Depot-medroxyprogesterone acetate is a long-acting, synthetic, progestin-only injectable contraceptive that works primarily by preventing ovulation. Marketed as Depo-Provera® (Pfizer, NY, USA), it is available in over 90 countries and is a widely used method of contraception in Africa, Thailand and New Zealand. Although first reviewed by the FDA in 1973, only 20 years later, in 1992, was approval finally granted after concerns regarding the risk of breast cancer development were allayed. Since receiving FDA approval, DMPA use has increased in the developed world. The number of users of this method in the USA is increasing – gaining popularity among younger women and in particular adolescents.[60,61] DMPA is now available in two forms (both 3-monthly dosing intervals). In its original form it is administered as an aqueous microcrystalline suspension (dose: 150 mg) as a deep intramuscular injection (Depo-Provera®: DMPA-IM). A more recent formulation approved by the FDA in 2004 goes under the name Depo-SubQ Provera 104™ and was launched in the USA in 2005. This lower dose of 104 mg is administered as a subcutaneous injection and is also known as DMPA-SC. The new dose allows for a 30% reduction of progestin and the method of administration is easier in terms of training providers. Both the effectiveness and side effects are reported to be similar to DMPA-IM.
The majority of data available on DMPA and weight change have come from investigations of DMPA-IM,[3,4,13–30] although some studies have been carried out with regard to DMPA-SC.[62–64] Weight and DMPA-IM use has been investigated in both adult[3,4,15–22,29–31] and adolescent women.[23–28] Some of the key studies that have included a comparative group are shown in Table 1. The debate on weight increase as a consequence of DMPA-IM use continues, as well as the amount of weight reportedly gained over time, varying from approximately 1–2 kg after 1 year of use[3,4] to between 4 and 10 kg after longer use (3–5 years).[15–18,28] An early WHO multicenter, Phase III comparative trial that investigated side effects and reasons for discontinuation of DMPA-IM found that adult women gained a mean of 1.9 kg in the first year of DMPA-IM use, and weight gain was cited as one of the main reasons for discontinuation. The comparison group of NET-EN users gained a comparable amount of weight over the same time period. However, this trial did not include a control group of nonhormonal contraceptive users. In a 5-year follow-up of adult DMPA-IM and intrauterine device (IUD) users, DMPA-IM users gained 4.3 kg over 5 years compared with 1.8 kg in the IUD users. An even greater increase was found in Indian women, who gained more than 7 kg over a 2-year period compared with nonhormonal contraceptive users who gained just under 2 kg.
However, other studies have found that although DMPA-IM users may gain weight, the increase is not significantly more than among a control group of nonhormonal users[30,31] or COC users. One of these studies was a retrospective review of long-term users (10 years) of DMPA-IM and IUDs. However, this study was limited by a lack of information on women who discontinued use.
With increasing concerns regarding weight gain and the wide ranges of weight increases documented, researchers are now not only moving beyond simply reporting mean weight change, but the intention is to investigate and identify specific subgroups of women who may be more at risk of weight gain than others. Mean weight gains seen in study populations often mask individual responses to DMPA-IM-associated weight change. In a study with a 1-year follow-up, 40% of DMPA-IM users either stayed within approximately 2 kg of their baseline weight or lost more than 2 kg in weight, while over a quarter (27.3%) gained over 6 kg. In this study population the mean weight increase at 1 year was 3.0 kg overall, which may give the impression that "all women gain some weight" while using DMPA-IM. In fact, the story is far more complex.
There are now several emerging areas of focus:
The influence of baseline weight on prospective weight gain. In particular responses in adults and adolescents who fall into normal or overweight/obese categories at initiation of DMPA-IM use;
Early weight gain (within the first 6 months of DMPA-IM use) as a predictor of further and greater weight gain compared with those who do not exhibit early weight gain;
Population differences in response to DMPA-IM-associated weight gain.
These three areas may be linked and influence each other.
Influence of Baseline Weight on Predicted Weight Gain Several studies have evaluated whether the baseline weight category (normal/overweight/obese) is a potential predictor of weight gain in both adults[16,21,22] and adolescents.[23,25–28] Some studies carried out in adolescents have found that overweight and obese adolescents gained more weight compared with those in the normal-weight category.[26,27] In one of the largest studies of DMPA-IM with a comparison group of COC and nonhormonal users, adolescents in the USA aged 12–18 years who were classified as obese by baseline BMI gained significantly more weight over an 18-month period: obese DMPA-IM users gained 9.4 kg compared with 0.2 and 3.1 kg among the obese COC users and obese controls, respectively. These gains in weight were greater than those seen in all non-obese categories using all three study methods. The adolescents in this study were almost all African–American, so this result may not be representative of other population groups. A 5-year follow-up study of older (15–19 years) South African adolescents found that, although the DMPA-IM and NET-EN users gained most weight (compared with COC users and nonhormonal user controls), there was no relationship between baseline weight category and pattern of gain.
Data from obese adult women present a different picture entirely and do not support an increased risk of weight gain in obese DMPA-IM users compared with normal-weight women.[17,18,21,22] A systematic review published in 2009 evaluated progestogen-only contraceptive use in obese women. Data were only found on DMPA, and one study on implants and the review concluded that adolescents, but not adult users, may be at risk of weight gain. The authors acknowledged that much of the data evaluated was limited by its heterogeneity and study design. The findings of this review were evaluated by a WHO Expert Working Group in order to assess the appropriateness of the medical eligibility criteria for the use of progestogen-only contraceptives (POCs) among obese women. The group recommended that adolescents under the age of 18 years with a BMI of 30 kg/m2 or more should be moved from category 1, which states "can use all POC methods", to category 2, "generally use the method", for DMPA-IM, and category 1 for other POC methods. For obese adult users, DMPA-IM category 1 still applies for all POC methods.
Since the latter review was released, several studies have been published that suggest that non-obese adult DMPA-IM users may be more likely to gain weight compared with obese users, in contrast to adolescents.[18,20,22] In one of these studies, non-obese women using DMPA-IM gained more weight than obese women; this was not seen in the COC or nonhormonal user controls. Similarly, Pantoja found normal and overweight DMPA-IM users gained weight, while obese women experienced no weight change after 3 years of use. In summary, although limited in number, the few studies focusing on adolescents suggest that overweight and obese younger women may be at greater risk of weight gain compared with those within normal weight ranges. The situation in adult women may be more complex.
Influence of Early Weight Gain on Initiation of DMPA-IM Another possible area of weight-related influence in DMPA-IM users is that of early weight gain. Some women may gain weight more steadily over time, while others appear to exhibit an initial rapid gain during the first few months of use.[20,23] A recent 3-year follow-up in the USA investigated early weight gain in DMPA-IM users aged between 16 and 33 years. In this study, women were classified as 'early' gainers if they gained over 5% of baseline weight within 6 months of DMPA-IM initiation, and were compared with 'regular' gainers who gained weight but less than 5% by 6 months of use. Mean weight gain increased over 36 months in the total study population, but the group exhibiting early weight gain increased by an average of 7 kg more than the regular weight gainers. Interestingly, this study found that one of the three predictors for early weight gain was a BMI of less than 30 kg/m2, and users who were in this weight category were more likely than the regular gainers to experience early weight gain. Other predictors included increased appetite and parity of one or more. Similarly, in a study of adolescents, almost all those who gained more than 5% of their baseline weight at 3 months gained even more at 12 months.
Ethnicity and DMPA-IM-associated weight gain is also quite contradictory. One study found only marginal evidence to support findings that African–American women were more likely to gain weight over time compared with white women. Another study found strong evidence for ethnic differences, with African–American subjects gaining significantly more weight compared with white women, even though there were no baseline differences in weight. On the contrary, Berenson et al. were not able to show this, and in their study found that white non-obese women gained significantly more than all obese women as well as African–American women.
Mechanism of Weight Change in DMPA-IM Users The exact mechanism of reported weight gain in DMPA-IM is not clear. An early study investigated weight changes in a small sample of Thai women and found no significant changes in fluid retention, creatinine excretion rate or nitrogen metabolism, and concluded that weight gain was associated with fat deposition. This is in agreement with more recent studies, which suggest that an increase in fat mass and not lean mass is responsible for the weight gain.[17,18] One study found an increase in self-reported appetite in women after 6 months of DMPA-IM use, although other studies have found no association between appetite and DMPA-IM-associated weight gain.[18,25] Berenson et al. also found that calory intake and fat consumption did not affect weight gain, and concluded that this may indicate that the weight gain is the result of appetite regulation and energy expenditure.
Discontinuation of DMPA-IM & Weight Change If weight gain is likely in DMPA-IM users it would be important to know whether this weight gain can be reversed after discontinuation of the method. However, few studies have followed up users who discontinued their methods of contraception and these data are rarely recorded in retrospective studies. One study found that DMPA-IM users lost weight after discontinuation at a rate of just under 0.5 kg for every 6 months postdiscontinuation. However, this was not found in women who switched to COCs after DMPA-IM use. White women discontinuers in this study were more likely to record a decrease in percent body fat compared with African–American women. A study in South Africa looked at those who discontinued DMPA-IM and NET-EN and found that over half (56%) maintained their weight within 2 kg of their weight at their last hormonal contraceptive use visit at 1 year postdiscontinuation, and just under one-quarter either lost or gained weight, although the numbers were too small to analyze by individual method.
Some data are available on the effect of DMPA-SC and weight change.[62–64] Westhoff conducted an analysis of three trials: two 1-year contraceptive efficacy trials of DMPA-SC in different population groups and one trial where users were randomized to DMPA-IM or DMPA-SC. Results of the weight-change analyses found that users of both DMPA types gained similar amounts of weight (Table 1). The mean weight gain in the 1-year trials was less than 2 kg over the 12-month period. The 3-year trial found that weight gain was on average 4.5 kg in the DMPA-SC group and slightly higher in the DMPA-IM group. No difference was found in age or baseline weight subgroups. Other smaller studies have found modest increases in weight over 1 year in DMPA-SC users.
Expert Rev of Obstet Gynecol. 2011;6(1):45-56. © 2011
Expert Reviews Ltd.
Cite this: Weight Change and Hormonal Contraception: Fact and Fiction - Medscape - Jan 01, 2011.