madman
Super Moderator
ABSTRACT
Introduction
Testosterone deficiency (TD) is relatively common in aging men, affecting around 2% of the general population. Testosterone replacement therapy (TRT) represents the most common medical approach for subjects who are not interested in fathering.
Areas covered
This review summarizes advances in TRT, including approved or non-approved pharmacological options to overcome TD. When possible, a meta-analytic approach was applied to minimize subjective and biased interpretations of the available data.
Expert opinion
During the last decade, several new TRT formulations have been introduced on the market, including oral, transdermal, and parenteral formulations. Possible advantages and limitations have been discussed appropriately. Anti-estrogens, including selective estrogen modulators or aromatase inhibitors still represent further possible off-label options. However, long-term side effects on sexual function and bone parameters constitute major limitations. Glucagon-like peptide 1 analogues can be an alternative option in particular for massive obesity-associated TD. Weight loss obtained through lifestyle modifications including diet and physical exercise should be encouraged in all overweight and obese patients. A combination of TRT and lifestyle changes can be considered in those subjects in whom a reversal of the condition cannot be expected in a reasonable time frame.
3. Approved medications for the treatment of TD
Considering that there are no major, recent developments on Gns in the treatment of male secondary HG, this topic will not be covered in this review, also because it has been recently covered by us elsewhere [15].
During the last ten years several new formulations of the testicular hormone T for TRT have been available (see also Figure 1). TRT can be obtained in hypogonadal men through several routes of administration, including oral, parenteral, transdermal, intranasal, and implants. The specific analysis of the well-established TRT preparations is behind the aim of the present paper and has been revised elsewhere [15,16]. Similar considerations should be done for patient evaluation and monitoring during TRT therapy [5,7,9–11]. Briefly, although no general agreement has been reported in the different guidelines, patients should be evaluated after three months of treatment and then every six months or annually, according to patient characteristics and blood examinations [5,7,9–11].
3.1. New oral formulation for TRT
The oral route for drug delivery is often considered the most convenient way for several reasons, including safety considerations, convenience of administration, suitability for long term use, and flexibility in dosage adjustment. Hence, it is the one most often desired, even at the patient level [17–20]. Native T administered via oral route passes through the small intestinal wall and reaches the liver before being transported via the bloodstream to its target site. However, after the first-pass through the liver, T is substantially metabolized into inactive byproducts, and, therefore, only a minimal amount reaches the systemic circulation [16–18,20]. Its alkylation in the 17α position increases its bioavailability, but it results in liver toxicity [15,16,19]. Adding a mid-chain length fatty acid at the 17β position of the D ring strongly increases its lipophilicity, allowing absorption in part through the lymphatic system of the small intestine, therefore bypassing liver metabolism and, finally reaching the internal jugular or subclavian veins [16,21]. Although a T undecanoate (TU) preparation (Andriol®) has been available in Europe for more than 50 years, it was never approved by the United States Food and Drug Administration (FDA) because of its erratic absorption, which is essentially possible only when administered with fatty meals. In the last ten years, several other lipid-based formulations of native T were developed and introduced on the market with improved efficacy than Andriol (Table 1).
The first FDA-approved TU preparation is JATENZO (Tolmar Pharmaceuticals, Inc., Buffalo Grove, IL, USA), whose absorption is based on a self-emulsifying delivery system (SEDDS) ([22], Table 1). SEDDS is a technology consisting of a mixture of lipophilic and lipophobic matrice able to increase the solubility and bioavailability of poorly soluble substances, such asTU. Endogenous esterases allow the liberation of T from the prodrug TU. JATENZO is available in three dosing formulations (158, 198, and 237 mg) that should be taken b.i.d. and need titration. At variance with Andriol, it does not need a fat meal for absorption, although it should be taken with meals. Two open-label randomized trials, reviewed elsewhere [23,24],demonstrated that eugonadal T levels were obtained in more than 80% of the treated hypogonadal men (total T <10.4 nmol/L) for up to one year. In addition, JATENZO was able to improve body composition, bone mineral density, at the spine, and hip, mood and sexual complaints (Psychosexual Daily Questionnaire, PDQ), similar to what was observed with the comparator (T gel formulations) [23,24]. Considering that sex hormone binding globulin (SHBG) decreased more in the JATENZO arm than in the T gel arm, calculated free T levels were higher in the former arm [23]. Accordingly, the mean increase of hematocrit was higher (6.8%) in the JATENZO arm than in the T gel arm (3.1%). A 12-month extension of a previous one-year JATENZO arm [25] further demonstrated significant increases from baseline in sexual enjoyment,mood, and satisfaction with erection [26]. In addition, an open-label study enrolling a small number of hypogonadal subjects previously treated with other T formulations, suggests that patient satisfaction was higher upon JATENZO than with previous other routes of T administration [27]
Another TU preparation, based on a different SEDDS technology (predigested triglycerides), is Tlando (Lipocine, Salt Lake City,UT, USA), approved by the FDA in March 2022 (Table 1). At variance with JATENZO, Tlando does not need dose titration and is available in 112.5 mg capsules that should be taken twice daily with regular meals, without the need for a high-fat content. In a small trial enrolling 95 hypogonadal men (total T<10.4 nmol/L), eugonadism was reached in up to 80% of the treated subjects with a 450 mg daily dose for 28 days. In a preliminary open-label study (reviewed in [28,29]) involving 315 hypogonadal subjects for 52 weeks, Tlando was not inferior to topic T in improving patient-reported outcomes in sexual and mental domains with an equal proportion of subjects reaching the eugonadal state. An increase of 3.2% in hematocrit was observed after dosing 450 mg of Tlando for 4 months [30]
The most recent FDA-approved TU preparation is Kyzatrez (Marius Pharmaceuticals, Raleigh, NC; USA), a TU preparation dissolved in a combination of lipids and other solubilizers contained in a softgel capsule. It has been approved in three dosages: 100, 150, and 200 mg (Table 1), with the recommended starting dose of 200 mg twice a day at meals, followed by dose titration [29]. It is reported that this formulation is able to normalize serum T in up to 88% of the treated hypogonadal subjects [29].
Common side-effects of these recently approved three TU formulations are mild gastrointestinal symptoms along with a 2–5 mm HG increase in systolic 24-hour ambulatory blood pressure (ABP) and a minor elevation in diastolic blood pressure (BP)[23,24,28,29]. In a study with Tlando, a greater increase in ABP was observed in those showing a more sustained increase in hematocrit upon TU dosing, whereas in a study with Kyzatrez no relationship was observed [31]. In the Kyzatrez study [31], the ABP increase was relatively less evident than in other studies and greater in those taking anti-hypertensive medications [31].
Considering that in recent meta-analyses of randomized controlled trials (RCTs) a TRT-induced BP increase was never observed [32,33], these results are surprising. However, a modest (0.3 mm Hg), although significant, increase in mean systolic blood pressure was observed in the recently published TRAVERSE study, a large trial investigating the cardiovascular(CV) effects of T gel administration in subjects at high CV risk [34]. Interestingly, however, in that trial no signal for an increased rate of major CV events (MACE, primary endpoint) was reported in the treated arm [34]. Hence, it is possible that these modest increases in BP are clinically insignificant. Nonetheless, the FDA required a black box warning that these drugs can induce a BP rise that might increase the risk of MACE. Due to this risk, the use of oral TU preparations should be limited to hypogonadal conditions associated with structural or genetic etiologies (the so called organic hypogonadism; see before).
3.2. New nasal formulation for TRT
The nasal mucosa shows interesting properties for drug delivery because it is not subject to first-pass metabolism, therefore allowing high bioavailability of the applied medications [35].Natesto (Acerus Biopharma Inc.,) is a nasal formulation of T for treating male hypogonadism, approved by the FDA almost 10years ago. Natesto nasal gel is available as a metered-dose pump. One pump actuation delivers 5.5 mg of T. The recommended dose of Natesto is 11 mg of T (2 pump actuation; 1 actuation per nostril) administered intranasally three times daily for a total daily dose of 33 mg. Natesto should be administered once in the morning, once in the afternoon, and once in the evening (6 to 8 hours apart), preferably at the same time each day [36]. At this recommended dosage, 90% of hypogonadal subjects (total T <10.4 nmol/L) reached eugonadism in a ninety day, randomized, open-label study [37]. A phase IV, prospective, randomized, non-blinded, multi-institutional study is ongoing to compare results with the aforementioned dosage of Natesto and intramuscular administration of 200 mg of T cypionate (TC) twice a month (ClinicalTrials.gov ID NCT04439799, ClinicalTrials.gov) In a preliminary release of that study, Natesto administration for four months was associated with a lower risk of polycythemia and an overall lower hematocrit increase thanTC [38]. This positive finding could be associated with the intrinsic properties of Natesto, i.e. a rapid, transient, rise and fall of circulating T upon nasal administration [36]. For the aforementioned characteristics it was postulated that nasal T (NT) administration could be associated with lower suppressive activity on the HPT axis and, therefore, on spermatogenesis. In a short-duration (six months) single-center, uncontrolled trial, NT(11 mg t.i.d) maintained spermatogenesis in the majority of the 60 hypogonadal (T < 12 nmol/L) men enrolled, reducing in a non-significant manner serum Gn levels [39,40]. According to this hypothesis, NT induced, after 16 weeks, a lower suppression of 17-hydroxyprogesterone (17-OHP, taken as a surrogate marker of testicular activity) than other T preparations, i.e. subcutaneous pellets and TC [41]. Considering that an increase in hematocrit and reduced fertility are the major problems with TRT [16], these results could be of interest. However, their uncontrolled nature, short duration, and enrollment in small cohort of hypogonadal subjects are the main limitations of the aforementioned studies that need confirmation. In addition,the number of patients who dropped out of the study [40] due to azoospermia or severe oligospermia was not included in the final analysis. An alternative explanation of the positive results on hematocrit and spermatogenesis is that NT has lower biological activity than other T preparations, therefore resulting inless effectiveness in rescuing hypogonadal symptoms. However,two uncontrolled trials reported a significant increase in International Index of Erectile Function (IIEF) scoring over baseline [40,42] which was in line to that derived from available meta-analyses [43,44]. The most common side effects of Natesto are associated with its route of administration and include headache, rhinorrhea, epistaxis, nasal discomfort, and nasopharyngitis [36].
3.3. New intramuscular formulation for TRT
Although TU intramuscular formulations have been available worldwide for more than 20 years and are approved in more than 100 countries and marketed in more than 80 parts of the world, including Europe (Nebido, originally by Bayer AG, Kaiser Wilhelm-Allee 1 51,373 Leverkusen, Germany [45]), in the USA injectable TU was FDA-approved only in 2014 with the brandname AVEED (Endo Pharmaceuticals Solutions Inc.). The main difference between Nebido and AVEED is in their single-use vial dose, i.e. 1000 mg in 4 mL for the former and 750 mg in 3 mL for the latter. At variance with Nebido, following the first intramuscular injection of 3 mL of AVEED (750 mg), a second 3 mL dose isinjected four weeks later, and then 3 mL is injected every ten weeks thereafter. The approval of AVEED is based on data from an 84-week Phase 3 trial of hypogonadal men in the USA. The men enrolled in the study had an average age of 54 years and a serum total T level of less than 10.4 nmol/l. In the Phase 3 study, AVEED increased mean serum T levels, maintaining them for up to 10 weeks at a steady state (between weeks 14–24) [46]. Clinical experience in the USA with TU 750 mg provides evidence for good patient satisfaction and persistence with treatment, together with a favorable safety profile [47]. However, its prescription is available only through a Risk Evaluation and Mitigation Strategies (REMS) program. In addition, AVEED carries a black box warning for serious pulmonary oil microembolism(POME) reactions (the urge to cough, dyspnea, throat tightening,chest pain, dizziness, syncope) and episodes of anaphylaxis. However, of the 633 individual case safety reports in the Endo Pharmaceuticals Inc. safety database, 28 spontaneously reported adverse events were classified as POME, for a yearly spontaneously reported adverse event per injection rate of <0.1% [48]. Most (21/22) events resolved, and of those with a resolution time reported, most (13/17) were resolved in less than 30 minutes (32).More than 60% (13/21) of patients required no medical intervention [48]. In a meta-analysis of injectable TU preparations, it was found that in either controlled or uncontrolled trials, injectable TU was associated with a reduction of fat mass and HbA1c and an improvement of erectile function, without an increased risk of prostate cancer or severe CV events [45]. A recent Australian RCT[49] - the T4DM trial enrolling more than 1.000 men aged 50 years with prediabetes or newly diagnosed type 2 diabetes mellitus (T2DM) with a mild TD (total T < 14 nmol/L) – reported that a two-year treatment with TU 1000 mg, along with a lifestyle program, reduced the likelihood of T2DM diagnosis by 40% compared to placebo. This effect was accompanied by a decrease in fasting serum glucose and was associated with favorable changes in body composition, hand grip strength,bone mineral density, skeletal microarchitecture, and sexual function [49,50]. Interestingly, a recent network meta-analysis showed that the rate of hematocrit increase upon injectable TUis lower than with other injectable preparations and similar to that associated with gels, patches, or oral TU preparations [51].
4. Non-approved preparations for the treatment of TD
Several non-approved medications are frequently used for the management of male hypogonadism (Figure 1). Some classes, such as selective estrogen modulators (SERMs) or aromatase inhibitors (AIs), are frequently used in an off-label manner to treat patients with functional secondary hypogonadism, particularly in subjects with metabolic derangements, to preserve fertility and sperm count [52]. Conversely, other medications such as glucagon-like peptide 1 (GLP-1) analogues are still not routinely used. The following section will better analyze these possible approaches.
4.1. Selective estrogen modulators
4.2. Aromatase inhibitors
4.3. GLP-1 analogues
5. Conclusions
During the last ten years there have been important FDA approvals for new TRT formulations, including oral and nasal preparations. However, all these formulations are not still available in other countries. All three new oral formulations for TRT employ T undecanoate (TU) and are based on the self emulsifying delivery system; (SEDDS) technology, although with differences in the relative constituents. The main advantage over the older oral formulation of TU (Andriol) is theiri ndependence from being tacked with a fat meal, although regular meals favor their absorbance. Besides class-associated side effects (increase in hematocrit), gastrointestinal side effects and a mild increase in blood pressure (BP) are reported in trials [23,24,28,29]. Hence, the FDA required a black box warning that these drugs can induce a BP rise that might increase the risk of MACE. According to the FDA, the use of oral TU preparations should be limited to hypogonadal conditions associated with structural or genetic etiologies (the so called organic hypogonadism) [115]. However, all the trials available with these oral preparations did not enroll subjects with organic HG but subjects with the functional form [23–30]. In addition, a modest increase in BP was also noted in the recently published TRAVERSE trial employing a T gel formulation, although no increased MACE events over placebo were observed [34]. Both the JATENZO and Tlando trials showedi mprovement in HG symptoms, including sexual ones [23–28]. According to published trials, nasal T (NT) administration is less often associated with a hematocrit increase [38] and with suppression of the HPT axis [39–41], although 90% of treated subjects reached eugonadism [37]. However, these studies with NT are often uncontrolled, of short duration, and based on small cohorts of treated subjects. In addition, multiple administrations of NT are needed to reach physiological levels,therefore non-respecting physiological rhythms of T oscillation. The same problem is shared by the new oral TU preparations. Even the new injectable TU preparation, recently approved by the FDA (AVEED), does not respect the normal circadian rhythmicity of T, and although it guarantees a relatively constant level of T in the treated patients over a 10 week period [46]. This property of injectable TU preparations suggests its main employment in subjects with a chronic, often irreversible, HG condition, as suggested by a recent guideline[7]. Although there is an FDA black box for POME with these injectable TU preparations, real-life data are reassuring [48].Considering that the risk of forthcoming prostate cancer upon TRT seems not to be consistent according to all guidelines [5–11] hematocrit increase is the main concern with all TRT preparations, and clinicians should routinely check for it duringany TRT treatment [51].
Another important concern for TRT is fatherhood desire inthe future, and no TRT preparation is indicated in this case,with Gns treatment as the main indication for subjects with secondary HG [15]. Apart from Gns, off-label antiestrogen administration is widely used to treat male infertility in those with and without TD, with relative success. In fact, meta analyses of infertile populations demonstrated improvement in semen parameters either with SERMs [53–55] or with AIs [81,82]. Considering that with both SERMs and AIs, an increase in HPT activity was often observed (see also Figures 2 and 3), these medications were also tried for the treatment of male HG. However, the available results were overall discouraging [15,84,85]. We here meta-analyzed the side effects reported by several trials with AIs in male infertility and found that treatment increased the risk by 44% of any degree of low sexual desire (Figure 4). The effect of SERMs treatment on sexual symptoms is less clear. Upon SERMs, a meta-analysis of observational trials found some improvement in scoring in the ADAM questionnaire [55], a rather nonspecific instrument to evaluate HG symptoms [66]. However, three RCTs [67–69] did not confirm such a result, and in one RCT [68], the improvement in ADAM scoring in the placebo arm was similar to that reported in the meta-analysis of uncontrolled trials [55]. A similar figure was observed with body composition. In two RCTs, no significant amelioration was observed on metabolic parameters or on WC [68,70], while with TRT, the effect was clearly apparent [32,71,72]. In addition, results with SERMs on bone health were quite discordant [73–77], most probably depending on the rate of agonistic activity on the skeletal estrogen receptor (ER) of the SERMs tested.
Encouraging results were obtained with GLP-1RAs, a class of anti-diabetic medications approved for obesity treatment [97,99]. In particular, semaglutide (2.4 mg weekly subcutaneous injections) not only improved body composition but was also superior to placebo in reducing the incidence of a composite of death from CVD (including nonfatal myocardial infarction, or nonfatal stroke) at a mean follow-up of 39.8 months [116].
6. Expert opinion
Introduction
Testosterone deficiency (TD) is relatively common in aging men, affecting around 2% of the general population. Testosterone replacement therapy (TRT) represents the most common medical approach for subjects who are not interested in fathering.
Areas covered
This review summarizes advances in TRT, including approved or non-approved pharmacological options to overcome TD. When possible, a meta-analytic approach was applied to minimize subjective and biased interpretations of the available data.
Expert opinion
During the last decade, several new TRT formulations have been introduced on the market, including oral, transdermal, and parenteral formulations. Possible advantages and limitations have been discussed appropriately. Anti-estrogens, including selective estrogen modulators or aromatase inhibitors still represent further possible off-label options. However, long-term side effects on sexual function and bone parameters constitute major limitations. Glucagon-like peptide 1 analogues can be an alternative option in particular for massive obesity-associated TD. Weight loss obtained through lifestyle modifications including diet and physical exercise should be encouraged in all overweight and obese patients. A combination of TRT and lifestyle changes can be considered in those subjects in whom a reversal of the condition cannot be expected in a reasonable time frame.
3. Approved medications for the treatment of TD
Considering that there are no major, recent developments on Gns in the treatment of male secondary HG, this topic will not be covered in this review, also because it has been recently covered by us elsewhere [15].
During the last ten years several new formulations of the testicular hormone T for TRT have been available (see also Figure 1). TRT can be obtained in hypogonadal men through several routes of administration, including oral, parenteral, transdermal, intranasal, and implants. The specific analysis of the well-established TRT preparations is behind the aim of the present paper and has been revised elsewhere [15,16]. Similar considerations should be done for patient evaluation and monitoring during TRT therapy [5,7,9–11]. Briefly, although no general agreement has been reported in the different guidelines, patients should be evaluated after three months of treatment and then every six months or annually, according to patient characteristics and blood examinations [5,7,9–11].
3.1. New oral formulation for TRT
The oral route for drug delivery is often considered the most convenient way for several reasons, including safety considerations, convenience of administration, suitability for long term use, and flexibility in dosage adjustment. Hence, it is the one most often desired, even at the patient level [17–20]. Native T administered via oral route passes through the small intestinal wall and reaches the liver before being transported via the bloodstream to its target site. However, after the first-pass through the liver, T is substantially metabolized into inactive byproducts, and, therefore, only a minimal amount reaches the systemic circulation [16–18,20]. Its alkylation in the 17α position increases its bioavailability, but it results in liver toxicity [15,16,19]. Adding a mid-chain length fatty acid at the 17β position of the D ring strongly increases its lipophilicity, allowing absorption in part through the lymphatic system of the small intestine, therefore bypassing liver metabolism and, finally reaching the internal jugular or subclavian veins [16,21]. Although a T undecanoate (TU) preparation (Andriol®) has been available in Europe for more than 50 years, it was never approved by the United States Food and Drug Administration (FDA) because of its erratic absorption, which is essentially possible only when administered with fatty meals. In the last ten years, several other lipid-based formulations of native T were developed and introduced on the market with improved efficacy than Andriol (Table 1).
The first FDA-approved TU preparation is JATENZO (Tolmar Pharmaceuticals, Inc., Buffalo Grove, IL, USA), whose absorption is based on a self-emulsifying delivery system (SEDDS) ([22], Table 1). SEDDS is a technology consisting of a mixture of lipophilic and lipophobic matrice able to increase the solubility and bioavailability of poorly soluble substances, such asTU. Endogenous esterases allow the liberation of T from the prodrug TU. JATENZO is available in three dosing formulations (158, 198, and 237 mg) that should be taken b.i.d. and need titration. At variance with Andriol, it does not need a fat meal for absorption, although it should be taken with meals. Two open-label randomized trials, reviewed elsewhere [23,24],demonstrated that eugonadal T levels were obtained in more than 80% of the treated hypogonadal men (total T <10.4 nmol/L) for up to one year. In addition, JATENZO was able to improve body composition, bone mineral density, at the spine, and hip, mood and sexual complaints (Psychosexual Daily Questionnaire, PDQ), similar to what was observed with the comparator (T gel formulations) [23,24]. Considering that sex hormone binding globulin (SHBG) decreased more in the JATENZO arm than in the T gel arm, calculated free T levels were higher in the former arm [23]. Accordingly, the mean increase of hematocrit was higher (6.8%) in the JATENZO arm than in the T gel arm (3.1%). A 12-month extension of a previous one-year JATENZO arm [25] further demonstrated significant increases from baseline in sexual enjoyment,mood, and satisfaction with erection [26]. In addition, an open-label study enrolling a small number of hypogonadal subjects previously treated with other T formulations, suggests that patient satisfaction was higher upon JATENZO than with previous other routes of T administration [27]
Another TU preparation, based on a different SEDDS technology (predigested triglycerides), is Tlando (Lipocine, Salt Lake City,UT, USA), approved by the FDA in March 2022 (Table 1). At variance with JATENZO, Tlando does not need dose titration and is available in 112.5 mg capsules that should be taken twice daily with regular meals, without the need for a high-fat content. In a small trial enrolling 95 hypogonadal men (total T<10.4 nmol/L), eugonadism was reached in up to 80% of the treated subjects with a 450 mg daily dose for 28 days. In a preliminary open-label study (reviewed in [28,29]) involving 315 hypogonadal subjects for 52 weeks, Tlando was not inferior to topic T in improving patient-reported outcomes in sexual and mental domains with an equal proportion of subjects reaching the eugonadal state. An increase of 3.2% in hematocrit was observed after dosing 450 mg of Tlando for 4 months [30]
The most recent FDA-approved TU preparation is Kyzatrez (Marius Pharmaceuticals, Raleigh, NC; USA), a TU preparation dissolved in a combination of lipids and other solubilizers contained in a softgel capsule. It has been approved in three dosages: 100, 150, and 200 mg (Table 1), with the recommended starting dose of 200 mg twice a day at meals, followed by dose titration [29]. It is reported that this formulation is able to normalize serum T in up to 88% of the treated hypogonadal subjects [29].
Common side-effects of these recently approved three TU formulations are mild gastrointestinal symptoms along with a 2–5 mm HG increase in systolic 24-hour ambulatory blood pressure (ABP) and a minor elevation in diastolic blood pressure (BP)[23,24,28,29]. In a study with Tlando, a greater increase in ABP was observed in those showing a more sustained increase in hematocrit upon TU dosing, whereas in a study with Kyzatrez no relationship was observed [31]. In the Kyzatrez study [31], the ABP increase was relatively less evident than in other studies and greater in those taking anti-hypertensive medications [31].
Considering that in recent meta-analyses of randomized controlled trials (RCTs) a TRT-induced BP increase was never observed [32,33], these results are surprising. However, a modest (0.3 mm Hg), although significant, increase in mean systolic blood pressure was observed in the recently published TRAVERSE study, a large trial investigating the cardiovascular(CV) effects of T gel administration in subjects at high CV risk [34]. Interestingly, however, in that trial no signal for an increased rate of major CV events (MACE, primary endpoint) was reported in the treated arm [34]. Hence, it is possible that these modest increases in BP are clinically insignificant. Nonetheless, the FDA required a black box warning that these drugs can induce a BP rise that might increase the risk of MACE. Due to this risk, the use of oral TU preparations should be limited to hypogonadal conditions associated with structural or genetic etiologies (the so called organic hypogonadism; see before).
3.2. New nasal formulation for TRT
The nasal mucosa shows interesting properties for drug delivery because it is not subject to first-pass metabolism, therefore allowing high bioavailability of the applied medications [35].Natesto (Acerus Biopharma Inc.,) is a nasal formulation of T for treating male hypogonadism, approved by the FDA almost 10years ago. Natesto nasal gel is available as a metered-dose pump. One pump actuation delivers 5.5 mg of T. The recommended dose of Natesto is 11 mg of T (2 pump actuation; 1 actuation per nostril) administered intranasally three times daily for a total daily dose of 33 mg. Natesto should be administered once in the morning, once in the afternoon, and once in the evening (6 to 8 hours apart), preferably at the same time each day [36]. At this recommended dosage, 90% of hypogonadal subjects (total T <10.4 nmol/L) reached eugonadism in a ninety day, randomized, open-label study [37]. A phase IV, prospective, randomized, non-blinded, multi-institutional study is ongoing to compare results with the aforementioned dosage of Natesto and intramuscular administration of 200 mg of T cypionate (TC) twice a month (ClinicalTrials.gov ID NCT04439799, ClinicalTrials.gov) In a preliminary release of that study, Natesto administration for four months was associated with a lower risk of polycythemia and an overall lower hematocrit increase thanTC [38]. This positive finding could be associated with the intrinsic properties of Natesto, i.e. a rapid, transient, rise and fall of circulating T upon nasal administration [36]. For the aforementioned characteristics it was postulated that nasal T (NT) administration could be associated with lower suppressive activity on the HPT axis and, therefore, on spermatogenesis. In a short-duration (six months) single-center, uncontrolled trial, NT(11 mg t.i.d) maintained spermatogenesis in the majority of the 60 hypogonadal (T < 12 nmol/L) men enrolled, reducing in a non-significant manner serum Gn levels [39,40]. According to this hypothesis, NT induced, after 16 weeks, a lower suppression of 17-hydroxyprogesterone (17-OHP, taken as a surrogate marker of testicular activity) than other T preparations, i.e. subcutaneous pellets and TC [41]. Considering that an increase in hematocrit and reduced fertility are the major problems with TRT [16], these results could be of interest. However, their uncontrolled nature, short duration, and enrollment in small cohort of hypogonadal subjects are the main limitations of the aforementioned studies that need confirmation. In addition,the number of patients who dropped out of the study [40] due to azoospermia or severe oligospermia was not included in the final analysis. An alternative explanation of the positive results on hematocrit and spermatogenesis is that NT has lower biological activity than other T preparations, therefore resulting inless effectiveness in rescuing hypogonadal symptoms. However,two uncontrolled trials reported a significant increase in International Index of Erectile Function (IIEF) scoring over baseline [40,42] which was in line to that derived from available meta-analyses [43,44]. The most common side effects of Natesto are associated with its route of administration and include headache, rhinorrhea, epistaxis, nasal discomfort, and nasopharyngitis [36].
3.3. New intramuscular formulation for TRT
Although TU intramuscular formulations have been available worldwide for more than 20 years and are approved in more than 100 countries and marketed in more than 80 parts of the world, including Europe (Nebido, originally by Bayer AG, Kaiser Wilhelm-Allee 1 51,373 Leverkusen, Germany [45]), in the USA injectable TU was FDA-approved only in 2014 with the brandname AVEED (Endo Pharmaceuticals Solutions Inc.). The main difference between Nebido and AVEED is in their single-use vial dose, i.e. 1000 mg in 4 mL for the former and 750 mg in 3 mL for the latter. At variance with Nebido, following the first intramuscular injection of 3 mL of AVEED (750 mg), a second 3 mL dose isinjected four weeks later, and then 3 mL is injected every ten weeks thereafter. The approval of AVEED is based on data from an 84-week Phase 3 trial of hypogonadal men in the USA. The men enrolled in the study had an average age of 54 years and a serum total T level of less than 10.4 nmol/l. In the Phase 3 study, AVEED increased mean serum T levels, maintaining them for up to 10 weeks at a steady state (between weeks 14–24) [46]. Clinical experience in the USA with TU 750 mg provides evidence for good patient satisfaction and persistence with treatment, together with a favorable safety profile [47]. However, its prescription is available only through a Risk Evaluation and Mitigation Strategies (REMS) program. In addition, AVEED carries a black box warning for serious pulmonary oil microembolism(POME) reactions (the urge to cough, dyspnea, throat tightening,chest pain, dizziness, syncope) and episodes of anaphylaxis. However, of the 633 individual case safety reports in the Endo Pharmaceuticals Inc. safety database, 28 spontaneously reported adverse events were classified as POME, for a yearly spontaneously reported adverse event per injection rate of <0.1% [48]. Most (21/22) events resolved, and of those with a resolution time reported, most (13/17) were resolved in less than 30 minutes (32).More than 60% (13/21) of patients required no medical intervention [48]. In a meta-analysis of injectable TU preparations, it was found that in either controlled or uncontrolled trials, injectable TU was associated with a reduction of fat mass and HbA1c and an improvement of erectile function, without an increased risk of prostate cancer or severe CV events [45]. A recent Australian RCT[49] - the T4DM trial enrolling more than 1.000 men aged 50 years with prediabetes or newly diagnosed type 2 diabetes mellitus (T2DM) with a mild TD (total T < 14 nmol/L) – reported that a two-year treatment with TU 1000 mg, along with a lifestyle program, reduced the likelihood of T2DM diagnosis by 40% compared to placebo. This effect was accompanied by a decrease in fasting serum glucose and was associated with favorable changes in body composition, hand grip strength,bone mineral density, skeletal microarchitecture, and sexual function [49,50]. Interestingly, a recent network meta-analysis showed that the rate of hematocrit increase upon injectable TUis lower than with other injectable preparations and similar to that associated with gels, patches, or oral TU preparations [51].
4. Non-approved preparations for the treatment of TD
Several non-approved medications are frequently used for the management of male hypogonadism (Figure 1). Some classes, such as selective estrogen modulators (SERMs) or aromatase inhibitors (AIs), are frequently used in an off-label manner to treat patients with functional secondary hypogonadism, particularly in subjects with metabolic derangements, to preserve fertility and sperm count [52]. Conversely, other medications such as glucagon-like peptide 1 (GLP-1) analogues are still not routinely used. The following section will better analyze these possible approaches.
4.1. Selective estrogen modulators
4.2. Aromatase inhibitors
4.3. GLP-1 analogues
5. Conclusions
During the last ten years there have been important FDA approvals for new TRT formulations, including oral and nasal preparations. However, all these formulations are not still available in other countries. All three new oral formulations for TRT employ T undecanoate (TU) and are based on the self emulsifying delivery system; (SEDDS) technology, although with differences in the relative constituents. The main advantage over the older oral formulation of TU (Andriol) is theiri ndependence from being tacked with a fat meal, although regular meals favor their absorbance. Besides class-associated side effects (increase in hematocrit), gastrointestinal side effects and a mild increase in blood pressure (BP) are reported in trials [23,24,28,29]. Hence, the FDA required a black box warning that these drugs can induce a BP rise that might increase the risk of MACE. According to the FDA, the use of oral TU preparations should be limited to hypogonadal conditions associated with structural or genetic etiologies (the so called organic hypogonadism) [115]. However, all the trials available with these oral preparations did not enroll subjects with organic HG but subjects with the functional form [23–30]. In addition, a modest increase in BP was also noted in the recently published TRAVERSE trial employing a T gel formulation, although no increased MACE events over placebo were observed [34]. Both the JATENZO and Tlando trials showedi mprovement in HG symptoms, including sexual ones [23–28]. According to published trials, nasal T (NT) administration is less often associated with a hematocrit increase [38] and with suppression of the HPT axis [39–41], although 90% of treated subjects reached eugonadism [37]. However, these studies with NT are often uncontrolled, of short duration, and based on small cohorts of treated subjects. In addition, multiple administrations of NT are needed to reach physiological levels,therefore non-respecting physiological rhythms of T oscillation. The same problem is shared by the new oral TU preparations. Even the new injectable TU preparation, recently approved by the FDA (AVEED), does not respect the normal circadian rhythmicity of T, and although it guarantees a relatively constant level of T in the treated patients over a 10 week period [46]. This property of injectable TU preparations suggests its main employment in subjects with a chronic, often irreversible, HG condition, as suggested by a recent guideline[7]. Although there is an FDA black box for POME with these injectable TU preparations, real-life data are reassuring [48].Considering that the risk of forthcoming prostate cancer upon TRT seems not to be consistent according to all guidelines [5–11] hematocrit increase is the main concern with all TRT preparations, and clinicians should routinely check for it duringany TRT treatment [51].
Another important concern for TRT is fatherhood desire inthe future, and no TRT preparation is indicated in this case,with Gns treatment as the main indication for subjects with secondary HG [15]. Apart from Gns, off-label antiestrogen administration is widely used to treat male infertility in those with and without TD, with relative success. In fact, meta analyses of infertile populations demonstrated improvement in semen parameters either with SERMs [53–55] or with AIs [81,82]. Considering that with both SERMs and AIs, an increase in HPT activity was often observed (see also Figures 2 and 3), these medications were also tried for the treatment of male HG. However, the available results were overall discouraging [15,84,85]. We here meta-analyzed the side effects reported by several trials with AIs in male infertility and found that treatment increased the risk by 44% of any degree of low sexual desire (Figure 4). The effect of SERMs treatment on sexual symptoms is less clear. Upon SERMs, a meta-analysis of observational trials found some improvement in scoring in the ADAM questionnaire [55], a rather nonspecific instrument to evaluate HG symptoms [66]. However, three RCTs [67–69] did not confirm such a result, and in one RCT [68], the improvement in ADAM scoring in the placebo arm was similar to that reported in the meta-analysis of uncontrolled trials [55]. A similar figure was observed with body composition. In two RCTs, no significant amelioration was observed on metabolic parameters or on WC [68,70], while with TRT, the effect was clearly apparent [32,71,72]. In addition, results with SERMs on bone health were quite discordant [73–77], most probably depending on the rate of agonistic activity on the skeletal estrogen receptor (ER) of the SERMs tested.
Encouraging results were obtained with GLP-1RAs, a class of anti-diabetic medications approved for obesity treatment [97,99]. In particular, semaglutide (2.4 mg weekly subcutaneous injections) not only improved body composition but was also superior to placebo in reducing the incidence of a composite of death from CVD (including nonfatal myocardial infarction, or nonfatal stroke) at a mean follow-up of 39.8 months [116].
6. Expert opinion