Pharmacokinetics of a combined oral contraceptive in obese and normal-weight women

Background

This study was conducted to compare oral contraceptive (OC) pharmacokinetics (PK) in normal-weight [body mass index (BMI) 19.0–24.9] and obese (BMI 30.0–39.9) women.

Study Design

During the third week of the third cycle of OC use, we admitted 15 normal-weight and 15 obese women for collection of 12 venous specimens over 24 h. Using radioimmunoassay techniques, we measured levels of ethinyl estradiol (EE) and levonorgestrel (LNG). During the same cycle, women underwent twice-weekly sonography to assess ovarian follicular development and blood draws to measure endogenous estradiol (E2) and progesterone levels.

Results

Obese women had a lower area under the curve (AUC; 1077.2 vs. 1413.7 pg?h/mL) and lower maximum values (85.7 vs. 129.5 pg/mL) for EE than normal-weight women (p=.04 and <0.01, respectively); EE trough levels were similar between BMI groups. The similar, but smaller, differences in their LNG levels for AUC and maximum values (C_max) were not statistically significant. While peak values differed somewhat, the LNG trough levels were similar for obese and normal-weight women (2.6 and 2.5 ng/mL, respectively). Women with greater EE AUC had smaller follicular diameters (p=.05) and lower E2 levels (p=.04). While follicular diameters tended to be larger among obese women, these differences were not statistically significant.

Conclusion

OC hormone peak levels are lower among obese women compared to normal-weight women, but their trough levels are similar. In this small study, the observed PK differences did not translate into more ovarian follicular activity among obese OC users.     

Effects of a low-dose and ultra-low-dose combined oral contraceptive use on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study

In this prospective, controlled, randomized study, we compared the effect of a low-dose 21-day combined oral contraceptive (COC) containing 20 microg ethinyl estradiol (EE) and 75 microg gestodene (GTD) (Group A; n = 19) with an ultra-low-dose 24-day COC containing 15 microg EE and 60 microg GTD (Group B; n = 18) on bone turnover and bone mineral density (BMD) in young, fertile women. Nineteen healthy fertile women were used as untreated controls (Group C). At 3, 6, 9 and 12 months of the study serum osteocalcin (BGP), urinary pyridinoline (PYD) and deoxypyridinoline (D-PYD) were measured in all subjects. At baseline and after 12 months BMD was determined at lumbar spine by dual-energy X-ray absorptiometry in all patients. In both Groups A and B, urinary levels of PYD and D-PYD at 6, 9 and 12 months, were significantly reduced in comparison with basal values and with control subjects (p < 0.05). No significant differences in urinary PYD and D-PYD levels were observed between Groups A and B during the entire period of treatment. At 12 months, no statistically significant difference in spinal BMD values was detected between the three groups and in comparison with basal values. The present study suggests that the two COCs could exert a similar positive effect on bone turnover in young postadolescent women, without any significant and appreciable modification of BMD.     

Bone mineral density at various anatomic bone sites in women receiving combined oral contraceptives and depot-medroxyprogesterone acetate for contraception

The association between users of combined oral contraceptives and depot-medroxyprogesterone acetate (DMPA) for contraception and bone mineral density (BMD) has been controversial because of variations among studies. Like other studies, this cross-sectional study compares BMD in users of combined oral contraceptives and DMPA with that in nonusers. Unlike previous studies, we defined long-term use as >2 years, and we measured more bone sites than previous studies including lumbar spines, femurs, and forearms. The study group consisted of 59 women aged 30 years to 34 years who had been using combined oral contraceptives for 57.36 ± 27.02 months with a minimum period of 24 months, 34 women of the same age who had been using DMPA as contraceptive for 55.76 ± 35.31 months, and 62 women of the same age who had not used any steroid hormonal contraceptives for more than 6 months. BMD was measured by dual energy photon absorptiometer at lumbar spine 2–4, neck of femur, Ward’s triangle of femur, greater trochanter of femur, ultradistal radius, and distal ulnar, respectively. Age, body mass index, and lifestyles of both groups were matched with nonusers. Mean BMD at lumbar spine (L2–4) in the DMPA users was significantly lower than in the controls (1.031 ± 0.090 vs. 1.096 ± 0.116, P = 0.007). There were no significant differences in BMD values at bone sites other than lumbar spine between DMPA users and the controls. There were no significant differences in BMD values at all bone sites between combined oral contraceptives users and the controls. We conclude that combined oral contraceptives are not associated with changes in values of BMD, while DMPA is associated with decreased BMD only at lumbar spine. We comment that steroid hormonal contraceptives are safe to use for long-term contraception regarding bone mass effects.     

Combined oral contraceptive and intrauterine device use among women with gestational trophoblastic disease

Background

Women diagnosed with gestational trophoblastic disease (GTD) need safe and effective contraception because they are advised to delay a subsequent pregnancy.

Study Design

We searched MEDLINE and The Cochrane Library for articles in any language on use of combined oral contraceptives (COC), copper-bearing or levonorgestrel-releasing IUDs among women with benign or malignant GTD, from database inception through November 2008. One review and nine articles were identified and evaluated.

Results

Incidence of postmolar trophoblastic disease was lower among COC users compared with nonusers in six studies, but higher among COC users in three studies. Five studies reported shorter human chorionic gonadotropin (hCG) regression duration among COC users compared with other methods. Development of postmolar trophoblastic disease did not differ significantly among IUD users compared with COC users or nonusers in three studies.

Conclusions

Evidence shows that postmolar trophoblastic disease risk does not increase among women using COCs or an IUD following molar pregnancy evacuation compared with use of other contraceptive methods or no method.     

Bone mineral density in adolescent and young Thai girls receiving oral contraceptives compared with depot medroxyprogesterone acetate: a cross-sectional study in young Thai women

This cross-sectional study of bone mineral density in adolescent and young Thai girls receiving oral contraceptives compared with depot medroxyprogesterone acetate was performed to evaluate the differences among these groups. Thirty current OC users and 30 current depot medroxyprogesterone acetate (DMPA) users were included in the study. The mean duration of OC use was 28.8 +/- 3.4 months and of DMPA 24.6 +/- 3.3 months. Dual energy X-ray absorptiometry (DEXA) was used to measure bone mineral density (BMD) at distal and ultradistal forearm of the nondominant side. The BMD of ultradistal forearm of OC users and that of DMPA users were 0.423 +/- 0.048 and 0.403 +/- 0.039 g/cm(2) and at distal forearm of OC and DMPA users were 0.566 +/- 0.043 and 0.571 +/- 0.064 g/cm(2), respectively. However, there were no statistical differences in BMD in these two groups.     

Efficacy and safety of a low-dose combined oral contraceptive containing drospirenone 3 mg and ethinylestradiol 20 mcg in a 24/4-day regimen

Objective

The study was conducted to assess the efficacy of a low-dose combined oral contraceptive (COC) containing drospirenone (drsp) 3 mg/ethinylestradiol (EE) 20 mcg administered for 24 days of active treatment followed by a 4-day hormone-free interval (24/4 regimen).

Study Design

In this open-label uncontrolled study conducted in 50 European centers, healthy females aged 18-35 years with a body mass index of less than 30 kg/m² received drsp 3 mg/EE 20 mcg 24/4 over 13 cycles. The primary efficacy variable was the number of unintended pregnancies.

Results

Five pregnancies occurred among 1101 women over 13,248 treatment cycles, resulting in a Pearl Index (PI) of 0.49 with an upper two-sided 95% CI limit of 1.14. Of these pregnancies, three were attributed to noncompliance with tablet use resulting in an adjusted PI for ‘perfect use’ of 0.22 (upper limit of two-sided 95% CI: 0.80) based on 11,755 cycles.

Conclusion

Drospirenone 3 mg/EE 20 mcg 24/4 is a highly effective COC in nonobese women.     

Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone

The aim of this open-label, multicenter, noncomparative study was to determine the efficacy, safety and bleeding profile of a new low-dose, monophasic combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone administered daily for 24 days followed by a 4-day hormone-free interval. Contraceptive efficacy was analyzed for 1018 women completing 11,140 treatment cycles. Eleven pregnancies occurred, giving a Pearl Index (PI) of 1.29 (upper limit of the 95% confidence interval [CI], 2.30); of these pregnancies, five were considered due to method failure, giving an adjusted PI of 0.72 (upper limit of the 95% CI, 1.69). A total of 7 (0.7%) women discontinued study medication because of irregular bleeding, suggesting a favorable bleeding profile. Overall, the treatment was well tolerated with an excellent safety profile. The majority of women (86%) stated that they were satisfied or very satisfied with the treatment and over 70% of women would have continued with the study medication.     

Combined oral contraceptive use among women with hypertension: a systematic review

Women with hypertension are at increased risk for cardiovascular events. Combined oral contraceptive (COC) use, even among low-dose users, has been associated with a small excess risk for cardiovascular events among healthy women. In this systematic review, we examined cardiovascular risks among COC users with hypertension. After searching MEDLINE for all articles published from 1966 through February 2005 relevant to COC use, hypertension and cardiovascular disease, we identified 25 articles for this review. Overall, these studies showed that hypertensive COC users were at higher risk for stroke and acute myocardial infarction (AMI) than hypertensive non-COC users, but that they were not at higher risk for venous thromboembolism (VTE). Women who did not have their blood pressure measured before initiating COC use were at higher risk for ischemic stroke and AMI, but not for hemorrhagic stroke or VTE, than COC users who did not have their blood pressure measured.     

Pharmacokinetic differences between Caucasian and Japanese subjects after single and multiple doses of a potential combined oral contraceptive (Org 30659 and EE)

OBJECTIVES: To compare the pharmacokinetic parameters and safety of the progestagen, Org 30659, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one), and ethinyl estradiol (EE) in Caucasian and Japanese women after single and multiple doses. METHODS: This was an open-label parallel design of a single dose followed by a multiple dose period in healthy young Japanese and Caucasian subjects. RESULTS: The area under the curve (AUC) of Org 30659 after single dosing was increased by a factor of 1.75 [90% confidence interval (CI): 1.48-2.08] in Japanese women compared to Caucasian women. At steady state, this difference increased to a factor of 1.90 (90% CI: 1.60-2.25). The AUC of EE after single dosing was similar in Caucasian and Japanese women, but at steady state it was increased by a factor 1.38 (90% CI: 1.15-1.64) in the Japanese group. Weight normalization reduced, but did not remove, all the observed differences. Sex hormone binding globulin played no significant role in the differences between Caucasian and Japanese subjects. Both the single- and multiple-dose treatments with Org 30659/EE were generally well tolerated by all subjects. The Japanese population reported more and different treatment-related adverse events than the Caucasian population. CONCLUSIONS: The peak concentration and extent of exposure of Org 30659, and to a lesser extent of EE, in Japanese women are higher than in Caucasian women. Furthermore, the peak concentration and extent of exposure at steady state of Org 30659, and to a lesser extent of EE, are higher than would be predicted assuming linear pharmacokinetics over time. No major safety issues were observed.     

Bone mineral density in women aged 40-49 years using depot-medroxyprogesterone acetate, norethisterone enanthate or combined oral contraceptives for contraception

Most studies show that depot-medroxyprogesterone acetate (DMPA) has a negative effect on bone mass. There are conflicting reports with respect to recovery of bone mass with long-term use of DMPA. No information is available on the effect of norethisterone enanthate (NET-EN) on bone mass, and combined oral contraceptives (COCs) have not been found to be associated with loss of bone mass. The aim of this study was to investigate bone mineral density (BMD) in older women (40-49 years) in relation to use of DMPA, NET-EN and COCs for at least 12 months preceding recruitment into the study. One-hundred twenty-seven users of DMPA, 102 NET-EN users and 106 COC users were compared to 161 nonuser controls. Bone mineral density was measured at the distal radius and midshaft of the ulna using dual X-ray absorptiometry. There was no significant difference in BMD between the four contraceptive user groups (p=.26) with and without adjustment for age. Although a small decrease in BMD was noted in the age range of 40-49 years, this was not statistically significant (p=.7). The BMD was found to be significantly associated with body mass index (BMI) (por=25.8 mIU/mL was associated with a decrease of 0.017 g/cm2 in radius BMD relative to women with FSH <25.8 mIU/mL. Significant interaction between FSH and BMI in their effect on BMD was observed (p=.006). This study found no evidence that long-term use of DMPA, NET-EN and COCs affects BMD in this population.     

Long-term effects of combined oral contraceptives on markers of endothelial function and lipids in healthy premenopausal women

The aim of this prospective cross-over study was to investigate the effect of two low-dosed oral contraceptives on markers of endothelial function and plasma lipids. Twelve healthy, nonsmoking women (mean age: 21.7 years) were recruited from the family planning clinic of the university hospital Zurich. For 6 months the participants received a treatment with two contraceptive pills containing 30 microg ethinyl estradiol/150 microg levonorgestrel (three cycles) and 30 microg ethinyl estradiol/75 microg gestodene (three cycles). Plasma levels of endothelin-1, nitric oxide, cholesterol, and HDL were measurement before and during treatment with both oral contraceptive treatments.No significant changes in the plasma levels of nitric oxide and endothelin-1, both important regulators of the vascular tone, were observed during oral contraceptive use. A significant negative correlation was found between nitric oxide and endothelin-1 and nitric oxide and cholesterol. There was a positive correlation between endothelin-1 and cholesterol. In conclusion, the investigated contraceptive pills did not cause major changes in circulating nitric oxide and endothelin-1 plasma levels.     

Effects of two low-dose combined oral contraceptives containing drospirenone on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study

BACKGROUND: The effects of a 21-day combined oral contraceptive containing 30 mcg ethinyl estradiol plus 3 mg drospirenone with a 21-day preparation containing 20 mcg ethinyl estradiol plus 3 mg drospirenone on bone turnover and bone mineral density (BMD) in young fertile women were compared. METHODS: A randomized, controlled trial was conducted on healthy fertile women treated with 30 mcg ethinyl estradiol plus 3 mg drospirenone (Group A; n=21), 20 mcg ethinyl estradiol plus 3 mg drospirenone (Group B; n=23) and healthy controls (Group C; n=21). At 3, 6, 9 and 12 months, serum and urinary calcium, osteocalcin (BGP), urinary pyridinoline and deoxypyridinoline were measured. At baseline and after 12 months, lumbar bone mineral density was determined by dual-energy X-ray absorptiometry. RESULTS: In Groups A and B, urinary pyridinoline and deoxypyridinoline at 6, 9 and 12 months were significantly reduced in comparison with basal values and Group C (p<.05). In Groups A and B, serum calcium levels were significantly increased after 6 months. No significant difference was detected between Groups A and B in urinary levels of pyridinoline and deoxypyridinoline, in calcium levels and in BGP levels. At 12 months, no significant difference was detected in spinal BMD values between the three groups and in comparison with basal values. CONCLUSION: Both combined oral contraceptives exert a similar positive influence on bone turnover in young postadolescent women.     

Use of combined oral contraceptives among women with migraine and nonmigrainous headaches: a systematic review

This systematic review examines evidence evaluating whether women with headaches who use combined oral contraceptives (COCs) have a greater risk of stroke than women with headaches who do not use COCs. We searched MEDLINE for articles published from 1966 through March 2005 relevant to headaches and COC use as risk factors for stroke. Of the 79 articles identified, nine met our selection criteria (eight reports of six observational studies plus one meta-analysis). All studies reported specifically on migraine headaches. Evidence from six case-control studies suggested that COC users with a history of migraine were two to four times as likely to have an ischemic stroke as nonusers with a history of migraine. The odds ratios for ischemic stroke ranged from 6 to almost 14 for COC users with migraine compared with nonusers without migraine. The three studies that provided evidence on hemorrhagic stroke reported low or no risk associated with migraine or with COC use.     

Interactive associations of physical activity,adiposity, and oral contraceptive use on C-reactive protein levels in young women

ABSTRACT

Oral contraceptives (OCs) are the most frequently used type of birth control among young women. OC-users have higher C-reactive protein (CRP) values, an indicator of systemic inflammation, than do non-OC-users. In addition, adiposity (percent fat) is positively associated with CRP, and physical activity (PA) is inversely associated with CRP. The present study determined the interactive associations of PA, percent fat, and OC-use with CRP. Data were collected during 2012–2015 at the University of Georgia. Objective PA was measured via pedometers. Percent fat was measured via dual X-ray absorptiometry. The current OC-use was self-reported. High-sensitivity (hs) CRP was determined using venipuncture. Multivariate linear regression determined the interactive associations of percent fat, OC-use, and PA with hs-CRP. Participants (n = 247; mean age 18.9 ± 1.4 years, 60.7 percent white) accumulated a mean of 10,075.7 ± 3,593.4 steps/day. One-third of participants were categorized as overweight/obese by BMI (mean = 24.5 ± 4.8 kg/m², mean percent fat = 35.2 ± 6.8). The current OC-use was reported by 26.2 percent of the sample (n = 61). A significant three-way interaction (β = 0.01, p = .03) indicated that higher PA was associated with lower hs-CRP in non-OC-users with higher percent fat, but not among OC-users with higher percent fat. These results highlight the need to measure and account for the current OC-use in studies examining the relationship between PA and CRP.     

Injectable and oral contraception and the incidence and progression of cervical disease in HIV-infected women in South Africa

Background

Few data exist regarding the effect of hormonal contraception (HC) on incidence and progression of cervical disease (e.g., cervical dysplasia, squamous intraepithelial lesions, cervical intraepithelial neoplasia) in HIV-infected African women.

Study Design

We conducted an observational study of HIV-seropositive women in Johannesburg, South Africa. The effect of individual HC types on the incidence and progression of cervical disease was determined using Poisson regression to obtain adjusted incidence rate ratios.

Results

We evaluated 594 HIV-infected women, with median follow-up time of 445 days; 75 of these women were receiving some form of HC (largely DMPA, NET-EN, or COCs) at baseline. Risks of incidence and progression of cervical disease were similar comparing women not receiving HCs to women receiving DMPA, NET-EN, or COCs both individually by HC-type and considering all HC together.

Conclusions

There was no statistically significant effect of particular HC methods or of HC use in general on rates of incidence or progression of cervical disease in this study. These results should reassure us that use of HC is unlikely to substantially increase risks of cervical disease among HIV-positive women.     

Bone mineral density in adolescents using norethisterone enanthate, depot-medroxyprogesterone acetate or combined oral contraceptives for contraception

PURPOSE: Most studies have shown a negative effect of depot-medroxyprogesterone acetate (DMPA) on the bone mineral density (BMD) of adolescents. There is no information available on the effect of norethisterone enanthate (NET-EN) on BMD in adolescents and the effect of combined oral contraceptives (COCs) on adolescent BMD is inconclusive. The aim of this longitudinal study was to investigate BMD in adolescent (aged 15-19 years) new users of hormonal contraception (DMPA, NET-EN and COCs). METHOD: New users of DMPA (n=115), NET-EN (n=115), COCs (n=116) and 144 nonuser controls were recruited. BMD was measured at the distal radius and midshaft of the ulna using dual X-ray absorptiometry. RESULTS: In total, 275 women were included in this interim analysis and total follow-up time was 553 person-years. There was no significant difference in radius BMD between users of different contraceptive methods at baseline (p=.40). Overall, an increase in radius BMD of 0.00522 per person-year was observed. This result was similar when adjusting for BMI in the random effects regression model (p=.88). The regression model showed that BMI was significantly associated with radius BMD, with each unit increase in BMI corresponding to an increase of 0.0029 g/cm2 in BMD (95% CI 0.0023 to 0.0036, p<.001). Interaction between contraceptive method and follow-up time adjusted for BMI was not significant (p=.07). The increase in BMD for NET-EN users of 0.0013 g/cm2 per person-year (95% CI -0.0017 to 0.0043) was significantly lower than that of nonusers (p=.017). For DMPA and COC users, the increase in BMD was not significantly different compared to the nonusers. This study suggests that NET-EN users had lower increase in BMD over time compared to the other user groups.     

Gestodene: A review of its pharmacology,potency and tolerability in combined contraceptive preparations

Combined progestin–estrogen pills are an established and reliable contraceptive option used by women worldwide. Combined oral contraceptives (COCs) containing the progestins – gestodene, desogestrel or norgestimate – were developed to minimize androgenic side effects and are considered an effective, well-tolerated contraceptive option. Gestodene achieves contraceptive efficacy with the lowest dose of any progestin in a COC, and has an established and favorable short- and long-term tolerability profile. In this review we present an overview of the pharmacology, potency and tolerability of gestodene.     

Efficacy of the low-dose combined oral contraceptive chlormadinone acetate/ethinylestradiol: physical and emotional benefits

Background

This study investigated the effects of the low-dose combined oral contraceptive (COC) 2.0 mg chlormadinone acetate (CMA)/0.03 mg ethinylestradiol (EE) (Belara®, Balanca®) on cycle-related physical and emotional disorders in women ≥25 years of age.

Study Design

A prospective, non-interventional, observational study of 3772 women over six cycles was conducted in 303 office-based gynecological centers throughout Germany.

Results

CMA/EE provided high contraceptive efficacy with a Pearl index of 0 (95% confidence interval=0.00-0.22) and was generally well tolerated, with no statistically significant weight changes during the observation period (p=.147). CMA/EE intake resulted in a statistically significant improvement in cycle-related physical and emotional symptoms, with a 67% overall reduction in sum score for number and intensity of cycle-related symptoms per patient.

Conclusions

The results of this study in women ≥25 years of age support previous findings that 2.0 mg CMA/0.03 mg EE is an effective low-dose COC, with an excellent tolerability profile, with the additional benefits of significantly reducing both cycle-related physical and emotional symptoms (p≤.001); women with the respective preexisting symptoms may, therefore, benefit from CMA/EE contraceptive treatment. Further research is warranted.     

The combined use of oral medroxyprogesterone acetate and methyltestosterone in a male contraceptive trial programme

A male contraceptive trial was undertaken in 23 men using a combination of oral medroxyprogesterone acetate (MPA) and oral methyltestosterone (MeT). The men were divided into four groups according to varying drug dosages and were followed for 15 months (control - 3 months, treatment - 6 months, follow-up - 6 months). The parameters assessed included sperm count and motility, serum gonadotropins and sex steroids, and several biochemical and hematological tests. A questionnaire dealing with side-effects and changes in sexual function was administered intermittently. Although sperm count was suppressed (most dramatically at the highest drug doses, MPA 20mg,MeT 20mg), it was not suppressed to infertile levels. Sperm motility was unaltered; LH was modestly suppressed, FSH was not suppressed; testosterone was suppressed even at low doses; dihydrotestosterone responses were inconsistent. No significant biochemical abnormalities or side-effects occurred although some men experienced mild transient acne, gynecomastia and decreased testicular size. We conclude that in the doses used in this trial, the combination of MPA and MeT is not effective for male contraceptive, purposes and that higher doses may induce severe and undesirable side-effects.