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Pharmacology of testosterone preparations
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... Esterification increases the solubility of T in oil, allowing for slower release of T with IM injection. 13,33 The three IM formulations that are approved by the FDA for use as TTh are testosterone cypionate (TC), TE, and testosterone undecanoate (TU). Depending on the formulation and dosage, following IM injection of TE or TC, supraphysiologic levels occur within a week after administration, decreasing to subtherapeutic levels in between dosing intervals, resulting in large TT peak-to-trough ratios. ...
... Esterification of T at the 17-position with undecanoic acid results in a longer-acting IM TTh option that increases treatment intervals compared with that of other T esters. 33,38 The efficacy and safety of 750 mg IM TU were evaluated in an open-label, 84-week, phase 3 clinical trial of 130 men with TD. 39 Enrolled men received 750 mg TU in 3 mL of castor oil (250 mg/mL) by deep IM injections administered at baseline, week 4, and every 10 weeks thereafter through 9 injections. Serum T levels peaked approximately 7 days after each injection, with a mean C max of 30.9 ± 11.9 nmol/L (890.6 ng/dL) after the third IM TU injection. ...
... These mixtures have not been recently studied, but in a 1974 study, 3 men with TD treated with 115.7 mg TE and 20 mg T propionate reported approximately 40 nmol/L (1,154 ng/dL) increase of serum T over baseline one day post-IM injection, suggesting combining these so-called -short-acting‖ T esters only worsens the PK profile and increases the initial undesired T peak. 33,43 ...
Background
: To improve symptoms associated with testosterone deficiency (TD), many testosterone therapies (TTh) 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 (PK) 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 TTh as men age.
Materials and methods
: A literature search of studies examining the diurnal variation of endogenous T in healthy men and men with TD was performed using PubMed in January 2020. Additional searches for serum T PK profiles of various TTh 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 TD 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 TTh can exactly mimic the normal diurnal T patterns seen in younger men and the blunted circadian T secretion of older men.
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... Intramuscular (IM) testosterone has been utilized for TRT since the 1950s [7]. Since unmodified testosterone has a short half-life of about ten minutes, it must be modified via esterification of the 17-B carbon, this modification allows prolonged duration of action and foregoes the need for multi-dosing regimens to achieve and maintain therapeutic levels [15]. Advantages of IM administration of testosterone include less frequent dosing, which increases compliance. ...
... Patients may also experience fluctuations in mood and libido as serum testosterone levels vary between doses. In the 1980s, the initial transdermal patch discovered to be effective were scrotal transdermal patches [15]. This application generated the greatest T absorption via a thinskinned area. ...
Testosterone is the primary sex hormone and anabolic steroid in males and serves a crucial role in the development of male reproductive tissues (testes, prostate). It also exerts its effects on various organs including brain, liver, muscle, bone, skin, and penis and as a result, maintains physical and emotional wellbeing in men. Thus, testosterone deficiency disrupts the normal homeostatic effects of testosterone and manifests as metabolic dysfunction, cognitive impairment, osteopenia/osteoporosis, anemia, and sexual dysfunction. Therefore, men on testosterone replacement therapy may experience a significant improvement in their mood, energy, sexual function, and increase in bone and muscle mass. Testosterone is available in a variety of preparations including transdermal patches and gels, intramuscular injections, and subcutaneous pellets. Each of these delivery systems is associated with unique challenges and adverse effects rendering them unsuitable for certain patients. For years, oral formulations were elusive due to poor efficacy and hepatoxicity. However, Jatenzo (oral testosterone undecanoate) obtained FDA approval in 2019. Oral testosterone is an appealing option due to its convenience and ease of administration when compared to alternate formulations. In this review we will discuss the history of oral testosterone, the distinct formulations and compare the benefits and risks of oral testosterone to alternate routes of administration.
... To eliminate the impact of maternal sex hormones, which are known to penetrate the placental barrier [37], the study did not include infants younger than two weeks of age. Between 15 and 30 days of life (the age at which all boys started participation in the study), maternal sex hormones were almost certainly absent in the infant's saliva due to their short halflives (10 min for testosterone and 20-30 min for estradiol) [38,39]. ...
Background/Objectives: Minipuberty is thought to play an important role in the sexual maturation of infants. Maternal disorders during pregnancy were found to have an impact on the activity of the reproductive axis in the first year of life. This prospective, matched, cohort study was aimed at investigating whether the course of minipuberty in boys is affected by maternal gestational diabetes mellitus (GDM). Methods: The study population consisted of three matched groups of boys: infants born to women with poorly controlled GDM, sons of women with adequately controlled GDM, and infants of healthy women with normal carbohydrate tolerance during pregnancy (control group). Salivary levels of testosterone, androstenedione, DHEA-S and estradiol, and uri-nary concentrations of FSH and LH were repeatedly measured over the first 12 months of life. Hormone levels were correlated with the size of genital organs (testicular volume and penile length), which were measured at each visit. Results: Compared with the remaining groups, the male offspring of women with poorly controlled GDM were characterized by higher concentrations of both gonadotropins, higher salivary testosterone levels, lower salivary DHEA-S concentrations, and longer periods of detection for LH and testosterone. Levels of gonadotropin, testosterone and DHEA-S in sons of mothers with poorly controlled GDM correlated with mean levels of glycated hemoglobin during pregnancy. Moreover, the infant boys assigned to this group were characterized by larger sizes of the testes and penis. Over the entire study period, there were no differences in hormone levels, testicular volume and penile length between sons of adequately treated women with GDM and sons of healthy women. Conclusions: The obtained results indicate that GDM, if poorly controlled, may affect the activity of the reproductive axis and postnatal growth of male genital organs in the offspring.
... Although TTh has been in clinical use for nearly a century, prior to 2013, few publications supported an increased CV risk in patients treated with TTh; in fact, most showed beneficial CV effects of TTh and that low T levels were generally associated with an increased risk of atherosclerosis, CV risk factors, and mortality. 38,39 Since 2013, published studies have contradicted this body of literature, contributing to ongoing debates in the medical community regarding the effects of TTh on cardiovascular health. 40e43 As the literature is replete with studies demonstrating beneficial impacts of TTh on CV and overall health, we limited our review to the literature supportive of negative effects of TTh on CVD and summarize the available data on the putative mechanisms underlying increased CV risk. ...
Background
Treatment of “adult-onset hypogonadism” (AOH) with exogenous testosterone therapy (TTh) to raise serum testosterone (T) levels may influence cardiovascular (CV) risk factors in patients with AOH, whereas low endogenous T levels are associated with an increased CV risk and mortality.
Aim
To critically evaluate studies reporting increased CV risk associated with TTh and to provide an overview of the risks and benefits of restoring T levels through exogenous TTh.
Methods
A review of publications focusing on the association between TTh and increased CV risk was conducted, and the study methodologies and conclusions of each were critically evaluated. Further, recent clinical and epidemiological studies associating AOH or TTh with a change in CV risk, and pertinent hematologic and vascular effects noted in animal studies and in vitro, as well as in clinical practice were also reviewed.
Outcomes
A review of the literature shows that untreated testosterone deficiency and/or low T is associated with an increase in CV risk and adverse outcomes, with numerous studies and meta-analyses to support a positive association between exogenous TTh and an improvement in CV risk factors in men with AOH.
Results
Numerous studies in the literature demonstrate the positive benefits of using TTh; however, since 2013, some publications have suggested a link to increased CV risk associated with TTh. A number of these studies retrospectively analyzed insurance claims databases using diagnosis codes, procedures codes, and prescription information. Many reviews published since have pointed out the methodological flaws and debatable conclusions of these studies.
Clinical Implications
A careful assessment of the patient's current health status and CV risk factors should be weighed against the benefits and possible risks resulting from TTh, and consideration should be given to deferring treatment pending resolution or stabilization of CV disease or risk factors.
Strengths & Limitations
In this review, we provide an in-depth analysis of studies reporting increased CV risk with TTh. Many of the studies were not well-designed, randomized, double-blind, prospective clinical trials but rather post hoc analyses of cohort data. These studies may reflect bias in how treatment and nontreatment decisions are made or reflect conclusions based on widely cited methodological flaws.
Conclusion
Appropriate patient selection supported by low pre-treatment T levels and monitoring T levels during treatment with the goal of achieving and maintaining physiologic levels all contribute to the safe and effective use of TTh in men with AOH.
Khera M, Miner M, Jaffe J, et al. Testosterone Therapy and Cardiovascular Risk: A Critical Analysis of Studies Reporting Increased Risk. J Sex med 2020;XX:XXX–XXX.
... The detection could most probably be extended because the limit of detection (LOD) of the This is not surprising because, for transdermal testosterone replacement therapy, it is recommended to cover the surface on which the gel is applied with clothing, in order to avoid the transfer of testosterone by direct skin contact to family or relatives. 18 In the following experiment performed (#2), the objective was to reduce the dosage and the interaction between the two volunteers. ...
The detection of clostebol misuse in sports has been growing recently, especially in Italy, due to the ample availability of pharmaceutical formulations containing clostebol acetate (Trofodermin®) and the use of more sensitive instrumentation by the antidoping laboratories. Most of these cases have been claimed to be related to a nonconscious use of the drug or through contact with relatives or teammates using it. We have investigated, through the application of the well‐known and currently used gas chromatographic mass spectrometric procedures, the likelihood of these allegations and have demonstrated that after a single transdermal administration of 5 mg of clostebol acetate and a transient contact with the application area, it is possible to generate adverse analytical findings in antidoping controls. We have reviewed the Phase I and Phase II clostebol metabolism in order to generate evidences that may help the sport authorities reviewing these cases. The main clostebol metabolite (4‐chloro‐androst‐4‐en‐3α‐ol‐17‐one, M1) generally used at the screening level as well as other three metabolites (M2–M4) are mainly excreted as glucuronides, whereas M5 (4ζ‐chloro‐5ζ‐androstan‐3β‐ol‐17‐one) is predominantly excreted as sulfate. Neither the 5α‐reductases activity (impaired by the presence of the chlorine in C4) nor specific sulfotransferases present in the skin allowed a clear distinction of the administration route. Studies with a larger number of volunteers and probably investigating another physiological fluid allowed in antidoping such as blood are needed for a deeper investigation. It is not unreasonable to establish a reporting level for M1, maybe creating some false negatives but excluding nonintentional doping scenarios.
All forms of hypogonadism require therapy with testosterone. Even in secondary hypogonadism, testosterone substitution is indicated in the long-term, which is only interrupted for the duration of GnRH or gonadotropin therapy if the patient wishes to be fertile. For many decades, substitution with testosterone enanthate or cypionate was the leading form of testosterone substitution. In the 1970s, orally active testosterone undecanoate was added and in the 1990s, the first transdermal preparations in the form of membranes and patches were introduced. Later, testosterone gels became available allowing physiological serum testosterone levels to be reached. With injectable testosterone undecanoate, a true depot preparation came into clinical use. Regular monitoring of testosterone substitution must observe the positive effects and, due to possible undesirable side effects, especially monitor red blood count and prostate.
Background:
This is a proof of concept, as a pilot study, with the aim to evaluate continuous glucose monitoring metrics (CGM) in subjects with type 2 diabetes (T2DM), treated with nutritional therapy and metformin, before and after testosterone replacement therapy (TRT).
Methods:
In this longitudinal observational study, subjects affected by T2DM and starting TRT for documented ED and hypogonadism were enrolled. All subjects mounted a CGM system during the v0 visit, one week before the beginning of the TRT (week-1), during v2, four weeks after the start of TRT (week 4), and v4 (week 12). CGM was worn for about 144 h after each visit.
Results:
A total of seven patients, referring to our clinic for erectile dysfunction (ED), were studied (aged 63.3 ± 2.3 years). Mean (± standard deviation) total testosterone level was 2.3 ± 0.6 ng/mL at baseline. After TRT, total testosterone level was 4.6 ± 3.04 ng/mL at week 4 and 3.93 ± 4.67 ng/mL at week 12. No significant differences were observed in TIR, TAR, TBR, estimated HbA1c, AUC below, and AUC above limit during the intervention period.
Conclusions:
This is the first study evaluating the effects of TRT on daily glucose excursions in subjects with T2DM and hypogonadism. Though we did not find any significant difference in key CGM metrics during the 12 weeks of TRT, this study confirms the glycometabolic safety of the TRT even on the most novel standardized glycemic targets.
Suppression of serum LH and FSH, by testosterone (T) alone or in combination with other agents, has proved to be the most promising approach to male contraception. T enanthate, the only androgen preparation tested in male contraceptive efficacy trials so far, must be injected every week due to its short terminal elimination half-life of 4.5 days and leads to supraphysiological T serum levels. A new T ester synthesized under WHO and NIH auspices, testosterone buciclate (TB), showed a favorable pharmacokinetic profile, with a terminal half-life of 29.5 days when tested in hypogonadal men. Here we describe the results of the first clinical trial with TB for male contraception. After two control examinations, normal healthy male volunteers were given a single im injection of 600 mg TB (group I; n = 4) and 1200 mg TB (group II; n = 8) on day 0. Follow-up examinations were performed every 2 weeks up to week 32. In both groups mean serum T levels remained in the normal physiological range throughout the study course. Serum levels of dihydrotestosterone (DHT) showed a dose- and time-dependent increase, with serum levels slightly above the normal range in group II for several weeks and a maximal concentration of 3.8 +/- 0.5 nmol/L (mean +/- SE) in week 6. No suppression of spermatogenesis to oligozoospermia was observed in group I. However, in group II, spermatogenesis was suppressed to azoospermia in three of eight volunteers in week 10 that persisted up to weeks 14, 20, and 22, respectively. In these three men, LH and FSH were suppressed by TB injections to the respective assay detection limits, whereas in the other five subjects, mean serum levels were only decreased to values near the lower normal limit for LH and FSH, respectively. In addition, throughout the study course, a significant difference in serum sex hormone-binding globulin was detected between the responders (mean values, 21.2-26.4 nmol/L) and nonresponders (mean values, 36.2-46.3 nmol/L). Serum levels of LH as well as total and free T at baseline and after TB injection were lower in the responders than in the nonresponders. Both subgroups showed similar increases in serum LH and FSH after GnRH stimulation. In a newly introduced GnRH antagonist suppression test, serum LH and T were decreased to significantly lower levels in the responders. These results indicate a different hormonal equilibrium and probably different susceptibility to feedback regulation of the responders compared to the nonresponders.(ABSTRACT TRUNCATED AT 400 WORDS)
PIP
Testosterone alone and the combination of gestagens and gonadotropin-releasing hormone antagonists with testosterone represent the most feasible potential agents for hormonal male contraception. The World Health Organization's Special Program of Research, Development, and Research Training in Human Reproduction has initiated a testosterone ester synthesis program and identified testosterone buciclate (TB) as the most promising approach to suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This paper presents the results of the first clinical trial of TB. 12 men were given a single intramuscular injection of 600 mg (group I) or 1200 mg (group II) of TB and followed every 2 weeks for up to 32 weeks. Mean serum testosterone levels in both groups remained in the normal physiological range throughout the study period. Serum levels of dihydrotestosterone showed a time- and dose-dependent increase in group II. Although no suppression of spermatogenesis was observed in the 4 men in group I, azoospermia occurred in 3 of the 8 volunteers in group II beginning at week 10 and persisting to weeks 14, 20, and 22, respectively. In the remaining 5 men in group II, mean serum LH and FSH values were depressed to values near the lower limit of normal. Serum sex hormone-binding globulin and free testosterone were lower in responders than non-responders to TB. The range of responses recorded in group II suggests that men have a different hormonal equilibrium or different set-point for regulation of gonadotropin secretion and, thus, susceptibility to exogenous hormonal steroids.
Due to unfavorable pharmacokinetics of the available androgen esters for substitution therapy of male hypogonadism, there is a demand for new testosterone (T) preparations producing constant serum levels in the physiological range. To assess the pharmacokinetics and pharmacodynamics of the new ester testosterone buciclate (TB) [20 Aet-1] in hypogonadal men a clinical phase I-study was performed. After two control examinations 8 male patients with primary hypogonadism were randomly assigned to 2 treatment groups (n = 2 x 4) given single doses of either 200 (group I) or 600 mg (group II) TB im. Blood samples were obtained 1, 2, 3, 5, and 7 days post injection and then weekly in the course of 4 months. In group I serum androgen levels did not rise to normal values. However, in group II androgens increased significantly and were maintained in the normal range up to 12 weeks with maximal serum levels of 13.1 +/- 0.9 nmol/L (mean +/- SE) in study week 6. No initial peak release of T was observed in either study...
Excerpt
The relation between various methods of administration of testosterone preparations and the excretion of 17-ketosteroids in man has been the subject of four previous publications by the author and his associates (Hamburger & Kaae, 1949, Hamburger, 1949, Hamburger, Birket-Smith & Kaae, 1952, Hamburger, 1956). Last year the author had the pleasure of reading an historical and geographical review on the use of suppositories in human medicine by the Danish pharmacist Else Ifversen (Ifversen, 1957). In view of the advantages of the rectal administration of therapeutic agents, an attempt was made to explore the possibility of applying androgens per rectum. Suppositories containing androgens had apparently not been on the market, and in the literature no references to the subject were found. The results of some preliminary experiments were very encouraging, and on the author's request 'Leo Pharmaceutical Products', Copenhagen, kindly prepared suppositories and tablets containing testosterone and some of its esters.