested twice daily at equal intervals also gives rise to variable TT levels of distinct 12 h patterning, with prominent Cmax following 2 to 4 h after each ingestion and rapidly declining levels thereafter (Figure 3B).
Xyosted®, a patient subcutaneously injected TRT at weekly intervals, has yet to be rigorously evaluated for its TT day-night pattern. Available data based upon rather infrequent blood sampling indicate Cmax occurs approximately 12 h following each weekly administration and that TT is maintained within the therapeutic range in a relatively stable manner, at least throughout the initial days of the 7-day dosing period (Figure 3C).
*The TT concentration produced by the Androderm® transdermal patch applied to the skin of the back, stomach, upper arms, or thighs nightly before retiring to sleep more closely reproduces the normative TT circadian pattern of young adult males than any of the other marketed PA-TRTs. Following application, TT concentration progressively rises during sleep and peaks around the time of morning awakening; it progressively declines during late morning and afternoon, reaching its nadir (Cmin) in the evening before the next scheduled patch application (Figure 3D).
Testosterone Replacement Therapy and Blood Pressure
Elevation of BP and new-onset and worsened HTN are adverse effects of TRTs; they are of major concern because they are predisposing to MACE, especially when accompanied by a treatment-induced increase of low-density lipoprotein cholesterol, a decrease of high-density lipoprotein cholesterol, and polycythemia. The package insert of each PA-TRT reports by type and frequency of the likely medication-caused adverse effects recorded in company-sponsored safety trials. There is a great disparity between the 10 unique PA-TRTs in the reported effects upon BP. BP safety trials conducted prior to 2018 entailed only daytime OBPM; nonetheless, in most package inserts the actual mean numerical change in diastolic (D) and systolic (S) BP (DBP, SBP) from baseline and scheduled clinical patient visits during treatment is not specified. Furthermore, the exact incidence of new-onset and progressed HTN is not always conveyed; instead, their incidence is categorized along with other adverse effects as proportions, for example, less than 1% or less than 3%, of trialed participants so affected. With these limitations in mind, the incidence based on OBPM of new-onset HTN of five of the six gel and solution PA-TRTs, that is, of Axiron® (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/ 022504s013lbl.pdf),Fortesta®(https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021463s020lbl.pdf), Natesto® (https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2014/205488s000lbl.pdf), Testim® (https://www.accessdata .fda.gov/drug/satfda_docs/label/2009/021454s008lbl.pdf) [and its biosimilar Vogelxo® (https://www.accessdata.fda .gov/drugsatfda_docs/label/2019/204399s010lbl.pdf)], and Striant® (https://www.accessdata.fda.gov/drugsatfda_docs/ label/2004/21543s002lbl.pdf), is reported to be less than 1%. Even though the package insert of the other PA-TRTs warns of BP elevation and HTN as adverse effects, as later discussed few list specific incidences.
Accurate determination of the actual effect of the individual PA-TRTs on BP and induced incidence of HTN in hypogonadal men is difficult because of the inherent limitations of OBPM to ascertain representative DBP and SBP values, even though it is the recommended method of assessing BP and diagnosing HTN.
Discussion
Reports of animal model and human studies concerning the mechanisms mediating T-induced effects on BP are inconsistent (30, 37, 58, 72, 80, 82, 83, 90, 121, 157, 158, 178). According to Dubey et al. (37), T acts as a pro-hypertension hormone by stimulating catecholamine synthesis, modulating the renin-angiotensin-aldosterone system, altering endothelin-1 level, inducing endothelial damage to further atherosclerosis, and injuring glomerular endothelial cells to negatively affect renal function. Although some of the cited reports assert T constricts blood vessels and raises BP, some others assert T dilates blood vessels and lessens arterial stiffness and thus reduces BP.
The major focus of this article has been to compare the PK and achieved 24 h patterning of T concentration in relation to the adverse effects of BP elevation and HTN, known risk factors for MACE, of the different FDA-approved nonbiosimilar PA-TRTs. Serum TT, FT, and DHT concentrations in young adult men exhibit pronounced predictable-in-time 24 h variation. However, in men with an androgen hormone deficiency, these T concentrations are not only abnormally low but lack prominent circadian patterning. Accordingly, we characterized each PA-TRT according to its ability to simulate the normal TT circadian rhythm (Figure 1A). We developed five criteria for this purpose: (i) elevated and near peak TT level during nighttime sleep, (ii) peak TT level around the time of morning awakening, (iii) moderately elevated TT level during the initial hours of wakefulness, (iv) reduced TT level in the late afternoon, and (v) lowest TT level in the evening. Because at this time it is unknown whether any one of these criteria, for example, circadian time of highest or lowest TT level, is of greater biological importance than the others, we weighted each one of them equally.
*As shown in the graphs of Figures 2 and 3, the PK of most FDA-approved PA-TRTs gives rise to TT 24 h patterns that deviate greatly from the normative one thereby failing to satisfy one or more of the five specified criteria.
*AndroGel® 1%, AndroGel® 1.62%, Xyosted®, and Striant®, which achieve relatively constant serum hormone concentration throughout the 24 h, seem to have been incorrectly conceptualized, perhaps because of the presumed necessity to maintain nonvarying, that is, homeostatic, TT concentration to achieve consistency of biological effects.
*The FDA-approved gel and solution PA-TRTs when applied as directed, that is, morning after awakening from nighttime sleep, while achieving TT levels within the normal range to remedy androgen hormone deficiency, fail to restore the normal physiologic TT circadian variation.
*The temporal patterns of these PA-TRTs differ from normal, either in the timing of the peak and/or nadir TT concentrations, by achieving the highest hormone levels generally between midmorning and noon and lowest (rather than near peak) ones during sleep (Figure 2A-2F).
*The TT level produced by the Androderm® transdermal patch system when applied as recommended in the evening before bedtime most closely simulates the normal physiologic pattern. In this regard, the high and low limits of normal TT in the graph of this PA-TRT found in the package insert are unique (Figure 3D); they are depicted in a time-varying cyclic, rather than a time invariable constant, manner that takes into consideration the normal high-amplitude TT circadian variation of diurnally active healthy young men (https://www.accessdata.fda.gov/ drugsatfda_docs/label/2011/020489s025lbl.pdf). This is in distinct contrast to the manner in which the high and low limits of normal are depicted in the package insert of all the other PA-TRTs (Figure 2A-2F and Figure 3A-3C), that is, as constant values consistent with the presumed homeostatic perspective of human biology and endocrinology. Such a homeostatic perspective drives the recommended procedures of dose assessment and titration, although with inconsistencies between the different PA-TRTs in the recommended time of day when to conduct them (Table 2).
The package insert of AndroGel® 1.62%, Testim® 1% (and its biosimilar Vogelxo®), and Striant® specifies blood sampling be done in the morning before the next scheduled dose, the likely time of achieved TT Cmin; that of Axiron® and Fortesta® specifies blood sampling be done 2 h or more after morning administration, the likely time of achieved TT Cmax; that of Jatenzo® 6 h after morning ingestion of the first dose of its twice-daily administration, the likely time of achieved TT Cavg; and that of Androderm® approximately 8 h following application the previous evening, the likely time of TT Cmax.
In summary, the basis—TT Cmax, Cmin, or Cavg—for the timing of blood sampling, that is, immediately before the next, immediately after the last, or much later after the previous TRT administration, to assess the suitability and safety of the prescribed dose varies to a great extent between the various FDA-approved PA-TRTs. Moreover, the advocated procedure for identifying whether or not the prescribed dose is appropriate at the commencement of the daily activity span provides no information about its suitability some hours later, especially during sleep, in accordance with perspectives of circadian medicine, that is, the normal circadian patterning of TT in healthy young adult men and preservation of normal circadian time structure
The foregoing discussion regarding the circadian-rhythm-based treatment of adrenal insufficiency (Addison’s disease) seems of relevance to PA-TRT and raises several pertinent questions in need of answers. For example, would before bedtime, as opposed to the now recommended morning time, application of solution and gel formulations result in a closer simulation of the normative TT circadian rhythm and improved safety and efficacy of treatment, perhaps even in a reduced dose? Would unequal dosing of the oral soft gel capsule Jatenzo® TRT, for example, a higher dose in the evening before bedtime and a lower dose in the morning upon arising from slumber, better simulate the normative T circadian rhythm of day-active young men and lead to improved therapeutic outcomes and reduced risk for BP elevation, HTN, and MACE? The Phase 3 OBPM-based safety trials of the evening-applied Androderm® transdermal patch system that most closely approximates the normative 24 h hormone pattern of healthy young adult males, based on thus far reported trial findings, presents a very low risk for BP elevation and new-onset HTN (https://www.accessdata.fda.gov/drugsatfda_ docs/label/2011/020489s025lbl.pdf). Hopefully, findings of the recently concluded ABPM-based postmarketing Androderm® transdermal patch (Efficacy and Safety of a 'Graft/Prosthesis, Biomaterial (DKM410)' in the Treatment of Both Nasolabial Folds - Full Text View - ClinicalTrials.gov NCT04320745) plus ongoing ABPM-based AndroGel® 1.62% (A Study of the Effect of Topical Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism - Full Text View - ClinicalTrials.gov) safety trails, even if ABPM is conducted only for a duration of 24 h and the primary outcome variable is the 24 h SBP, DBP, or MAP mean, from our perspective all suboptimal choices, will lead to a better understanding of the relevance of the substituted TT 24 h pattern on the risk for BP elevation and MACE. The issues raised herein are not only pertinent to the proper management of T deficiency of primary and secondary hypogonadism but that to senior men and women. Moreover, the issues raised herein concerning the methods used to assess the pressor effects of TRT through ABPM are additionally pertinent to the conduct of safety trials to assess the potential for such effects of other classes of medications, such as nonsteroidal anti-inflammatory drugs (12, 78, 102, 141, 156, 170).
