1 Instituto Chileno de Medicina Reproductiva, Consultorio de Planificación Familiar, J.V. Lastarria 29, Depto. 101 and 2 Departamento de Endocrinología, Facultad de Medicina, Universidad Católica de Chile, Santiago, Chile
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: bone density/bone metabolism/lactation/Norplant® implants/progesterone rings
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Although non-hormonal contraceptives are considered to be the first choice for lactating women, progestin only methods are a good option when non-hormonal methods are contra-indicated or are not acceptable (IPPF, 1989). They have no deleterious effect upon breast-feeding, infant growth or early development (Díaz et al., 1997) but, to avoid early transference of small amounts of steroid to the infant, it is recommended that their use be initiated not before 6 weeks postpartum (WHO, 1996).
However, there are only limited data about the impact of progestin only contraceptive methods upon bone mass and turnover during breast-feeding (Prior, 1990). A small study carried out during the first postpartum year suggested that progestin only pills may protect against bone loss (Caird et al., 1994
). Further information is required to enable adequate counselling to be given to lactating women about potential risks of osteoporosis related to contraceptive choice.
The progestins selected for the present study were progesterone and levonorgestrel. Progesterone plays a role in bone turnover and may be a bone trophic factor (Prior, 1990), despite its weak anti-oestrogenic effect. Levonorgestrel has a strong progestogenic effect and a weak androgenic activity (Phillips et al., 1987
), and may also be a bone trophic factor. However, its potent anti-oestrogenic effect may also have deleterious consequences with regard to bone metabolism.
The purpose of this study was to characterize the changes in bone density and turnover which occur during breast-feeding and after weaning in healthy lactating women who used Norplant® levonorgestrel implants or progesterone vaginal rings as their contraceptive method. The control group consisted of users of the Copper T 380A intrauterine device.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Additional requirements were: body mass index (BMI) between 20 and 30 kg/m2; haemoglobin above 10 g/dl; first delivery after 20 years of age; smoking <20 cigarettes/week; alcohol ingestion <200 g/week; no chronic illness which could affect bone mass (kidney disease, hyper- or hypoparathyroidism, hyper- or hypothyroidism, etc.); and no consumption of drugs such as glucocorticoids, anticonvulsants, thiazides, calcium or thyroid hormones. All women had a sedentary lifestyle.
Admission and follow-up procedures
Volunteers were recruited in the first 2 days after delivery and follow-up visits were scheduled at days 710, 20 and 30 after delivery, at monthly intervals up to the end of the first year and at 3 month intervals thereafter. At each visit, the medical history of mother and infant and the bleeding and breast-feeding patterns were recorded. Pelvic and breast examinations were performed. Each child had a general physical examination, including determination of body weight. The clinical management of all subjects was similar, as described below.
Contraceptive management
During the second month postpartum, women were informed of the contraceptive methods available and of the purpose of the study, as well as of their freedom to participate or withdraw at any time, for any reason. Volunteers read and signed detailed informed consents, approved by the institution's Ethical Review Board. Methods were administered according to each woman's choice. Treatment was initiated at day 57 ± 3 after delivery while the women were fully breast feeding and the infant had adequate weight increase. Investigators from the Universidad Católica de Chile were not involved in contraceptive provision or services, which were the responsibility of the Instituto Chileno de Medicina Reproductiva.
Contraceptive devices
Types of contraceptives used were Norplant® levonorgestrel implants (NOR, n = 36), progesterone vaginal rings (PVR, n = 36) and Copper T 380 A intrauterine devices (T-Cu, n = 57). Women in the PVR group and in the NOR group were enrolled into the study in 19921993 and in 1994 respectively; each group had contemporary T-Cu controls. The sample size was estimated considering that, using analysis of variance (ANOVA), 28 subjects in each group would be needed to detect a difference of 0.050.1 g/m2 in bone density with a level of significance of 0.05 and a power of 90% (López et al., 1996).
Norplant® implants consist of six Silastic® capsules, inserted under the skin of the arm, that release ~85 µg/day of levonorgestrel initially, falling to ~35 µg/day in the second year of use (Fraser et al., 1998). The PVR is a homogeneous Silastic® ring that releases ~10 mg of progesterone per day for a 3 month period and provides progesterone plasma concentrations of ~25 nmol/l and 10 nmol/l during the first week and the third month of use respectively. The ring was replaced every 3 months, according to the study protocol (Sivin et al., 1997
). Change to a more effective method at the time of weaning was recommended to women who selected the PVR because it is not considered effective in non-lactating women.
Breast-feeding management
Verbal and written instructions for breast-feeding on demand were given in the maternity ward and were reinforced at each visit. Mothers were instructed to use the breast as the only source of nutrients in the first 6 months. A midday meal was indicated at the seventh month of age and an evening meal at the ninth month. Each woman received powdered milk and rice as food supplements in the first postpartum year.
Infant weight increase was used as the main indicator of the adequacy of milk output. During the first 5 months of age, a weight increase of <20 g per day (mean since last visit) was considered an indication of inadequate milk output. Supplements were indicated if the growth rate was below this threshold, unless the child continued in the same weight percentile curve (within 10 percentile points) as before or had a normal weight for age and length. The Boston weight curve for boys (Nelson, 1964) was used as reference.
Bone evaluation
Women were studied at month 1 (PM1), month 6 (PM6) and month 12 (PM12) postpartum and at month 6 (PVR group) or month 12 (NOR and T-Cu groups) after weaning. Month 6 after weaning was chosen in the PVR group because all women changed method when weaned and a longer interval may have reflected the influence of other contraceptives used upon bone turnover. Month 12 after weaning was chosen in the NOR group to allow a longer period for an eventual impact of levonorgestrel on bone density to be detected. At these four time points, blood and urine samples were obtained and an estimation of daily calcium intake in the preceding week (López et al., 1996) was performed. Bone densitometry (bone density) took place at PM1, PM12 and post-weaning.
Biochemical measurements
Blood
All volunteers were fasting at the time of blood sampling and at least 2 h had passed since the last episode of breast feeding. A total of 30 ml of blood was obtained. Samples were obtained between the fifth and tenth day of the menstrual cycle in those women who had reinitiated cycles. Serum was divided into separate aliquots for each of the following tests and stored at 20°C. Haemoglobin concentration (colorimetric method) and magnesium concentration (colorimetric method, Merck kit No. 3338) were measured and a biochemical profile was obtained (SMA-II autoanalyzer) of calcium, phosphorus, blood urea nitrogen, glucose, total proteins, albumin, cholesterol, uric acid, total alkaline phosphatases, bilirubin, serum glutamic-oxaloacetic transaminase (SGOT) and lactate dehydrogenase (LDH).
Parathyroid hormone (PTH) was determined by radioimmunoassay using TYR 4368 labelled iodine-125 and a specific antibody for 4468 fraction developed in sheep (donated by Dr D.Hesh, University of Hannover, Germany). The fragment 4468 corresponds to the mid-region of PTH or M-PTH. The tracer used was this fragment, to which tyrosine (TYR) is attached in order to be able to label it with iodine. For this reason it is called TYR 4468-labelled iodine-125. The fragment 4468 TYR was obtained from Sigma. The I-labelling was carried out locally. A specific antibody for the 4468 fraction was developed in sheep, also locally. The assay was set up and validated in the Endocrine Laboratory of the Faculty of Medicine in the Catholic University (Campino et al., 1987). The sensitivity of the assay was 20 ng/l and the interassay coefficients of variation for low concentration (35 ng/l) and high concentration (54.2 ng/l) pools were 20 and 11.1% respectively. Follicle stimulating hormone (FSH), prolactin and oestradiol determinations were performed using the reagents supplied by the WHO Programme for the Provision of Matched Assay Reagents for the Radioimmunoassay of Hormones in Reproductive Physiology (WHO, 1987). The intra-assay coefficients of variation for FSH, prolactin and oestradiol were 3.9, 6.4 and 5.0% for the high concentration pool and 18.5, 6.3 and 14.9% for the low concentration pool respectively. The inter-assay coefficients for the same hormones were 8.0, 16.6 and 12.5% for the high concentration pool and 24.9, 11.6 and 33.5% for the low concentration pool respectively. Assays were run simultaneously at the end of the study.
Urine
Morning fasting samples were collected to measure hydroxyproline and creatinine after 24 h on a diet free from hydroxyproline.
Bone
The mineral content and bone density (bone density) were measured in the total body, lumbar spine (L2L4), right femoral neck and right trochanter by dual-energy X-ray absorptiometry using a Lunar Densitometer with a precision of 12%. A quality assurance programme devised at the Quality Assurance Center, Portland, Oregon, was incorporated into the study protocol.
Data analysis
Women were considered to be fully breast feeding when the breast was the infant's only source of nutrients up to 6 months of age and the only source of milk thereafter. Infant growth rate had to be adequate according to the criteria described above to classify a case in this category. Weaning was defined as less than one suckling episode per day during a week. The end of lactational amenorrhoea was marked by the occurrence of the first postpartum bleed, consisting of at least 1 day of normal bleeding or 3 consecutive days of spotting, followed by another bleed within 60 days.
Volunteers who weaned early (before 6 months postpartum), who had severe intercurrent systemic disease or who had their contraceptive device removed, were excluded from the study at the time of the event. Out of 129 women enrolled, 21 were excluded from the analysis because they participated only in the first evaluation (PM1).
Values obtained in the T-Cu controls contemporary to the PVR (n = 38) and the NOR (n = 13) groups were pooled because there were no significant differences between them. In addition, values obtained in the control group at 6 (n = 34) and 12 (n = 9) months after weaning were pooled because there were no significant differences between these two sampling times; this pooled value was used for the comparisons with values obtained in the treated groups during lactation. Values obtained in non-lactating women in a previous study performed using the same methods (López et al., 1996) were used as reference values (0%) to establish percentage changes in hydroxyproline, alkaline phosphatases and bone density during lactation. Non-lactating controls were 26 women of similar admission characteristics to those involved in the present study, except that they were slightly older (29 years) than the lactating women (2627 years). The women were sampled at three different times, providing 74 points for the basal values used. Baseline values used in Figure 1
were 52.3 for alkaline phosphatase and 40.0 for hydroxyproline/creatinine ratio in urine. Baseline values used in Figure 2
were 1.23 for bone density in L2L4 and 0.989 for bone density in right femoral neck. The data from both studies were analysed in a similar way.
|
|
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Our study also confirms that lactation is associated with a transient decrease in bone mass, that is reversed after weaning, and with changes in bone turnover. The lack of deleterious effects ascribable to the contraceptive methods studied has to be considered against this particular physiological background. The devices may have a different influence on bone metabolism at other stages of life. However, it is reassuring that a limited study carried with Norplant® implants showed no negative impact in adolescents (Cromer et al., 1996) or in women aged 1942 years (Intaraprasetrt et al., 1997
), while a positive effect was found in perimenopausal women (Naessen et al., 1995
).
A similar study of eight women showed a slight positive effect of progestin only pills upon bone turnover during lactation (Caird et al., 1994). Our data do not support this beneficial effect, since bone recovery after weaning was similar in the Norplant® and the control T-Cu groups. Whether or not the various progestins may have different effects attributable to their pharmacological profile or the route of administration remains to be established.
This study covered only a relatively short period after weaning. The long term impact of progestin-only methods also needs to be assessed, particularly because the information obtained from non-lactating women is contradictory. Negative effects on bone metabolism have been reported following long term use of Depo-Provera in some (Cundy et al., 1991) but not all (Virutamasen et al., 1994
; Naessen et al., 1995
) the studies. If such a deleterious effect on bone mass occurs during long term administration of medroxyprogesterone acetate, it may be explained by the ability of this progestin to exert a stronger inhibition of the endogenous secretion of oestrogens in comparison to that of progesterone rings or levonorgestrel implants.
Oestrogens protect bone mass in other situations and it has been suggested that progesterone may have a trophic effect on bone mass (Prior, 1990). We found no differences in bone parameters between the three contraceptive groups although endogenous concentrations of steroids differed significantly between them. Norplant® users had lower oestrogen concentrations than PVR and IUD users. We assume that all women in the Norplant® group remained anovulatory, since they had prolonged amenorrhoea and implants inhibit ovulation during the first year of use in almost all cycling women (Croxatto et al., 1982
). Progesterone ring users were exposed continuously to relatively high plasma progesterone concentrations, ranging from ~25 nmol/l to 10 nmol/l between the first week and the third month of use (Sivin et al., 1997
). These women also remained in prolonged amenorrhoea and are unlikely to have ovulated (Díaz et al., 1991
). On the other hand, women using a Copper T IUD were exposed to variable oestrogen and progesterone concentrations, since menstruation resumed in half of this group within the first 7 months postpartum. These three different patterns of plasma oestrogen and progesterone concentrations were not translated into differences in bone turnover or density.
The findings of this study have implications for the counselling of lactating women on contraceptive choices. Progestin-only methods initiated after 6 weeks postpartum are safe regarding lactation and infant growth (WHO, 1996). Our results suggest that the two progestin-only methods studied do not interfere with changes in bone turnover and in bone mass that occur during lactation or with the recovery of bone mass after weaning.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Campino, C., Bruggendieck, B., Pumarino, H. et al. (1987) Desarrollo de un radioimmunoanalisis para la fraccion media de hormona paratiroidea (m-PTH): comparacion con dos kits comerciales para carboxilo terminal. Revista Medica de Chile, 115, 763767.[ISI][Medline]
Cromer, B.A., McArdle Blair, J., Mahan, J.D. et al. (1996) A prospective comparison of bone density in adolescent girls receiving depot medroxyprogesterone acetate (Depo-Provera), levonorgestrel (Norplant), or oral contraceptives. J. Pediatr., 129, 671676.[ISI][Medline]
Croxatto, H.B., Díaz, S., Pavez, M. et al. (1982) Plasma progesterone levels during long-term treatment with levonorgestrel silastic implants. Acta Endocrinol., 10, 307311.
Cundy, T., Evans, M., Roberts, H. et al. (1991) Bone density in women receiving depot medroxyprogesterone acetate for contraception. Br. Med. J., 303, 1316.[ISI][Medline]
Díaz, S., Miranda, P., Brandeis, A. et al. (1991) Mechanism of action of progesterone as contraceptive for lactating women. In Seppala, M. and Hamberger, L. (eds) Frontiers in Human Reproduction. The New York Academy of Sciences, New York, NY, USA, pp. 1121.
Díaz, S., Zepeda, A., Maturana, X. et al. (1997) Fertility regulation in nursing women: IX. Contraceptive performance, duration of lactation, infant growth and bleeding patterns during use of progesterone vaginal rings, progestin-only pills, Norplant® implants and Copper T 380-A intrauterine devices. Contraception, 56, 223232.[ISI][Medline]
Fraser, I.S., Tiitinen, A., Affandi, B. et al. (1998) Norplant® consensus statement and background review. Contraception, 57, 19.[ISI][Medline]
Hollander, M. and Wolfe, D. (eds) (1972) Nonparametric Statistical Methods. John Wiley & Sons, New York, pp. 115125, 131.
Intaraprasetrt, S., Taneepanichskul, S., Theppisai, U. and Chaturachinda, K. (1997) Bone density in women receiving Norplant® implants for contraception. J. Med. Assoc. Thai., 80, 738741.[Medline]
International Planned Parenthood Federation (1989) Statement on Breast Feeding, Fertility and Post-partum Contraception. Statement by the International Medical Advisory Panel, November, 15.
Kalkwarf, H.J., Specker, B.L., Bianchi, D.C. et al. (1997) The effect of calcium supplementation on bone density during lactation and after weaning. N. Engl. J. Med., 337, 523558.
López, J.M., González, G., Reyes, M.V. et al. (1996) Bone turnover and density in healthy women during breast-feeding and after weaning. Osteoporosis Int., 6, 153159.[ISI][Medline]
Naessen, T., Olsson, S.-V. and Gudmundson, J. (1995) Differential effects on bone density of progestogen-only methods for contraception in premenopausal women. Contraception, 52, 3539.[ISI][Medline]
Nelson, W.E. (ed) (1964) Textbook of Pediatrics, 8th edn. W.B. Saunders Company, Philadelphia, 42 pp.
Phillips, A., Hahn, D.W., Klimek, S. et al. (1987) A comparison of the potencies and activities of progestogens used in contraceptives. Contraception, 36, 181192.[ISI][Medline]
Prior, J.C. (1990) Progesterone as a bone-trophic hormone. Endocrine Rev., 1, 386398.
Riggs, B.L., Peck, W.A. and Bell, N.H. (eds) (1991) Physician's Resources Manual on Osteoporosis. 2nd edn. Current Medical Directions, New York, 19 pp.
Sivin, I., Díaz, S., Croxatto, H.B. et al. (1997) Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD. Contraception, 55, 225232.[ISI][Medline]
SAS Institute Inc. (1987) SAS/STATTM Guide for Personal Computers, 6th edn. SAS Institute Inc., Cary, NC.
SAS/STAT Software (1991) The PHREG Procedure, Preliminary Documentation. SAS Institute Inc., Cary, NC.
Sowers, M. (1996) Pregnancy and lactation as risk factors for subsequent bone loss and osteoporosis. J. Bone Miner. Res., 11, 10521060.[ISI][Medline]
Virutamasen, P., Wangsuphachart, S., Reinprayoon, D. et al. (1994) Trabecular bone in long-term depot-medroxyprogesterone acetate users. AsiaOceania, J. Obstet. Gynaecol., 20, 269274.
World Health Organization (1987) Special programme of research development and research training in human reproduction. Programme for the provision of matched assay reagents for the RIA of hormones in reproductive physiology. Method Manual, 11th edn. WHO, Geneva.
World Health Organization (1996) Improving access to quality care in family planning. Medical Eligibility Criteria for Contraceptive Use. WHO/FRH/FPP Geneva.
Submitted on February 5, 1999; accepted on June 21, 1999.