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Depot-medroxyprogesterone versus norethisterone enantate for long-acting progestogenic contraception

RHL Commentary by Gray A

1. EVIDENCE SUMMARY

A systematic review has examined the differences between two progestogen-only injectable contraceptives, depot medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-EN) (1). Only evidence from randomized controlled trials (RCTs) in which DMPA was given at a dose of 150mg every 3 months and NET-EN at a dose of 200mg every 2 months were included.

Only two trials met the inclusion criteria. Both had been conducted under the auspices of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction. One involved a single site and the other was a multi-site study. The multi-site study was reported separately for the 13 sites, and each of these was treated in the meta-analysis as a separate study. This study had recruited 10331 women, but data from a third arm (in which NET-EN was given every 2 months for 6 doses and every 3 months thereafter) were excluded. The single site study provided data from 400 women over 12 months. In total, data were available from 3572 women over 6 months, 2776 over 12 months and 2376 over 24 months of treatment.

No difference cold be detected between the two treatments in the frequency of discontinuation at 12 months (the risk difference (RD) was 0.00, 95% confidence interval (CI) was between -0.06 and 0.06). There were no differences in the frequency of discontinuation due to accidental pregnancy, amenorrhoea, bleeding problems or other medical reasons. Users of NET-EN were, however, more likely to discontinue for personal reasons (RD -0.04; 95% CI -0.07 to -0.01). While the differences in bleeding or spotting (whether events or duration) at 12 and 24 months were not significant, there was a 21% higher risk of amenorrhoea in DMPA users at both time points (95% CI 8-35% at 12 months; 14-29% at 24 months). Weight changes and blood pressure changes were not significantly different. Importantly, no data were available on the major adverse effects of interest (vaginal shedding of HIV; susceptibility to HIV and other STIs). Data on bone mineral density would also not have been available from studies conducted in the 1970s and 1980s.

An extensive search was conducted, using the methods developed by the Cochrane Fertility Regulation Group. The authors did concede that, due to the time that had elapsed between completion of retrieved studies and the review, few additional details could be obtained from the authors.

Data extraction for the review was done in the standard fashion, but the analysis was somewhat unusual in that the results from the 13 sites used in the 1977-1982 multi-site study were treated separately. The graphics therefore represent the results as if they were independent trials. Though not explained in any way, it was noted that loss to follow up varied considerably between the two included studies. The multi-site study reported a surprisingly low 1% loss over 2 years. In the shorter (1-year) single site study, 27% of DMPA users and 40% of NET-EN users were lost to follow up.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

The patterns of hormonal contraceptive use vary considerably between settings, and reflect local preferences as well as provider biases (1, 2). In resource-constrained settings, programme managers may be under pressure to reduce the range of method options. Where such choices can be made without unnecessarily restricting access to meaningfully different methods, identifying methods that are substantially the same may provide opportunities for rational choices. Both DMPA and NET-EN are extensively used in developing countries, but may be priced very differently. This can have a considerable impact on health expenditure. South Africa provides one such example (3). In other countries the acquisition costs may be closer, but total programmatic costs may still be higher where the dose frequency is higher. Based on data from the Management Sciences for Health International Drug price Indicator Guide 2005, the acquisition cost per couple-year of protection in Namibia was $6.0056 for DMPA and $6.2094 for NET-EN (4). Both DMPA and NET-EN appear on the core list of the WHO Model Essential Medicines List (14th edition)(5). A recent cross-sectional study in 893 South African women has shown that expressed preferences for DMPA or NET-EN were based on misperceptions (6). Women who preferred DMPA thought it was more effective in preventing pregnancy, whereas those who preferred NET-EN believed that return to fertility was more likely with this agent.

2.2. Applicability of the results

The data included in this systematic review were generated in a variety of settings. The single site study was conducted in Egypt, and the multi-site study in developed (Luxembourg, Italy, the Netherlands), transitional (Yugoslavia) and developing (Egypt, Thailand, Nigeria, Pakistan, Zambia, Philippines, Mexico, Brazil, Chile) countries. Attitudes towards the one significant difference detected between DMPA and NET-EN (amenorrhoea) may well be important in determining discontinuation rates in a particular setting.

2.3. Implementation of the intervention

Structures entrusted with medicines selection need to carefully consider whether to provide both of these progestogen-only injectable contraceptives. Efforts to widen contraceptive choices may entail making choices between these and once-a-month injectables or longer-acting implantable contraceptives. Local knowledge about cultural attitudes to amenorrhoea may help guide such decisions. However, other endpoints may be considered to be more important, and the evidence for such endpoints may not as yet be available. Some data on endpoints not considered in the review are available, such as on the effect of progestogen-only injectable contraceptives on carbohydrate metabolism (7) and lipids (8). Newer presentations of progestogen-only contraceptives have become available. Subcutaneous administration of DMPA has, however, been shown to be associated with amenorrhoea, with an increase over time of use (9). Bleeding patterns in users of once-a-month combined injectable contraceptives are also not normal (10). Choosing between alternative injectable methods on this criterion alone is therefore difficult.

3. RESEARCH

Future research needs to focus on two areas of concern – the effect of the long-acting injectable contraceptives on bone health and HIV risk.

Systematic reviews of the available evidence for the effects of combined hormonal contraceptives (11) and progestogen-only contraceptives (12) on bone health have recently been published. The second of these concluded that “[limited evidence suggested that the use of progestogen-only contraceptives other than DMPA did not affect [bone mineral density]”. Although recovery of bone mineral density (BMD) after discontinuation of DMPA has been shown (13), sequential use of DMPA and then a combined oral contraceptive may also be problematic (14). More recently still, it has been reported that once-a-month combined injectable contraceptives did not have a measurable effect on BMD (15). Until more evidence of a significant difference between injectable contraceptives is available, it would seem prudent to follow the advice given by the WHO (16). Noting that “there should be no restriction on the use of DMPA, including no restriction on duration of use, among women aged 18-45 years who are otherwise eligible to use the method”, the WHO also stated that “recommendations regarding DMPA use also pertain to the use of NET-EN”. This is in line with the advice provided by the Society for Adolescent Medicine in the United States, which has recommended “to continue prescription of DMPA, with counseling about the risks and benefits, in most of the adolescent population desiring to use this contraceptive method” (17).

Further data are also needed before any new recommendations can be made regarding the use of hormonal contraceptives (including injectables) and increased risk of acquiring HIV or other STIs. A 2005 statement released after a WHO regional meeting in Nairobi stated that “[t]here should be no restrictions on the use of COCs and DMPA by women at risk of acquiring HIV, consistent with the current WHO Medical Eligibility Criteria for Contraceptive Use guidelines” (18).

Sources of support: Department of Therapeutics and Medicines Management, Nelson R Mandela School of Medicine

References

• Sullivan TM, Bertrand JT, Rice J, Shelton JD. Skewed contraceptive method mix: why it happens, why it matters. Journal of Biosocial Science 2006;8:501-521.
• Bongaarts J, Johansson E. Future trends in contraceptive prevalence and method mix in the developing world. Studies in Family Planning 2002;33(1):24-36.
• Smit J, Gray A, McFadyen L, Zuma K. Counting the costs: comparing depot medroxyprogesterone acetate and norethisterone oenanthate utilisation patterns in South Africa. BMC Health Services Research 2001;1(1):4.
• Management Sciences for Health. International Drug price Indicator Guide 2005. Accessible at http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2005_En.pdf. ;.
• World Health Organization. WHO Model List (14th edition). March 2005. Accessible at http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf. ;.
• Morroni C, Myer L, Moss M, Hoffman M. Preferences between injectable contraceptive methods among South African women. Contraception 2006;73(6):598-601.
• Fahmy K, Abdel-Razik M, Shaaraway M, al-Kholy G, Saad S, Wagdi A, al-Azzony M. Effect of long-acting progestagen-only injectable contraceptives on carbohydrate metabolism and its hormonal profile. Contraception 1991;44(4):419-430.
• Enk L, Landgren BM, Lindberg UB, Silverstolpe G, Crona N. A prospective, one-year study on the effects of two long-acting injectable contraceptives (depot-medtroxyprogesterone acetate and norethisterone oenanthate) on serum and lipoprotein lipids. Hormone and Metabolic Research 1992;24(2):85-89.
• Arias RD, Jain JK, Brucker C, Ross D, Ray A. Changes in bleeding patterns with depot medroxyprogesterone acetate subcutaneous injection 104mg. Contraception 2006;74(3):234-238.
• Fraser IS. Vaginal bleeding patterns in women using once-a-month injectable contraceptives. Contraception 1994;49(4):399-420.
• Martins SL, Curtis KM, Glasier AF. Combined hormonal contraception and bone health: a systematic review. Contraception 2006;73:445-469.
• Curtis KM, Martins SL. Progestogen-only contraception and bone mineral density: a systematic review. Contraception 2006;73:470-487.
• Kaunitz AM, Miller PD, Rice VM, Ross D, McClung MR. Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception 2006;74:90-99.
• Albertazzi P, Bottazzi M, Steel SA. Bone mineral density and depot medroxyprogesterone acetate. Contraception 2006;73:577-583.
• Bahamondes L, Juliato, CT, Villareal M, Sobreira-Lima B, Simões, JA, dos Santos Fernandes AM. Bone mineral density in users of two kinds of once-a-month combined injectable contraceptives. Contraception 2006;74:259-263.
• Department of Reproductive Health and Research, World Health Organization. WHO statement on hormonal contraception and bone health. Contraception 2006;73:443-444.
• Cromer BA, Scholes D, Berenson A, Cundy T, Clark MK, Kaunitz AM. Depot medroxyprogesterone acetate and bone mineral density in adolescents – the black box warning: a position paper of the Society for Adolescent Medicine. Journal of Adolescent Medicine 2006;39:296-301.
• World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction. Hormonal contraception and HIV: science and policy. Africa Regional Meeting. Nairobi 19-21 September 2005. Accessible at http://www.who.int/reproductive-health/stis/hc_hiv/nairobi_statement.html. ;.

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This document should be cited as: Gray A. Depot medroxyprogesterone versus Norethisterone oenanthate for long-acting progestogenic contraception: RHL commentary (last revised: 15 December 2006). The WHO Reproductive Health Library; Geneva: World Health Organization.

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