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Evidence that in healthy young women, a six-cycle treatment with oral contraceptive containing 30 mcg of ethinylestradiol plus 2 mg of chlormadinone acetate reduces fat mass
Contraception 79 (2009) 117 – 121
Original research article
Evidence that in healthy young women, a six-cycle treatment with oral contraceptive containing 30 mcg of ethinylestradiol plus 2 mg of chlormadinone acetate reduces fat mass Roberto Uras, Marisa Orrù, Rossella Etzi, Giangavino Peppi, Maria Francesca Marotto, Monica Pilloni, Pierina Zedda, Stefano Lello, Gian Benedetto Melis⁎, Anna Maria Paoletti Department of Obstetrics and Gynaecology, University of Cagliari, 09124 Cagliari, Italy Received 18 April 2008; revised 26 August 2008; accepted 26 August 2008
Abstract Background: We aimed to evaluate whether a six-cycle treatment with oral contraceptive containing 30 mcg of ethinylestradiol (EE2) plus 2 mg of chlormadinone acetate (CMA) (EE2+CMA) alters body weight (BW) and body composition of healthy young women with normal menstrual cycles. The results in treated subjects were compared to those obtained in nontreated women as control. Study Design: Multifrequency bioelectrical impedance analysis (MF-BIA) was performed in 48 healthy young women during the follicular phase of their menstrual cycle. Of this group, 24 women were treated with EE2+CMA, and the MF-BIA was repeated at the third and sixth cycle of treatment. The remaining 24 women were submitted to the same examinations after three and six cycles without any treatment. Total body water (TBW), intracellular water (ICW), extracellular water (ECW), fat mass (FM) and fat-free mass (FFM) were calculated. Waist-tohip ratio (WHR), BW, blood pressure, and the plasma concentrations of electrolytes were also measured at each visit. Results: Mean FM significantly (pb.05) decreased in the EE2+CMA group from basal levels of 14.23±1.03 to 13.51±1.09 and 12.71±1.02 kg at the third and sixth cycle of treatment, respectively. Stable values were seen in the control group. During observation, other parameters (BW, WHR, TBW, ECW, ICW, FFM) remained unchanged in all subjects. Conclusions: EE2+CMA reduces FM without altering TBW, ICW, ECW. These preliminary results suggest that progestational activity of CMA could balance both fluid retention and weight gain elicited by EE2. © 2009 Elsevier Inc. All rights reserved. Keywords: Chlormadinone acetate; Oral contraceptives; Body composition; Multifrequency bioelectrical impedance; Fat mass
1. Introduction Estrogen and progesterone differently modulate body composition. Estrogens activate the Renin-angiotensinaldosterone-system (RAAS) [1–3], regulating intravascular fluid and electrolyte balance and inducing sodium retention. Estrogens also favour weight gain [4]. Progesterone counteracts estrogen-mediated sodium retention [3] and interferes with fat composition because of its stimulation of resting metabolic rate (RMR) [5], which represents about 75% of ⁎ Corresponding author. Clinica Ginecologica Ostetrica e di Fisiopatologia della Riproduzione Umana del Dipartimento Chirurgico Materno-Infantile e di Scienze delle Immagini, Università degli Studi di Cagliari, Via Ospedale 46, 09124 Cagliari, Italy. Tel.: +39 070 652797; fax: +39 070 668575. E-mail address: [email protected] (G.B. Melis). 0010-7824/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2008.08.007
daily energy expenditure [6]. Low RMR is predictive of weight gain and is associated with low lean body mass [7,8]. Ethinylestradiol (EE2), the estrogen compound of combined oral contraceptives (OC), generally exerts higher biological activities than natural estrogens. In particular, EE2 exerts a stronger stimulatory effect on RAAS than natural estrogens [2]. The availability of a progestational molecule that selectively binds progesterone receptors without acting upon other steroid receptors could be advantageous to balance the activity of EE2 on both fluid retention and weight gain. Weight gain is a side effect frequently reported by OC users [9], even though no studies have shown that body weight (BW) and body mass index (BMI) increase during OC intake [10,11]. However, the evaluation of BW and BMI alone is not sufficient to examine
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body fluid compartments. Multifrequency bioelectrical impedance analysis (MF-BIA) at five selected frequencies was shown to permit an accurate measurement of all compartments [12–14]. Chlormadinone acetate (CMA) is a progesterone derivative molecule with a chlorine atom at C6. Similar to natural progesterone, CMA exerts a slight glucocorticoid activity and a potent antiandrogenic effect [15–17] but does not exert estrogenic or androgenic activity [15–17]. In association with 30 mcg of EE2, these properties of CMA could be advantageous to balance the effects of EE2 on fluid retention and body fat composition. Our study was designed with the primary outcome to investigate the effects on BW and body composition measured by MF-BIA in a group of healthy young women treated for six cycles with the monophasic OC formulation containing 30 mcg EE2 plus 2 mg CMA (EE2+CMA). The results obtained in the treated group were compared with a similar group of women not taking OC followed up through six menstrual cycles.
2. Materials and methods The subjects included in the study were 48 healthy women (mean age, 25.0±0.8 years; range, 18–38 years) with normal BMI (greater than 21 but less than 24) and regular menstrual cycles (menstrual cycle length: 28.0±2.0 days). They were recruited from women requesting contraceptive advice at the outpatient Family Planning Clinic of the Department of Obstetrics and Gynecology, University of Cagliari, Italy, and gave their consent to participate in the study as volunteers. A group of 24 subjects with a mean age of 24.8±1.0 years asked for OC (OC group). The remaining 24 women (mean age: 25.2±0.7 yrs) asked for contraception with natural methods and participated in the study as the control group (control group). No significant differences in mean age (24.8±1 vs. 25.2±0.7 years), menstrual cycle length (27.8±2 vs. 28.1±2 days), basal BMI and body composition were found between the groups (see Table 1). The study was approved by the local ethical committee and by the institutional review board of the department participating in the study. The 48 women selected for the study were instructed on protocol and informed consent was obtained. None of the subjects had contraindications to use of OC. They had no history of eating disorders; they were not dieting or intending to start any kind of diet and they were not using psychoactive or antidepressant drugs or other drugs that might interfere with BW and body composition. Moreover, they were free of metabolic or endocrine disorders that may affect BW or composition. Subjects who had used estroprogestin formulations or other steroid therapy in the 3 months before the enrollment interview and women who smoked cigarettes were excluded. Women were instructed not to change their diet or physical activity habits during the
Table 1 Mean±standard error (SE) of BW, BMI, WHR, the parameters of body composition evaluated by MF-BIA (TBW, ECW, ICW, FFM, FM) and diastolic and systolic BP evaluated at first visit in control group women (24 subjects who did not receive oral contraceptives during the following six menstrual cycles of the study) and in EE2+CMA group (24 subjects who received the oral contraceptive EE2+CMA during the following six cycles) Parameter
Control group
EE2+CMA group
Body weight (kg) BMI [weight (kg)/height (m2)] WHR TBW (L) ICW (L) ECW (L) FFM (kg) FM (kg) Diastolic BP (mmHg) Systolic BP (mmHg)
57.5±1.5 21.7±0.6 0.73±0.02 30.8±1.0 17.7±0.8 13.1±0.5 43.0±0.7 14.5±1.1 115.0±7.0 70.0±5.0
55.4±1.5 21.4±0.5 0.74±0.01 30.3±0.8 18.1±0.7 12.3±0.5 41.4±0.7 14.0±1.0 118.0±8.0 72.0±6.0
study period. No subject suffered from premenstrual syndrome or premenstrual dysphoric disorder. All subjects underwent an interview, with questionnaires that aimed to evaluate baseline physical activity and diet. Those subjects who fulfilled the criteria were asked to return for one baseline visit performed on a day of the follicular phase of the menstrual cycle (5–7 days from the onset of spontaneous menstrual bleeding) (first visit). Thereafter, the women requesting OC were treated with EE2+CMA (Belara; Grunenthal-Formenti, Milan, Italy). The women were instructed to take one tablet per day for 21 days, followed by a seven-day pill-free interval for six cycles. Subjects included in the study returned for follow-up visits at the third (second visit) and the sixth (third visit) cycle of treatment. The follow-up visits for EE2+CMA-treated subjects occurred during the 15th to 18th day of pill use. Control group women were asked to return for follow-up visits at the third (second visit) and sixth (third visit) menstrual cycle subsequent to the first visit. In all control subjects, the follow-up visits were scheduled on a day of the follicular phase of the menstrual cycle, as previously described. These periods were chosen on the basis of previous studies to reduce bias due to hormone patterns [18,19]. All visits were scheduled in the morning between 8 and 10 a.m. At each visit, BMI, waist-to-hip ratio (WHR) and body composition were measured in all subjects. Blood pressure (BP) and plasma sodium and potassium concentrations were also evaluated at each visit. Moreover, an interview was carried out to ascertain any changes in physical activity, smoking habits and diet. After an overnight fast, the women came to the laboratory for anthropometric measurements. The participants were wearing light indoor clothing without shoes when anthropometric measurements were taken. The same investigator took all measurements prior to and during the study. Measurements included height and BW, which were determined using a stadiometer and a calibrated scale, respectively. Waist circumference was measured at minimum circumference between the rib cage and iliac crest (cm), and
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hip circumference was measured at the level of the largest circumference around the buttocks. Subjects were measured in the upright position. The circumference measurements were taken on a horizontal plane using a 15-mm-width flexible metric tape held close to the body but not tight enough to indent the skin. Body composition includes fat mass (FM), fat-free mass (FFM), total body water (TBW), intracellular water (ICW) and extracellular water (ECW), which were measured by MF-BIA analysis at 5 selected frequencies (Dyetosystem, Milan, Italy). The five frequencies allow an accurate measurement of all compartments [12–14]. MF-BIA was determined for each patient after the anthropometric measurements on the same day, during morning hours (08-10 a.m.). 2.1. Multifrequency bioelectrical impedance Determination of total body impedance (Z) was made with tetrapolar MF-BIA [12–14]. All measurements were adjusted for stature as impedance index (height/Z2). Each woman was supine on a table made of nonconductive materials. Aluminum foil spot electrodes were placed in the middle of the dorsal surface of the hands and feet in proximity to the metacarpal–phalangeal and metatarsal– phalangeal joints, respectively. They were also placed medially between the distal prominences of the radius and the ulna and between the medial and lateral malleoli at the ankle. In particular, the proximal edge of one detector electrode was in line with the proximal edge of the ulna tubercule at the wrist. In the same way, the proximal edge of the other detecting electrode was in line with the medial malleolus of the ankle. The current-introducing electrodes were placed at minimum distance of the diameter of the wrist or ankle beyond the paired detector electrode. The bioelectrical impedance analysis (BIA) index was measured at five specific frequencies (1, 5, 10, 50 and 100 KHz). The sensitivity and reliability of the technique were good and they were evaluated by previous studies [12–14,18,19].
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2.2. Statistical analysis Statistical analysis of the results was performed using the Student's t test for paired or unpaired data. Two-factor analysis of variance (ANOVA) for repeated measures followed by Scheffe's post hoc test was also used to analyze the data. Differences were considered significant if p was less than .05. The normal distribution of the results was calculated by the frequency distribution. We assumed that a clinically important treatment difference in FM would be 10%. For that effect, a sample size of 24 subjects in each group yields an alpha of .05 and a beta of .76 [20]. 3. Results All results, expressed as mean±standard error, were normally distributed and are reported in Table 1, Table 2 and Fig. 1. At the first visit, BW, BMI, WHR and all parameters evaluated by MF-BIA (TBW, ICW, ECW, FM, FFM) did not differ between control group and EE2+CMA group subjects (Table 1). Similarly, mean diastolic (72.0±6.0 vs. 70.0±5.0 mmHg) and systolic (118.0±8.0 vs. 115.0±7.0 mmHg) BP did not differ between the groups (Table 1). All values were in the normal range for subjects. During the study period, none of the enrolled women smoked, changed their physical activity habits or started any kind of diet. No side effects were reported during the study by the two groups of subjects. Mean diastolic and systolic BP and electrolyte levels did not change during the study for any subject enrolled. Mean values of BW, BMI and WHR did not vary during the period of the study in control group or in the EE2+CMA group subjects (Table 2). With regard to the parameters evaluated by MF-BIA, during the study period, no changes of mean TBW, ECW,
Table 2 Mean±S.E. of body weight, BMI, WHR, the parameters of body composition evaluated by MF-BIA (TBW, ECW, ICW, FFM) evaluated at first, second and third visit of the six-cycle period of the study in control group (24 subjects who did not receive oral contraceptives) and in EE2+CMA group (24 subjects who received the oral contraceptive EE2+CMA) Parameter
Study group
1st visit
2nd visit
3rd visit
Body weight (kg)
Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group
57.5±1.4 55.6±1.6 21.7±0.6 21.5±0.6 0.73±0.02 0.74±0.01 43.0±0.6 41.4±0.7 30.8±1.0 30.4±0.8 13.0±0.5 12.2±0.5 17.7±0.8 18.1±0.7
58.0±1.2 55.2±1.5 21.9±0.5 21.3±0.6 0.73±0.02 0.73±0.01 43.1±0.5 41.7±0.6 31.1±1.0 30.2±0.6 13.5±0.5 12.0±0.6 17.7±0.8 18.1±0.6
58.1±1.2 55.0±1.6 22.0±0.5 21.2±0.6 0.73±0.02 0.72±0.01 43.1±0.5 42.3±0.7 31.0±1.0 31.3±1.0 13.8±0.5 12.7±0.5 17.7±0.8 18.6±0.7
BMI [weight (kg)/height (m2)] WHR FFM (kg) TBW (L) ECW (L) ICW (L)
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Fig. 1. Mean±standard error of fat mass (FM) values measured by MF-BIA in normally cycling young women before (1st visit) and at third (2nd visit) and sixty cycle (3rd visit) of a six-cycle period of the study in which 24 of the subjects (black bars) assumed the oral contraceptive formulation containing 30 mcg of ethinylestradiol plus 2 mg of chlormadinone acetate (EE2+CMA group) and 24 subjects did not assume any treatment (control group, white bars). The values of FM were significantly reduced (pb.05) in EE2+CMA group at second and third visit vs. corresponding values at the first visit, with a significant difference vs. corresponding control group by ANOVA (pb.05).
ICW and FFM occurred in the two groups of women (Table 2). During EE2+CMA treatment, the mean values of FM were 13.5±1.0 at the second visit and 12.7±1.0 kg at the third visit, respectively (Fig. 1). These values were significantly lower (pb.05) than the basal values (first visit; 14.2±1.0 kg) (Fig. 1). In the control group, the mean values of FM were 14.5±1.1 kg at the first visit, 14.8±1.1 kg at the second visit and 15.0±1.1 kg at the third visit (Fig. 1), without significant differences. In the control group, the mean values of FM at the second (14.8±1.1 kg ) and third visit (15.0±1.1 kg ) were significantly different (pb.05) to the corresponding values in EE2+CMA-treated subjects (13.5±1.0 at the second visit and 12.7±1.0 kg at the third visit, respectively) (Fig. 1). The percentage change of FM calculated at the second and third visit vs. basal values was significantly different in the two groups (Fig. 2).
FM and FFM. Many studies have demonstrated the validity of this method to estimate body composition in women [12–14]. However, this is the first study to describe the action of an OC containing CMA on body composition. Nevertheless, using the same MF-BIA method, previous studies of ours [18,19] and those of other groups [21–23] did not show a similar effect on FM by contraceptive treatments containing different progestin compounds (levonorgestrel, gestodene, drospirenone) and different doses (20 and 30 mcg) of EE2 [19,22,23]. Total body fluid, ICW and ECW are not affected by EE2+CMA treatment. It is known that increased values of TBW and ECW are due to an enhanced stimulation of RAAS [12– 14], but this did not occur in EE2+CMA treated women in spite of the daily doses of 30 mcg EE2. Despite the lack of antimineralcorticoid activity, the strong progesteronelike property of CMA seems to be sufficient to balance RAAS stimulation by EE2. The selective action of CMA on progesterone receptors also seems to be the mechanism through which EE2 +CMA treatment is capable of reducing FM. Cagnacci et al. [5] demonstrated that, in perimenopausal women, a decrease in FM occurs at the 12th cycle of a treatment with only nomegestrol acetate, a pure progestational molecule. Similarly, our study shows that CMA is capable of counteracting the weight gain caused by EE2, with a selective decrease in fat mass. It is known that increased fat mass can cause cardiovascular disease, diabetes and also breast cancer [24,25]. Therefore, the availability of this OC with CMA offers many advantages in oral contraception. In addition, this property of EE2+CMA could be useful in promoting its use in women for whom OC intake is inadvisable merely because they are overweight or are afraid of gaining weight. In conclusion, in women with normal body composition requiring contraception, these preliminary data show that OC containing CMA, in spite of the presence of 30 mcg of EE2, has a positive influence on body composition with a neutral effect on TBW, ECW and ICW and a decrease in fat mass.
4. Discussion The findings of the study seem to show that, in a selected population of healthy young women with normal body composition, a six-cycle treatment with the OC containing EE2+CMA is associated with a decrease in FM. The nonrandomized selection and the timing of assessment of effect could result in some bias. However, these results seem to depend on the EE2+CMA treatment, since unchanged values of mean FM were found in the control group women with no treatment. MF-BIA permits the determination of body composition: TBW, ICW, ECW,
Fig. 2. Mean±standard error of percent change of FM observed in control group (white bars) and in EE2+CMA group (black bars) at the 2nd visit and at the 3rd visit. *pb.05 vs. corresponding control group by ANOVA.
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Acknowledgment The authors thank Franca Fadda for typing the manuscript and Kate Jenkins for revising the manuscript. This research was partially supported by Benessere Donna Onlus Foundation (Cagliari, Italy). References [1] Walters WAW, Lim YL. Haemodynamic changes in women taking oral contraceptives. J Obstet Gynaecol Br Commonw 1970;77: 1088–99. [2] Crane MG, Harris JJ. Effect of oestrogens and gestagens on exchangeable sodium. In: Fregly MJ, Fregly MS, editors. Oral contraceptives and high blood pressure. Gainesville (FL): Dolphin Press; 1974. p. 159–69. [3] Oelkers WK. Effects of estrogens and progestogens on the reninaldosterone system and blood pressure. Steroids 1996;61:166–71. [4] Cagnacci A, Zanin R, Cannoletta M, Generali M, Caretto S, Volpe A. Menopause, estrogens, progestins, or their combination on body weight and anthropometric measures. Fertil Steril 2007; 88:1603–8. [5] Cagnacci A, De Toni A, Caretto S, et al. Cyclic progestin administration increases energy expenditure and decreases body fat mass in perimenopausal women. Menopause 2006;13:197–201. [6] Poehlman ET. Menopause, energy expenditure, and body composition. Acta Obstet Gynecol Scand 2002;81:603–11. [7] Arciero PJ, Goran MI, Poehlman ET. Resting metabolic rate is lower in women than in men. J Appl Physiol 1993;75:2514–20. [8] Buchholz AC, Rafii M, Pencharz PB. Is resting metabolic rate different between men and women? Br J Nutr 2001;86:641–6. [9] Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons. Am J Obstet Gynecol 1998;179:577–82. [10] Rosenberg M. Weight change with oral contraceptive use and during the menstrual cycle. Contraception 1998;58:345–9. [11] Gallo MF, Grimes DA, Schulz KF, Helmerhorst FM. Combination estrogen-progestin contraceptives and body weight: systematic review of randomized controlled trials. Obstet Gynecol 2004;103: 359–73.
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Original research article
Evidence that in healthy young women, a six-cycle treatment with oral contraceptive containing 30 mcg of ethinylestradiol plus 2 mg of chlormadinone acetate reduces fat mass Roberto Uras, Marisa Orrù, Rossella Etzi, Giangavino Peppi, Maria Francesca Marotto, Monica Pilloni, Pierina Zedda, Stefano Lello, Gian Benedetto Melis⁎, Anna Maria Paoletti Department of Obstetrics and Gynaecology, University of Cagliari, 09124 Cagliari, Italy Received 18 April 2008; revised 26 August 2008; accepted 26 August 2008
Abstract Background: We aimed to evaluate whether a six-cycle treatment with oral contraceptive containing 30 mcg of ethinylestradiol (EE2) plus 2 mg of chlormadinone acetate (CMA) (EE2+CMA) alters body weight (BW) and body composition of healthy young women with normal menstrual cycles. The results in treated subjects were compared to those obtained in nontreated women as control. Study Design: Multifrequency bioelectrical impedance analysis (MF-BIA) was performed in 48 healthy young women during the follicular phase of their menstrual cycle. Of this group, 24 women were treated with EE2+CMA, and the MF-BIA was repeated at the third and sixth cycle of treatment. The remaining 24 women were submitted to the same examinations after three and six cycles without any treatment. Total body water (TBW), intracellular water (ICW), extracellular water (ECW), fat mass (FM) and fat-free mass (FFM) were calculated. Waist-tohip ratio (WHR), BW, blood pressure, and the plasma concentrations of electrolytes were also measured at each visit. Results: Mean FM significantly (pb.05) decreased in the EE2+CMA group from basal levels of 14.23±1.03 to 13.51±1.09 and 12.71±1.02 kg at the third and sixth cycle of treatment, respectively. Stable values were seen in the control group. During observation, other parameters (BW, WHR, TBW, ECW, ICW, FFM) remained unchanged in all subjects. Conclusions: EE2+CMA reduces FM without altering TBW, ICW, ECW. These preliminary results suggest that progestational activity of CMA could balance both fluid retention and weight gain elicited by EE2. © 2009 Elsevier Inc. All rights reserved. Keywords: Chlormadinone acetate; Oral contraceptives; Body composition; Multifrequency bioelectrical impedance; Fat mass
1. Introduction Estrogen and progesterone differently modulate body composition. Estrogens activate the Renin-angiotensinaldosterone-system (RAAS) [1–3], regulating intravascular fluid and electrolyte balance and inducing sodium retention. Estrogens also favour weight gain [4]. Progesterone counteracts estrogen-mediated sodium retention [3] and interferes with fat composition because of its stimulation of resting metabolic rate (RMR) [5], which represents about 75% of ⁎ Corresponding author. Clinica Ginecologica Ostetrica e di Fisiopatologia della Riproduzione Umana del Dipartimento Chirurgico Materno-Infantile e di Scienze delle Immagini, Università degli Studi di Cagliari, Via Ospedale 46, 09124 Cagliari, Italy. Tel.: +39 070 652797; fax: +39 070 668575. E-mail address: [email protected] (G.B. Melis). 0010-7824/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2008.08.007
daily energy expenditure [6]. Low RMR is predictive of weight gain and is associated with low lean body mass [7,8]. Ethinylestradiol (EE2), the estrogen compound of combined oral contraceptives (OC), generally exerts higher biological activities than natural estrogens. In particular, EE2 exerts a stronger stimulatory effect on RAAS than natural estrogens [2]. The availability of a progestational molecule that selectively binds progesterone receptors without acting upon other steroid receptors could be advantageous to balance the activity of EE2 on both fluid retention and weight gain. Weight gain is a side effect frequently reported by OC users [9], even though no studies have shown that body weight (BW) and body mass index (BMI) increase during OC intake [10,11]. However, the evaluation of BW and BMI alone is not sufficient to examine
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body fluid compartments. Multifrequency bioelectrical impedance analysis (MF-BIA) at five selected frequencies was shown to permit an accurate measurement of all compartments [12–14]. Chlormadinone acetate (CMA) is a progesterone derivative molecule with a chlorine atom at C6. Similar to natural progesterone, CMA exerts a slight glucocorticoid activity and a potent antiandrogenic effect [15–17] but does not exert estrogenic or androgenic activity [15–17]. In association with 30 mcg of EE2, these properties of CMA could be advantageous to balance the effects of EE2 on fluid retention and body fat composition. Our study was designed with the primary outcome to investigate the effects on BW and body composition measured by MF-BIA in a group of healthy young women treated for six cycles with the monophasic OC formulation containing 30 mcg EE2 plus 2 mg CMA (EE2+CMA). The results obtained in the treated group were compared with a similar group of women not taking OC followed up through six menstrual cycles.
2. Materials and methods The subjects included in the study were 48 healthy women (mean age, 25.0±0.8 years; range, 18–38 years) with normal BMI (greater than 21 but less than 24) and regular menstrual cycles (menstrual cycle length: 28.0±2.0 days). They were recruited from women requesting contraceptive advice at the outpatient Family Planning Clinic of the Department of Obstetrics and Gynecology, University of Cagliari, Italy, and gave their consent to participate in the study as volunteers. A group of 24 subjects with a mean age of 24.8±1.0 years asked for OC (OC group). The remaining 24 women (mean age: 25.2±0.7 yrs) asked for contraception with natural methods and participated in the study as the control group (control group). No significant differences in mean age (24.8±1 vs. 25.2±0.7 years), menstrual cycle length (27.8±2 vs. 28.1±2 days), basal BMI and body composition were found between the groups (see Table 1). The study was approved by the local ethical committee and by the institutional review board of the department participating in the study. The 48 women selected for the study were instructed on protocol and informed consent was obtained. None of the subjects had contraindications to use of OC. They had no history of eating disorders; they were not dieting or intending to start any kind of diet and they were not using psychoactive or antidepressant drugs or other drugs that might interfere with BW and body composition. Moreover, they were free of metabolic or endocrine disorders that may affect BW or composition. Subjects who had used estroprogestin formulations or other steroid therapy in the 3 months before the enrollment interview and women who smoked cigarettes were excluded. Women were instructed not to change their diet or physical activity habits during the
Table 1 Mean±standard error (SE) of BW, BMI, WHR, the parameters of body composition evaluated by MF-BIA (TBW, ECW, ICW, FFM, FM) and diastolic and systolic BP evaluated at first visit in control group women (24 subjects who did not receive oral contraceptives during the following six menstrual cycles of the study) and in EE2+CMA group (24 subjects who received the oral contraceptive EE2+CMA during the following six cycles) Parameter
Control group
EE2+CMA group
Body weight (kg) BMI [weight (kg)/height (m2)] WHR TBW (L) ICW (L) ECW (L) FFM (kg) FM (kg) Diastolic BP (mmHg) Systolic BP (mmHg)
57.5±1.5 21.7±0.6 0.73±0.02 30.8±1.0 17.7±0.8 13.1±0.5 43.0±0.7 14.5±1.1 115.0±7.0 70.0±5.0
55.4±1.5 21.4±0.5 0.74±0.01 30.3±0.8 18.1±0.7 12.3±0.5 41.4±0.7 14.0±1.0 118.0±8.0 72.0±6.0
study period. No subject suffered from premenstrual syndrome or premenstrual dysphoric disorder. All subjects underwent an interview, with questionnaires that aimed to evaluate baseline physical activity and diet. Those subjects who fulfilled the criteria were asked to return for one baseline visit performed on a day of the follicular phase of the menstrual cycle (5–7 days from the onset of spontaneous menstrual bleeding) (first visit). Thereafter, the women requesting OC were treated with EE2+CMA (Belara; Grunenthal-Formenti, Milan, Italy). The women were instructed to take one tablet per day for 21 days, followed by a seven-day pill-free interval for six cycles. Subjects included in the study returned for follow-up visits at the third (second visit) and the sixth (third visit) cycle of treatment. The follow-up visits for EE2+CMA-treated subjects occurred during the 15th to 18th day of pill use. Control group women were asked to return for follow-up visits at the third (second visit) and sixth (third visit) menstrual cycle subsequent to the first visit. In all control subjects, the follow-up visits were scheduled on a day of the follicular phase of the menstrual cycle, as previously described. These periods were chosen on the basis of previous studies to reduce bias due to hormone patterns [18,19]. All visits were scheduled in the morning between 8 and 10 a.m. At each visit, BMI, waist-to-hip ratio (WHR) and body composition were measured in all subjects. Blood pressure (BP) and plasma sodium and potassium concentrations were also evaluated at each visit. Moreover, an interview was carried out to ascertain any changes in physical activity, smoking habits and diet. After an overnight fast, the women came to the laboratory for anthropometric measurements. The participants were wearing light indoor clothing without shoes when anthropometric measurements were taken. The same investigator took all measurements prior to and during the study. Measurements included height and BW, which were determined using a stadiometer and a calibrated scale, respectively. Waist circumference was measured at minimum circumference between the rib cage and iliac crest (cm), and
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hip circumference was measured at the level of the largest circumference around the buttocks. Subjects were measured in the upright position. The circumference measurements were taken on a horizontal plane using a 15-mm-width flexible metric tape held close to the body but not tight enough to indent the skin. Body composition includes fat mass (FM), fat-free mass (FFM), total body water (TBW), intracellular water (ICW) and extracellular water (ECW), which were measured by MF-BIA analysis at 5 selected frequencies (Dyetosystem, Milan, Italy). The five frequencies allow an accurate measurement of all compartments [12–14]. MF-BIA was determined for each patient after the anthropometric measurements on the same day, during morning hours (08-10 a.m.). 2.1. Multifrequency bioelectrical impedance Determination of total body impedance (Z) was made with tetrapolar MF-BIA [12–14]. All measurements were adjusted for stature as impedance index (height/Z2). Each woman was supine on a table made of nonconductive materials. Aluminum foil spot electrodes were placed in the middle of the dorsal surface of the hands and feet in proximity to the metacarpal–phalangeal and metatarsal– phalangeal joints, respectively. They were also placed medially between the distal prominences of the radius and the ulna and between the medial and lateral malleoli at the ankle. In particular, the proximal edge of one detector electrode was in line with the proximal edge of the ulna tubercule at the wrist. In the same way, the proximal edge of the other detecting electrode was in line with the medial malleolus of the ankle. The current-introducing electrodes were placed at minimum distance of the diameter of the wrist or ankle beyond the paired detector electrode. The bioelectrical impedance analysis (BIA) index was measured at five specific frequencies (1, 5, 10, 50 and 100 KHz). The sensitivity and reliability of the technique were good and they were evaluated by previous studies [12–14,18,19].
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2.2. Statistical analysis Statistical analysis of the results was performed using the Student's t test for paired or unpaired data. Two-factor analysis of variance (ANOVA) for repeated measures followed by Scheffe's post hoc test was also used to analyze the data. Differences were considered significant if p was less than .05. The normal distribution of the results was calculated by the frequency distribution. We assumed that a clinically important treatment difference in FM would be 10%. For that effect, a sample size of 24 subjects in each group yields an alpha of .05 and a beta of .76 [20]. 3. Results All results, expressed as mean±standard error, were normally distributed and are reported in Table 1, Table 2 and Fig. 1. At the first visit, BW, BMI, WHR and all parameters evaluated by MF-BIA (TBW, ICW, ECW, FM, FFM) did not differ between control group and EE2+CMA group subjects (Table 1). Similarly, mean diastolic (72.0±6.0 vs. 70.0±5.0 mmHg) and systolic (118.0±8.0 vs. 115.0±7.0 mmHg) BP did not differ between the groups (Table 1). All values were in the normal range for subjects. During the study period, none of the enrolled women smoked, changed their physical activity habits or started any kind of diet. No side effects were reported during the study by the two groups of subjects. Mean diastolic and systolic BP and electrolyte levels did not change during the study for any subject enrolled. Mean values of BW, BMI and WHR did not vary during the period of the study in control group or in the EE2+CMA group subjects (Table 2). With regard to the parameters evaluated by MF-BIA, during the study period, no changes of mean TBW, ECW,
Table 2 Mean±S.E. of body weight, BMI, WHR, the parameters of body composition evaluated by MF-BIA (TBW, ECW, ICW, FFM) evaluated at first, second and third visit of the six-cycle period of the study in control group (24 subjects who did not receive oral contraceptives) and in EE2+CMA group (24 subjects who received the oral contraceptive EE2+CMA) Parameter
Study group
1st visit
2nd visit
3rd visit
Body weight (kg)
Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group Control group EE2+CMA group
57.5±1.4 55.6±1.6 21.7±0.6 21.5±0.6 0.73±0.02 0.74±0.01 43.0±0.6 41.4±0.7 30.8±1.0 30.4±0.8 13.0±0.5 12.2±0.5 17.7±0.8 18.1±0.7
58.0±1.2 55.2±1.5 21.9±0.5 21.3±0.6 0.73±0.02 0.73±0.01 43.1±0.5 41.7±0.6 31.1±1.0 30.2±0.6 13.5±0.5 12.0±0.6 17.7±0.8 18.1±0.6
58.1±1.2 55.0±1.6 22.0±0.5 21.2±0.6 0.73±0.02 0.72±0.01 43.1±0.5 42.3±0.7 31.0±1.0 31.3±1.0 13.8±0.5 12.7±0.5 17.7±0.8 18.6±0.7
BMI [weight (kg)/height (m2)] WHR FFM (kg) TBW (L) ECW (L) ICW (L)
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Fig. 1. Mean±standard error of fat mass (FM) values measured by MF-BIA in normally cycling young women before (1st visit) and at third (2nd visit) and sixty cycle (3rd visit) of a six-cycle period of the study in which 24 of the subjects (black bars) assumed the oral contraceptive formulation containing 30 mcg of ethinylestradiol plus 2 mg of chlormadinone acetate (EE2+CMA group) and 24 subjects did not assume any treatment (control group, white bars). The values of FM were significantly reduced (pb.05) in EE2+CMA group at second and third visit vs. corresponding values at the first visit, with a significant difference vs. corresponding control group by ANOVA (pb.05).
ICW and FFM occurred in the two groups of women (Table 2). During EE2+CMA treatment, the mean values of FM were 13.5±1.0 at the second visit and 12.7±1.0 kg at the third visit, respectively (Fig. 1). These values were significantly lower (pb.05) than the basal values (first visit; 14.2±1.0 kg) (Fig. 1). In the control group, the mean values of FM were 14.5±1.1 kg at the first visit, 14.8±1.1 kg at the second visit and 15.0±1.1 kg at the third visit (Fig. 1), without significant differences. In the control group, the mean values of FM at the second (14.8±1.1 kg ) and third visit (15.0±1.1 kg ) were significantly different (pb.05) to the corresponding values in EE2+CMA-treated subjects (13.5±1.0 at the second visit and 12.7±1.0 kg at the third visit, respectively) (Fig. 1). The percentage change of FM calculated at the second and third visit vs. basal values was significantly different in the two groups (Fig. 2).
FM and FFM. Many studies have demonstrated the validity of this method to estimate body composition in women [12–14]. However, this is the first study to describe the action of an OC containing CMA on body composition. Nevertheless, using the same MF-BIA method, previous studies of ours [18,19] and those of other groups [21–23] did not show a similar effect on FM by contraceptive treatments containing different progestin compounds (levonorgestrel, gestodene, drospirenone) and different doses (20 and 30 mcg) of EE2 [19,22,23]. Total body fluid, ICW and ECW are not affected by EE2+CMA treatment. It is known that increased values of TBW and ECW are due to an enhanced stimulation of RAAS [12– 14], but this did not occur in EE2+CMA treated women in spite of the daily doses of 30 mcg EE2. Despite the lack of antimineralcorticoid activity, the strong progesteronelike property of CMA seems to be sufficient to balance RAAS stimulation by EE2. The selective action of CMA on progesterone receptors also seems to be the mechanism through which EE2 +CMA treatment is capable of reducing FM. Cagnacci et al. [5] demonstrated that, in perimenopausal women, a decrease in FM occurs at the 12th cycle of a treatment with only nomegestrol acetate, a pure progestational molecule. Similarly, our study shows that CMA is capable of counteracting the weight gain caused by EE2, with a selective decrease in fat mass. It is known that increased fat mass can cause cardiovascular disease, diabetes and also breast cancer [24,25]. Therefore, the availability of this OC with CMA offers many advantages in oral contraception. In addition, this property of EE2+CMA could be useful in promoting its use in women for whom OC intake is inadvisable merely because they are overweight or are afraid of gaining weight. In conclusion, in women with normal body composition requiring contraception, these preliminary data show that OC containing CMA, in spite of the presence of 30 mcg of EE2, has a positive influence on body composition with a neutral effect on TBW, ECW and ICW and a decrease in fat mass.
4. Discussion The findings of the study seem to show that, in a selected population of healthy young women with normal body composition, a six-cycle treatment with the OC containing EE2+CMA is associated with a decrease in FM. The nonrandomized selection and the timing of assessment of effect could result in some bias. However, these results seem to depend on the EE2+CMA treatment, since unchanged values of mean FM were found in the control group women with no treatment. MF-BIA permits the determination of body composition: TBW, ICW, ECW,
Fig. 2. Mean±standard error of percent change of FM observed in control group (white bars) and in EE2+CMA group (black bars) at the 2nd visit and at the 3rd visit. *pb.05 vs. corresponding control group by ANOVA.
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