Pharmacokinetics and pharmacodynamics of a new long-acting androgen ester : Maintenance of physiological androgen levels for 4 months after a single injection

Rajalakshmi, M.; Ramakrishnan, P.

doi:10.1016/0010-7824(89)90048-6

Cited by 35 publications

(9 citation statements)

References 10 publications

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“…Recently, a new testosterone ester, testosterone buciclate (TB), was demonstrated to maintain testoster¬ one serum levels in the normal range in castrated or GnRH antagonist-treated monkeys for several months (19)(20)(21)(22)(23)(24). In humans, a single injection of TB in men with primary hypogonadism was shown to yield lownormal testosterone levels for 12 weeks (25).…”

mentioning

confidence: 99%

Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate

Partsch¹,

Weinbauer²,

Fang³

et al. 1995

European Journal of Endocrinology

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Testosterone preparations producing constant physiological testosterone serum levels are desirable for long-term treatment of androgen deficiency. However, all injectable testosterone esters used clinically for substitution of male hypogonadism are characterized by unfavourable pharmacokinetics. We therefore tested two groups of five long-term orchidectomized cynomolgus monkeys (Macaca fascicularis), which received a single intramuscular injection of 10 mg/kg body weight of an injectable testosterone undecanoate (TU) preparation or testosterone enanthate (TE) in a preclinical study to assess the pharmacokinetic and pharmacodynamic characteristics of TU in comparison to TE. The dose was equivalent to 6.3 and 7.2 mg of pure testosterone per kilogram body weight in the TU and TE group, respectively. Following injection of TU, mean serum testosterone rose to 58 +/- 18 nmol/l on day 1 and remained at moderately supraphysiological levels of 40-68 nmol/l for 45 days. Thereafter, testosterone levels were maintained in the normal range of intact monkeys for another 56 days. The TE injection resulted in highly supraphysiological levels of 100-177 nmol/l from immediately after the injection to day 5. A rapid decline followed and testosterone levels reached the lower limit of normal after 31 days. Serum testosterone levels were significantly higher in the TE-than in the TU-treated animals on days 0.5-7 (p < 0.05). Significantly lower testosterone levels were seen in the TE than in the TU group on days 16, 22, 25 and 31 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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mentioning

confidence: 99%

Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate

Partsch¹,

Weinbauer²,

Fang³

et al. 1995

European Journal of Endocrinology

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“…The rhesus monkey was used in the present study since baseline data was available on the hormone profile and semen parameters in this species. The close similarity in the pattern of metabolic capabilities of human and rhesus monkey 0 1992 WILEY-LISS, INC. ejaculated spermatozoa (Rajalakshmi et al, 1983) and the use of this species in the pharmacokinetic and pharmacodynamic evaluation of newly developed long acting androgen (Rajalakshmi and Ramakrishnan, 1989) also favoured the use of rhesus monkey as the animal model for the present study. But our knowledge of the structure and the functions of the epididymis of rhesus monkey is limited (Arslan et al, 1976;Prakash et al, 1979;Ramos and Dym, 1979) compared to similar information available for rodents even though the epididymis is considered as an ideal extragonadal site for targeting male fertility regulating agents.…”

mentioning

confidence: 99%

“…However, any contraceptive formulation that decreases serum testosterone levels would be unacceptable for family planning programs, particularly in developing countries, due to its implications on nitrogen balance in subjects of marginal nutritional status, as is prevalent in these countries. The development of a new and long-acting androgen ester of testosterone (Rajalakshmi and Ramakrishnan, 1989) with highly promising pharmacokinetic profile has renewed interest in the use of CPA for male contraception in combination with this androgen ester when it is cleared for clinical use. Before such trials can be undertaken in human volunteers, it was essential to evaluate the effects of a low dose of CPA on spermatogenesis, morphology of epididymal epithelium, changes in polypeptide profile of spermatozoa during epididymal maturation and the role of epididy-ma1 proteins in this process.…”

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confidence: 99%

Effect of cyproterone acetate on structure and function of rhesus monkey reproductive organs

1992

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A low dose of Cyproterone acetate (CPA; 1 mg/kg body weight/day for 70 days) was administered to adult male rhesus monkeys to assess its effects on testicular and epididymal structure and function in a nonhuman primate species. CPA caused extensive degenerative changes in morphology of seminiferous, efferent duct, and epididymal epithelia, including decrease in diameter of seminiferous and epididymal tubules and their lumen, height of epididymal epithelium, and an increase in intertubular connective tissue. The protein profile of spermatozoa showed alterations during their epididymal transit in control and CPA-treated monkeys. In CPA-treated animals, 19 polypeptides were acquired and nine were eliminated during epididymal transit in contrast to acquisition of 12 and loss of 14 polypeptides in control animals. Treatment with CPA also resulted in the appearance of 14 new polypeptides in epididymal cytosol and luminal fluid, probably of lysosomal origin. The protein pattern of caput and cauda epididymal tubule cytosol, maintained in organ culture and exposed to 100 microM CPA for 3 days, showed absence of eight polypeptides. These results indicate that even at the low dose used in this study, CPA has caused spermatogenic arrest, degenerative changes in the epididymal structure, and alterations in epididymal and sperm protein profile. Suppression of serum testosterone levels indicates the need for androgen supplementation if CPA is to be used for male contraception.

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“…Many agencies are involved in developing longer acting androgens with better pharmacokinetic profiles than TE. Preclinical and limited clinical trials have shown that testosterone buciclate (TB), which was developed by the WHO Program, has better pharmacokinetic and pharmacodynamic profiles than TE (Rajalakshmi and Ramakrishnan, 1989;Behre and Nieschlag, 1992). It is likely that the use of TB for male contraception would not induce any adverse effects on prostate, because it is able to maintain androgen levels in the physiological range for long durations.…”

Section: Discussionmentioning

confidence: 99%

Changes in structure and functions of prostate by long-term administration of an androgen, testosterone enanthate, in rhesus monkey (Macaca mulatta)

et al. 1998

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The increasing use of androgens in clinical trials for developing a safe, effective, and reversible male contraceptive has necessitated a critical evaluation of the effects of their long-term use on the structure and functions of the prostate gland, which is androgen dependent. Combination regimens using progestogens, gonadotropin-releasing hormone antagonists, or antiandrogens along with androgens are undergoing clinical evaluation as antispermatogenic agents. The majority of these regimens have used testosterone enanthate (TE) as the androgen of choice, but very limited information is available on the side effects of long-term androgen use. The present study is the first report that critically evaluates the effects of long-term use of TE on prostate structure and functions. Adult male rhesus monkeys received intramuscular injections of 50 mg of TE once in 14 days for 33 months. The cranial and caudal lobes of the prostate, which were removed under ketamine anesthesia, were processed for the preparation of semithin sections to evaluate histological changes. The DNA distribution in the cells was studied in single cell suspensions of cranial and caudal lobes of the prostate by using flow cytometry. Changes in the levels of testosterone, estradiol, prostate-specific acid phosphatase (PAP), and prostate-specific antigen (PSA) in samples collected during the pretreatment period and at the time of removal of the prostate were estimated by using conventional procedures. Control samples were processed simultaneously. The administration of TE for 33 months caused the following changes: 1) significant increase in the weight of both lobes of the prostate, 2) cellular hypertrophy and increase in secretory material in the cells and in the lumen of the acini in the central and peripheral zones of the two lobes of the prostate, 3) cellular hyperplasia indicated by flow cytometric analysis of DNA content, 4) significant increase in the secretion of PAP and levels of estradiol, and 5) a marked increase in fibromuscular stroma in the central and peripheral zones of both the lobes of the prostate. The present study is the first report to provide evidence that long-term androgen treatment has caused hypertrophy of the prostatic epithelial cells, which showed increased secretory activity. The hyperplastic changes indicate a need for the development of new androgens with a better pharmacokinetic profile for use in male contraceptive regimens.

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Pharmacokinetics and pharmacodynamics of a new long-acting androgen ester : Maintenance of physiological androgen levels for 4 months after a single injection

Cited by 35 publications

References 10 publications

Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate

Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate

Effect of cyproterone acetate on structure and function of rhesus monkey reproductive organs

Changes in structure and functions of prostate by long-term administration of an androgen, testosterone enanthate, in rhesus monkey (Macaca mulatta)

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