Prolonged inhibition of normal ovarian cycles in the rat and cynomolgus monkeys following a single s.c. injection of danazol

Abstract

In castrated male rats, a single s.c. injection of danazol has been shown to result in an inordinately prolonged inhibition of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations. In the present study, we have examined whether the same and similar routes of administration suppresses ovarian function in normally cycling rats and cynomolgus monkeys. Normally cycling female rats received danazol as a single administration either orally, i.m. or s.c. and a separate group also received danazol in silastic capsules. The duration of the dioestrous interval until the next oestrous smear was followed daily and cycle lengths were compared with vehicle-treated groups. Six normally cycling cynomolgus monkeys were followed by daily observation and blood sampling at 2-3 day intervals. After one normal cycle, danazol (200 mg/kg) was administered as a single s.c. injection. Monkeys were followed until the next menses and one cycle thereafter and blood samples were assayed for oestradiol, progesterone and bioactive LH. Oestrous cycle length in vehicle-treated control rats was 4.7 days. A single administration of danazol s.c. at the higher dose prolonged the dioestrous interval to 31.3 days (P <0.001) and a similar prolongation was observed with this high dose when administered i.m. (27.7 days; P <0.001). In normally cycling monkeys, the menstrual cycle length was 30.2 days, but following a single danazol administration, the mean duration to the next menses was prolonged to 117.5 days (P <0.001). In five out of six monkeys, there was a decrease in LH and an absence of normal oestradiol and progesterone patterns. After this prolonged hiatus, a subsequent menstrual cycle was normal in length and endocrine pattern. A single s.c. administration of danazol resulted in a prolonged suppression of ovarian cyclicity in both normally cycling rats and cynomolgus monkeys.

Male and Female Fertility Assessment in the Cynomolgus Monkey Following Administration of ABT‐874, a Human Anti‐IL‐12/23p40 Monoclonal Antibody

“…Although one low‐dose female and one high‐dose female exhibited prolonged menstrual cycles, this was within the facility historical control range and thus was not considered ABT‐874‐related (Weinbauer et al., ). Furthermore, during the dosing period, ABT‐874‐dosed animals exhibited mean menstrual cycle lengths of 28 to 34 days, which is comparable to previously published ranges (Shaikh et al., ; Butterstein et al., ). This fact that the menstrual cycle was not adversely altered following administration of ABT‐874 is also consistent with a previously conducted study in IL‐12p40 knockout mice (Enright et al., ).…”

Physiology and Endocrinology of the Ovarian Cycle in Macaques

“…Shaikh, Naqvi, and Shaikh (1978) observed a cycle duration of 29.2 days (range 22–37 days) in a total of 647 cycles. Butterstein et al (1997) reported an average cycle duration of 30.2 ± 1.4 (range 29–35) days. Another study on twenty individually housed cynomolgus monkeys reported a vaginal smear-based average cycle duration of 35.9 ± 1.6 days (range 26–45 days; Attia 1998).…”

Delay of Ovulation Due to Diets Containing Levonorgestrel in Cynomolgus Monkeys (<i>Macaca fascicularis</i>)

“…There are a few reports showing that progestins are useful for control of ovulation in monkeys. Three out of 4 rhesus monkeys showed ovulation synchrony after daily administration of a progestin, altrenogest, mixed with fruit juice [8], and daily intramuscular injections with LNG [6] or a single subcutaneous injection with danazol [3] inhibited ovulation in cynomolgus monkeys. Although these studies suggested the possibility for that progestins control ovulation, the suitable doses and the effect of the treatment at different phases of the menstrual cycle on the time of ovulation had not been studied.…”

“…Daily intramuscular injection with a commonly used progestin contraceptive, levonorgestrel (LNG), inhibited follicular maturation and ovulation in cynomolgus monkeys [6]. A single subcutaneous administration of a synthetic progestogen, danazol, induced a prolonged suppression of ovarian cyclicity in cynomolgus monkeys [3]. Although these findings suggest that the use of progestogens is effective for control of ovulation in monkeys, suitable doses and effects of the treatment at different phases during the menstrual cycle had not been studied.…”