TESTOSTERONE
DESCRIPTION
Testosterone USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one.
CLINICAL PHARMACOLOGY
Testosterone--General Androgen Effects:
Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, alterations in body musculature, and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Symptoms associated with male hypogonadism include impotence and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics and osteoporosis. Hypogonadism is a risk factor for osteoporosis in men.
Drugs in the androgen class also promote retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein.
Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing erythropoietin production.
During exogenous administration of androgens, endogenous testosterone release may be inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH).
There is a lack of substantial evidence that androgens are effective in accelerating fracture healing or in shortening post-surgical convalescence.
Pharmacokinetics
Absorption
TESTOSTERONE™ is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. In a study with the 10 G dose (to deliver 100 mg testosterone), all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within the normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady state level by the end of the first 24 hours and are at steady state by the second or third day of dosing.
With single daily applications of TESTOSTERONE™, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for patients maintained on 5 G or 10 G of TESTOSTERONE™ (to deliver 50 or 100 mg of testosterone, respectively) for 30 days. The average (±SD) daily testosterone concentration produced by TESTOSTERONE™ 10 G on Day 30 was 792 (±294) ng/dL and by TESTOSTERONE™ 5 G 566 (±262) ng/dL.
When TESTOSTERONE™ treatment is discontinued after achieving steady state, serum testosterone levels remain in the normal range for 24 to 48 hours but return to their pretreatment levels by the fifth day after the last application.
Distribution
Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be bioactive. The portion of testosterone bound to SHBG is not considered biologically active. The amount of SHBG in the serum and the total testosterone level will determine the distribution of bioactive and nonbioactive androgen. SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.
Metabolism
There is considerable variation in the half-life of testosterone as reported in the literature, ranging from ten to 100 minutes. Testosterone is metabolized to various 17-ketosteroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT. DHT binds with greater affinity to SHBG than does testosterone. In many tissues, the activity of testosterone depends on its reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription and cellular changes related to androgen action. In reproductive tissues, DHT is further metabolized to 3-(alpha) and 3-(beta) androstanediol.
DHT concentrations increased in parallel with testosterone concentrations during TESTOSTERONE™ treatment. After 180 days of treatment, mean DHT concentrations were within the normal range with 5 G TESTOSTERONE™ and were about 7% above the normal range after a 10 G dose. The mean steady state DHT/T ratio during 180 days of TESTOSTERONE™ treatment remained within normal limits (as determined by the analytical laboratory involved with this clinical trial) and ranged from 0.23 to 0.29 (5 G/day) and from 0.27 to 0.33 (10 G/day).
Excretion
About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.
Special Populations
In patients treated with TESTOSTERONE™, there are no observed differences in the average daily serum testosterone concentration at steady-state based on age, cause of hypogonadism or body mass index. No formal studies were conducted involving patients with renal or hepatic insufficiencies.
CLINICAL STUDIES
TESTOSTERONE™ 1% was evaluated in a multicenter, randomized, parallel-group, active-controlled, 180-day trial in 227 hypogonadal men. The study was conducted in 2 phases. During the Initial Treatment Period (Days 1-90), 73 patients were randomized to TESTOSTERONE™ 5 G daily (to deliver 50 mg testosterone), 78 patients to TESTOSTERONE™ 10 G daily (to deliver 100 mg testosterone), and 76 patients to a non-scrotal testosterone transdermal system (5 mg daily). The study was double-blind for dose of TESTOSTERONE™ but open-label for active control. Patients who were originally randomized to TESTOSTERONE™ and who had single-sample serum testosterone levels above or below the normal range on Day 60 were titrated to 7.5 G daily (to deliver 75 mg testosterone) on Day 91. During the Extended Treatment Period (Days 91-180), 51 patients continued on TESTOSTERONE™ 5 G daily, 52 patients continued on TESTOSTERONE™ 10 G daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received TESTOSTERONE™ 7.5 G daily.
Mean peak, trough and average serum testosterone concentrations within the normal range (298-1043 ng/dL) were achieved on the first day of treatment with doses of 5 G and 10 G. In patients continuing on TESTOSTERONE™ 5 G and 10 G, these mean testosterone levels were maintained within the normal range for the 180-day duration of the study. Figure 2 summarizes the 24-hour pharmacokinetic profiles of testosterone administered as TESTOSTERONE™ for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed TESTOSTERONE™ treatment.
Table 1 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 5 G, 7.5 G, or 10 G of TESTOSTERONE™. The 7.5 G dose produced mean concentrations intermediate to those produced by 5 G and 10 G of TESTOSTERONE™.
Table 1: Mean (±SD) Steady-State Serum Testosterone
Concentrations During Therapy (Day 180)
5 G N = 44 7.5 G N = 37 10 G N = 48
C avg 555 ± 225 601 ± 309 713 ± 209
C max 830 ± 347 901 ± 471 1083 ± 434
C min 371 ± 165 406 ± 220 485 ± 156
Of 129 hypogonadal men who were appropriately titrated with TESTOSTERONE™ and who had sufficient data for analysis, 87% achieved an average serum testosterone level within the normal range on Treatment Day 180.
TESTOSTERONE™ 5 G/day and 10 G/day resulted in significant increases over time in total body mass and total body lean mass, while total body fat mass and the percent body fat decreased significantly. These changes were maintained for 180 days of treatment. Changes in the 7.5 G dose group were similar. Bone mineral density in both hip and spine increased significantly from Baseline to Day 180 with 10 G TESTOSTERONE.™
TESTOSTERONE™ treatment at 5 G/day and 10 G/day for 90 days produced significant improvement in libido (measured by sexual motivation, sexual activity and enjoyment of sexual activity as assessed by patient responses to a questionnaire). The degree of penile erection as subjectively estimated by the patients, increased with TESTOSTERONE™ treatment, as did the subjective score for "satisfactory duration of erection." TESTOSTERONE™ treatment at 5 G/day and 10 G/day produced positive effects on mood and fatigue. Similar changes were seen after 180 days of treatment and in the group treated with the 7.5 G dose.
DHT concentrations increased in parallel with testosterone concentrations at TESTOSTERONE™ doses of 5 G/day and 10 G/day, but the DHT/T ratio stayed within the normal range, indicating enhanced availability of the major physiologically active androgen. Serum estradiol (E2) concentrations increased significantly within 30 days of starting treatment with TESTOSTERONE™ 5 or 10 G/day and remained elevated throughout the treatment period but remained within the normal range for eugonadal men. Serum levels of SHBG decreased very slightly (1 to 11%) during TESTOSTERONE™ treatment. In men with hypergonadotropic hypogonadism, serum levels of LH and FSH fell in a dose- and time-dependent manner during treatment with TESTOSTERONE.™
Potential for testosterone transfer:
The potential for dermal testosterone transfer following TESTOSTERONE™ use was evaluated in a clinical study between males dosed with TESTOSTERONE™ and their untreated female partners. Two to 12 hours after TESTOSTERONE™ (10 G) application by the male subjects, the couples (N=38 couples) engaged in daily, 15-minute sessions of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the TESTOSTERONE™ application sites. Under these study conditions, all unprotected female partners had a serum testosterone concentration >2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented.
INDICATIONS AND USAGE
TESTOSTERONE™ is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone:
Primary hypogonadism (congenital or acquired)--testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter' syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone levels and gonadotropins (FSH, LH) above the normal range.
Hypogonadotropic hypogonadism (congenital or acquired)--idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum levels but have gonadotropins in the normal or low range.
TESTOSTERONE™ has not been clinically evaluated in males under 18 years of age.
CONTRAINDICATIONS
Androgens are contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate.
TESTOSTERONE™ is not indicated for use in women, has not been evaluated in women, and must not be used in women.
Pregnant women should avoid skin contact with TESTOSTERONE™ application sites in men. Testosterone may cause fetal harm. In the event that unwashed or unclothed skin to which TESTOSTERONE™ has been applied does come in direct contact with the skin of a pregnant woman, the general area of contact on the woman should be washed with soap and water as soon as possible. In vitro studies show that residual testosterone is removed from the skin surface by washing with soap and water.
TESTOSTERONE™ should not be used in patients with known hypersensitivity to any of its ingredients.
WARNINGS
Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatitis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatitis can be a life-threatening or fatal complication. Long-term therapy with testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Testosterone is not known to produce these adverse effects.
Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hyperplasia and prostatic carcinoma.
Geriatric patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men (see PRECAUTIONS : Carcinogenesis, Mutagenesis, Impairment of Fertility and Laboratory Tests ).
Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.
Gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism.
The treatment of hypogonadal men with testosterone esters may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases.
PRECAUTIONS
Transfer of testosterone to another person can occur when vigorous skin-to-skin contact is made with the application site (see Clinical Studies ). The following precautions are recommended to minimize potential transfer of testosterone from TESTOSTERONE™-treated skin to another person:
Patients should wash their hands immediately with soap and water after application of TESTOSTERONE.™
Patients should cover the application site(s) with clothing after the gel has dried (e.g. a shirt).
In the event that unwashed or unclothed skin to which TESTOSTERONE™ has been applied does come in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible. In vitro studies show that residual testosterone is removed from the skin surface by washing with soap and water.
Changes in body hair distribution, significant increase in acne, or other signs of virilization of the female partner should be brought to the attention of a physician.
General
The physician should instruct patients to report any of the following:
Too frequent or persistent erections of the penis.
Any nausea, vomiting, changes in skin color, or ankle swelling.
Breathing disturbances, including those associated with sleep.
Information for Patients
Advise patients to carefully read the information brochure that accompanies each carton of 30 TESTOSTERONE™ single-use packets.
Advise patients of the following:
TESTOSTERONE™ should not be applied to the scrotum.
TESTOSTERONE™ should be applied once daily to clean dry skin.
After application of TESTOSTERONE™, it is currently unknown for how long showering or swimming should be delayed. For optimal absorption of testosterone, it appears reasonable to wait at least 5-6 hours after application prior to showering or swimming. Nevertheless, showering or swimming after just 1 hour should have a minimal effect on the amount of TESTOSTERONE™ absorbed if done very infrequently.
Laboratory Tests
Hemoglobin and hematocrit levels should be checked periodically (to detect polycythemia) in patients on long-term androgen therapy.
Liver function, prostatic specific antigen, cholesterol, and high-density lipoprotein should be checked periodically.
To ensure proper dosing, serum testosterone concentrations should be measured (see DOSAGE AND ADMINISTRATION ).
Drug Interactions
Oxyphenbutazone: Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.
Insulin: In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.
Propranolol: In a published pharmacokinetic study of an injectable testosterone product, administration of testosterone cypionate led to an increased clearance of propranolol in the majority of men tested.
Corticosteroids: The concurrent administration of testosterone with ACTH or corticosteroids may enhance edema formation; thus these drugs should be administered cautiously, particularly in patients with cardiac or hepatic disease.
Drug/Laboratory Test Interactions
Androgens may decrease levels of thyroxin-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal Data: Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.
Human Data: There are rare reports of hepatocellular carcinoma in patients receiving long-term oral therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases.
Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hyperplasia and prostatic carcinoma.
Geriatric patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy.
In men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men.
Pregnancy Category X (see Contraindications )--Teratogenic Effects: TESTOSTERONE™ is not indicated for women and must not be used in women.
Nursing Mothers: TESTOSTERONE™ is not indicated for women and must not be used in women.
Pediatric Use: Safety and efficacy of TESTOSTERONE™ in pediatric patients have not been established.
ADVERSE REACTIONS
In a controlled clinical study, 154 patients were treated with TESTOSTERONE™ for up to 6 months (see Clinical Studies ). Adverse Events possibly, probably or definitely related to the use of TESTOSTERONE™ and reported by >/=1% of the patients are listed in Table 2.
Table 2. Adverse Events Possibly, Probably or Definitely Related
to Use of TESTOSTERONE in the Controlled Clinical Trial Adverse Event
5 G N =77 7.5 G N = 40 10 G N = 78
Acne 1% 3% 8%
Alopecia 1% 0% 1%
Application Site Reaction 5% 3% 4%
Asthenia 0% 3% 1%
Depression 1% 0% 1%
Emotional Lability 0% 3% 3%
Gynecomastia 1% 0% 3%
Headache 4% 3% 0%
Hypertension 3% 0% 3%
Lab Test Abnormal * 6% 5% 3%
Libido Decreased 0% 3% 1%
Nervousness 0% 3% 1%
Pain Breast 1% 3% 1%
Prostate Disorder ** 3% 3% 5%
Testis Disorder 3% 0% 0%
* Lab test abnormal occurred in nine patients with one or more of the following events: elevated hemoglobin or hematocrit, hyperlipidemia, elevated triglycerides, hypokalemia, decreased HDL, elevated glucose, elevated creatinine, or elevated total bilirubin.
** Prostate disorders included five patients with enlarged prostate, one patient with BPH, and one patient with elevated PSA results.
The following adverse events possibly related to the use of TESTOSTERONE™ occurred in fewer than 1% of patients: amnesia, anxiety, discolored hair, dizziness, dry skin, hirsutism, hostility, impaired urination, paresthesia, penis disorder, peripheral edema, sweating, and vasodilation.
In this clinical trial of TESTOSTERONE™, skin reactions at the site of application were occasionally reported with TESTOSTERONE™, but none was severe enough to require treatment or discontinuation of drug.
Six (4%) patients in this trial had adverse events that led to discontinuation of TESTOSTERONE™. These events included the following: cerebral hemorrhage, convulsion (neither of which were considered related to TESTOSTERONE™ administration), depression, sadness, memory loss, elevated prostate specific antigen and hypertension. No TESTOSTERONE™ patients discontinued due to skin reactions.
In an uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with TESTOSTERONE™; these were asthenia and depression in one patient and increased libido and hyperkinesia in the other. Among 17 patients in foreign clinical studies there was 1 instance each of acne, erythema and benign prostate adenoma associated with a 2.5% TESTOSTERONE formulation applied dermally.
One hundred six (106) patients have received TESTOSTERONE™ for up to 12 months in a long-term follow-up study for patients who completed the controlled clinical trial. The preliminary safety results from this study are consistent with those reported for the controlled clinical trial. Table 3 summarizes those adverse events possibly, probably or definitely related to the use of TESTOSTERONE™ and reported by at least 1% of the total number of patients during long-term exposure to TESTOSTERONE.™
Table 3. Incidence of Adverse Events Possibly, Probably or
Definitely Related to the Use of TESTOSTERONE™ in the
Long-Term, Follow-up Study Dose of TESTOSTERONE™
Adverse Event 5 G 7.5 G 10 G
Lab Test Abnormal * 4.2% 0.0% 6.3%
Peripheral Edema 1.4% 0.0% 3.1%
Acne 2.8% 0.0% 12.5%
Application Site Reaction 9.7% 10.0% 3.1%
Prostate Disorder ** 2.8% 5.0% 18.8%
Urination Impaired 2.8% 0.0% 0.0%
* Lab test abnormal included one patient each with elevated GGTP, elevated hematocrit and hemoglobin, increased total bilirubin, worsened hyperlipidemia, decreased HDL, and hypokalemia.
** Prostate disorders included enlarged prostate, elevated PSA results, and in one patient, a new diagnosis of prostate cancer; three patients (one taking 7.5 G daily and two taking 10 G daily) discontinued TESTOSTERONE™ treatment during the long-term study because of such disorders.
DRUG ABUSE AND DEPENDENCE
TESTOSTERONE™ contains testosterone, a Schedule III controlled substance as defined by the Anabolic Steroids Control Act.
Oral ingestion of TESTOSTERONE™ will not result in clinically significant testosterone concentrations due to extensive first-pass metabolism.
OVERDOSAGE
There is one report of acute overdosage by injection of testosterone enanthate: testosterone levels of up to 11,400 ng/dL were implicated in a cerebrovascular accident.
DOSAGE AND ADMINISTRATION
The recommended starting dose of TESTOSTERONE™ 1% is 5 G (to deliver 50 mg of testosterone) applied once daily (preferably in the morning) to clean, dry, intact skin of the shoulders, and upper arms and/or abdomen. Upon opening the packet(s), the entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Application sites should be allowed to dry for a few minutes prior to dressing. Hands should be washed with soap and water after TESTOSTERONE™ has been applied.
Do not apply TESTOSTERONE™ to the genitals.
Serum testosterone levels should be measured approximately 14 days after initiation of therapy to ensure proper dosing. If the serum testosterone concentration is below the normal range, or if the desired clinical response is not achieved, the daily TESTOSTERONE™ 1% dose may be increased from 5 G to 7.5 G and from 7.5 G to 10 G as instructed by the physician.
Andriol Testocaps1 product profile
• Andriol Testocaps® is the only non-hepatotoxic oral preparation that adequately delivers testosterone to the body.
• With adequate dosing (in most hypogonadal patients TU 2x80 mg/day), treatment with Andriol Testocaps® restores serum testosterone to levels within the normal range.
• For optimal absorption, Andriol Testocaps® must be taken with food.
• Treatment with Andriol Testocaps® reduces serum SHBG levels by ± 30%, which contributes to a further increase of bioavailable testosterone.
• Treatment with Andriol Testocaps® decreases serum gonadotropin levels by 25%.
TARGETED TESTOSTERONE THERAPY
Although testosterone itself is well absorbed after oral administration, it is quickly metabolized during its first pass through the liver, inactivating thereby 98% of the amount absorbed. As a consequence, oral administration of pure crystalline testosterone does not increase plasma testosterone levels. Therefore, such preparations are not suitable for oral administration, as they do not result in sustained physiological plasma levels. Various solutions to this problem have been developed, including injectable and transdermal routes of administration as well as sophisticated systems for oral administration that circumvent hepatic first-pass metabolism.
Early attempts to develop a suitable orally administered derivative made use of methyltestosterone or fluoxymesterone, which both have appropriate pharmacokinetics, but unfortunately are metabolized in vivo into metabolites with a significant risk of liver toxicity. As a result, methyltestosterone and fluoxymesterone have become obsolete. Mesterolone, an orally administered derivative of DHT, also has suitable pharmacokinetics, but has become obsolete since it demonstrates only those activities mediated by DHT but none of those mediated by testosterone. Therefore, mesterolone does not stimulate libido and sex drive, does not increase bone mineral density and has hardly any effect on the secretion of LH and FSH (in other words, mesterolone does not exert a full androgenic effect).
Formulations that have overcome the problems of oral administration of crystalline testosterone include intramuscular injections of testosterone esters (100-250 mg every 2-3 weeks), which produce high, even supraphysiological plasma levels of testosterone for a few days, followed by a gradual decline. As a result, patients may experience side effects resulting from the supraphysiological testosterone plasma levels during the first few days after injection, such as mood disturbances and unfavorable changes in plasma lipid profile. Moreover, toward the end of administration interval, plasma testosterone levels often drop below the normal range, which may result in the recurrence of hypogonadal symptoms.
Testosterone can also be delivered successfully from slow-release, subcutaneous pellets, which last for 4-5 months. However, the implantation of these testosterone pellets requires a minimal surgical procedure and they are only available in a few countries.
Transdermal testosterone patches are also an effective means of delivering physiological levels of testosterone, but as many as 60% of patients discontinue their use due to skin irritation or allergic contact dermatitis (which happens to occur especially in hot and humid climates). Other problems associated with testosterone patches are that they are relatively large and therefore visible, which is not appreciated by the patient. Moreover, testosterone patches often do not stick very well, which contributes further to the inconvenience. Currently, there are two forms of patches, a body patch and a patch that must be applied to the shaved scrotal skin. Finally, a transdermal gel has become available for application on the skin.
From the above, it appears that each testosterone formulation and administration route has advantages and disadvantages and the ultimate choice is one that clinicians make on the basis of therapeutic indication and patient preferences. Most of these problems with administration of testosterone have been overcome with the development of Andriol Testocaps®, which consists of a solution of the undecanoate ester of testosterone (TU) in castor oil, contained in a soft gelatin capsule. If taken with a meal, the TU molecules are included in chylomicrons and a significant part of the administered TU thereby bypasses the liver and gains access to the peripheral circulation via the intestinal lymphatic system (Figure 7), a process that has been demonstrated in both rats and men. Moreover, TU is an ester of natural testosterone, which is metabolized after absorption by esterase into natural testosterone. Therefore, and this is in contrast to methyltestosterone and fluoxymesterone, TU is not hepatotoxic. Another advantage of oralTU over injectable testosterone preparations is that treatment can be interrupted immediately if necessary. As most male patients seem to prefer oral administration to injectable or transdermal administration of testosterone, Andriol Testocaps® appears to be the optimal preparation from the perspective of patient convenience. This is emphasized by the fact that oralTU has maintained a strong worldwide market position from the early 1990s onward, despite introductions of transdermal application forms of testosterone.
PHARMACOKINETICS OF ANDRIOL TESTOCAPS®
Many studies on the pharmacokinetics of oralTU have demonstrated that testosterone levels within the normal range are achieved in hypogonadal patients.64'65'66-67 Many of the initial pharmacokinetic studies have been performed in the 1970s and 1980s and most are of appropriate quality taking into account the time period when they were performed. The original oralTU preparation (Andriol®) had the disadvantage that, for stability reasons, the capsules had to be stored in the refrigerator at the pharmacy. On the other hand, in order to facilitate optimal absorption, patients had to store them at room temperature, under which conditions the shelf-life was only 3 months. These relatively complicated storage conditions carry the risk of non-adherence, which might result in administration of inactive drug. To allow more convenient storage conditions, a new and more stable pharmaceutical formulation of oralTU was developed, Andriol Testocaps®, in which the solvent oleic acid has been replaced by castor oil and propylene glycol laurate. This improved formulation allows storage at room temperature for 3 years. A new set of well-controlled studies have been performed, providing a more detailed view on the pharmacokinetic and pharmacodynamic properties of this oral preparation. Andriol Testocaps® has been reported to be bioequivalent with Andriol® (Data on file) and data obtained with the old oral TU formulation therefore do also apply to the new formulation. As a consequence, new and well-controlled studies performed with Andriol Testocaps® have been included in this product monograph and have, where appropriate, replaced those from studies with the old formulation.
Absorption
Oral TU was first formulated after extensive studies of various testosterone esters in various fatty acid vehicles that induce the creation of chylomicrons.The active ingredient (TU) is sufficiently lipophilic to be transported together with other lipids, by natural processes, contained within relatively large chylomicrons in the lymph. In contrast to crystalline testosterone, TU dissolved in a lipophilic solvent significantly enhances absorption (Figure 8). De-esterification of TU to produce testosterone takes place rapidly in the intestinal wall as well as in the peripheral circulation.68'69 Since the oral bioavailability is estimated at 7% and the metabolic clearance of oralTU is relatively high,70 physiological levels of testosterone are sustained by taking capsules several times daily. It can be calculated that, with an absolute bioavailability of ±7%, oral administration of 160 mgTU (which is equivalent to 100 mg testosterone) results in a systemic testosterone exposure of 7 mg per day. This exposure level fits well with the normal testosterone production of a healthy man, which is 4-9 mg testosterone per day.
Andriol Testocaps® has been designed to deliver testosterone to the systemic circulation via the intestinal lymphatic route, thereby circumventing first-pass inactivation in the liver. By means of stable isotope methodology in cannulated thoracic lymph ducts, the lymphatic transport and oral bioavailability of TU was recently studied in a validated dog model.7zMean absolute bioavailability of TU was 2.9% when administered orally as AndriolTestocaps® and lymphatically transported TU accounted for 99.7% of the systemically available ester. Pharmacokinetic analysis further indicated that 84% of the systemically available testosterone was due to systemic hydrolysis of lymphatically transported TU. Because of its lipophilic properties, it has long been suggested that administration of TU with a meal enhances absorption and thus increases bioavailability of testosterone.73 The effect of food on the bioavailability of AndriolTestocaps® was investigated in post-menopausal women. In this single-dose, randomized cross-over study, the effect of a meal (standard breakfast: 460 kcal, 23 g fat, 48 g carbohydrates and 14 g protein) on the pharmacokinetics of AndriolTestocaps® was compared with administration in a fasting state. It was concluded that in the fasting state hardly any TU was absorbed and that administration of TU with food significantly enhances the bioavailability of TU. It is therefore concluded that for optimal absorption, Andriol Testocaps® must be taken with food.
In a recently completed four-way cross-over study in 24 post-menopausal women, the effect of four types of meals with different caloric and lipid contents was investigated on the bioavailability of TU.75The results showed that a normal meal, containing approximately 19 g of lipids, is sufficient for efficient absorption of TU from AndriolTestocaps®.
Distribution and bioavailability
As a consequence of the oral administration route, serum testosterone levels may fluctuate during treatment with AndriolTestocaps®.Therefore, with this preparation assessment of the clinical response to treatment may be a better guide to dose requirements than biochemical variables, regardless of serum testosterone levels. The time to reach optimal clinical response may range from 3 to 6 months. If necessary, serum testosterone levels should be measured 2-4 hours after intake of oralTU. Serum total testosterone levels below and above the normal range may require adjustment of the dose.
Several studies have indicated that oralTU is properly absorbed, providing physiological plasma levels of testosterone64'65'66'67 Moreover, a recent study with AndriolTestocaps® has shown that the increase of plasma testosterone level is proportional with the dose administered.
In a randomized dose-selection study with AndriolTestocaps®, the pharmacokinetic behavior of oralTU in 49 hypogonadal men (total testosterone < 10.4 nmol/L) was investigated (Data on file). Subjects were randomized to one of four dose regimens:
• oralTU 120 mg/day (40-40-40 mg/d);
• oralTU 160 mg/day (40-40-80 mg/d);
• oralTU 160 mg/day (80-0-80 mg/d);
• oral TU 240 mg/day (80-80-80 mg/d).
All doses were to be taken with meals and blood samples were collected before the morning dose on days 1, 3, 7, 14, and 21 of treatment. Blood samples were collected for up to 48 hours after the morning dose on day 28. Steady-state levels of total testosterone were reached after 3 days, whereas steady state of bioavailable testosterone was reached after 7 days of treatment. Mean serum total testosterone concentrations were restored
to the normal range for 76% (120 mg/day) to 100% (160-240 mg/day) of the day at steady state (Figure 10). The data also suggested dose-proportional pharmacokinetics over the dose range of 120-240 mg/day (Figure 11).
It was concluded that an oralTU dose of 2x 80 mg/day (administered with the morning and evening meals) was the optimal regimen to restore testosterone levels to the normal range (Data on file). Finally, in a previous study in hypogonadal men in which oralTU 120 mg/day was compared with mesterolone 75 mg/day, there was a restoration of mean plasma total testosterone to the mid-normal range (from 3.5 to 23 nmol/L) with oralTU, whereas no increase was observed with mesterolone.
Metabolism and excretion
After oral administration, approximately one-third of TU is converted in the intestinal wall to 5a-DHT and both the parent compound and metabolite are then absorbed into the lymphatic system.6869 De-esterification is believed to occur rapidly in the intestinal wall and the peripheral circulation, as well as in the peripheral organs, including the prostate.
Testosterone is largely metabolized in the liver, where it is converted into an active metabolite androstenedione. This compound is further metabolized into the weakly androgenic androsterone and the inactive etiocholanolone. Both of these are excreted, mainly in the urine, with only 6% passing into the feces via the enterohepatic circulation.
Studies with tritium-labeled TU, orally administered to patients with thoracic duct catheters, have shown that excretion in the urine peaks about 2 hours after peaks are reached in plasma and lymph. About 40% of the radioactive product was excreted in urine during the first 24 hours and 45-48% after the first week.68
Drug interactions
The effects of three enzyme-inducing drugs (antipyrine, phenobarbital and rifampicin) on the pharmacokinetic behavior of a single oral dose of TU in healthy volunteers were investigated. Antipyrine and phenobarbital reduced the AUC of testosterone in TU-treated men by about 20%, whereas rifampicin increased testosterone AUC in TU-treated men by 78%. Moreover, the urinary excretion of testosterone was not altered by antipyrine or rifampicin, but was increased by 15% by phenobarbital.
PHARMACODYNAMICS OF ANDRIOL TESTOCAPS®
The many interrelations between the compounds in the HPG axis and related pathways mean that the administration of testosterone is accompanied by changes in other key factors.
Effects on gonadotropins
Testosterone treatment variably results in a dose-dependent suppression of plasma LH and FSH. These effects are attributable to negative feedback from testosterone, and show considerable variability between different preparations, study groups and treatment protocols. Overall, studies with oralTU show either no effects on gonadotropin levels" or show slight decreases in levels of LH and/or FSH, with an indication that, in patients with hypogonadotropic hypogonadism, the effect of treatment on gonadotropins is small.65 In the randomized dose-selection study with AndriolTestocaps® in hypogonadal men, there was a dose-dependent
suppression of both LH and FSH. After 28 days of treatment in the 80-0-80 mg/day group, the median reductions of plasma LH and FSH levels were 21% and 26%, respectively (Data on file). In a study in middle-aged men treated with oralTU 160 mg/day for 8 months, the fall of plasma FSH was 33%, whereas no changes of serum LH were observed.
Effects on sex hormones other than testosterone
Testosterone therapy not only increases plasma testosterone levels but also those of its major active metabolites, including estradiol, DHT and androstenedione.
A gradual increase in serum estradiol levels has been demonstrated with oralTU in most,6481 but not all studies77 in hypogonadal men. One study with oralTU 40-160 mg/day showed such an increase, with a plateau being reached after 4-6 weeks.81 In another study, treatment with oralTU 160 mg/day resulted in estradiol levels in the mid-normal range, whereas injections of 250 mg of mixed testosterone esters produced supraphysiological levels of plasma estradiol.64 A long-term safety study of oralTU showed that estradiol levels were slightly above normal, with no tendency to increase over time.82 In the randomized dose-selection study with Andriol Testocaps® in hypogonadal men, there was a slight increase of plasma estradiol. After 28 days of treatment, plasma estradiol levels increased from 101 to 111 pmol/L in the 40-40-40 mg group, from 96 to 99 pmol/L in the 40-40-80 mg group, from 93 to 115 pmol/L in the 80-0-80 mg group and from 94 to 117 pmol/L in the 80-80-80 mg group, respectively (Data on file).
Treatment with oralTU results in a dose-dependent increase in plasma DHT levels in most subjects,77'82 although one study with oralTU 80 mg/day in elderly men showed no significant change.83 A long-term safety study of oral TU showed that DHT levels and the DHT/testosterone ratio were slightly above normal, with no tendency to increase over time.81'82 In the randomized dose-selection study with Andriol Testocaps® in hypogonadal men, there was a significant increase of plasma DHT. After 28 days of treatment, plasma DHT levels increased from 0.3 to 4.5 nmol/L in the 40-40-40 mg group, from 0.6 to 5.8 nmol/L in the 40-40-80 mg group,
from 1.0 to 8.6 nmol/L in the 80-0-80 mg group and from 0.7 to 11.1 nmol/L in the 80-80-80 mg group, respectively (Data on file). Older studies in hypogonadal men have shown that oralTU treatment is associated with an increase of plasma androstenedione to normal levels, whilst DHEA(S) is unaffected.77'84
Effects on sex hormone-binding globulin
Plasma levels of the binding protein SHBG usually decrease following all forms of testosterone treatment, including oralTU.55'80'8586 In a study in middle-aged men treated with oralTU 160 mg/day for 8 months, the fall of SHBG was about 15%.80 In the randomized dose-selection study with AndriolTestocaps® in hypogonadal men, there was a suppression of plasma SHBG. After 28 days of treatment, the reduction of plasma SHBG level was 29% in the 40-40-40 mg group, 35% in the 40-40-80 mg group, 32% in the 80-0-80 mg group and 31% in the 80-80-80 mg group, respectively (Data on file). The reduction of plasma SHBG, as seen with Andriol Testocaps® facilitates a shift from SHBG-bound to albumin-bound testosterone, which may contribute to a further increase of bioavailable testosterone level.
Efficacy of Andriol Testocaps® in the treatment of (late-onset) hypogonadism
• Testosterone supplementation is indicated for treatment of testosterone deficiency, including hypogonadism, late-onset hypogonadism, and related conditions such as delayed puberty in boys.
• There is considerable evidence that treatment of hypogonadism and late-onset hypogonadism with testosterone improves a variety of associated clinical conditions, including bone mineral density, body composition, sexual function, mood and general well-being.
INTRODUCTION
It is widely accepted that testosterone supplementation should be offered to males with hypogonadism. In addition to classical hypogonadism as a therapeutic indication for testosterone treatment, delayed puberty in boys can be considered as a transient form of hypogonadism and it is well established that low-dose testosterone treatment can induce puberty in these boys. Increasingly, testosterone may also be indicated for older men with low testosterone levels in combination with clinical symptoms such as sexual dysfunction, reduced general well-being and osteoporosis. In addition, the anabolic effects of testosterone are investigated for treating muscle wasting associated with aging, AIDS and cancer. Finally, the use of testosterone in women with sexual desire disorders is currently being investigated because there are indications that a reduced libido in women may also be related to testosterone deficiency.
In men with testosterone deficiency, oralTU has been shown to improve clinical symptoms including libido, erectile function, bone mineral density, muscle mass and strength and general well-being, whereas it may also increase cognitive function and physical functioning. The oral administration route of TU makes it especially suitable for treatment over other routes
because of the following specific product characteristics: convenience of oral administration, dose flexibility and possibility of instant interruption if necessary.
TESTOSTERONE TREATMENT OF HYPOGONADISM
Bone
Although the pathogenesis of osteoporosis in men is multifactorial, testosterone is known to play an important role in maintenance of the male skeleton. Long-term testosterone deficiency leads to loss of bone mass and increased risk of osteoporosis. Studies have unequivocally shown that testosterone treatment in men with hypogonadal osteoporosis improves bone mineral density (Figure 12). This increase of BMD with testosterone treatment is relatively quick (with the most pronounced increase during the first year of treatment) and appears independent of type of hypogonadism, age or preparation.8788
After 6 months of treatment, dose-dependent increases of BMD were achieved with all investigated androgen preparations. In the oralTU group (TU 160 mg/day), a nonsignificant BMD increase of 3,4% at the distal radius was achieved after 6 months of treatment.
Muscle status and body composition
Muscle atrophy and muscle weakness are both well-recognized symptoms of hypogonadism in men and one study has demonstrated that maintenance of plasma testosterone levels within the normal range is sufficient to maintain a normal metabolic state with respect to protein, carbohydrate and lipid metabolism.90 In another trial, testosterone replacement was shown to induce changes in fat-free mass, muscle size, strength and power, fat mass, hemoglobin, HDL cholesterol, and IGF-I levels, in a dose- and concentration-dependent manner. The trial was performed in 61 eugonadal men, between 18-35 years of age, who received monthly injections of a long-acting GnRH agonist to suppress endogenous testosterone secretion, and who were randomized to one of five dose groups of weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate for 20 weeks.9' The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1345, and 2370 ng/dL at the 25, 50, 125, 300, and 600 mg doses, respectively. The different androgen-dependent changes observed showed a single linear dose-response relationship.
Testosterone appears to exert its effect on muscle size and strength through an activation of muscle protein synthesis.92'93 Several studies in hypogonadal men have investigated the effects of testosterone treatment on muscle mass and muscle strength. Depending on the testosterone preparation, studies in hypogonadal men have shown that testosterone increases muscle mass by 2-15%, which was usually also accompanied by an increase of muscle strength.92'93'94'95 Although, in these studies, an effect on muscle mass and muscle strength has been observed, it is not yet clear whether this also translates into improved functionality in daily life.
Hypogonadism is also associated with an increase of body fat, especially around the waist40'94 and this increase of abdominal adiposity in men is
thought to contribute to an increased risk of cardiovascular disease and mortality.43 The cause of the increase of abdominal adiposity in aging men is not exactly clear, but inactivity and a reduction of the testosterone/ estradiol ratio are thought to be involved. In studies of testosterone treatment in hypogonadal men, an effect on body fat mass was reported, ranging from no effect to a significant reduction by -\4% *&•*>*& Testosterone treatment is thought to be associated with increased lipolysis96 as well as with increased abdominal lipid metabolic breakdown.
Libido and erectile function
Although erectile dysfunction may be due to physical disease (e.g. diabetes, cardiovascular disease), to psychological problems, or may have a multifactorial etiology, this condition is also known to occur in hypogonadal men when testosterone levels fall below a certain threshold level. Although erectile dysfunction is rarely caused by hypogonadism (estimations of the proportion that is due to hypogonadism has been estimated at approximately 7-15%), evidence suggests that testosterone plays a role in erectile function by increasing nitric oxide production and facilitating hemodynamic changes in the corpus cavernosum.
In hypogonadal men suffering from erectile dysfunction, testosterone therapy can improve erectile function, with the greatest benefits likely to be in those with the most severe testosterone deficiencies. The physiological range for testosterone in plasma (12-35 nmol/L) is considerably higher than that necessary for maintaining normal sexual function. Testosterone levels found to be critical for sexual functioning in men lay around 12 nmol/L and show considerable inter-subject variability. Testosterone treatment of hypogonadal men (it has been recommended to start with a 3-6 months' course) has been shown to have a stimulant effect on sexual interest and fantasies, sexual arousal, spontaneous nocturnal and morning erections, ejaculation, sexual activity and orgasm.101
Many studies provide firm evidence that oralTU is an effective treatment for hypogonadal men with libido problems.77'85'102'103'104-105 For example, the well-designed study of O'Carroll and colleagues in hypogonadal men showed that, with oralTU 40, 80, 120 or 160 mg/day on an escalating or
reducing basis, sexual thoughts, sexual excitement and morning erections were all dose-dependently improved.105 In another study,85 with a double-blind cross-over design, comparing oralTU 160 mg/day and placebo in 12 hypogonadal men, oralTU produced significant improvements in a range of measures of sexual interest and behavior. Sexual interest increased within the first week of oralTU therapy, and ejaculation usually within the second week. In hypogonadal subjects with residual testicular androgen production, such as in cases of Klinefelter's syndrome, oral TU may have an advantage over intramuscular injections of testosterone esters, which suppress endogenous androgen production. Such effects also suppress testosterone precursors, which may themselves have independent effects on well-being and sexual behavior. Other studies in hypogonadal men show that oralTU treatment has significant effects on libido, sexual activity, and responses such as sexual enjoyment, erections and ejaculation.8586103 That this is a real effect of increases in testosterone levels is suggested by the fact that, in one study of hypogonadal men aged 22-50 years, oralTU 160 mg/day improved sexual function in men with low free testosterone levels, but not in those subjects with normal levels.
In a clinical study in hypogonadal men most of whom had been treated with testosterone implants previously, an overall subjective clinical response (as measured using a questionnaire rating libido and erectile function) was observed in 60 out of 66 men (91%) who completed a 9-week trial with oral TU 160 mg/day. In total, 69% of the participants felt that oral TU was superior to testosterone implants, 10% thought that there was no difference between the two preparations and 21% of patients rated implants superior to oral TU.107
In a randomized double-blind study in hypogonadal men, the effects of oral TU 120 mg/day were compared with mesterolone 150 mg/day with the help of rating scales. After 4 weeks of treatment, patients using oral TU showed significant improvements of libido score, whereas, in the mesterolone group, no improvement was reported (Figure 14).103 These between-group differences in improvement of libido were confirmed in the study by Papadimas et al."
In a study in hypogonadal men with erectile dysfunction, treatment with oralTU 120 mg/day resulted in an improvement of erectile function in 43% of patients,104 whereas, in a multiple-dose study, there were also significant improvements in erectile function (measured by penile circumference, duration of erection and latency time to first erection).100 Remarkable improvements of erectile function were demonstrated in a double-blind study of hypogonadal men that compared oralTU 120 mg/day for 4 weeks with mesterolone at the relatively high dose of 150 mg/day from the third week onward. With mesterolone, no beneficial effects were observed.
In eugonadal men with erectile dysfunction, the effects of testosterone therapy are not so clear-cut and efficacy has often been marginal.102, Nevertheless, one study reported a favorable response with oral TU on erectile function in a trial in eugonadal men with known arterial insufficiency.
Hematopoiesis
Hypogonadal men often have anemia and testosterone therapy is known to increase the production of red blood cells by stimulating erythropoietin as well as the erythropoietic stem cells. This results in an increase in blood hemoglobin and hematocrit levels110 and the magnitude of the effect is largely dose-dependent.111
A comparative study of the effects of oralTU and other androgen preparations on erythropoiesis in hypogonadal men showed dose-dependent increases in both hemoglobin and hematocrit levels with all four preparations (Figure 15).112 Maximal stimulation of erythropoiesis required subjects to have testosterone levels at least within the low-normal range. Similar effects were seen in the same study with intramuscular injections of testosterone esters and testosterone implants, but not with the DHT derivative, mesterolone.
Mood and general well-being
It is well accepted that hypogonadal men often have depressed mood. Well-controlled studies have shown that restoration of physiological plasma testosterone levels improves mood in hypogonadal men. It was reported that testosterone therapy reduced anger, irritability, sadness, tiredness and nervousness, whereas improvements were reported in energy level, friendliness and sense of well-being.113 Testosterone treatment did not have a significant effect on depression score in hypogonadal men with major depressive disorder. It has therefore been proposed that testosterone may improve depressed mood (dysthymia), which is a well-known symptom of hypogonadism. In major depression, however, no improvement of depressive symptoms may be expected from testosterone intervention.
There is considerable evidence that oralTU may improve mood in hypogonadal men with depressed mood. In one double-blind, placebo-controlled study, for example, oralTU 160 mg/day significantly reduced anxiety/tension and also showed trends toward less fatigue and greater vigor.85 In addition, in a randomized dose-finding study, there was a significant dose-response relationship between oralTU dose and mood scores.105 In another randomized, double-blind trial, 80% of hypogonadal
men treated with oralTU 120 mg/day showed a significant improvement in mental activity, whereas those treated with mesterolone (75 mg/day) showed no such improvement.77 Finally, in a randomized, double-blind study in hypogonadal men, the effects of oralTU 120 mg/day were compared with mesterolone 150 mg/day with the help of rating scales. In this 4-week study, patients using oralTU showed significant improvements of mental state score from week 2 onward, whereas in the mesterolone group, no improvement was reported.103
Cognitive function
There is conflicting evidence that testosterone treatment enhances memory in hypogonadal men. An intervention study in hypogonadal men suggested that testosterone therapy induced some improvement of verbal fluency, but did not improve visuospatial ability and perceptual speed.115 A prospective longitudinal study on the other hand, in which 407 volunteers of 50-91 years of age were followed for an average of 10 years, showed a relationship between age-associated decreases in endogenous serum testosterone and free testosterone concentrations and declines in neuropsychological behavior.116 A higher free testosterone index was associated with better scores on visual and verbal memory, visuospatial functioning and visuomotor scanning, and a reduced rate of longitudinal decline in visual memory. Men classified as hypogonadal had significantly lower scores on measures of memory and visuospatial performance and a faster rate of decline in visual memory. No relations between total testosterone or the free testosterone index and measures of verbal knowledge, mental status or depressive symptoms were observed.116
TESTOSTERONE TREATMENT OF LATE-ONSET HYPOGONADISM
Testosterone treatment of aging males with low testosterone plasma levels has been shown to have substantial benefits for a wide variety of age-related parameters, including bone mass, body composition, muscle strength, libido, sexual function, spatial cognition and memory.117-118119120 The results of studies so far performed on the use of oralTU have been most encouraging, although relatively small numbers of subjects have been involved and treatment has lasted for up to 12 months.
Treatment of hypogonadism with testosterone has been demonstrated to improve bone mineral density and such findings have prompted studies of elderly men with total plasma testosterone around the lower normal limit (Table 8).
From this table the picture emerges that the effects of testosterone on bone are varied. This is probably related to differences between studies in testosterone formulation and dose, treatment duration, inclusion criteria and sample size. In general, the following can be derived from the data:
• testosterone treatment in aging hypogonadal men increases or has no significant effect on markers of bone formation;2'15-121-122-123-124
• testosterone treatment in aging hypogonadal men decreases or has no significant effect on markers of bone resorption;2'15'123'124'125
• testosterone treatment in aging hypogonadal men increases bone mineral density at the spine in most studies;15-124-125'126'127
• testosterone treatment in aging hypogonadal men increases or has no significant effect on bone mineral density at other skeletal sites.1!
An early study on bone metabolism in aging hypogonadal men has shown that treatment with oralTLJ 160 mg/day is associated with significantly increased calcitonin responses to administered intravenous calcium, with serum calcitonin levels increasing from 40 pg/ml at baseline to 70 pg/ml after oralTU treatment (p < 0.02).
Another placebo-controlled study in aging hypogonadal men also demonstrated that treatment with oral TU 240 mg/day for 1 year was able to increase BMD significantly at the lumbar spine by 1.7%, whereas the placebo group lost 1.0%. Also BMD at the hip (femoral neck) increased with oralTU (+0.7%), but, due to a concomitant increase in the placebo group (+1.5%), the difference between the groups was not statistically significant.