madman
Super Moderator
Testosterone Replacement Options (2023)
Andrew Richard McCullough, MD, *, Mehvish Khan, MD
INTRODUCTION
Testosterone plays a critical role in the regulation of male sexual, somatic, and behavioral functions important to lifelong well-being. Testosterone deficiency is a consequence of reduced testosterone production because of hypothalamic-pituitary-gonadal axis pathology or senescence. Hypogonadism, which can be multifactorial, is diagnosed based on a constellation of clinical symptoms and signs and confirmed biochemically by documentation of consistently low serum total testosterone levels.
The treatment of hypogonadism by medical providers can be challenging. Owing to market development and availability of no less than 15 treatment options, both clinicians and patients must decide on the optimal formulation by taking multiple factors into consideration including cost, mode of delivery, ease of use, compliance, and the pharmacokinetics of each preparation. The provider and patient must navigate conflicting scientific evidence about the definition of hypogonadism and indications for treatment, uncertain target clinical and biochemical endpoints, the ambiguity of benefits and risks, and regulatory constraints, the overabundance of media hype and internet marketing with its attendant misinformation, the lack of formal education during training in male hypogonadism and the confusing number of options of treatment and schedules of administration. The purpose of this article was to review the physiology of hypogonadism and the differences between the current treatment modalities to equip the reader with the tools to make thoughtful choices among the multitude of modalities available in the treatment of hypogonadism.
PHYSIOLOGY
In order to understand the therapy of hypogonadism, it is important to understand the basic physiology of endogenous testosterone production.
Testosterone Production and Transport
Testosterone is an anabolic steroid that is derived from cholesterol. More than 95% is synthesized in the mitochondria and endoplasmic reticulum of the Leydig cells of the testes, under the regulation of pituitary gonadotropin LH, and the remainder is produced in the adrenal glands. The daily production is between 3 to 11 mg per day.1 Testosterone has a short half-life of 10 to 100 min. LH stimulates testosterone production in a pulsatile fashion, with peaks every one to 3 h. With age, both the frequency and the amplitude of the pulses decrease. In addition, the Leydig cells become less responsive to LH, and their total number decreases with age.2 Given the short half-life of testosterone, the frequency of natural LH pulses is not surprising.
Testosterone is transported in the serum, tightly bound to sex hormone-binding globulin (SHBG) (w70%) and loosely bound to albumin (w30%). Approximately 2% is totally free. The SHBG molecule is produced by the liver and binds two testosterone molecules. Typically, SHBG is close to equimolar to testosterone (20 nmoles/L). An abnormally high SHBG can result in low free testosterone despite what might seem like normal total testosterone. In a patient with cirrhosis or hepatitis, the SHBG levels can exceed 100 nmoles/L. For such a patient to have a midrange calculated free testosterone level, his total testosterone would have to be more than 1000 ng/dL. As men age, their SHBG increases, sometimes resulting in low free testosterone levels with total testosterone levels in the normal range. Other conditions associated with increased SHBG are hyperthyroidism, use of anticonvulsants, use of estrogens, or HIV disease.3
Testosterone Metabolism
Testosterone is metabolized hepatically and peripherally. It is metabolized into active and inactive metabolites. The two active metabolites produced are dihydrotestosterone (5%–8%) and estradiol (0.3%–5%) by the 5a-reductase and aromatase enzymatic systems, respectively.4 The 5areductase enzymes are found in the prostate and skin and the aromatase enzymes are found in the peripheral fat tissue and testis.
The hepatic cytochrome P450 system is responsible for approximately 95% of the metabolism of testosterone through a series of inactivating hydroxylation reactions followed by glucuronidation and to a lesser extent sulfation. The hydrophilic conjugates are excreted in the urine and bile.5 Less than 5% of testosterone is excreted unchanged in the urine. Medications, medical conditions, or inherent individual biodiversity of the cytochrome P450 system can significantly increase or decrease the half-life of testosterone.
The first-pass absorption of oral testosterone from the liver and intestine is rapid, as is the clearance. Testosterone injected intravenously has been shown to have a half-life of less than 60 min.6 The efficient absorption of oral testosterone and its rapid clearance make replacement with oral non-esterified testosterone impractical. To counter the rapid metabolism, esterification of the molecule is necessary.
Testosterone Natural Biologic Activity
The endogenous natural biological activity of testosterone is complex and can be affected by the concentration of testosterone, the differential expression of the androgen receptor in the target tissue types, polymorphism of the androgen receptor, the concentration of androgen binding hormones produced in the liver, and testes, tissue-specific levels of 5a-reductase and aromatase enzymes, and tissue-specific levels of androgen receptor (AR) promoters.7 This may partly explain why different symptoms of hypogonadism (sexual dysfunction vs muscle strength) respond to different levels of testosterone replacement.8
Classical and Non-classical Mechanisms of Action
Testosterone has both genomic (classical) and nongenomic actions (non-classical). Classical action mediates its effects via a cytoplasmic ligand-dependent nuclear transcription factor AR. The AR is expressed to different degrees in a diverse range of tissues including bone, muscle, prostate, adipose tissue, and the reproductive, cardiovascular, neural, and hematopoietic systems. Testosterone exerts its genomic effect by binding to the AR to regulate target gene transcription. The genomic signaling, also referred to as the DNA binding-dependent action of the AR, occurs when androgens bind to the AR leading to a conformational change in the receptor and translocation of the androgen-AR complex into the nucleus. This complex with promoters then binds to the specific androgen response elements (AREs) within target genes via the DNA binding domain (DBD) of the AR to modulate gene transcription and translation.
Non-genomic effects are rapidly occurring when the androgen-AR complex is at the cell membrane level. This complex activates kinase signaling cascades and initiates initiating phosphorylation of a second messenger signaling cascade. In addition, activation of membrane-bound protein receptors such as G-protein coupled receptors and iron-regulated transported-like protein 9 (ZIP9) can trigger intracellular signaling pathways.7,9–11 It is important for the reader to understand that the differential contribution of genomic vs non-genomic effects on clinical presentation is not understood.
General principles
*Conditions for treatment
*Are morning testosterones necessary? When to measure testosterone levels?
*Fasting measurements or not?
*Goals for treatment
*When to evaluate therapeutic levels
*Therapeutic success challenges
*Unrealistic patient expectations
*Costs
*Provider barriers
*Compliance
TESTOSTERONE PREPARATIONS
Topical/Transdermal Gels
General principles
*All dermal gels are poorly absorbed. Only 10% to 15% of the gel applied is bioavailable The rest remains on the body until it is washed off
*Secondary exposure: To prevent inadvertent exposure of women and children to testosterone gels, patients are instructed to wash their hands after using the product. Treated sites are covered with clothing once the gel has dried and to wash treated skin areas if skin-skin contact is anticipated. Currently, all testosterone liquids and gels in the United States contain a US Food and Drug Administration (FDA) warning for the risk of transference
*Daily application is mandatory as levels return to baseline at 48 h
*Gonadotropin levels were suppressed in the registry trials. Failure to find suppressed levels despite good T levels in follow-up suggests poor compliance. Failure to find suppressed levels with poor T levels suggests poor application technique, poor absorption, or non-compliance with the application
Patches Androderm
General principles
*Following patch application, Tmax is at approximately 8 h
*Nadir is achieved within 24 h of patch removal
*The patch is applied at night to mimic the normal circadian patterns and the testosterone levels are measured in the morning, 12 h after the application which may not reflect nadir levels
*Skin rash is the most observed adverse effect leading to discontinuation of its use
Intranasal gels Natesto
General principles
*Absorption is rapid, with Tmax occurring at 1 h, requiring multiple daily doses to achieve adequate levels of testosterone
*Levels fluctuate widely in a 24-h period with long periods at hypogonadal levels
*Meant to “mimic” normal circadian variation of testosterone levels throughout the day which is depicted by decreased LH and FSH levels 2 h after dosing with eventual recovery
*TID compliance is problematic and long-term adherence to therapy is questionable
*Replacement strategy with the least effect on sperm count and hematocrit
Oral testosterone JATENZO
General principles
*Low bioavailability due to first-pass hepatic and intestinal metabolism
*Low bioavailability is illustrated in the requirement of large doses of twice-daily TU to achieve therapeutic efficacy
*Higher bioavailability is achieved when taken with a fat-containing meal
*Dose adjustments are based on serum levels measured 6 h after the morning dose and do not reflect the nadir levels
*Most expensive therapy with poor insurance coverage
*BID dosing may present a compliance problem
Parenteral Testosterone Preparations Intramuscular injections
General principles
*The oldest testosterone product
*FDA package insert is anachronistic, confusing, and does not reflect the pharmacokinetics of the product
*Least expensive with self-administration
*Most painful administrations lead to poor long-term adherence to therapy
*Modality with maximum dosage variability
*The highest rate of erythrocytosis
Subcutaneous pellets Testopel
General principles
*Testopel provides adequate levels of testosterone for at least 3 months
*Current FDA-approved dosing schedules are based on anachronistic labels without pharmacokinetic backup resulting in underdosing (see Table 4)
*The convenience of not having a daily application but the inconvenience of a quarterly office visit for a surgical procedure
*Repeated insertions cause scarring, leading to insertional pain, hematomas, and extrusions
*Levels are tested at the nadir, shortly before re-insertion, to give dosage adjustment
*Package insert restricts flexible dosing
Subcutaneous injections (Xyosted)
General principles
*Generic testosterone enanthate in an expensive proprietary injector
*Convenient, well tolerated, and easily administered
*Poorly reimbursed by insurance companies
*Excellent pharmacokinetics
*Validates the concept of SC testosterone enanthate
*Poor insurance coverage
Long-acting testosterone AVEED
General principles
*Long-acting testosterone is dispensed in castor oil with enhances its ability to release over time
*Injected every 10 weeks requiring a 30-minute office visit
*Rare cases of spontaneous POME have been reported as adverse event per-injection rate of <1%
*Patients are required to remain in the doctor’s office for 30 min after their dose to observe for POME
*Package insert limits the flexibility of the dosing schedule and amounts
SUMMARY
There is a vast abundance of therapeutic modalities for hypogonadism, each with its own mode of delivery, pharmacokinetic profile, dosing sequence, and side effect profile leading to various advantages and disadvantages. It is important to understand the physiology of hypogonadism and the pharmacokinetics of each testosterone formulation to be able to make the right choice for the patient. Factors contributing to adherence to therapy include patient expectations, follow-up, knowledge about each formulation, access, cost, insurance coverage, and ease of use. The practitioner is best using the modality with which he/she is most familiar. Careful consideration of the needs of the patient is important. Continuation of therapy should be predicated on achieving amelioration of hypogonadal symptoms, achieving therapeutic levels in a compliant patient
Andrew Richard McCullough, MD, *, Mehvish Khan, MD
INTRODUCTION
Testosterone plays a critical role in the regulation of male sexual, somatic, and behavioral functions important to lifelong well-being. Testosterone deficiency is a consequence of reduced testosterone production because of hypothalamic-pituitary-gonadal axis pathology or senescence. Hypogonadism, which can be multifactorial, is diagnosed based on a constellation of clinical symptoms and signs and confirmed biochemically by documentation of consistently low serum total testosterone levels.
The treatment of hypogonadism by medical providers can be challenging. Owing to market development and availability of no less than 15 treatment options, both clinicians and patients must decide on the optimal formulation by taking multiple factors into consideration including cost, mode of delivery, ease of use, compliance, and the pharmacokinetics of each preparation. The provider and patient must navigate conflicting scientific evidence about the definition of hypogonadism and indications for treatment, uncertain target clinical and biochemical endpoints, the ambiguity of benefits and risks, and regulatory constraints, the overabundance of media hype and internet marketing with its attendant misinformation, the lack of formal education during training in male hypogonadism and the confusing number of options of treatment and schedules of administration. The purpose of this article was to review the physiology of hypogonadism and the differences between the current treatment modalities to equip the reader with the tools to make thoughtful choices among the multitude of modalities available in the treatment of hypogonadism.
PHYSIOLOGY
In order to understand the therapy of hypogonadism, it is important to understand the basic physiology of endogenous testosterone production.
Testosterone Production and Transport
Testosterone is an anabolic steroid that is derived from cholesterol. More than 95% is synthesized in the mitochondria and endoplasmic reticulum of the Leydig cells of the testes, under the regulation of pituitary gonadotropin LH, and the remainder is produced in the adrenal glands. The daily production is between 3 to 11 mg per day.1 Testosterone has a short half-life of 10 to 100 min. LH stimulates testosterone production in a pulsatile fashion, with peaks every one to 3 h. With age, both the frequency and the amplitude of the pulses decrease. In addition, the Leydig cells become less responsive to LH, and their total number decreases with age.2 Given the short half-life of testosterone, the frequency of natural LH pulses is not surprising.
Testosterone is transported in the serum, tightly bound to sex hormone-binding globulin (SHBG) (w70%) and loosely bound to albumin (w30%). Approximately 2% is totally free. The SHBG molecule is produced by the liver and binds two testosterone molecules. Typically, SHBG is close to equimolar to testosterone (20 nmoles/L). An abnormally high SHBG can result in low free testosterone despite what might seem like normal total testosterone. In a patient with cirrhosis or hepatitis, the SHBG levels can exceed 100 nmoles/L. For such a patient to have a midrange calculated free testosterone level, his total testosterone would have to be more than 1000 ng/dL. As men age, their SHBG increases, sometimes resulting in low free testosterone levels with total testosterone levels in the normal range. Other conditions associated with increased SHBG are hyperthyroidism, use of anticonvulsants, use of estrogens, or HIV disease.3
Testosterone Metabolism
Testosterone is metabolized hepatically and peripherally. It is metabolized into active and inactive metabolites. The two active metabolites produced are dihydrotestosterone (5%–8%) and estradiol (0.3%–5%) by the 5a-reductase and aromatase enzymatic systems, respectively.4 The 5areductase enzymes are found in the prostate and skin and the aromatase enzymes are found in the peripheral fat tissue and testis.
The hepatic cytochrome P450 system is responsible for approximately 95% of the metabolism of testosterone through a series of inactivating hydroxylation reactions followed by glucuronidation and to a lesser extent sulfation. The hydrophilic conjugates are excreted in the urine and bile.5 Less than 5% of testosterone is excreted unchanged in the urine. Medications, medical conditions, or inherent individual biodiversity of the cytochrome P450 system can significantly increase or decrease the half-life of testosterone.
The first-pass absorption of oral testosterone from the liver and intestine is rapid, as is the clearance. Testosterone injected intravenously has been shown to have a half-life of less than 60 min.6 The efficient absorption of oral testosterone and its rapid clearance make replacement with oral non-esterified testosterone impractical. To counter the rapid metabolism, esterification of the molecule is necessary.
Testosterone Natural Biologic Activity
The endogenous natural biological activity of testosterone is complex and can be affected by the concentration of testosterone, the differential expression of the androgen receptor in the target tissue types, polymorphism of the androgen receptor, the concentration of androgen binding hormones produced in the liver, and testes, tissue-specific levels of 5a-reductase and aromatase enzymes, and tissue-specific levels of androgen receptor (AR) promoters.7 This may partly explain why different symptoms of hypogonadism (sexual dysfunction vs muscle strength) respond to different levels of testosterone replacement.8
Classical and Non-classical Mechanisms of Action
Testosterone has both genomic (classical) and nongenomic actions (non-classical). Classical action mediates its effects via a cytoplasmic ligand-dependent nuclear transcription factor AR. The AR is expressed to different degrees in a diverse range of tissues including bone, muscle, prostate, adipose tissue, and the reproductive, cardiovascular, neural, and hematopoietic systems. Testosterone exerts its genomic effect by binding to the AR to regulate target gene transcription. The genomic signaling, also referred to as the DNA binding-dependent action of the AR, occurs when androgens bind to the AR leading to a conformational change in the receptor and translocation of the androgen-AR complex into the nucleus. This complex with promoters then binds to the specific androgen response elements (AREs) within target genes via the DNA binding domain (DBD) of the AR to modulate gene transcription and translation.
Non-genomic effects are rapidly occurring when the androgen-AR complex is at the cell membrane level. This complex activates kinase signaling cascades and initiates initiating phosphorylation of a second messenger signaling cascade. In addition, activation of membrane-bound protein receptors such as G-protein coupled receptors and iron-regulated transported-like protein 9 (ZIP9) can trigger intracellular signaling pathways.7,9–11 It is important for the reader to understand that the differential contribution of genomic vs non-genomic effects on clinical presentation is not understood.
General principles
*Conditions for treatment
*Are morning testosterones necessary? When to measure testosterone levels?
*Fasting measurements or not?
*Goals for treatment
*When to evaluate therapeutic levels
*Therapeutic success challenges
*Unrealistic patient expectations
*Costs
*Provider barriers
*Compliance
TESTOSTERONE PREPARATIONS
Topical/Transdermal Gels
General principles
*All dermal gels are poorly absorbed. Only 10% to 15% of the gel applied is bioavailable The rest remains on the body until it is washed off
*Secondary exposure: To prevent inadvertent exposure of women and children to testosterone gels, patients are instructed to wash their hands after using the product. Treated sites are covered with clothing once the gel has dried and to wash treated skin areas if skin-skin contact is anticipated. Currently, all testosterone liquids and gels in the United States contain a US Food and Drug Administration (FDA) warning for the risk of transference
*Daily application is mandatory as levels return to baseline at 48 h
*Gonadotropin levels were suppressed in the registry trials. Failure to find suppressed levels despite good T levels in follow-up suggests poor compliance. Failure to find suppressed levels with poor T levels suggests poor application technique, poor absorption, or non-compliance with the application
Patches Androderm
General principles
*Following patch application, Tmax is at approximately 8 h
*Nadir is achieved within 24 h of patch removal
*The patch is applied at night to mimic the normal circadian patterns and the testosterone levels are measured in the morning, 12 h after the application which may not reflect nadir levels
*Skin rash is the most observed adverse effect leading to discontinuation of its use
Intranasal gels Natesto
General principles
*Absorption is rapid, with Tmax occurring at 1 h, requiring multiple daily doses to achieve adequate levels of testosterone
*Levels fluctuate widely in a 24-h period with long periods at hypogonadal levels
*Meant to “mimic” normal circadian variation of testosterone levels throughout the day which is depicted by decreased LH and FSH levels 2 h after dosing with eventual recovery
*TID compliance is problematic and long-term adherence to therapy is questionable
*Replacement strategy with the least effect on sperm count and hematocrit
Oral testosterone JATENZO
General principles
*Low bioavailability due to first-pass hepatic and intestinal metabolism
*Low bioavailability is illustrated in the requirement of large doses of twice-daily TU to achieve therapeutic efficacy
*Higher bioavailability is achieved when taken with a fat-containing meal
*Dose adjustments are based on serum levels measured 6 h after the morning dose and do not reflect the nadir levels
*Most expensive therapy with poor insurance coverage
*BID dosing may present a compliance problem
Parenteral Testosterone Preparations Intramuscular injections
General principles
*The oldest testosterone product
*FDA package insert is anachronistic, confusing, and does not reflect the pharmacokinetics of the product
*Least expensive with self-administration
*Most painful administrations lead to poor long-term adherence to therapy
*Modality with maximum dosage variability
*The highest rate of erythrocytosis
Subcutaneous pellets Testopel
General principles
*Testopel provides adequate levels of testosterone for at least 3 months
*Current FDA-approved dosing schedules are based on anachronistic labels without pharmacokinetic backup resulting in underdosing (see Table 4)
*The convenience of not having a daily application but the inconvenience of a quarterly office visit for a surgical procedure
*Repeated insertions cause scarring, leading to insertional pain, hematomas, and extrusions
*Levels are tested at the nadir, shortly before re-insertion, to give dosage adjustment
*Package insert restricts flexible dosing
Subcutaneous injections (Xyosted)
General principles
*Generic testosterone enanthate in an expensive proprietary injector
*Convenient, well tolerated, and easily administered
*Poorly reimbursed by insurance companies
*Excellent pharmacokinetics
*Validates the concept of SC testosterone enanthate
*Poor insurance coverage
Long-acting testosterone AVEED
General principles
*Long-acting testosterone is dispensed in castor oil with enhances its ability to release over time
*Injected every 10 weeks requiring a 30-minute office visit
*Rare cases of spontaneous POME have been reported as adverse event per-injection rate of <1%
*Patients are required to remain in the doctor’s office for 30 min after their dose to observe for POME
*Package insert limits the flexibility of the dosing schedule and amounts
SUMMARY
There is a vast abundance of therapeutic modalities for hypogonadism, each with its own mode of delivery, pharmacokinetic profile, dosing sequence, and side effect profile leading to various advantages and disadvantages. It is important to understand the physiology of hypogonadism and the pharmacokinetics of each testosterone formulation to be able to make the right choice for the patient. Factors contributing to adherence to therapy include patient expectations, follow-up, knowledge about each formulation, access, cost, insurance coverage, and ease of use. The practitioner is best using the modality with which he/she is most familiar. Careful consideration of the needs of the patient is important. Continuation of therapy should be predicated on achieving amelioration of hypogonadal symptoms, achieving therapeutic levels in a compliant patient
