Hormonal Suppression in Female Rhesus Macaques (Macaca mulatta) Implanted Subcutaneously with Deslorelin

Abstract

Providing effective contraception for nonhuman primates (NHP) is challenging. Deslorelin acetate is a commercially available gonadotropin-releasing hormone (GnRH) agonist that may provide a relatively noninvasive, long-lasting, and potentially reversible alternative to standard NHP contraception methods. This study evaluated the duration of suppression of progesterone and estradiol in 6 adult female rhesus macaques (Macaca mulatta) that received a single subcutaneous 4.7 mg deslorelin implant. We hypothesized that deslorelin would suppress production of these hormones for 6 mo with a correspond- ing cessation of menses. Prior to implantation, blood was collected over 1 mo for baseline hormone analyses. Macaques were sedated at the onset of the next menstrual cycle and a 4.7 mg deslorelin implant was placed in the interscapular region. Blood was collected over the subsequent month at the same intervals used for the baseline collection schedule, and then every 7 d thereafter. Results showed that estradiol and progesterone transiently increased 1 to 3 d after implantation, then fell to basal levels within 6 d of implantation. The duration of hormone suppression (progesterone <0.5 ng/mL) varied among animals. Two macaques returned to cyclicity by 96 d and 113 d after implantation, while hormones remained suppressed in the other 4 macaques at 6 mo after implantation. Cessation of menses correlated with hormone suppression except in 1 animal that continued to have sporadic vaginal bleeding despite progesterone remaining below 0.5 ng/mL. This study indicates that deslorelin is a noninvasive and long-lasting contraceptive method in female rhesus macaques. However, individual variation should be considered when determining reimplantation intervals.

Figure 1.

Timeline of blood collection and deslorelin implantation. Numbers correspond to days of the menstrual cycle (day 1 = first day of observed menstruation) in each month. Red circles indicate blood collection. * M3 only, † M1, M2, M5, and M6 only

Figure 2.

Hormonal profiles before and after implantation in 2 representative macaques, M4 (top) and M6 (bottom). M6 demonstrated the earliest return to cyclicity at 96 d after implantation while M4 remained suppressed at 6 mo after implantation. M5 showed a similar hormone profile to M6, returning to cyclicity 113 d after implantation. M1, M2, and M3 remained suppressed at 6 mo, similar to M4.

Figure 3.

Longitudinal changes of serum progesterone. Serum progesterone concentration (ng/mL) throughout the study shows acute suppression within 6 d after treatment, lasting at least 3 mo (M5 and M6) and to over 6 mo (M1 to M4). The smoother line shown is the spline (using δ of 0.05). Confidence of fit is shown using the bootstrap confidence region (gray area).

Figure 4.

Individual trends in mean uterine volume. Uterine volume decreased by 3 mo after implantation in all macaques. By 6 mo after implantation, uterine volume in M5 and M6 had returned to baseline while volume remained decreased in M1 to M4, correlating with their hormonal profiles.

Figure 5.

Ultrasound images of 2 representative macaques, M4 (top) and M6 (bottom), before implantation and at 3 mo and 6 mo after implantation. M1, M2, and M3 showed a similar progression of uterine size to M4 while M5 was similar to M6.

Figure 6.

Uterine size correlated strongly with progesterone levels. Pearson r = 0.73; 95% CI: 0.36-0.90. Shaded area represents density plot with 95% coverage.

Figure 7.

Normal ovarian hormone cycle of a rhesus macaque (adapted using preimplantation data from this study). Note the sharp peak in estradiol on day 12, followed by a sustained rise in progesterone during the luteal phase.