PURPOSEWe evaluate the pharmacodynamics, pharmacokinetics and tolerability of a sustained release depot formulation of avorelin, a new potent super agonist of luteinizing hormone-releasing hormone receptors, in patients with prostate cancer.MATERIALS AND METHODSA total of 60 patients were randomized to receive a 10 mg. (31) or 15 mg. (29) avorelin subcutaneous depot. Serum testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and plasma avorelin were measured regularly until depot exhaustion.RESULTSOf the 10 mg. group patients 3 withdrew from the study after 31 to 35 weeks due to disease progression. Of the 15 mg. group patients 1 did not complete the study for logistical reasons. After the expected flare in serum testosterone, LH and FSH during week 1, medical castration (testosterone concentration less than 1.735 nmol./l.) was achieved within 4 weeks of depot injection. Median duration of testosterone suppression was 40 weeks in the 10 mg. (95% confidence interval 35 to 42) and 39 in the 15 mg. (37 to 43) group. The reduction in serum LH was similar to that of testosterone, while that of FSH was less pronounced. Plasma avorelin was proportional to the dose and correlated with serum testosterone. Normalization of serum prostate specific (4 ng./ml. or less) at 6 months was achieved in 80 and 88% of the 10 and 15 mg. groups, respectively. During the (7 to 20-month) observation period 94 and 86% of the 10 and 15 mg. groups, respectively, complained of adverse events mainly related to androgen suppression (hot flushes, decreased libido and impotence) or the nature of the disease (skeletal pain). In each group 3 patients had serious adverse events requiring hospitalization for reasons unrelated to avorelin treatment. The depot was well tolerated locally.CONCLUSIONSSubcutaneous depot formulations of avorelin were well tolerated and had protracted inhibitory effects on pituitary gonadotropin secretion in patients with prostate cancer. Testosterone suppression was maintained for more than 6 months in all patients. Avorelin depots could be the first luteinizing hormone-releasing hormone agonist formulation to be administered at 6-month intervals.

01 Apr 1999·Hormones and BehaviorQ3 · MEDICINE

Investigation of the Role of Postnatal Testosterone in the Expression of Sex Differences in Behavior in Infant Rhesus Macaques (Macaca mulatta)

Q3 · MEDICINE

Article

Author: Alan F. Dixson ; Gillian R. Brown

In several primate species, males have been shown to exhibit a surge in circulating testosterone during the early postnatal period. This surge has been postulated to play a role in the development of sex differences in behavior. In this study, the role of postnatal testosterone in infant behavioral development was investigated in socially living rhesus macaques. Seven male infants were treated with a GnRH agonist, avorelin, from the first week of life onwards. Ten female infants were exposed to testosterone by implantation of capsules containing testosterone. The behavioral development of these and control infants was recorded from birth to 6 months of age. The sexually dimorphic patterns of play and mounting were not affected by manipulation of postnatal testosterone in either male or female infants. Similarly, most mother-infant interactions were not affected by the hormonal manipulation of infants. Mothers of testosterone-treated females were found to take more responsibility for moving into and out of arm's reach of their infants than mothers of some other groups of infants; however, this measure did not normally differ between mothers of male and female infants. Manipulation of the postnatal testosterone surge does significantly affect penile growth and development, but does not affect the expression of infant sex differences in behavior nor greatly affect the development of the mother-infant relationship in rhesus macaques.

01 Feb 1999·International Journal of Andrology

Manipulation of postnatal testosterone levels affects phallic and clitoral development in infant rhesus monkeys

Article

Author: Fraser ; Dixson ; Nevison ; Brown

Male primates exhibit marked elevation of circulating testosterone levels during the early postnatal period. The aim of this project was to test whether experimental manipulation of circulating testosterone levels in male and female infant rhesus monkeys affected development of the external genitalia during the first six months of life. Four groups of infants were studied. Seven control male infants exhibited high circulating testosterone levels during the first three months of life. Seven males were treated with a GnRH agonist (avorelin) from the first week of life onwards, which suppressed the postnatal testosterone surge. Ten control females exhibited low circulating testosterone levels during the early postnatal period. Administration of testosterone to 10 females resulted in high circulating levels in these infants. Fortnightly blood samples and genital measurements were taken from all infants during the first six months of life. Growth of the penes of avorelin‐treated males was significantly retarded when compared to control males. Average length of the penis at six months of age was significantly (p = 0.012) smaller for avorelin‐treated males (25.2 ± 2.8 mm) than for control males (37.3 ± 3.0 mm). Avorelin‐treated males attained only around 50% detachment of the prepuce from the glans of the penis, while control males averaged 90% detachment. Treatment of females with testosterone resulted in significant growth of the clitoris in comparison to control females. The growth rates of the penes of control males and clitorides of testosterone‐treated females were similar and greatest during the first two months of life. Gain in body weight was not affected by either hormonal manipulation. It is concluded that manipulation of circulating testosterone levels during the early postnatal period affects penile and clitoral development of infant rhesus monkeys. This postnatal period may therefore represent an important stage in penile development in primates.

100 Deals associated with Avorelin

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 2	-	Mediolanum Farmaceutici SpA	-
Breast Cancer	Phase 2	-	Europeptides	-
Endometriosis	Phase 2	-	Mediolanum Farmaceutici SpA	-
Endometriosis	Phase 2	-	Europeptides	-
Prostatic Cancer	Phase 2	-	Europeptides	-
Prostatic Cancer	Phase 2	-	Mediolanum Farmaceutici SpA	-

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