Androgel - Scientific Information
|Condition:||Hypogonadism, Male, Hypogonadism|
|Class:||Androgens and anabolic steroids|
|Form:||Cream, gel, liniment or balm, lotion, ointment, etc|
|Ingredients:||testosterone, alcohol, purified water, sodium hydroxide, Carbopol 980, isopropyl myristate|
|Proper name:||Testosterone USP|
|Chemical name:||17 β- hydroxyandrost-4-en-3-one|
Androst-4-en-3-one, 17- hydroxy-, (17 β )-
|Molecular formula and molecular mass:||C19H28O2|
|Description:||white to practically white crystalline powder.|
|Solubility:||Soluble in acetone, dioxane and vegetable oils|
In water: practically insoluble
In dehydrated alcohol: 1 in 6 of dehydrated alcohol
In chloroform: 1 in 2 of chloroform
In ether: 1 in 100 of ether
|CAS Registry No:||58-22-0|
|Melting point:||153°- 157°C|
ANDROGEL was evaluated in a multicenter, randomized, parallel-group, active-controlled, 180-day trial in 227 hypogonadal men (age = 18 to 68 years). The study was conducted in 2 phases. During the Initial Treatment Period (Days 1-90), 73 patients were randomized to ANDROGEL 5 g daily (to deliver 50 mg testosterone), 78 patients to ANDROGEL 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 doses of ANDROGEL but open-label for active control. Patients who were originally randomized to ANDROGEL 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 ANDROGEL 5 g daily, 52 patients continued on ANDROGEL 10 g daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received ANDROGEL 7.5 g daily. Upon completion of the initial study, 162 patients elected to enter and receive treatment in an open-label, long-term extension study of ANDROGEL for an additional period of 3 years. Patients in the original trial and in the long-term extension study were treated with ANDROGEL for up to 42 months.
Mean peak, trough and average serum testosterone concentrations within the normal range (10.3 - 36.2 nmol/L) were achieved on the first day of treatment with doses of 5 g and 10 g. In patients continuing on ANDROGEL 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 ANDROGEL for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed ANDROGEL treatment.
Figure 1: Mean Steady-State Testosterone Concentration in Patients with once-Daily ANDROGEL Therapy
Table 1 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 5 g, 7.5 g, or 10 g of ANDROGEL. The 7.5 g dose produced mean concentrations intermediate to those produced by 5 g and 10 g of ANDROGEL.
|5 g||7.5 g||10 g|
|N = 44||N = 37||N = 48|
|Cavg||19.3 ± 7.8||20.9 ± 10.7||24.7 ± 7.3|
|Cmax||28.8 ± 12.0||31.3 ± 16.3||37.6 ± 15.1|
|Cmin||12.9 ± 5.7||14.1 ± 7.6||16.8 ± 5.4|
Of 129 hypogonadal men who were appropriately titrated with ANDROGEL and who had sufficient data for analysis, 87% achieved an average serum testosterone level within the normal range on Treatment Day 180.
An open-labelled, randomized, non-placebo controlled, parallel-group, active-controlled trial indicated that ANDROGEL (5 g/day and 10 g/day) resulted in statistically significant increases in blood testosterone levels which were maintained in the eugonadal range through Days 30, 90, and 180. Treatment for 90 days was associated with an increase in total body lean mass and a decrease in total body fat. Bone mineral density (BMD) in both hip and spine increased from Baseline to Day 180 with the 10 g dose of ANDROGEL. These observed changes were maintained through the 180 day treatment period and sustained for a period of 24 months. Patients treated for up to 24 months with either 5 g, 7.5 g, or 10 g of ANDROGEL experienced a sustained improvement of bone mineral density of the spine and hip.
Subjective assessments by patients using a self-administered non-validated questionnaire indicated that ANDROGEL (5 g/day and 10 g/day) treatment for 90 days was associated with a perceived improvement in some hypogonadal symptoms (measured by sexual motivation, sexual activity and enjoyment of sexual activity, penile erection, mood and fatigue) when compared to the baseline score.
DHT concentrations increased in parallel with testosterone concentrations at ANDROGEL 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 ANDROGEL 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 ANDROGEL treatment. Reductions in mean FSH and LH levels were observed in all patients exposed to ANDROGEL, but the gonadotropin reductions were more pronounced in men with hypergonadotropic hypogonadism. Serum levels of LH and FSH fell in a dose- and time- dependent manner during treatment with ANDROGEL.
Compliance rate was over 93% and 96% for subjects receiving ANDROGEL 5g/ day and 10g/day, respectively, during Days 1 – 90 and remained at that level during Days 91 – 180.
Potential for Phototoxicity
The phototoxic potential of ANDROGEL was evaluated in a doubleblind, single-dose study in 27 subjects with photosensitive skin types. The Minimal Erythema Dose (MED) of ultraviolet radiation was determined for each subject. A single 24 (+1) hour application of duplicate patches containing test articles (placebo gel, testosterone gel, or negative control) was made to naïve skin sites on Day 1. On Day 2, each subject received five exposure times of ultraviolet radiation, each exposure being 25% greater than the previous one. Skin evaluations were made on Days 2-5. Exposure of test and control article application sites to ultraviolet light did not product increased inflammation relative to non-irradiated sites, indicating no phototoxic effect.
Potential for testosterone transfer to female partner
The potential for dermal testosterone transfer following ANDROGEL use was evaluated in a clinical study between males dosed with ANDROGEL and their untreated female partners. Two to 12 hours after ANDROGEL (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 ANDROGEL application sites. Under these study conditions, all unprotected female partners had a serum testosterone concentration greater than 2 times the baseline value at Day 7 when women were exposed at 2 hours and less so at 6 or 12 hours, after the application by the male. When a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented.
Testosterone was administered to rabbits in a 10-day dermal toxicity study using a gel formulation. Skin irritation at higher dosages was observed; however, there was no significant organ histopathology.
Testosterone propionate was administered intramuscularly in sesame oil to mature (approximately 2 year old) male and female dogs (2/sex) for 6 months at a dosage of 11 mg/kg. Animals were injected twice each week during the 6 month period. During the first 4 weeks of dose administration, dogs had an increase in body weight as well as a decrease of urine volume and decreased urinary excretion of nitrogen, sodium, potassium and phosphorus. Urine also contained glucose and protein. Throughout the study, serum cholesterol and phospholipids were decreased approximately 60% compared to pre-dose concentrations. At necropsy, renal changes (thickening of the glomerular capsule and degeneration of the tubular epithelial cells) were observed.
Reports on the effects of testosterone in in vitro and in vivo models for mutagenic potential have not been located in the literature.
The ability of testosterone to produce tumors of the prostate gland has been examined in several studies. Pollard et al used male L-W rats, which are susceptible to prostatic cancer. Animals were treated with testosterone propionate administered as a subcutaneous depot in silastic tubing. The dosage was 50 mg of testosterone propionate every 2 months; each treatment group contained 24 animals. Histopathological examination of the prostate, testes, kidneys, lungs,adrenals, pancreas, thyroid, thymus and pituitary was performed.
Mean serum testosterone concentrations were 16.1 ng/mL and 8.0 ng/mL at 2 weeks and 2 months after testosterone was implanted, respectively, demonstrating that animals were exposed to testosterone throughout the test period. Control animals had a mean serum testosterone concentration of 1.4 ng/mL. After 14 months of treatment, 24% of the rats treated with testosterone had developed macroscopic prostate adenocarcinomas while an additional 16% had microscopic in situ neoplasia. None of the control rats had macroscopic tumors, but control animals did have microscopic evidence of in situ neoplasia. Moreover, gross or microscopic evidence of adenocarcinomas in DHT-treated rats was not observed.
In another study, castrated F344 rats were treated with 3,2’-dimethyl-4-aminobiphenyl (DMBA) to induce prostatic tumors and then administered testosterone propionate or DHT implanted in silastic tubing. Additional groups were coadministered ethinyl estradiol. Male rats (20/group) approximately 6 weeks old and weighing 120 g were administered DMBA at 50 mg/kg subcutaneously every 2 weeks for a total of 10 injections. Animals were then castrated. After 40 weeks hormone treatment, animals were sacrificed and underwent gross and histopathological examination.
No control animals had tumors of the prostate or seminal vesicles. The 18 evaluated animals given testosterone had a total of 21 adenocarcinomas with one in the ventral prostate, 3 in the lateral prostate, 1 in the dorsal prostate and 9 in the anterior prostate. Eight adenocarcinomas of the seminal vesicles were observed. Tumors in the liver (44% in the treated versus 10% in control animals) were statistically significantly (p<0.05) increased. In addition, tumors of the small and large intestine, lung, preputial gland and subcutaneous tissue were present but not significantly increased over control animal tumors. Testosterone plus estrogen produced a synergistic effect on tumor incidence. Treatment with DHT did not have a carcinogenic effect nor did DHT plus estrogen have a synergistic effect.
In conclusion, the administration of testosterone following DMBA treatment produced invasive carcinomas in the lateral and anterior prostate and seminal vesicles, whereas animals not receiving hormone supplement or those treated with DHT had no proliferative lesions. The incidence of liver tumors was also increased in testosterone-treated rats.
Other studies reported in the literature confirm the findings that exposure to testosterone leads to an increase in various tumors. For example, a study in female mice demonstrated that animals with implanted testosterone had an increase in cervical-uterine tumors, some of which metastasized. Other studies in Noble (Nb) rats showed that testosterone coadministered with estradiol produced a 100% incidence of prostate cancer in these animals.
Segment I: Fertility and General Reproduction Performance
Because testosterone is an endogenous hormone required for the formation of male reproductive organs, alterations in testosterone concentrations during fetal development as well as postnatally lead to changes in morphology of fetuses and morphology and behavior of treated animals.
In order to assess the effect of testosterone administration on fertility, adult male rats (6/group) were treated with testosterone in capsules implanted subcutaneously for 90 days. Implants were reported by size rather than dosage and were 0.5, 1, 2, 3, 4 and 8 cm in length. Each male was paired for mating with 4 females over a 2 week period. Weights of sexual accessory tissues increased at the largest dosage while the weights of the testes decreased at the 3 highest dosages which also had the largest decrease in sperm counts. The 4 cm group had the greatest reduction in sperm count (15% of control). However, testosterone treatment had little effect on mating behavior as assessed by the number of vaginal plugs. Females mated with males treated with 3 or 4 cm dosages were sperm-positive but had a greatly lowered number of pregnancies. Animals that had litters had no difference in number of fetuses, fetal weights, post-implantation loss or malformations nor was there a difference in the sex ratio of the offspring. It appears that reduced sperm count could still lead to pregnancy but that rats with sperm did not necessarily become pregnant. In addition, there was no effect of testosterone on the offspring from the females mated to the treated males.
Segment II: Teratology Studies
Testosterone propionate in sesame oil was administered subcutaneously to pregnant DS mice and Wistar rats (approximately 13/group). Dose administration occurred from Days 8 through 12 of gestation at 7.5, 15 or 30 μg/kg/day for mice and 6.25, 125, 250, 500 or 1000 μg/kg/day for rats. There was little effect on fetal viability in mice; in rats, however, the number of viable fetuses was reduced in a dose-dependent fashion at dosages greater than 125μg/kg/day. No fetuses survived at 500 and 1000 μg/kg/day. In the mouse, the hind limb appeared to be most sensitive to the effects of testosterone propionate. There were also anomalies of the neural arches, cervical vertebrae and ribs with delayed ossification of the sternabrae. There were essentially no compound-related effects observed in the rat fetuses.
Rat embryo death was demonstrated in a study with female SD rats who were administered either 10 mg testosterone, estradiol, or Dianabol (8/group) as a subcutaneous implant from Day 10 of gestation until delivery or Day 27 of gestation, at which time all remaining rats were sacrificed. All of the embryos were resorbed in each rat administered either testosterone or estradiol, indicating that testosterone or estradiol at these levels was not compatible with the maintenance of viable fetuses.
Segment III: Perinatal and Postnatal Studies
Testosterone was studied for its effect on the female offspring of dams treated during pregnancy. Pregnant rats received a single injection of 5 mg testosterone on a single gestation day from 16 to 22; the female offspring of these dams were examined for morphology and behavior. The anogenital distance at 25 days after birth was significantly increased if testosterone was given on Gestation Days 16 to 18. In addition, vaginal opening was significantly delayed if testosterone was given between Gestation Day 16 and 20. Vaginal morphology, primarily enlarged clitoris, was observed in all treated groups. Offspring from dams receiving testosterone during Gestation Days 18 to 22 had decreased lordotic behavior.