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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
New TRT user and frustrated on 1.62 Gel
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<blockquote data-quote="madman" data-source="post: 239817" data-attributes="member: 13851"><p><strong>Testosterone Therapy: Transdermal Androgens (2017)</strong></p><p><em>Jonas Čeponis, Pavan Yadav, Ronald S. Swerdloff, and Christina Wang</em></p><p></p><p></p><p><strong>Introduction</strong></p><p></p><p><em>Transdermal administration of a medication is a method for delivering prescribed doses of the drug through the intact skin. <strong>The drug can be introduced through an attached patch with a drug reservoir, through a permeable membrane, or directly applied to the skin in the form of a gel or lotion. The subcutaneous tissues serve as a depot as small doses are being constantly released into the systemic circulation, thus achieving sustained serum levels. There may be a small peak of testosterone within the first few hours after application and then the transdermal testosterone preparation usually maintains serum testosterone within the adult male range for 24 h. </strong>Transdermal delivery systems have been available as patches or sprays for estrogen replacement in women and as patches, gels, or lotions for androgen replacement in men [1, 2]. Transdermal testosterone gels are the most commonly used formulation to treat hypogonadism in the US and several other countries [3, 4], while long-acting injectables are more widely used in European countries. Some acceptability studies have shown that men of different ages prefer topical gel products due to ease of use and avoidance of the more severe skin irritation seen with reservoir-based “patch” delivery systems [5]. Currently available topical products vary by their application methods and dosage adjustment strategies and are generally expensive. The growing availability of generic agents may lead to decreased costs and improved affordability.<strong> This chapter describes the advantages and disadvantages of currently available transdermal testosterone preparations, as well as recommendations for treatment and dosing strategies for hypogonadal men.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>Advantages and Disadvantages of Transdermal Testosterone Compared With Other Delivery Systems</strong></p><p></p><p><em><strong>Table 11.1 shows the advantages and disadvantages of transdermal testosterone preparations. Transdermal testosterone preparations usually result in less fluctuation of serum testosterone levels compared with oral preparations [6, 7]. However, recent studies suggest that serum testosterone varied with fluctuations within a day in older men after testosterone gel application [8].</strong> <strong><u>Furthermore, increases in serum testosterone levels may occur independently of time-related pharmacokinetics in individual patients</u>: these seemingly random measures may be related to changes in blood flow due to exercise and skin temperature. For some transdermal testosterone preparations, depending on the time of gel application, the serum testosterone profile mimics normal circadian variation observed in healthy young men [9]. </strong>Additionally, transdermal administration helps to avoid first-pass liver metabolism and has less effect on liver-secreted proteins such as lipoproteins. <strong>Slow-sustained delivery of testosterone may help to avoid adverse effects related to peaks and troughs of testosterone concentrations commonly seen with injectables or oral administration, which may result in adverse effects such as acne, mood swings, and erythrocytosis [6, 10]. </strong>It has also been suggested that transdermal preparations may have a better cardiovascular safety profile than injectables [11]. A discussion on testosterone replacement therapy and cardiovascular disease risk is found in Chap. 17</em></p><p></p><p></p><p><strong>Table 11.1 Advantages and disadvantages of transdermal testosterone for replacement in hypogonadal men</strong></p><p>[ATTACH=full]27150[/ATTACH]</p><p></p><p></p><p></p><p></p><p><em>Preliminary data also show lower levels of spermatogenesis suppression in comparison with injectable treatment [12], but these findings need to be validated in larger cohorts.</em></p><p><em></em></p><p><em><strong>Skin irritation is a common side effect with all transdermal preparations but is much more pronounced with testosterone patches. </strong>Additionally, as the pricing level of these transdermal preparations is generally higher than commonly available short-acting injectables (i.e., testosterone enanthate and cypionate), this makes these user-friendly methods less affordable to many hypogonadal men. <strong>Specific shortcomings for the different types of transdermal preparations will be discussed in detail in respective sections.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>Transdermal Gels</strong></p><p></p><p><em>Transdermal gels are becoming increasingly popular and have surpassed injectable preparations as the most common form of testosterone replacement in the US and United Kingdom over the past decade [3].</em></p><p><em></em></p><p><em>Testosterone gel is applied directly to the skin avoiding the requirement of a patch or a membrane and resulting in less skin irritation than that observed with transdermal patches. Testosterone gel is available as prepackaged single-dose packets or multi-dose pumps. <strong>Some manufacturers provide both options (Table 11.2). Most testosterone gel preparations are formulated as hydroalcoholic gel, others use other enhancers in lotions. When applied to the skin, testosterone is absorbed into the stratum corneum over time, which serves as a reservoir. Testosterone is slowly released into the circulatory system over several hours resulting in steady-state serum levels of the hormone [22]. <u>The release of testosterone from the reservoir continues for about 24 h</u>.<u> Only approximately 10 % of the testosterone applied on the skin surface is absorbed into the circulatory system during a 24-h period</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong>Table 11.2 Characteristics of some testosterone gels (based on manufacturer’s label) </strong></em></p><p><em><strong>[ATTACH=full]27151[/ATTACH]</strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong><u>The gel is applied to a large area of the skin, usually on the arms and shoulders, and the area of application may affect the absorption of testosterone</u> [23].</strong> <strong>Long-term studies with testosterone gel have shown that steady and relatively consistent serum levels of testosterone levels are attained [7], which results in significant improvement of sexual and body composition parameters [24–26].</strong></em></p><p><em></em></p><p><em>Several formulations of testosterone gels are available on the market [1, 2, 27]. <strong>Currently available gels vary in testosterone concentration and are usually applied once a day. Their pharmacokinetic profiles are also similar: Androgel 1 %®/ Testogel 1 %® [7], Testim® 1 % [28], Axiron®2 % [29] Fortesta Gel® 2 %/Tostran® 2 % [30], and Androgel 1.62 %® [31]. </strong>These transdermal preparations have been proven to be efficient in normalizing serum levels, as well as the reversal of androgen deficiency symptoms for long periods of treatment [24], and have been considered an acceptable form of testosterone substitution by users [5]. <strong>The maximum concentration of testosterone achieved is variable depending on the preparation but usually within 2–5 h of application and is maintained for 24 h. <u>When applied in the morning, a profile somewhat similar to the circadian rhythm in healthy men is maintained</u>.</strong> Recent studies in older hypogonadal men have shown that after testosterone gel application there were large fluctuations in serum testosterone concentration both within and between patients [8]. <strong>Skin structural differences may be one of the causes of these significant variations in the bioavailability of the drug, which poses challenges in predicting the effectiveness of medication and determining an adequate dose, as well as an appropriate time for testing serum testosterone levels [8, 32].</strong> <strong>Nontime-dependent pulses of serum testosterone also occur in relation to exercise and skin temperature. Both factors may be mediated through changes in dermal blood flow.</strong> Another important issue is the possibility of blood sample contamination when it is drawn at the gel application site, which has led to a spurious increase in measured testosterone levels [33].<strong> A sampling of blood after testosterone gel applications should be done away from the application sites.</strong></em></p><p><em></em></p><p><em>Different sites for drug application have been studied with various degrees of success. <strong><u>Scrotal skin is thin and highly vascular hence it leads to better and sustained absorption of testosterone, which made it one of the early targets in the development of transdermal patch preparations</u>. <u>Scrotal application is not used for the gels because of the relatively small area where the gel can be applied</u>.</strong> <strong>Application on the axillary region may enhance absorption and may cause less skin transfer, and has been shown to be beneficial to patients who failed other transdermal preparations in a single study [34].</strong> However, because the skin is sensitive in the area, skin irritation, edema, and erythema have been observed as in other transdermal preparations [35]. <strong>On the other hand, even though the application of 1.62 % testosterone gel on abdominal skin led to 30–40 % lower availability than on the upper arms and shoulders, application on all of these sites resulted in eugonadal testosterone levels [36]. While a selection of an application site may not be an issue for most patients, those failing to achieve sufficient systemic levels may benefit from a change of site.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Additionally, some gels include emollients that prevent skin drying and ensure better testosterone absorption. </strong>There are data to suggest that this may help achieve better bioavailability and higher serum concentrations [37].<strong> <u>Differences in gel formulations and their pharmacokinetic profiles are a reason why gels cannot be used and dosed interchangeably</u>. <u>Therefore, it is recommended to follow specific instructions on sites for application and dosing of the drug provided in the labeling</u>. Dosing information and recommendations for some of the preparations are presented in Table 11.2.</strong> It should be noted that some gels are marketed in various countries under different names but are in fact produced by the same manufacturer.</em></p><p><em></em></p><p><em>As most of the gels contain alcohol, they are flammable, therefore precautionary measures are required. <strong>More importantly, there is a risk of skin-to-skin transfer of the gel to other persons in close contact. This is particularly important in women and children whose endogenous testosterone levels are low. </strong>To avoid this risk, hands must be washed with soap and water after the application of the gel. Once applied, the gel on the application site dries within several minutes and should be kept covered with clothes at all times or washed thoroughly with soap and water to remove any residue of gel if close skin-to-skin contact is anticipated [38]. <strong>However, showering within a short period of time (15–30 min) after the application of the gel may result in lower serum testosterone levels [39] and should be avoided. <u>Manufacturer recommendations for a minimum time before washing after application vary from 2 to 5 h among different formulations</u> (Table 11.2). <u>It must be noted that washing within that time resulted in approximately 30 % decreased bioavailability of testosterone, however, serum testosterone levels within the normal range were sustained</u>. </strong>Even with these precautionary recommendations in place, skin-to-skin transfer continues to pose challenges including reports of virilization of prepubertal children [40–43]. <strong>Therefore, physicians prescribing the use of transdermal testosterone gels or lotions must discuss with the participants the risks of transfer and the measures to prevent the transfer, as well as other potential adverse events of testosterone discussed in Chaps. 14, 16, 17.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Elevation of DHT has been found to be more pronounced in transdermal gels compared to other formulations possibly due to high 5-α reductase expression in the skin (especially when applied on scrotal skin) [7].</strong> <strong>In contrast to transdermal patches, a much larger area of skin is exposed to testosterone, thus leading to an increase in systemic DHT concentration. </strong>Because DHT is the main androgen in the prostate, it may have more stimulating effects on prostate growth. <strong>While the serum DHT to testosterone ratio is increased after transdermal testosterone application, there are no data showing the association between higher DHT levels and adverse effects on prostatic hyperplasia or cancer of the prostate [17].</strong> Elevation of DHT has been associated with a higher risk of cardiovascular events in observational studies [44] but needs to be systematically assessed in large-scale long-term studies.<strong> On the other hand, this moderate increase in DHT levels that is seen in transdermal gel users usually remains within the reference range limits in healthy adult men and has not been related to adverse effects on primary DHT targets, such as the prostate.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Another important drawback of currently available testosterone gels is their cost. Compounded testosterone may be one of the alternatives but is not recommended as there is no quality control standard for compounded medications. </strong>A recent study from Canada reported large variations in testosterone levels in these preparations [45] and standardization strategies have been suggested [46]. <strong>The increasing availability of generic testosterone gels may lead to decreased costs and improved affordability in the near future.</strong></em></p><p></p><p><strong><em>As discussed above, there are distinct differences among the various transdermal preparations. <u>Decisions on the most appropriate treatment strategy should be based on an individual patient profile and personal preferences after all available strategies are discussed</u>. <u>It is of utmost importance that the patient is comfortable with the selected treatment as compliance is one of the major challenges with long-term treatment of chronic asymptomatic conditions</u> [47].</em></strong></p></blockquote><p></p>
[QUOTE="madman, post: 239817, member: 13851"] [B]Testosterone Therapy: Transdermal Androgens (2017)[/B] [I]Jonas Čeponis, Pavan Yadav, Ronald S. Swerdloff, and Christina Wang[/I] [B]Introduction[/B] [I]Transdermal administration of a medication is a method for delivering prescribed doses of the drug through the intact skin. [B]The drug can be introduced through an attached patch with a drug reservoir, through a permeable membrane, or directly applied to the skin in the form of a gel or lotion. The subcutaneous tissues serve as a depot as small doses are being constantly released into the systemic circulation, thus achieving sustained serum levels. There may be a small peak of testosterone within the first few hours after application and then the transdermal testosterone preparation usually maintains serum testosterone within the adult male range for 24 h. [/B]Transdermal delivery systems have been available as patches or sprays for estrogen replacement in women and as patches, gels, or lotions for androgen replacement in men [1, 2]. Transdermal testosterone gels are the most commonly used formulation to treat hypogonadism in the US and several other countries [3, 4], while long-acting injectables are more widely used in European countries. Some acceptability studies have shown that men of different ages prefer topical gel products due to ease of use and avoidance of the more severe skin irritation seen with reservoir-based “patch” delivery systems [5]. Currently available topical products vary by their application methods and dosage adjustment strategies and are generally expensive. The growing availability of generic agents may lead to decreased costs and improved affordability.[B] This chapter describes the advantages and disadvantages of currently available transdermal testosterone preparations, as well as recommendations for treatment and dosing strategies for hypogonadal men.[/B][/I] [B]Advantages and Disadvantages of Transdermal Testosterone Compared With Other Delivery Systems[/B] [I][B]Table 11.1 shows the advantages and disadvantages of transdermal testosterone preparations. Transdermal testosterone preparations usually result in less fluctuation of serum testosterone levels compared with oral preparations [6, 7]. However, recent studies suggest that serum testosterone varied with fluctuations within a day in older men after testosterone gel application [8].[/B] [B][U]Furthermore, increases in serum testosterone levels may occur independently of time-related pharmacokinetics in individual patients[/U]: these seemingly random measures may be related to changes in blood flow due to exercise and skin temperature. For some transdermal testosterone preparations, depending on the time of gel application, the serum testosterone profile mimics normal circadian variation observed in healthy young men [9]. [/B]Additionally, transdermal administration helps to avoid first-pass liver metabolism and has less effect on liver-secreted proteins such as lipoproteins. [B]Slow-sustained delivery of testosterone may help to avoid adverse effects related to peaks and troughs of testosterone concentrations commonly seen with injectables or oral administration, which may result in adverse effects such as acne, mood swings, and erythrocytosis [6, 10]. [/B]It has also been suggested that transdermal preparations may have a better cardiovascular safety profile than injectables [11]. A discussion on testosterone replacement therapy and cardiovascular disease risk is found in Chap. 17[/I] [B]Table 11.1 Advantages and disadvantages of transdermal testosterone for replacement in hypogonadal men[/B] [ATTACH type="full" alt="Screenshot (18796).png"]27150[/ATTACH] [I]Preliminary data also show lower levels of spermatogenesis suppression in comparison with injectable treatment [12], but these findings need to be validated in larger cohorts. [B]Skin irritation is a common side effect with all transdermal preparations but is much more pronounced with testosterone patches. [/B]Additionally, as the pricing level of these transdermal preparations is generally higher than commonly available short-acting injectables (i.e., testosterone enanthate and cypionate), this makes these user-friendly methods less affordable to many hypogonadal men. [B]Specific shortcomings for the different types of transdermal preparations will be discussed in detail in respective sections.[/B][/I] [B]Transdermal Gels[/B] [I]Transdermal gels are becoming increasingly popular and have surpassed injectable preparations as the most common form of testosterone replacement in the US and United Kingdom over the past decade [3]. Testosterone gel is applied directly to the skin avoiding the requirement of a patch or a membrane and resulting in less skin irritation than that observed with transdermal patches. Testosterone gel is available as prepackaged single-dose packets or multi-dose pumps. [B]Some manufacturers provide both options (Table 11.2). Most testosterone gel preparations are formulated as hydroalcoholic gel, others use other enhancers in lotions. When applied to the skin, testosterone is absorbed into the stratum corneum over time, which serves as a reservoir. Testosterone is slowly released into the circulatory system over several hours resulting in steady-state serum levels of the hormone [22]. [U]The release of testosterone from the reservoir continues for about 24 h[/U].[U] Only approximately 10 % of the testosterone applied on the skin surface is absorbed into the circulatory system during a 24-h period[/U]. Table 11.2 Characteristics of some testosterone gels (based on manufacturer’s label) [ATTACH type="full" alt="Screenshot (18797).png"]27151[/ATTACH] [U]The gel is applied to a large area of the skin, usually on the arms and shoulders, and the area of application may affect the absorption of testosterone[/U] [23].[/B] [B]Long-term studies with testosterone gel have shown that steady and relatively consistent serum levels of testosterone levels are attained [7], which results in significant improvement of sexual and body composition parameters [24–26].[/B] Several formulations of testosterone gels are available on the market [1, 2, 27]. [B]Currently available gels vary in testosterone concentration and are usually applied once a day. Their pharmacokinetic profiles are also similar: Androgel 1 %®/ Testogel 1 %® [7], Testim® 1 % [28], Axiron®2 % [29] Fortesta Gel® 2 %/Tostran® 2 % [30], and Androgel 1.62 %® [31]. [/B]These transdermal preparations have been proven to be efficient in normalizing serum levels, as well as the reversal of androgen deficiency symptoms for long periods of treatment [24], and have been considered an acceptable form of testosterone substitution by users [5]. [B]The maximum concentration of testosterone achieved is variable depending on the preparation but usually within 2–5 h of application and is maintained for 24 h. [U]When applied in the morning, a profile somewhat similar to the circadian rhythm in healthy men is maintained[/U].[/B] Recent studies in older hypogonadal men have shown that after testosterone gel application there were large fluctuations in serum testosterone concentration both within and between patients [8]. [B]Skin structural differences may be one of the causes of these significant variations in the bioavailability of the drug, which poses challenges in predicting the effectiveness of medication and determining an adequate dose, as well as an appropriate time for testing serum testosterone levels [8, 32].[/B] [B]Nontime-dependent pulses of serum testosterone also occur in relation to exercise and skin temperature. Both factors may be mediated through changes in dermal blood flow.[/B] Another important issue is the possibility of blood sample contamination when it is drawn at the gel application site, which has led to a spurious increase in measured testosterone levels [33].[B] A sampling of blood after testosterone gel applications should be done away from the application sites.[/B] Different sites for drug application have been studied with various degrees of success. [B][U]Scrotal skin is thin and highly vascular hence it leads to better and sustained absorption of testosterone, which made it one of the early targets in the development of transdermal patch preparations[/U]. [U]Scrotal application is not used for the gels because of the relatively small area where the gel can be applied[/U].[/B] [B]Application on the axillary region may enhance absorption and may cause less skin transfer, and has been shown to be beneficial to patients who failed other transdermal preparations in a single study [34].[/B] However, because the skin is sensitive in the area, skin irritation, edema, and erythema have been observed as in other transdermal preparations [35]. [B]On the other hand, even though the application of 1.62 % testosterone gel on abdominal skin led to 30–40 % lower availability than on the upper arms and shoulders, application on all of these sites resulted in eugonadal testosterone levels [36]. While a selection of an application site may not be an issue for most patients, those failing to achieve sufficient systemic levels may benefit from a change of site. Additionally, some gels include emollients that prevent skin drying and ensure better testosterone absorption. [/B]There are data to suggest that this may help achieve better bioavailability and higher serum concentrations [37].[B] [U]Differences in gel formulations and their pharmacokinetic profiles are a reason why gels cannot be used and dosed interchangeably[/U]. [U]Therefore, it is recommended to follow specific instructions on sites for application and dosing of the drug provided in the labeling[/U]. Dosing information and recommendations for some of the preparations are presented in Table 11.2.[/B] It should be noted that some gels are marketed in various countries under different names but are in fact produced by the same manufacturer. As most of the gels contain alcohol, they are flammable, therefore precautionary measures are required. [B]More importantly, there is a risk of skin-to-skin transfer of the gel to other persons in close contact. This is particularly important in women and children whose endogenous testosterone levels are low. [/B]To avoid this risk, hands must be washed with soap and water after the application of the gel. Once applied, the gel on the application site dries within several minutes and should be kept covered with clothes at all times or washed thoroughly with soap and water to remove any residue of gel if close skin-to-skin contact is anticipated [38]. [B]However, showering within a short period of time (15–30 min) after the application of the gel may result in lower serum testosterone levels [39] and should be avoided. [U]Manufacturer recommendations for a minimum time before washing after application vary from 2 to 5 h among different formulations[/U] (Table 11.2). [U]It must be noted that washing within that time resulted in approximately 30 % decreased bioavailability of testosterone, however, serum testosterone levels within the normal range were sustained[/U]. [/B]Even with these precautionary recommendations in place, skin-to-skin transfer continues to pose challenges including reports of virilization of prepubertal children [40–43]. [B]Therefore, physicians prescribing the use of transdermal testosterone gels or lotions must discuss with the participants the risks of transfer and the measures to prevent the transfer, as well as other potential adverse events of testosterone discussed in Chaps. 14, 16, 17. Elevation of DHT has been found to be more pronounced in transdermal gels compared to other formulations possibly due to high 5-α reductase expression in the skin (especially when applied on scrotal skin) [7].[/B] [B]In contrast to transdermal patches, a much larger area of skin is exposed to testosterone, thus leading to an increase in systemic DHT concentration. [/B]Because DHT is the main androgen in the prostate, it may have more stimulating effects on prostate growth. [B]While the serum DHT to testosterone ratio is increased after transdermal testosterone application, there are no data showing the association between higher DHT levels and adverse effects on prostatic hyperplasia or cancer of the prostate [17].[/B] Elevation of DHT has been associated with a higher risk of cardiovascular events in observational studies [44] but needs to be systematically assessed in large-scale long-term studies.[B] On the other hand, this moderate increase in DHT levels that is seen in transdermal gel users usually remains within the reference range limits in healthy adult men and has not been related to adverse effects on primary DHT targets, such as the prostate. Another important drawback of currently available testosterone gels is their cost. Compounded testosterone may be one of the alternatives but is not recommended as there is no quality control standard for compounded medications. [/B]A recent study from Canada reported large variations in testosterone levels in these preparations [45] and standardization strategies have been suggested [46]. [B]The increasing availability of generic testosterone gels may lead to decreased costs and improved affordability in the near future.[/B][/I] [B][I]As discussed above, there are distinct differences among the various transdermal preparations. [U]Decisions on the most appropriate treatment strategy should be based on an individual patient profile and personal preferences after all available strategies are discussed[/U]. [U]It is of utmost importance that the patient is comfortable with the selected treatment as compliance is one of the major challenges with long-term treatment of chronic asymptomatic conditions[/U] [47].[/I][/B] [/QUOTE]
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New TRT user and frustrated on 1.62 Gel
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