Ovulation suppression following subcutaneous administration of depot medroxyprogesterone acetate

Abstract

Objectives: To characterize the relationship between serum medroxyprogesterone acetate (MPA) concentrations and ovulation suppression, and to estimate the risk of ovulation for investigational subcutaneous regimens of Depo-Provera CI (Depo-Provera) and Depo-subQ Provera 104 (Depo-subQ).

Study design: We performed a secondary analysis of 2 studies that assessed the pharmacokinetics and pharmacodynamics of MPA when Depo-Provera is administered subcutaneously rather than by the labeled intramuscular route. Each woman received a single 45 mg to 300 mg subcutaneous injection of Depo-Provera, a single 104 mg subcutaneous injection of Depo-subQ, or 2 injections of Depo-subQ at 3-month intervals. We used an elevation of serum progesterone ≥4.7 ng/mL as a surrogate for ovulation and non-parametric statistical methods to assess pharmacokinetic and pharmacodynamic relationships.

Results: This analysis included 101 women with body mass index (BMI) 18 to 34 kg/m². Return of ovulation occurred at a median MPA concentration of 0.07 ng/mL (95% CI: 0.06-0.08) and the 90th percentile was 0.10 ng/mL (95% CI: 0.09-0.14). Neither age, race, nor BMI significantly influenced this relationship. The estimated probabilities of ovulation within 4 months of a 104 mg subcutaneous injection and within 7 months of a 150 mg subcutaneous injection (6 plus a 1-month grace) were each below 2.2%.

Conclusions: The typical MPA concentration associated with loss of ovulation suppression is substantially less than the commonly cited threshold of 0.2 ng/mL. Based on our results, MPA levels would rarely be low enough to permit ovulation if the Depo-subQ reinjection interval were extended to four months or if 150 mg Depo-Provera were injected subcutaneously every 6 months.

Implications: Extending the three-month Depo-subQ reinjection interval by one month would result in a 25% reduction in yearly MPA exposure, with little risk of pregnancy. Off-label subcutaneous administration of 150 mg Depo-Provera every 6 months would be a highly effective repurposing of an excellent product, with a similar reduction in cumulative exposure.

Keywords: DMPA; Depo-Provera; Depo-subQ Provera; Pharmacodynamics; Pharmacokinetics.

Fig. 1

Geometric mean MPA concentrations following subcutaneous administration of 45–300 mg Depo-Provera or 104 mg Depo-subQ in two trials conducted between 2015 and 2018 [10,11]. Solid lines and 95% confidence bands are based on locally re-weighted nonparametric regression. The first three months of data were pooled for participants receiving one (x1) or two (x2) injections of Depo-subQ. Abbreviation: MPA, medroxyprogesterone acetate.

Fig. 2

Cumulative probability of ovulation (progesterone ≥4.7 ng/mL) following subcutaneous administration of 45–300 mg Depo-Provera or 104 mg Depo-subQ in two trials conducted between 2015 and 2018 [10,11]. Shaded regions are 95% confidence bands. Numbers at-risk are below the x-axis. There were no events among subjects who received a single (x1) dose of Depo-subQ.

Fig. 3

Cumulative distribution of the MPA concentration when ovulation returns (progesterone ≥ 4.7 ng/mL) following subcutaneous administration of 45–300 mg Depo-Provera or 104 mg Depo-subQ in two trials conducted between 2015 and 2018 [10,11]. Dashed lines and 95% confidence bands are based on non-parametric maximum likelihood estimation. Solid curve is Weibull model fit, which was used to estimate covariate effects in Table 2. Abbreviation: MPA, medroxyprogesterone acetate.

Fig. 4

Cumulative distribution of MPA concentrations 4 months after a 104 mg subcutaneous injection (n = 95; left) and seven months after a 150 mg subcutaneous injection (n = 29; right), based on data from two trials conducted between 2015 and 2018 [10,11]. Dashed lines and 95% confidence bands are based on non-parametric maximum likelihood estimation. Solid curves are parametric model fits. Abbreviation: MPA, medroxyprogesterone acetate.