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An Ideal Hormonal Contraceptive at Lactation?

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An Ideal Hormonal Contraceptive at Lactation? Human Reproduction vol.14 no.8 pp.1993–1997, 1999 Parenteral administration of progestin Nestorone® to lactating cynomolgus monkeys: an ideal hormonal contraceptive at lactation? O.Heikinheimo1,2,6, S.Ranta1, A.Moo-Young3, Introduction 1 4,5 P.La¨hteenma¨ki and K.Gordon In the worldwide scheme of family planning, extension of the 1Steroid Research Laboratory, Institute of Biomedicine, interval between pregnancies would result in major improve- 2Department of Obstetrics and Gynecology, University of Helsinki, ment in maternal and child health (Thapa et al., 1988). Finland, 3The Population Council, Center for Biomedical Research, Lactation itself provides a reasonable contraceptive effect 4 New York, The Jones Institute for Reproductive Medicine, Eastern initially. However, the duration of lactational amenorrhoea Virginia Medical School, Norfolk, and 5Balance Pharmaceuticals Inc., Santa Monica, USA varies greatly (WHO, 1998), and even in fully nursing women ovulatory cycles are resumed in 26% at 6 months post-partum 6To whom correspondence should be addressed at: Steroid Research ´ Laboratory, Institute of Biomedicine, PO Box 8, FIN-00014, (Dıaz et al., 1988). Pregnancy and childbirth require women University of Helsinki, Finland to seek medical attention, thus providing an opportunity for contraceptive counselling and introduction. Thus, safe and ® Nestorone (NES) progestin is highly effective for contra- effective contraceptives which can be initiated during the post- ception following parenteral administration, but ineffective partum period and lactation are important assets in fertility after oral ingestion due to rapid first-pass metabolism. control. Thus, NES might be ideal for lactational contraception; Even though lactational contraception with progestin-only possible NES in milk should be metabolized by the nursing contraceptives has been endorsed by international family infant. We evaluated the distribution of NES, its endocrine planning organizations, hormonal methods are often viewed effects and infant weight gain in five cynomolgus monkeys cautiously during lactation. All the contraceptive progestins and their nursing infants. Nestorone® implants, releasing studied to date can be detected in the milk (Dı´az and Croxatto, ~40 g NES/day in vitro, were placed s.c. in the mothers µ 1993), thus concerns about the possible ill-effects on the 3–4 months following delivery, where they remained in situ suckling infant remain. for 4 weeks. Sampling (blood daily from the mother; milk An ideal molecule for lactational hormonal contraceptive and blood from the infant at 3 day intervals) was initiated would be one with high contraceptive efficacy in the mother, at 2 weeks prior to insertion, and continued for 2 weeks yet it would be without effects on lactation or the nursing following removal of the implant. NES, oestradiol, proges- infant. Nestorone® (NES, previously known as ST-1435) is terone and prolactin were measured by radioimmunoassays an orally inactive progestin, currently in phase II clinical and the infants were weighed weekly. The (mean K SD) contraceptive trials using implants, vaginal rings, and maternal serum and milk concentrations of NES were 337 intracervical or transdermal administration (Kurunma¨ki et al., K 90 and 586 K 301 pmol/l during the use of the implants. 1984; Laurikka-Routti et al., 1990; Haukkamaa et al., The ratio of milk/serum NES was 1.68 K 0.12 (mean 1991). NES has high binding affinity to the human K SE), and the serum and milk concentrations were progesterone receptor (La¨hteenma¨ki, 1986), yet due to rapid significantly correlated (r 5 0.75, P < 0.001). NES was first-pass metabolism, oral administration of NES is ineffective not detectable (<13 pmol/l) in any infant serum samples. Concentrations of prolactin (mean K SD) were 41.1 K 32, (Coutinho et al., 1981; Heikinheimo et al., 1994). However, 26.7 K 7.6 and 26.3 K 9.5 ng/ml before, during and after parenterally-administered NES is highly effective for contra- the use of the implants respectively. The (mean K SE) ception, and ovulation is inhibited with very low serum infant weight increased from 643 K 54 g 1 week prior to concentrations of NES (Coutinho et al., 1981; La¨hteenma¨ki insertion to 713 K 54 g 1 week following removal. These et al., 1982). data confirm that NES in milk is rapidly metabolized by NES, therefore, has several key features which may make the suckling infant. Therefore, NES appears to be an ideal it an optimal hormonal contraceptive to be used during hormonal contraceptive for use during lactation. lactation. While parenteral administration of NES to nursing Key words: distribution/lactation/pharmacokinetics/progestin- mothers would guarantee effective contraception, the NES only contraception/radioimmunoassay passed to the suckling infant via milk would be rapidly metabolized by the infant’s liver. The purpose of the present study was to examine the distribution as well as the hormonal effects of lactational Nestorone® is a registered trademark of The Population Council, use of NES in nursing cynomolgus monkeys and their New York, NY, USA infants. © European Society of Human Reproduction and Embryology 1993 O.Heikinheimo et al. Materials and methods Animals Five nursing cynomolgus monkeys (Macaca fascicularis) and their infants were used for the present study. The mother–infant couples were housed in individual cages under a 12 h:12 h light–dark schedule at 20–23°C; the mother was fed monkey chow (Agway, Elizabeth City, NJ, USA) twice per day with water available ad libitum. Blood samples were drawn by femoral venipuncture under ketamine-induced anaesthesia (10 mg/kg i.m.). Before enrolling the primates into the study, chronic jugular venous catheters were inserted in two of the adult monkeys under ketamine anaesthesia (20 mg/kg i.m.) supplemented with xylazine (1 mg/kg i.m.) to allow serial blood sampling for studies on prolactin secretion. The catheters ended in s.c. ports capped with silicone-coated latex diaphragms which allowed transcutaneous access to the venous system Figure 1. Concentrations (mean 6 SE) of Nestorone® (NES) in the via small (21–27)-gauge needles inserted into the ports. mothers’ serum (u), milk (r) and infants’ serum (d) during lactational use of NES implants. The ratio of milk/serum NES was Study protocol 1.68 6 0.12 (mean 6 SE); the concentrations of serum and milk Blood sampling (daily from the mother, every third day from the NES were significantly correlated (r 5 0.75, P , 0.001). NES was infant) was initiated at approximately 90 days following delivery. not detectable in any of the infant samples studied. The insert Pre-treatment samples were collected for 2 weeks, after which a shows the disappearance of NES following removal of the implant, 1 cm Nestorone® implant was inserted s.c. The implants were used the calculated t1/2 (6SD) of NES was 1.4 (60.4) h. for a total of 4 weeks, after which the implants were removed, and blood sampling continued for an additional 2 weeks. Based on in- vitro testing, the implants released ~40 µg NES/day. The infants were Serum oestradiol and progesterone were measured using commer- weighed weekly during the duration of the study. cially available radioimmunoassays from ICN Biomedicals Inc. (Costa To study more closely the dynamic variations in prolactin secretion Mesa, CA, USA). Serum prolactin was measured by specific radio- during NES administration, two of the monkeys had indwelling immunoassays developed for primate work, as described in detail jugular cannulae inserted prior to initiation of the study. Frequent elsewhere (Gordon et al., 1992). CV were calculated from pools of blood sampling (every 15 min between 8:00 and 14:00) was performed standard serum. Intra-assay and interassay CV were 11 and 18%; 10 at 2 weeks before insertion (pre-treatment), at 2 weeks after insertion and 15%; 10 and 12%; for the oestradiol, progesterone and prolactin (treatment) and at 2 weeks after (post-treatment) removal of the at the average hormone concentrations of 195 pmol/l, 4 nmol/l and Nestorone® implant. Due to blockade of the system, sample collection 10 µg/l respectively. The detection limits were 70 pmol/l, 1 nmol/l was successful in only one of these primates. On the preceding and 3 µg/l respectively. afternoon, the animals were fitted with special vests allowing lactation To study the possibility that NES is metabolized while being passed and mobile steel tethers, which protected the catheters passing from to milk, a fractionation of diethyl ether extracts of milk and serum the s.c. port to the back of the cage and into an adjacent room, where samples was carried out using high performance liquid chromato- the blood samples (2 ml) were drawn. graphy (HPLC) followed by detection of the immunoreactive NES metabolites with NES–radioimmunoassay. The HPLC–NES–radio- Animal welfare compliance immunoassay system for the studies on the NES metabolism has This study was approved by the Institutional Animal Care and Use been described previously (Heikinheimo et al., 1994). The milk Committee of the Eastern Virginia Medical School. The facilities of samples were processed for HPLC as for radioimmunoassay using the division of Animal Resources are fully accredited by the American ether extraction and Sep-Pak® C18 Cartridges. Association for the Accreditation of Laboratory Animal Care. Data analysis Radioimmunoassays A P value ø 0.05 was considered significant. One way analysis of Serum concentrations of NES were measured as previously variance (ANOVA) was used to evaluate the changes in serum 125 described (La¨hteenma¨ki et al., 1981) using I-labelled NES as tracer concentrations of prolactin. and polyclonal NES antibody, raised against NES-3-(O-carboxyme- thyl)oxime–BSA conjugate in rabbits. The intra- and interassay coefficients of variation (CV) of serum NES–radioimmunoassay were Results 5 and 7% respectively. The practical detection limit was 13 pmol/l.
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