Depot medroxyprogesterone acetate, the first popular long-acting progesterone-only contraceptive, is used by millions of women in more than 90 countries.1 Because of its efficacy, convenience, and safety, it is used postpartum in women who nurse their children. Clinically, there has been evidence that depot medroxyprogester-one acetate injection in lactating women increases milk volume and duration of lactation, although the exact mechanism is unknown.2
Prolactin influences the production and secretion of milk by the mammary glands, and its repeated elevation is necessary for milk production. Bromocriptine is used to inhibit prolactin, which inhibits milk production and secretion.3 Therefore, it has been proposed that increased milk production and prolongation of nursing after depot medroxyprogesterone acetate injection might be explained by its effect on serum prolactin levels. The objective of this study was to evaluate the effect of depot medroxyprogesterone acetate on basal serum prolactin levels in lactating women.
Materials and Methods
This study was an open-labeled study. Fifty women 6 weeks postpartum aged 15–40 years who nursed their infants at least 15 minutes five times daily were recruited from the family planning clinic at King Chulalongkorn Memorial Hospital between July 1999 and January 2000. All were healthy and were not taking any medication. They were seen postpartum and requested contraception. Eligible subjects had general medical and gynecologic examinations and were informed about the study. It required that they nurse their infants a minimum of 15 minutes at least five times daily throughout the study period, and that they attend every appointment. Written informed consent was obtained from each participant. All study procedures were approved by the Ethics Committees of Chulalongkorn University. The study group consisted of 25 women who received an injection of 150 mg IM depot medroxyprogesterone acetate and the control group consisted of 25 women who were fitted with a copper T380A intra-uterine device (IUD).
Upon entry into the study, the participants completed a baseline questionnaire of demographic characteristics, menstrual cycle information, pregnancy history, previous illness, and medication used. They were instructed not to eat or drink after midnight that night or nurse their infants for at least 3 hours before attending to the clinic the following day to give blood. Blood was drawn between 9:00–12:00 AM after at least 30 minutes of rest. Afterward, participants received either depot medroxyprogesterone acetate or a copper T380A IUD according to their request. Participants were instructed to return 3 and 6 weeks later to provide two more blood samples. Therefore, blood samples were taken three times in all women, 6 weeks postpartum before contraception, and 3 and 6 weeks after receiving contraception. At each appointment, participants were asked about their frequency and duration of lactation, illness, medication used, and any problems that could disturb their breast feeding. All were able to maintain their regular breast feeding without difficulty and participated throughout the study period.
The serum was separated from the blood samples and stored at −20C until assayed for prolactin by time-resolved fluoroimmunoassay (DELFIA prolactin kit, Fabricado, Wallace OY, Turku, Finland). The interassay and intra-assay variations were 5.7–6.2% and 2.0–3.3%, respectively.
The primary outcome measure was basal serum prolactin. Twenty-three women in each group were required in order to have 95% power to detect a significant difference.
Analysis was performed on data from subjects who completed 6 weeks of follow-up. Basal serum prolactin levels were reported as mean ± standard error of the mean (SEM) with 95% confidence interval (CI) of difference. Baseline characteristics such as age, weight, and height were reported as mean ± standard deviation (SD). Statistical analysis was done using unpaired t test for comparison of between-group means. Paired t test was used to compare within-group means. In addition, the χ2 test for categorical variables was used to compare frequency and duration of breast-feeding in both groups. All analyses were performed using the Statistic Package for Social Science (SPSS) for Windows 7.5.1 (SPSS Inc., Chicago, IL). P < .05 was considered significant.
Table 1 summarizes the distribution of demographic characteristics and factors affecting lactation. There were no statistically significant differences in age, weight, height, or frequency and duration of lactation between groups.
The basal levels of circulating prolactin at 6 weeks postpartum before contraception were not significantly different between groups (Table 2). Three weeks later, mean prolactin levels in the depot medroxyprogester-one acetate group had increased to 1156.12 mU/L, whereas mean prolactin levels in the control group had gradually decreased to 860.10 mU/L, but the difference was not statistically significant. In contrast, 6 weeks after initiating contraception, the mean prolactin level in the depot medroxyprogesterone acetate group remained similar at 1127.83 mU/L, whereas the mean prolactin level in the control group decreased to 710.97 mU/L. This difference was statistically significant between groups (P = .026, 95% CI 51.97, 781.73). However, the increase in mean prolactin levels in the study group at 3 and 6 weeks after depot medroxyprogester-one acetate injection compared with the mean prolactin level at 6 weeks postpartum before depot medroxyprogesterone acetate injection was not statistically significant (P > .05, 95% CI −452.90, 227.00, and −327.99, 243.02, respectively). In addition, the decrease in mean prolactin levels in the control group at 3 and 6 weeks after copper T380A IUD insertion compared with the mean prolactin level at 6 weeks postpartum before copper T380A IUD insertion was not statistically significant (P > .05, 95% CI −157.48, 334.97 and −46.76, 522.33, respectively).
The results of this investigation suggest that the lactating women who received depot medroxyprogesterone acetate had higher basal prolactin levels than the lactating women with a copper T380A IUD, and this effect was more obvious after longer follow-up.
In a previous study, Dicarlo et al4 studied the effect of medroxyprogesterone acetate on serum prolactin levels in mice and found that medroxyprogesterone acetate had no effect on serum prolactin. Moreover, Jeppsson et al5 studied the effect of depot medroxyprogesterone acetate on basal serum prolactin levels in reproductive-age women and found the same result. However, this result cannot be extrapolated to postpartum lactating women because the subjects were different in each study.
In contrast, Chaudhury et al6 studied the effect of depot medroxyprogesterone acetate on serum prolactin levels in lactating women and found that after depot medroxyprogesterone acetate injection four subjects who were 2 weeks postpartum had higher basal prolactin levels than four subjects who did not use contraception. However, this study was quite small. Therefore, we studied the effect of depot medroxyprogesterone acetate on basal serum prolactin levels in a larger group. Because it is likely that many factors will affect prolactin levels, such as lactation, stress, and diurnal variation, we strictly controlled those conditions by drawing blood from participants between 9:00 and 12:00 AM. Participants had no food or drink after midnight, had not nursed in at least 3 hours, and had rested at least 30 minutes. We used a control group of women with copper T380A IUDs because we could not recruit lactating women who did not use contraception, and a previous study determined that copper IUDs had no effect on prolactin levels.7,8
Although randomization was not done, all participants were recruited using the same inclusion criteria. They were healthy women 6 weeks postpartum aged 15–40 years who nursed their infants at least five times daily and more than 15 minutes each time. In addition, the results showed that baseline characteristics and basal levels of serum prolactin at 6 weeks postpartum before contraception initiation were not significantly different between the two groups.
Our result, the increase in mean prolactin levels in the study group 3 and 6 weeks after depot medroxyprogesterone acetate injection compared with mean prolactin levels 6 weeks postpartum before depot medroxyprogesterone acetate injection, was not statistically significant. In addition, the decrease in mean prolactin levels in the control group 3 and 6 weeks after copper T380A IUD insertion compared with mean prolactin level 6 weeks postpartum before IUD insertion was not statistically significant. However, basal serum prolactin levels in lactating women who had depot medroxyprogesterone acetate injection were higher than levels in the control group. Our findings are generally similar to those reported by Chaudhury et al.6 Moreover, the effect of depot medroxyprogesterone acetate on basal serum prolactin was more obvious after longer follow-up. It appears that depot medroxyprogesterone acetate acts by directly releasing prolactin from the anterior pituitary or by inhibiting normal secretion of prolactin-inhibiting factors from the hypothalamus.
1. Kaunitz AM. Injectable contraception. Clin Obstet Gynecol 1989;32:356–68.
2. Karim K, Ammar R, El Mahgoub S, El Ganzoury B, Fikri F, Abdon I. Injected progestogen and lactation. BMJ 1971;1:200–3.
3. Hooley RD, Campbell JJ, Findlay JK. The importance of prolactin for lactation in the ewe. J Endocrinol 1978;79:301–10.
4. Dicarlo F, Recea S, Conti G, Gallo E, Muccioli G, Sapino A, et al. Effect of long-term administration high doses of medroxyprogester-one acetate on hormone receptors and target organs in the female rats. J Endocrinol 1984;103:287–93.
5. Jeppsson S, Gershagen S, Johansson EB, Rannevik G. Plasma levels of medroxyprogesterone acetate (MPA), sex hormone binding globulin, gonadal steroids, gonadotrophins, and prolactin in women during long-term use of depo-MPA (Depo-Provera) as a contraceptive agent. Acta Endocrinol 1982;99:339–43.
6. Chaudhury RR, Chompootaweep S, Dusitsin N, Friesen H, Tankeyoon M. The release of prolactin by medroxyprogesterone acetate in human subjects. Br J Pharmacol 1977;59:433–4.
7. Parra M, Gabino F, Ramiraz A, Valencia H, Coria I, Espinosa A. Basal and metoclopramide-stimulated prolactin (PRL) serum levels in users and non-users of a copper intrauterine device (T Cu 380 IUD). Contraception 1991;44:541–7.
8. Wenof M, Aubert JM, Reyniak JV. Serum prolactin levels in short-term and long-term use of inert plastic and copper intrauterine device. Contraception 1979;19:21–7.