Combined oral contraceptives and body weight: do oral contraceptives cause weight gain? A primate model by swissestetix

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									                                  Hum. Reprod. Advance Access published December 1, 2010
Human Reproduction, Vol.0, No.0 pp. 1– 7, 2010
doi:10.1093/humrep/deq335


                                  ORIGINAL ARTICLE Reproductive endocrinology


                                  Combined oral contraceptives and
                                  body weight: do oral contraceptives
                                  cause weight gain? A primate model
                                  A. Edelman 1,2,*, J.T. Jensen 1,2, M. Bulechowsky2, and J. Cameron1,2,3
                                  1
                                    Department of Obstetrics & Gynecology, Mail code UHN 50, Oregon Health & Science University, Portland, OR 97239, USA 2Division of
                                  Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR 97006, USA 3Department of Psychiatry, University of
                                  Pittsburgh, Pittsburgh, PA 15213, USA

                                  *Correspondence address. Tel: +1-503-494-5949; Fax: +1-503-494-3111; E-mail: edelmana@ohsu.edu




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                                  Submitted on August 18, 2010; resubmitted on November 1, 2010; accepted on November 8, 2010


   background: The aim of this study was to determine if oral contraceptive (OC) use affects body weight, body composition and
   metabolism in primates.
   methods: Reproductive-age female rhesus monkeys of normal and obese BMI were studied to document baseline weight stability, then
   treated continuously with an OC (dosed to achieve equivalent human serum levels for a 30 mg ethinyl estradiol/150 mg levonorgestrel prep-
   aration) for 237 days. Monkeys were monitored for changes in body weight, levels of physical activity (measured by a triaxial Actical accel-
   erometer), food/caloric intake, percent body fat (dual energy X-ray absorptiometry, DEXA) and metabolism (24 h metabolic rate and serum
   metabolic substrate and hormone concentrations).
   results: All 10 monkeys completed the study protocol with no adverse events. While body weight (20.73% change) and percent body
   fat (21.78% change) of the normal BMI group did not significantly decrease from baseline, obese monkeys showed a significant decrease in
   body weight (28.58% change, P , 0.01) and percent body fat (212.13% change P ¼ 0.02) with OC treatment. In both the obese (P ¼
   0.03) and the normal BMI (P ¼ 0.01) groups, there was a significant increase in basal metabolic rate with OC use. No changes were
   seen in food intake, activity level or % lean muscle mass with OC use for either BMI-based group.
   conclusions: Overall, OC use appears to cause a slight increase in basal metabolic rate in female monkeys, leading to a decrease in
   body weight and percent body fat in obese individuals.
   Key words: oral contraceptives / weight gain / BMI / metabolism




                                                                                          recent Cochrane review (2004) of 42 randomized trials found that
Introduction                                                                              the available evidence is insufficient to determine if OCs have any
The USA has the highest unintended pregnancy rate of any developed                        effect on weight (Gallo et al., 2004). However, none of the studies
country (Darroch et al., 2001), with 49% of all pregnancies unintended                    in this meta analysis included obese women.
(Henshaw 1998). Oral contraceptives (OCs) are the most popular                               In general, adults tend to gain weight with age (Hedley et al., 2004).
form of birth control and discontinuation due to perceived side                           This is especially true in the USA where obesity is at epidemic pro-
effects, such as weight gain, plays an important role in contributing                     portions, currently at 30% and rising (WHO, 2006). It is not surprising
to this high unplanned pregnancy rate.                                                    that women often blame OCs for their weight gain, as OCs may
   Weight regulation is a major health concern for many women.                            be the only medication women take consistently throughout their
Weight gain is a common complaint (30– 75%) among OC users                                reproductive lifetime. Theoretically, the biological mechanism for
and has been found to be the leading reason cited for discontinuation                     contraceptive-induced weight gain could be due to fluid retention sec-
of OCs among U.S. women (Oddens et al., 1994; Rosenberg, 1998;                            ondary to mineralocorticoid and/or renin –angiotensin –aldosterone
Fletcher et al., 2001; Picardo et al., 2003). Many women who stop                         activation and/or an increase in subcutaneous fat secondary to a hor-
taking an OC out of concern for weight gain, substitute a less effective                  monally induced increase in appetite and food intake (Flegal and
method or no method, and increase their risk of unintended preg-                          Troiano, 2000; Gallo et al., 2004). However, the most likely reason
nancy. Despite the popular notion that OCs lead to weight gain, a                         for the growing girth of women in our population is a combination

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2                                                                                                                                        Edelman et al.


of genetic, environmental and lifestyle factors that have nothing to do       A combination OC with 30 mg ethinyl estradiol (EE)/150 mg levonor-
with OC use (Speroff et al., 1999). This is further supported by a         gestrel (LNG) (Seasonale, Pomona, NY, USA) was dosed in a continuous
wealth of data in rodent models showing that steroid hormones, in          fashion (no placebo days) for a treatment period of 8 months (237
particular estradiol, suppress food intake (Wade and Zucker, 1970;         days). Dosing studies prior to study initiation were performed for each
                                                                           monkey in order to ensure a comparable human equivalent dose for
Shinoda et al., 2002).
                                                                           this OC (EE 145 + 45 pg/ml, LNG 5.6 + 1.5 ng/ml) (Kunhz et al.,
   Detailed studies of the effect of combined hormonal contraceptives
                                                                           1994; Duramed, 2010). Each monkey had a set dose to achieve this
on weight gain have not been completed as it is difficult to control for
                                                                           plasma level, which ranged from 1/8 to 1/2 tablet daily. EE and LNG
factors such as caloric intake and activity level in women during long-    levels were stable over the course of the study, exhibiting a 7.5% and a
term trials. Non-human primates are ideal subjects in which to             10.1% variation, respectively.
examine the role of OCs on body weight since the control of repro-
ductive function, metabolism and food intake are similar in humans         Animals
and non-human primates (Hotchkiss and Knobil, 1994; Grove et al.,          Ten adult reproductive age (8– 16 years of age) female rhesus monkeys
2005; Wagner et al., 2006), and factors such as caloric intake and         (Macaca mulatta) living in individual stainless steel cages in a temperature-
activity level can be closely controlled and monitored. In this study,     controlled room (24 + 28C) with lights on for 12 h per day (07:00 –
we sought to investigate whether OCs influence body weight in               19:00 h) were studied. Animals were fed two meals a day of Purina
normal weight and obese non-human primates while measuring                 LabDiet fiber-balanced monkey chow (No. 5000, Purina Mills, St. Louis,
caloric intake, basal metabolic rate, activity level, total energy         MO, USA) at 09:30 and 15:30 h. Each animal’s allotment of monkey
                                                                           chow was individualized, based on caloric levels previously determined




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expenditure, thermic effect of food and serum biomarkers and
hormones.                                                                  to provide weight stability. Monkeys were fed 539 + 25 calories of
                                                                           monkey chow per day, with a range from 473 to 663 calories/day.
                                                                           Monkeys were also provided with portions of fresh fruits, vegetables
                                                                           and other small food items daily as part of the environmental enrichment
Materials and Methods                                                      program at the ONPRC.
All aspects of the study were reviewed and approved by the Oregon
National Primate Research Center (ONPRC) Animal Care and Use Com-          Experimental measures
mittee and were performed according to federal guidelines.                 Body weight and length
                                                                           Body length was measured once at the beginning of the study. Body weight
Experimental design                                                        was measured every other day for the entire study, before the morning
                                                                           meal.
The overall goal of this study was to determine if the use of OCs has an
effect on body weight. Two groups of adult female monkeys were selected
for the study based on their BMI: a normal BMI group (BMI: range 22.5 –    Dual energy X-ray absorptiometry scans
27.3 kg/m2; weight: mean 5.76 + SD 0.58 kg; n ¼ 5) and an obese group      Percent body fat and percent lean body mass were determined using dual
(BMI: range 32.5 –35.1 kg/m2; weight: mean 8.11 + SD 0.58 kg; n ¼ 5;       energy X-ray absorptiometry (DEXA). DEXA’s were performed under
Fig. 1). Of note, the obese group was inherently obese and not made        Ketaset (ketamine hydrochloride 10 mg/kg IM, Vedco, St. Joseph, MO,
so for the purposes of this study. This was a longitudinal study design    USA) sedation and then scanned with a Hologic Dexa scanner (Discovery
with a 3-month baseline period, an 8-month OC treatment period and         scanner, Hologic Inc., Bedford, MA, USA) in the whole body mode.
a 3-month post-treatment period. Experimental measures were per-           Animals were scanned at the end of the baseline period (pretreatment)
formed before, during, and after treatment.                                and at the end of the OC treatment period. During the post-treatment
                                                                           period, 5 of 10 animals were scanned, but for technical reasons accurate
                                                                           scans could not be obtained on the remaining five animals.


                                                                           Food/caloric intake
                                                                           At the beginning of the initial baseline period the number of calories
                                                                           required to keep each animal’s weight stable was determined by assessing
                                                                           what level of calorie intake was needed to maintain a stable body weight in
                                                                           each animal over a 3-month period. Animals were then maintained on this
                                                                           diet throughout the rest of the study. Food intake was monitored at each
                                                                           meal throughout the study.


                                                                           Physical activity
                                                                           Naturally occurring levels of physical activity for each animal were assessed
                                                                           continuously using triaxial Actical accelerometers (Phillips, Phoenix, AZ,
                                                                           USA) using previously published methods (Sullivan et al., 2006). Animals
                                                                           wore a loose-fitting metal collar with an attached metal casing that
                                                                           housed the activity monitor. The monitor was programmed to record
    Figure 1 Examples of the study participants: a normal weight (left     total activity counts per minute. Animals were sedated with Ketaset (keta-
    panel) and an obese (right panel) rhesus monkey.                       mine hydrochloride 10 mg/kg IM) and the monitors were downloaded
                                                                           and reprogrammed at least every 45 days.
Combined oral contraceptives and body weight in primates                                                                                           3


Metabolic rate                                                                Results
For each monkey, 24-h metabolic rate was measured at the end of the
baseline control period, at the end of OC treatment, and again at the         Body weight and length
end of the post-treatment period (Sullivan et al., 2006). For metabolic
rate measurement, each monkey was housed for a 24-h period in a               There was a significant but small decrease in body weight in all
sealed Lexan and stainless steel metabolic chamber (Columbus Instru-          monkeys (n ¼ 10) when comparing the baseline period to the end
ments, Columbus, OH, USA) and the amount of carbon dioxide produced           of OC treatment (4.65% change from baseline; from 6.93 + 0.41 to
and oxygen consumed was measured using a computer-controlled                  6.56 + 0.32 kg; P ¼ 0.04). Body weight returned to baseline after
indirect open circuit calorimeter (Oxymax system, Columbus Instru-            OC cessation (P ¼ 0.20). Analyzing weight change for each BMI
ments). During metabolic rate measurements, a familiar monkey was             group, the obese group showed a significant decrease in body
housed across from the test animal to ensure that they were in an accus-      weight with OC use (28.58% change from baseline; from 8.11 +
tomed social setting. Animals were placed in the chamber at 10:00 h on        0.58 to 7.41 + 0.45 kg; P , 0.01; Fig. 2A), whereas the normal BMI
the testing day and removed at the same time the next day. Prior to
                                                                              group had a smaller decline that was not statistically significant
testing, each monkey was fed their standard morning meal. A 110 g
                                                                              (20.73% change from baseline; from 5.76 + 0.58 to 5.72 +
banana was fed at 15:00 h during metabolic testing, by placing the
banana into the metabolic chamber through a small sealed window at            0.45 kg; P ¼ 0.80; Fig. 2A).
the top of the chamber.
                                                                              Dual energy X-ray absorptiometry




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Blood samples                                                                 There was a significant decrease in percent body fat with OC use
Fasting (overnight) blood samples (plasma and serum) were collected           when compared with baseline for the entire group (22.8 + 3.65–
every 2–3 weeks throughout the study for measurements of circulating          15.84 + 1.53%, P ¼ 0.02). As with body weight, the decrease in
levels of metabolic substrates and hormones, including glucose, insulin       body fat was significant in the obese monkeys (32.17 + 5.15–
and leptin.                                                                   20.04 + 2.17%, P ¼ 0.02; Fig. 2B) but not in the normal weight
                                                                              monkeys (13.42 + 5.15–11.64 + 2.17%, P ¼ 0.22; Fig. 2B). At the
                                                                              end of the post-treatment period, percent body fat had increased
Serum assays
                                                                              such that there was no difference from baseline percent body fat
Serum glucose concentrations were measured on an YSI 2300 Stat Plus
glucose analyzer (Yellow Spring Instruments, Yellow Sprigs OH), with
automatic calibration and linear detection to 900 mg/dl. Insulin, leptin
and testosterone were measured by the Endocrine Technology and
Support Lab, ONPRC (Beaverton, OR, USA) using double-antibody radio-
immunoassay (RIA) kits (Millipore-Linco, Billerica, MA, USA; Insulin: Cat.
#HI-14K; Leptin: Cat. #HL-84K; testosterone: DSL-4100, Diagnostic
Systems Laboratories, Inc., Webster, TX, USA). The human insulin
assay has a range of detection between 2 and 200 mU/ml. The detection
limit of the assay at 100 ml sample volume is 2 mU/ml. The leptin assay has
a range of detection between 0.5 and 100 ng/ml. The sensitivity of this
assay for a 100 ml sample is 0.5 ng/ml. For both hormones, all samples
in this study were included in one assay, and the intra-assay variation
was 6.51% for the insulin assay and 1.3% for the leptin assay. The sensi-
tivity of the Testosterone assay was 0.05 ng/ml and the intra-coefficient
of variation for the assays was 2.23%.
   EE and LNG levels were measured by the Endocrine Technology and
Support Lab, ONPRC (Beaverton, OR) using RIA kits (Immunometrics
Ltd, London, UK; EE2: Cat. # IM-1182; LNG: Cat. # IM-115). The EE
assay has a range of detection between 78 and 5000 pg/ml, and a detec-
tion limit of 100 pg/ml. The LNG assay has a range of detection between
23 and 750 fmol/tube, and a sensitivity of 36 pg/ml. The intra-assay and
inter-assay variations for the EE and LNG assays were 6.0 and 7.1% and
6.7 and 9.6%, respectively.

Data analysis
Mean body weight measures for a 1-month period during the baseline
period were calculated for each monkey and used as the baseline body
weight. For all analyses, normality and homoscedasticity were initially
tested and all data met the criteria for using parametric analyses.
Repeated-measures ANOVA was used to evaluate differences across
time, with specific post hoc analyses performed using Least Significant           Figure 2 Change in weight (A) and percent body fat (B) at base-
Difference tests. Data are presented as means + SE. Alpha values were           line (open bars) and during OC treatment (hatched bars) in obese
considered significant if P ≤ 0.05. Statistical analyses were performed          and normal BMI groups. *Designates P , 0.05.
with SPSS software, version 16.0 (SPSS, Chicago, IL, USA).
4                                                                                                                                                                                Edelman et al.




    Figure 3 Twenty-four hours metabolic rate during baseline (open bars), OC use (closed bars), and in the post-OC use (hatched bars) in the obese
    (A) and normal (B) BMI group. *Designates P , 0.05.




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     Table I Metabolic biomarkers (mean and standard deviation).

                Baseline            Glucose             Post-OC            Baseline             Insulin (mU/            Post-OC             Baseline         Leptin (ng/         Post-OC
                                    (mg/dL),                                                    ml), OC use                                                  ml), OC
                                    OC use                                                                                                                   use
    .............................................................................................................................................................................................
     All      69.7 (SD 13.8) 66.8 (SD 19)               67.6 (SD 19.1)         39 (SD 25.5) 101.5a,c (SD 58.4)            37 (SD 22.4)       2.9 (SD 2.1)       2.5 (SD 1.5)      2.3 (SD 1.6)
     subjects
     Normal 73.1 (SD 13.5) 74.6 (SD 16.3)                 67 (SD 5.1)      23.9b (SD 18)          74.2a,c (SD 27.4) 24.4 (SD 12.5) 1.1b (SD 0.5)               1.3b (SD 0.3)      1.4 (SD 1.2)
                                        a                                        b                                                             b                 b,c
     Obese      66.3 (SD 14.8)       59 (SD 19.7) 68.2 (SD 28.2) 54.1 (SD 24)                      128.8 (SD 71.2) 49.6 (SD 23.9) 4.7 (SD 1.1) 3.7                     (SD 1.2) 3.1a (SD 1.5)
     a
       P ≤ 0.05 for a within group comparison with baseline values.
     b
       P ≤ 0.05 for between group comparisons.
     c
      P ≤ 0.05 for a within group comparison with post values.



(P ¼ 0.28). There was no change across the study in lean body mass                                    day; P ¼ 0.33) or normal weight animals (281 806 + 100 524 activity
for the entire group or for either BMI group.                                                         counts/day; P ¼ 0.07). Post-treatment, there continued to be no sig-
                                                                                                      nificant changes in activity levels in either of the groups.
Food intake
There was no change in food intake across the study for the entire                                    Serum hormones
group or for either BMI group.                                                                        At baseline, no statistical differences in fasting glucose concentrations
                                                                                                      were found between groups but serum insulin and leptin levels were
Metabolic rate                                                                                        significantly higher in the obese versus the normal BMI animals
In both the obese (pre-OC 0.85 + 0.06 Kcal/h/kg, OC use 1.0 +                                         (Table I). The obese group had a significant decrease in glucose
0.107 Kcal/h/kg, P ¼ 0.03) and the normal BMI (pre-OC 0.83 +                                          levels with OC use whereas the normal BMI group had no change.
0.07 Kcal/h/kg, OC use 1.27 + 0.06 Kcal/h/kg, P ¼ 0.01) groups,                                       Insulin increased with OC use in both groups but only reached statisti-
there was a significant increase in metabolic rate at night (basal meta-                               cal significance for the entire group and the normal BMI group. Leptin
bolic rate) with OC use, that returned to baseline in the post-                                       levels were similar at all time points in the normal weight group but
treatment period (Fig. 3A and B). There were no significant changes                                    declined with OC use in the obese BMI group and this trend contin-
in metabolic rate during the day for either group (Fig. 3A and B).                                    ued post-OC use as well. Testosterone levels were not different
                                                                                                      between or within groups at any time point.
Physical activity
At baseline, mean physical activity levels for the entire group were
295 601 + 141 166 activity counts/day. Although obese animals
                                                                                                      Discussion
demonstrated lower activity levels (154 244 + 47 954 activity                                         The use of OCs in rhesus monkeys caused a decrease in body weight
counts/day) at baseline than normal BMI animals (436 957 +                                            and percent body fat, resulting from an increase in basal metabolic
180 750 activity counts/day), the difference was not statistically signifi-                            rate, without an impact on percent lean body mass, food intake or
cant (P ¼ 0.11). With OC use, there were no significant changes in                                     activity levels. Both obese and normal weight monkeys showed
activity for the obese monkeys (133 248 + 45 872 activity counts/                                     increases in basal metabolic rate during OC use; however,
Combined oral contraceptives and body weight in primates                                                                                             5


accompanying significant decreases in body weight and percent body             either the normal weight or obese monkeys. Testosterone levels did
fat were found only in the obese group. The decrease in body                  not appear to play a role in the weight and metabolic changes
weight in the obese group was significant (28.58%) and was                     observed in the monkeys on OCs as no changes in testosterone
accompanied by a decrease in percent body fat and fasting glucose             levels were found throughout the study in either group. We ques-
levels, and a trend toward a decrease in plasma leptin concentrations         tioned whether the loss of body fat, but not muscle mass, may have
that became significant in the post-treatment period. With OC cessa-           stemmed from androgenic capacity of the OC we chose; however,
tion, the changes in metabolic rate and body weight resolved and              we did not find evidence for this conclusion.
returned to baseline levels.                                                     It is possible that the reason we found a greater decrease in percent
   Human studies have not conclusively determined if OCs have a sig-          body fat in the obese group was that they had more fat stores available
nificant impact on body weight in reproductive aged women, but few             for fuel mobilization. It is also possible that weight loss was slower to
studies have included obese subjects (Gallo et al., 2004). However,           occur in the normal weight group, but would have occurred eventually
there are a number of human studies with similar findings to our               if OC treatment had been extended beyond 8 months. There are a
study demonstrating mild to moderate weight loss with OC use                  number of physiological systems that regulate body weight so body
(Rosenberg, 1998; Risser et al., 1999; Coney et al., 2001), or at             weight loss can be slow because when one system is altered other
least no weight gain (Berenson and Rahman, 2009; Uras et al.,                 systems change activity to counteract weight loss (Sullivan and
2009). The use of steroid hormones during menopause has also                  Cameron, 2010). Alternatively, obese animals may have a different
been reported to cause mild weight loss (Ongphiphadhanakul et al.,            endocrine response to OCs compared with normal weight animals,




                                                                                                                                                          Downloaded from humrep.oxfordjournals.org by guest on January 21, 2011
1998; Chmouliovsky et al., 1999), a decrease in weight gain (Espeland         leading to differences in weight loss. We did find differences in
et al., 1997; Gambacciani et al., 2001) or no effects on body weight          serum insulin and leptin between the obese and normal BMI
(Reubinoff et al., 1995; Salback et al., 2000; Sumino et al., 2003).          animals, as well as significant changes in these hormones with OC
Since detailed, controlled long-term metabolic studies are difficult to        treatment in the obese group. However, the changes in body
complete in women, the non-human primate offers the closest                   weight may have led to these hormonal differences rather than the
model to study this elusive outcome as certain factors such as                reverse.
caloric intake and energy expenditure can be more closely monitored.             Theoretically, our use of continuous OC dosing (no hormone-free
Non-human primates are particularly good for these complex integra-           interval) may have affected our results. The use of continuous OCs is
tive studies as the regulation of reproductive function, food intake and      becoming a common practice in humans to suppress menstruation for
body weight is very similar to the regulation of these processes in           both medical and social reasons (Edelman et al., 2009). In humans,
humans (Hotchkiss and Knobil, 1994; Grove et al., 2005).                      continuous OCs have been found to maintain hypothalamic –
   Our findings in ovary-intact monkeys treated with OCs conclusively          pituitary –ovarian axis suppression better than cyclic OCs (Birtch
show weight loss in obese individuals. Previous studies in ovari-             et al., 2006) and thus also decrease menstrual-associated symptoms
ectomized monkeys have also shown that estradiol treatment leads              (Edelman et al., 2009) but otherwise are seen to be fairly similar to
to decreased food intake and body weight (Czaja and Goy, 1975;                cyclic dosing. We chose to use continuous dosing to better maintain
Kemnitz et al., 1986). It is likely that the estrogen content of the          drug exposure in animals during the study. It is possible that our use of
OC is responsible for the slight increase in basal metabolic rate and         continuous OCs may have enhanced the effect of OCs to cause
loss of body weight in obese monkeys occurring with OC use. Estro-            weight and percent body fat loss in obese females.
gen is a known modulator of energy homeostasis and in rodents, plays             Along with a significant decrease in body weight and percent body
a similar role to leptin by increasing activity and basal metabolic rate      fat, the obese monkeys showed an improvement in metabolic regu-
and decreasing appetite, body weight and adipose tissue (Gao and              lation with a trend toward a decrease in circulating leptin with OC
Horvath, 2008; Roepke, 2009). These effects result in weight loss in          use, paralleling the decrease in percent body fat that occurred in
animals when calories are not increased to compensate. Our study              these animals during this time. This is not surprising as leptin plays a
design limited our ability to fully determine if OCs would increase           key role in communicating the size of body fat stores to central
appetite, as we set the maximum food intake available at an amount            nervous system pathways regulating body weight (Porte et al.,
that provided weight stability at baseline. Not allowing ad libitum           2002). Similarly, as the normal weight monkeys had no significant
food access may provide less of a ‘real world’ human experience,              change in weight, circulating leptin levels were stable over the
but this design allowed for the examination of OC effects on metab-           course of the study. The changes in fasting glucose and insulin with
olism and subsequent weight changes due to changes in metabolic               OC treatment appear consistent with steroid hormone exposure
rate. It is possible that an increase in appetite could offset the increase   and, in the obese group, weight loss, but overall do not appear clini-
in metabolic rate and result in weight gain in some women with a sus-         cally relevant (Ropero et al., 2008; Lopez et al., 2009).
ceptible phenotype. However, the randomized trials that have been                Our results demonstrate that combined OCs increase basal meta-
performed represent a natural exposure with unrestricted calories,            bolic rate and result in weight loss due to a reduction of body fat but
and do not clearly demonstrate a differential effect of OC exposure           not lean body mass in obese female macaques maintained on a stable
as a risk factor for weight gain (Gallo et al., 2004). Progestins provided    diet. None of the animals on OCs showed weight gain. This argues
as injectable contraceptives have been reported to lead to an increase        against OC discontinuation for weight loss purposes, as discontinu-
in body weight (Clark et al., 2005; Bonny et al., 2006), but progestins       ation places a woman at risk for an unplanned pregnancy, a known
delivered in OCs do not appear to lead to an overall increase in weight       cause for significant and rapid weight gain! Further studies need to
in clinical trials in women (Davidsen et al., 2007) and we found no evi-      be performed to demonstrate whether an ad libitum diet affects
dence in this study of weight gain with combined OC administration to         these findings in obese and normal weight individuals, and to
6                                                                                                                                          Edelman et al.


determine whether progestin-only contraceptives affect weight and            Gallo M, Grimes DA, Schulz K, Helmerhorst F. Combination
metabolism differently.                                                         estrogen-progestin contraceptives and body weight: systematic review
                                                                                of randomized controlled trials. Obstet Gynecol 2004;103:359– 373.
                                                                             Gambacciani M, Ciaponi M, Cappagli B, Genazzani AR. Effects of low-dose
                                                                                continuous combined conjugated estrogens and medroxyprogesterone
Authors’ roles                                                                  acetate on menopausal symptoms, body weight, bone density, and
                                                                                metabolism in postmenopausal women. AJOG 2001;185:1180 – 1185.
Drs A.E., J.T.J. and J.C. significantly contributed to the study design,
                                                                             Gao Q, Horvath TL. Cross-talk between estrogen and leptin signaling in
execution, analysis, manuscript drafting and discussion. Ms M.B.
                                                                                the hypothalamus. Am J Physiol Endocrinol Metab 2008;294:E817 – E826.
played a key role in study execution, database maintenance, analysis
                                                                             Grove KL, Grayson BE, Glavas MM, Xiao XQ, Smith MS. Development of
and manuscript drafting.                                                        metabolic systems. Physiol Behav 2005;86:646 – 660.
                                                                             Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM.
                                                                                Overweight and obesity among US children, adolescents, and adults,
Funding                                                                         1999 – 2002. J Am Med Assoc 2004;291:2847 – 2850.
                                                                             Henshaw SK. Unintended pregnancy in the United States. Fam Plann
This study was funded by Society of Family Planning.                            Perspect 1998;30:24 – 29,46.
                                                                             Hotchkiss J, Knobil E. The menstrual cycle and its neuroendocrine control.
                                                                                In: Knobil E, Neill JD (eds). The Physiology of Reproduction, Vol. 2, 2nd
                                                                                edn. New York: Raven Press, Ltd., 1994,711– 749.
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