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Effects of testosterone on IKs and ICa,L.
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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.
... 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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... 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.
... The IM preparations approved for the treatment are T cypionate (TC), T enanthate (TE), T propionate (TP) (not approved in the USA for TRT in hypogonadism) and T undecanoate (TU). The absorption kinetics of different T esters increase when the esterified fatty acids to the 17β position of T have a longer chain,in addition, pharmacokinetics are also influenced by the oily vehicle, the injection site and the injection volume.11 TU has the longest carbon side chain, consisting of 11 carbon atoms compared to seven and eight for TC and TE, respectively, which accounts for its longer duration of action.A disadvantage of these formulations is the necessity for IM injection. ...
... sulting in wide fluctuations of T serum concentrations and maximal injection intervals of three days for the 50 mg dose.11 Testosterone cypionate TC is supplied in 100 mg/mL (10 mL vial) and 200 mg/mL (1 and 10 mL vials) concentrations, prepared in cottonseed oil. ...
Background:
The aim of testosterone replacement therapy (TRT) is to improve symptoms and signs of testosterone deficiency including decreased libido, erectile dysfunction, depressed mood, anaemia, loss of muscle and bone mass, by increasing serum testosterone levels to physiologic range. TRT has been used in the last 70 years, and overtime, numerous preparations and formulations have been developed to improve pharmacokinetics (PKs) and patient compliance. The routes of delivery approved for use in the Western world include buccal, nasal, subdermal, transdermal and intramuscular (IM).
Objectives:
The aim of this narrative review was to describe and compare all available and approved testosterone preparations according to pharmacology, PKs and adverse effects.
Materials and methods:
We have performed an extensive PubMed review of the literature on TRT in clinical practice. Contraindications and monitoring of TRT were analyzed by comparing available guidelines released in the last five years. We provide a review of advantages and disadvantages of different modalities of TRT and how to monitor treatment to minimize the risks.
Results:
TRT is associated with multiple benefits highly relevant to the patient. However, the recommendations given in different guidelines on TRT are based on data from a limited number of randomized controlled trials (RCTs), as well as non-randomized clinical studies and observational studies. This is the case for the safety of a long-term TRT in late-onset hypogonadism (LOH). No evidence is provided indeed on the effects of TRT on endpoints such as deterioration of heart failure suggesting a cautious approach to T replacement in older men with a history of heart failure.
Conclusion:
Clinicians must consider the unique characteristics of each patient and make the necessary adjustments in the management of LOH in order to provide the safest and most beneficial results.
... Non-specific esterases in liver, tissue, and blood cellular components hydrolyze inactive steroid esters (e.g., androgen prodrugs) into a biologically active form. The use of ester prodrugs for oral administration of androgens allows greater systemic bioavailability and a longer half-life than the active moiety (Behre, 2004). However, when blood samples are collected, the prodrug in the sample can continue to undergo hydrolysis, ex vivo, by non-specific esterases present in the blood (mainly in red and white blood cells) thus leading to overestimation of circulating androgen levels (Williams, 1985). ...
Background
Ex vivo androgen prodrug conversion by blood esterases after oral androgen ester administration may result in an overestimation of the measured blood androgens.
Objective
We investigated whether blood collection tubes with esterase inhibitors decreased the conversion of testosterone undecanoate (TU) and dimethandrolone undecanoate (DMAU) to their active metabolites, testosterone (T), and dimethandrolone (DMA), providing a more accurate assessment of circulating T/DMA levels.
Methods
Blood was collected in tubes with/without esterase inhibitors from: (i) four healthy and four hypogonadal men receiving no androgens and spiked ex vivo with TU/DMAU; (ii) four men taking oral TU (Andriol®); and (iii) eight hypogonadal men dosed with oral 316 mg TU and 15 healthy men with 200 mg DMAU. T/DMA levels were measured by LC‐MS/MS.
Results
Sodium fluoride (NaF, an esterase inhibitor) decreased measured T levels by 14.2% in men not receiving TU. Increasing amounts of TU/DMAU added to blood collected into plain tubes resulted in a concentration‐dependent overestimation of T/DMA that was reduced by collecting blood into NaF tubes (by 30–85%), and keeping samples at 4 °C and minimizing time prior to centrifugation. After oral TU/DMAU administration to men, when TU/DMAU levels were >15/10 ng/mL, respectively, blood collected in NaF tubes yielded lower measured T concentrations by 15–30% and DMA by 22% due to an additional inhibitory effect of NaF on blood esterases.
Conclusion
NaF directly lowers plasma T/DMA levels measured by LC‐MS/MS and also inhibits blood esterase activity. Overestimation of T/DMA in blood collected in tubes without NaF after oral TU/DMAU administration is important for pharmacokinetics studies in drug development clinical trials but may have limited impact in clinical practice/utilization because the differences between measured and true androgen values are modest and the wide therapeutic androgen efficacy ranges obviate the need for highly accurate androgen measurements during therapy.
... However, its rapid metabolism in the liver makes it ineffective when delivered orally or parenterally (Bruggemier, 1986;Kadam et al., 2008). In contrast, synthetic androgens such as 17α-methyltestosterone (17α-MT) are more active having prolonged stability after injection or oral administration (Behre et al., 2004). There are many reports on the use of 17α-MT for sex reversal in fish (Pompa and Green, 1990;Pandian and Sheela, 1995). ...
Chitosan nanoparticles conjugated with 17α-methyltestosterone (CS + MT) were used for studying their effect on the testicular development of Clarias batrachus during different reproductive phases. The size of chitosan nanoparticles was 127.2 nm and the nano-conjugated 17α methyltestosterone (17α-MT) was 196.1 nm (20 mg/100 ml of chitosan). Single injections of CS + MT at different doses such as 0.01, 0.1 and 0.5 μg/g body weight were administered to adults during the pre-spawning, spawning and post-spawning phase. Nano-conjugated steroid was effective at the lower dose; showing an increase in the Gonadosomatic Index (GSI) and 11-ketotestosterone level compared to the control group. Histological observations confirmed the dose-dependent advancement in spermatogenesis. These findings indicate the possibility of using CS + MT for enhancing gonadal maturity of C. batrachus.
... Tables 3 and 4 display surveillance recommendations for trans men and women. Hormones should be carefully monitored to avoid a prolonged hypogonadal state if dosing is too low, which can lead to significant losses in bone mineral density; and to avoid exposures to supraphysiologic levels, which could have significant physiologic and metabolic effects (24). ...
Many transgender men and women seek hormone therapy as part of the transition process. Exogenous testosterone is used in transgender men to induce virilization and suppress feminizing characteristics. In transgender women, exogenous estrogen is used to help feminize patients, and antiandrogens are used as adjuncts to help suppress masculinizing features. Guidelines exist to help providers choose appropriate candidates for hormone therapy, and act as a framework for choosing treatment regimens and managing surveillance in these patients. Cross-sex hormone therapy has been shown to have positive physical and psychological effects on the transitioning individual and is considered a mainstay treatment for many patients. Bone and cardiovascular health are important considerations in transgender patients on long-term hormones, and care should be taken to monitor certain metabolic indices while patients are on cross-sex hormone therapy.
... Subdermal testosterone pellets were the first effective formulation for androgen replacement therapy, developed in the 1940s (20). Testosterone pellets consist of crystalline testosterone and are created through high-temperature molding and designed for consistent and prolonged release (21). Absorption occurs through uniform erosion of the pellet's surface in correspondence to the solubility of testosterone in extracellular fluid. ...
... The most common adverse event is pellet extrusion, with an incidence of 10% (21). Other adverse events include site infections, bleeding, and fibrosis at the insertion site (12). ...
... The first transdermal patches found to be efficacious were scrotal patches in the 1980s (21). This application allowed for maximal absorption through a thin-skinned area. ...
The goal of testosterone replacement therapy (TRT) is to return serum testosterone levels to within physiologic range and improve symptoms in hypogonadal men. Some of the symptoms aimed to improve upon include decreased libido, erectile dysfunction, infertility, hot flashes, depressed mood, and loss of muscle mass or hair. Clinical use of testosterone for replacement therapy began approximately 70 years ago. Over the decades, numerous preparations and formulations have been developed primarily focusing on different routes of delivery and thus pharmacokinetics (PKs). Currently the routes of delivery approved for use by the United States Food and Drug Administration encompasses buccal, nasal, subdermal, transdermal, and intramuscular (IM). Many factors must be considered when a clinician is choosing the most correct formulation for a patient. As this decision depends highly on the patient, active patient participation is important for effective selection. The aim of this review is to describe and compare all testosterone preparations currently available and approved by the United States Food and Drug Administration. Areas of focus will include pharmacology, PKs, adverse effects, and specifics related to individual delivery routes.
... Currently, they are the main forms of injections used in the clinic. 5,6 However, intramuscular injections often yield supra-and subphysiological testosterone levels. ...
The current investigation aimed to evaluate the transdermal potential of novel testosterone propionate (TP) ethosomes and liposomes prepared by surfactant modification. The effect of hexadecyl trimethyl ammonium bromide and cremophor EL-35 on the particle size and zeta potential of the prepared vesicles was investigated. The entrapment efficiency and stability, as well as in vitro and in vivo skin permeation, were studied with the various techniques, such as differential scanning calorimetry, confocal laser scanning microscopy, transmission electron microscopy, dynamic light scattering, and so on. The results indicated that the ethosomes were defined as spherical, unilamellar structures with low polydispersity (0.100 ± 0.015) and nanometric size (156.5 ± 3.5 nm). The entrapment efficiency of TP in ethosomal and liposomal carriers was 92.7% ± 3.7% and 64.7% ± 2.1%, respectively. The stability profile of the prepared TP ethosomal system assessed for 120 days revealed very low aggregation and very low growth in vesicular size. TP ethosomes also provided an enhanced transdermal flux of 37.85 ± 2.8 μg/cm²/hour and a decreased lag time of 0.18 hours across mouse skin. The skin permeation efficiency of the TP ethosomes as further assessed by confocal laser scanning microscopy revealed enhanced permeation of rhodamine red-loaded formulations to the deeper layers of the skin (260 μm) than that of the liposomal formation (120 μm).
