madman
Super Moderator
ABSTRACT
Introduction
The specific role of testosterone (T) replacement therapy in patients with late-onset hypogonadism is still conflicting. Several available preparations have been developed to restore either fertility and normal testosterone (T) levels (secondary hypogonadism) or just T levels (primary hypogonadism).
Areas covered
Advantages and limitations related to available new treatments will be discussed in detail. In addition, possible news related to preparations in the pipeline will be discussed.
Expert opinion
The selection of a specific T preparation should be adequately discussed with each subject. Transdermal T preparations are those that can preserve, after a unique morning administration, the circadian rhythmicity of T secretion. Conversely, short-acting preparations (such as oral or intranasal) need two- or three times daily administration, potentially reducing patient compliance. Long-acting T preparations, such as injectable T undecanoate have the advantage of bimestrial or trimestral administration, reducing the required number of administrations. The use of non-steroidal selective androgen receptor modulators (SARM), a heterogeneous class of compounds selectively acting on androgen receptor targets, remains investigational due to the lack of the full spectrum of T’s action and the possible risk of side effects, despite their potential use the treatment of muscle wasting and osteoporosis.
3.1. Patient’s need for fertility
3.1.1. Challenges
3.1.2. Possible solutions with available or in development T preparations
3.2. Secondary erythrocytosis
3.2.1. Challenges
3.2.2. Possible solutions with available or in development T preparations
*The Endocrine Society [3] and the European Academy ofAndrology [11] guidelines suggest considering not starting TRT or using lower dosages in subjects with a hematocrit >50% [3], or > 52% [11], at baseline, particularly in those patients at high CV risk [11]. Nevertheless, it is important to recognize that all the meta-analyses published so far indicate that TRT increases mean hematocrit by up to 5% and the risk of erythrocytosis by up to 7-fold [22,46,47] (see also Figure 1). However, the rise could be even higher [48] especially in older men [40,49] or in those with associated morbidities such as sleep apnea or chronic obstructive pulmonary diseases [42].
3.3. Patient’s preference
3.3.1. Challenges
3.3.2. Possible solutions with available or in development T preparations
3.4. Prostate-related unwanted effects
3.4.1. Challenges
3.4.2. Possible solutions with available or in development T preparations
*The aforementioned T-induced prostate growth has historically raised many concerns about the safety of TRT in hypogonadal subjects, even though it is obviously more related to the normalization of T (i.e. T shifting from a hypogonadal to a eugonadal range) than to an abnormal proliferative burst. Actually, there are still warning labels on the available T preparations regarding the risk of BPH and urinary retention.
4. Conclusions
Apart from the relative contraindications reported in the guidelines [3–5,7–9,11], one of the main limitations related to TRT administration in hypogonadal men is erythrocytosis which can develop in a dose-dependent manner with almost all the available T preparations [13,47]. Preliminary results with nasal T [43], showing a minor effect on erythropoiesis, need to be confirmed by larger studies because they involve a very small cohort of hypogonadal subjects.
Another important issue is related to fertility desire. Although the preliminary results with intranasal T administration are interesting [33,34], the data published so far are inconclusive in suggesting this formulation above the others for men interested in fathering. Hence, a rapid switch to Gn administration is still the best option, at least in all subjects with a diagnosis of secondary hypogonadism.
SEDDS technology has greatly improved the oral availability of non-hepatotoxic T undecanoate formulations, but FDA-approved preparations are still not yet available in Europe. In addition, these formulations should still be taken with meals twice a day [92,93]and are associated with mild adverse events such as gastrointestinal side effects and with an unexpected increase in blood pressure, not reported with the other preparations [66–68]
Historical concerns about the negative effect of TRT on the prostate prompted the development of AR ligands with prostate-sparing properties by negating the formation of DHT. Considering that DHT is important for normal sexual functioning, its lower formation might justify the disappointing results with SARM when sexual dysfunction was an issue [87]. In addition, the lack of the full spectrum of T actions and the possible risk of side effects represent other limitations related to the use of SARMS, despite their potential utility in the treatment of muscle wasting and osteoporosis.
5. Expert opinion
A large body of evidence has clearly documented that TRT is useless for eugonadal patients [15]. Although the suggested cutoffs to start TRT differ among available guidelines, the European position emphasized that total T levels below 12 nM represent the best threshold [5,9,11]. The utility of calculated free T (<220 pM) has been recently proposed by the Italian Society of Sexual Medicine and Andrology [9] but is not completely supported by other European positions [5,11]. An accurate diagnosis based on the presence of specific symptoms and the biochemical determination of reduced T levels represents the cornerstone of a successful treatment. In particular, we want to emphasize that during the last two decades, a tremendous increase in T prescriptions has been observed, particularly in the US market [94]. Accordingly, a previous survey indicated that up to 30% of men who were prescribed T in the US were not checked for T levels prior to their TRT prescription or underwent T evaluation only after the prescription [94]. Considering the possible aforementioned side effects related to TRT, particularly when TRT is not prescribed according to recommended guidelines [95] the latter finding can justify, at least partially, the different positions released by the FDA [96] and EMA [97] on CV safety related to TRT. However, it should be recognized that the long-term CV safety of TRT still represents a conflicting issue. One of the most recent meta-analyses showed that TRT does not increase short-term or medium-term CV risk in men with hypogonadism [69]. The same study emphasized the paucity of data evaluating TRT-related long-term CV safety. In addition, although the TRAVERSE study did not report any differences in MACE risk after 2 years of treatment, a mild, although significant, increased risk of arrhythmias, and atrial fibrillation, in particular, as well as of venous thromboembolism, has been reported in the active arm when compared to placebo [23]. The high (>60%) dropout observed during the study and the lack of formal adjudication of the latter events, which were secondary endpoints (venous thromboembolism) and investigator-reported (arrhythmias), represent crucial bias in the data interpretation [23].
Following the above consideration, it is our opinion that when a symptomatic man (particularly when sexual symptoms are present) has a low T level for any reason, the best solution is to replace his deficiency with any of the available T preparations (Table 1). Lifestyle modifications and weight loss should be strongly encouraged in all overweight and obese subjects since they can result in better outcomes when compared to TRT alone. Data from the Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle program(T4DM) – a large double-blind placebo-controlled RCT, including more than 1000 subjects with a waist circumference ≥95cm, total T ≤ 14•0 nmol/L, and impaired glucose tolerance or newly diagnosed T2DM – are in line with the latter observation. The included subjects were treated with long-acting injectable TU or placebo for 2 years, along with a detailed lifestyle program. Final results showed that the active treatment arm resulted in a better improvement in body composition, glycometabolic profile, and in International Index of Erectile Function Domain scores [48]. The latter benefits seem to disappear in a recent long-term analysis performed five years after the cessation of TU treatment [98]. However, the inclusion of around 600 out of 1007 represents a possible source of bias in the data analysis [98].
T is not only a hormone but also a prohormone with the ability to be converted into two biologically active hormones: DHT and estradiol. Both of them play important physiological roles, including bone metabolism, sexual functioning, and supporting male skin and body hair characteristics. Hence, the use of compounds (steroid and non-steroid) unsuitable for aromatization and/or 5α-reduction may not completely correct the hypogonadal state and its associated symptoms. Accordingly, the available evidence derived from the use of SARM for the treatment of male hypogonadism is essentially not satisfactory [89]. Similar considerations can be derived from the use of aromatase inhibitors or estrogen selective responsive elements (SERM), frequently advocated for the treatment of hypogonadism, particularly in those subjects with an intact hypothalamus-pituitary-testis axis who request to preserve fertility [99].
Other options have been tested for the treatment of male hypogonadism, but still at experimental levels. Both kisspeptin agonists (such as TAK-448 or TAK-683 [100,101] and neurokinin-B agonists (such as Senktide and [MePhe7]NKB [101] have been proven to stimulate gonadotropin secretion. However, the requirement of a pulsatile administration for the former and the lack of clinical data for the latter option, represent crucial limitations. Similarly, the promising preliminary data on restoring T levels in men with MetS, obtained by the use of anakinra, a recombinant human IL-1 receptor antagonist, have never been confirmed by other authors [102].
In young individuals, circadian rhythmicity of T secretion by the testis was described in the late 1960s [103] and later confirmed by data modeling in the elderly [93]. Hence, a physiological T substitution is obtained more through T transdermal administration [93] than with other preparations, either short- or long-acting. In fact, transdermal preparations allow for higher T levels in the morning and lower levels at night [93]. In contrast, short-acting preparations (oral or intranasal) need two- or three-times daily administration, including in the evening. Long-acting preparations (parenteral) act as a depot and obviously do not allow any circadian rhythmicity.
However, very long-acting preparations, such as injectable TU, have the great advantage of bimestrial or trimestral administration. In fact, four to six yearly T injections can relieve the patient from being reminded daily that they suffer from an irreversible condition, such as Klinefelter Syndrome [9].
In conclusion, considering that the use of TRT in LOH remains a controversial issue and that many T preparations are available on the market, we strongly suggest discussing with each individual patient the advantages and disadvantages of each preparation, therefore allowing a metered prescription of TRT. It should be noted that despite their intrinsic pharmacological and clinical advantages, the cost of the newer T formulations including gels, long-acting parenteral formulations, and nasal or new oral preparations, is much higher when compared to older oral or T-ester products. This aspect represents another point to be adequately discussed with the patient before a T prescription, particularly in those counties where TRT is not reimbursed by the National Health Care Service. Weight loss and lifestyle modification programs should be discussed with patients in order to plan a multiple-step approach characterized by a potential progression improvement. In subjects with LOH, weight loss achievement, along with underlying symptom improvement, may prompt TRT withdrawal and a new T-level evaluation after a reasonable washout period.
Introduction
The specific role of testosterone (T) replacement therapy in patients with late-onset hypogonadism is still conflicting. Several available preparations have been developed to restore either fertility and normal testosterone (T) levels (secondary hypogonadism) or just T levels (primary hypogonadism).
Areas covered
Advantages and limitations related to available new treatments will be discussed in detail. In addition, possible news related to preparations in the pipeline will be discussed.
Expert opinion
The selection of a specific T preparation should be adequately discussed with each subject. Transdermal T preparations are those that can preserve, after a unique morning administration, the circadian rhythmicity of T secretion. Conversely, short-acting preparations (such as oral or intranasal) need two- or three times daily administration, potentially reducing patient compliance. Long-acting T preparations, such as injectable T undecanoate have the advantage of bimestrial or trimestral administration, reducing the required number of administrations. The use of non-steroidal selective androgen receptor modulators (SARM), a heterogeneous class of compounds selectively acting on androgen receptor targets, remains investigational due to the lack of the full spectrum of T’s action and the possible risk of side effects, despite their potential use the treatment of muscle wasting and osteoporosis.
3.1. Patient’s need for fertility
3.1.1. Challenges
3.1.2. Possible solutions with available or in development T preparations
3.2. Secondary erythrocytosis
3.2.1. Challenges
3.2.2. Possible solutions with available or in development T preparations
*The Endocrine Society [3] and the European Academy ofAndrology [11] guidelines suggest considering not starting TRT or using lower dosages in subjects with a hematocrit >50% [3], or > 52% [11], at baseline, particularly in those patients at high CV risk [11]. Nevertheless, it is important to recognize that all the meta-analyses published so far indicate that TRT increases mean hematocrit by up to 5% and the risk of erythrocytosis by up to 7-fold [22,46,47] (see also Figure 1). However, the rise could be even higher [48] especially in older men [40,49] or in those with associated morbidities such as sleep apnea or chronic obstructive pulmonary diseases [42].
3.3. Patient’s preference
3.3.1. Challenges
3.3.2. Possible solutions with available or in development T preparations
3.4. Prostate-related unwanted effects
3.4.1. Challenges
3.4.2. Possible solutions with available or in development T preparations
*The aforementioned T-induced prostate growth has historically raised many concerns about the safety of TRT in hypogonadal subjects, even though it is obviously more related to the normalization of T (i.e. T shifting from a hypogonadal to a eugonadal range) than to an abnormal proliferative burst. Actually, there are still warning labels on the available T preparations regarding the risk of BPH and urinary retention.
4. Conclusions
Apart from the relative contraindications reported in the guidelines [3–5,7–9,11], one of the main limitations related to TRT administration in hypogonadal men is erythrocytosis which can develop in a dose-dependent manner with almost all the available T preparations [13,47]. Preliminary results with nasal T [43], showing a minor effect on erythropoiesis, need to be confirmed by larger studies because they involve a very small cohort of hypogonadal subjects.
Another important issue is related to fertility desire. Although the preliminary results with intranasal T administration are interesting [33,34], the data published so far are inconclusive in suggesting this formulation above the others for men interested in fathering. Hence, a rapid switch to Gn administration is still the best option, at least in all subjects with a diagnosis of secondary hypogonadism.
SEDDS technology has greatly improved the oral availability of non-hepatotoxic T undecanoate formulations, but FDA-approved preparations are still not yet available in Europe. In addition, these formulations should still be taken with meals twice a day [92,93]and are associated with mild adverse events such as gastrointestinal side effects and with an unexpected increase in blood pressure, not reported with the other preparations [66–68]
Historical concerns about the negative effect of TRT on the prostate prompted the development of AR ligands with prostate-sparing properties by negating the formation of DHT. Considering that DHT is important for normal sexual functioning, its lower formation might justify the disappointing results with SARM when sexual dysfunction was an issue [87]. In addition, the lack of the full spectrum of T actions and the possible risk of side effects represent other limitations related to the use of SARMS, despite their potential utility in the treatment of muscle wasting and osteoporosis.
5. Expert opinion
A large body of evidence has clearly documented that TRT is useless for eugonadal patients [15]. Although the suggested cutoffs to start TRT differ among available guidelines, the European position emphasized that total T levels below 12 nM represent the best threshold [5,9,11]. The utility of calculated free T (<220 pM) has been recently proposed by the Italian Society of Sexual Medicine and Andrology [9] but is not completely supported by other European positions [5,11]. An accurate diagnosis based on the presence of specific symptoms and the biochemical determination of reduced T levels represents the cornerstone of a successful treatment. In particular, we want to emphasize that during the last two decades, a tremendous increase in T prescriptions has been observed, particularly in the US market [94]. Accordingly, a previous survey indicated that up to 30% of men who were prescribed T in the US were not checked for T levels prior to their TRT prescription or underwent T evaluation only after the prescription [94]. Considering the possible aforementioned side effects related to TRT, particularly when TRT is not prescribed according to recommended guidelines [95] the latter finding can justify, at least partially, the different positions released by the FDA [96] and EMA [97] on CV safety related to TRT. However, it should be recognized that the long-term CV safety of TRT still represents a conflicting issue. One of the most recent meta-analyses showed that TRT does not increase short-term or medium-term CV risk in men with hypogonadism [69]. The same study emphasized the paucity of data evaluating TRT-related long-term CV safety. In addition, although the TRAVERSE study did not report any differences in MACE risk after 2 years of treatment, a mild, although significant, increased risk of arrhythmias, and atrial fibrillation, in particular, as well as of venous thromboembolism, has been reported in the active arm when compared to placebo [23]. The high (>60%) dropout observed during the study and the lack of formal adjudication of the latter events, which were secondary endpoints (venous thromboembolism) and investigator-reported (arrhythmias), represent crucial bias in the data interpretation [23].
Following the above consideration, it is our opinion that when a symptomatic man (particularly when sexual symptoms are present) has a low T level for any reason, the best solution is to replace his deficiency with any of the available T preparations (Table 1). Lifestyle modifications and weight loss should be strongly encouraged in all overweight and obese subjects since they can result in better outcomes when compared to TRT alone. Data from the Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle program(T4DM) – a large double-blind placebo-controlled RCT, including more than 1000 subjects with a waist circumference ≥95cm, total T ≤ 14•0 nmol/L, and impaired glucose tolerance or newly diagnosed T2DM – are in line with the latter observation. The included subjects were treated with long-acting injectable TU or placebo for 2 years, along with a detailed lifestyle program. Final results showed that the active treatment arm resulted in a better improvement in body composition, glycometabolic profile, and in International Index of Erectile Function Domain scores [48]. The latter benefits seem to disappear in a recent long-term analysis performed five years after the cessation of TU treatment [98]. However, the inclusion of around 600 out of 1007 represents a possible source of bias in the data analysis [98].
T is not only a hormone but also a prohormone with the ability to be converted into two biologically active hormones: DHT and estradiol. Both of them play important physiological roles, including bone metabolism, sexual functioning, and supporting male skin and body hair characteristics. Hence, the use of compounds (steroid and non-steroid) unsuitable for aromatization and/or 5α-reduction may not completely correct the hypogonadal state and its associated symptoms. Accordingly, the available evidence derived from the use of SARM for the treatment of male hypogonadism is essentially not satisfactory [89]. Similar considerations can be derived from the use of aromatase inhibitors or estrogen selective responsive elements (SERM), frequently advocated for the treatment of hypogonadism, particularly in those subjects with an intact hypothalamus-pituitary-testis axis who request to preserve fertility [99].
Other options have been tested for the treatment of male hypogonadism, but still at experimental levels. Both kisspeptin agonists (such as TAK-448 or TAK-683 [100,101] and neurokinin-B agonists (such as Senktide and [MePhe7]NKB [101] have been proven to stimulate gonadotropin secretion. However, the requirement of a pulsatile administration for the former and the lack of clinical data for the latter option, represent crucial limitations. Similarly, the promising preliminary data on restoring T levels in men with MetS, obtained by the use of anakinra, a recombinant human IL-1 receptor antagonist, have never been confirmed by other authors [102].
In young individuals, circadian rhythmicity of T secretion by the testis was described in the late 1960s [103] and later confirmed by data modeling in the elderly [93]. Hence, a physiological T substitution is obtained more through T transdermal administration [93] than with other preparations, either short- or long-acting. In fact, transdermal preparations allow for higher T levels in the morning and lower levels at night [93]. In contrast, short-acting preparations (oral or intranasal) need two- or three-times daily administration, including in the evening. Long-acting preparations (parenteral) act as a depot and obviously do not allow any circadian rhythmicity.
However, very long-acting preparations, such as injectable TU, have the great advantage of bimestrial or trimestral administration. In fact, four to six yearly T injections can relieve the patient from being reminded daily that they suffer from an irreversible condition, such as Klinefelter Syndrome [9].
In conclusion, considering that the use of TRT in LOH remains a controversial issue and that many T preparations are available on the market, we strongly suggest discussing with each individual patient the advantages and disadvantages of each preparation, therefore allowing a metered prescription of TRT. It should be noted that despite their intrinsic pharmacological and clinical advantages, the cost of the newer T formulations including gels, long-acting parenteral formulations, and nasal or new oral preparations, is much higher when compared to older oral or T-ester products. This aspect represents another point to be adequately discussed with the patient before a T prescription, particularly in those counties where TRT is not reimbursed by the National Health Care Service. Weight loss and lifestyle modification programs should be discussed with patients in order to plan a multiple-step approach characterized by a potential progression improvement. In subjects with LOH, weight loss achievement, along with underlying symptom improvement, may prompt TRT withdrawal and a new T-level evaluation after a reasonable washout period.
