Are the Effects of Oral and Vaginal Contraceptives on Bone Formation in Young Women Mediated via the Growth Hormone-IGF-I Axis?

Abstract

Purpose: Combined hormonal contraceptive therapy has been associated with negative bone mineral density outcomes that may be route-dependent [i.e., combined oral contraception (COC) vs. contraceptive vaginal ring (CVR)] and involve the hepatic growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. The objective of the pilot study was to assess the impact of route of contraceptive administration on IGF-I and procollagen type I N-terminal propeptide (PINP) responses to an IGF-I Generation Test. We hypothesized that the peak rise in IGF-I and PINP concentration and area under the curve (AUC) would be attenuated following COC, but not CVR, use. Methods: Healthy, premenopausal women not taking hormonal contraception were recruited. Women were enrolled in the control group (n = 8) or randomly assigned to COC (n = 8) or CVR (n = 8) for two contraceptive cycles. IGF-I Generation Tests were used as a probe to stimulate IGF-I release and were completed during the pre-intervention and intervention phases. Serum IGF-I and PINP were measured during both IGF-I Generation Tests. The study was registered at ClinicalTrials.gov (NCT02367833). Results: Compared to the pre-intervention phase, peak IGF-I concentration in response to the IGF-I Generation Test in the intervention phase was suppressed in the COC group (p < 0.001), but not the CVR or Control groups (p > 0.090). Additionally, compared to the pre-intervention phase, PINP AUC during the intervention phase was suppressed in both COC and CVR groups (p < 0.001), while no difference was observed in the control group (p = 0.980). Conclusion: These data suggest that changes in recombinant human GH-stimulated hepatic IGF-I synthesis in response to combined hormonal contraception (CHC) use are dependent on route of CHC administration, while the influence on PINP is route-independent. Future research is needed to expand these results with larger randomized control trials in all age ranges of women who utilize hormonal contraception. Clinical Trial Registration: www.ClinicalTrials.gov registration NCT02367833.

Keywords: IGF-I generation test; contraceptive vaginal ring; insulin-like growth factor-I; oral contraception; procollagen type I N-terminal propeptide.

Figure 1

Schematic of the study design. (A) Screening lasted 2–4 weeks. (B) The pre-intervention phase was one menstrual cycle in duration. (C) The intervention phase was two contraception cycles or menstrual cycles in duration. (D) Schematic of the 8-day protocol for the IGF-I Generation Test. Participants had rhGH injections subcutaneously on days 2–5 of the 8-day protocol. Blood samples were taken from participants on days 1,2,4,6, and 8 of the 8-day protocol. COC, combined oral contraception; CVR, contraceptive vaginal ring; DXA, dual x-ray absorptiometry; rhGH, recombinant human growth hormone.

Figure 2

Progression of study participants through the pilot study. Total study N is provided as well as n per study site in brackets (PSU; Purdue). COC, combined oral contraception; CVR, contraceptive vaginal ring.

Figure 3

Compliance to study period and study group. SHBG concentrations for the COC (triangle), CVR (square), and control (circle), groups for pre-intervention, intervention cycle 1, and intervention cycle 2 compliance assessments. COC, combined oral contraception; CVR, contraceptive vaginal ring. * indicates difference from control group at same time point p < 0.05.

Figure 4

Pre-intervention (black bars) and intervention (open bars) IGF-I (A) basal concentrations and response to the IGF-I Generation Test measured as (B) AUC and (C) peak concentrations for the COC, CVR, and Control Groups. (D–F) Daily concentrations of IGF-I for pre-intervention (solid lines and filled symbols) and intervention (dashed lines and open symbols) phase IGF-I Generation Tests. (D) COC group (triangles); (E) CVR group (squares); (F) Control group (circles). Basal IGF-I concentrations were subtracted from day 4, 6, and 8 concentrations for each study group and study phase (pre-intervention and intervention. COC, combined oral contraception; CVR, contraceptive vaginal ring; IGF-I, insulin-like growth factor-I; AUC, area under the curve. * indicates difference from pre-intervention phase within study group P < 0.05. ^∧ indicates difference from Control group within study phase P < 0.05.

Figure 5

Pre-intervention (black bars) and intervention (open bars) PINP (A) basal concentrations and response to the IGF-I Generation Test measured as (B) AUC and (C) peak concentrations for the COC, CVR, and Control Groups. (D–F) Daily concentrations of PINP for pre-intervention (solid lines and filled symbols) and intervention (dashed lines and open symbols) phase IGF-I Generation Tests. (D) COC group (triangles); (E) CVR group (squares); (F) Control group (circles). Basal PINP concentrations were subtracted from day 4, 6, and 8 concentrations for each study group and study phase (pre-intervention and intervention). COC, combined oral contraception; CVR, contraceptive vaginal ring; PINP, procollagen type I N-terminal propeptide; AUC, area under the curve. * indicates difference from pre-intervention phase within study group P < 0.05. ^∧ indicates difference from Control group within study phase P < 0.05.