A randomized cross-over study on various hormonal parameters of two triphasic oral contraceptives.

The effect of two triphasic oral contraceptives (Triquilar [TRQ] and Trisiston [TRS]) containing ethinyl estradiol (EE) and levonorgestrel (LNG) on various hormonal parameters was investigated in 26 women during a cross-over study. TRS consisted of 0.03 mg EE + 0.05 mg LNG (six tablets), 0.04 mg EE + 0.075 mg LNG (six tablets), and 0.03 mg EE + 0.15 mg LNG (nine tablets), whereas TRQ was different in the second phase (five tablets) and third phase (10 tablets). Blood samples were taken on days 6, 11, 21, and 28 of the control and washout cycles and the third treatment cycle. Both formulations inhibited ovulation reliably and decreased the serum levels of gonadotropins, free testosterone, and dehydroepiandosterone sulfate in a time-dependent manner, whereas estradiol and testosterone were already suppressed on day 6, indicating a direct suppressive effect on ovarian steroid synthesis. Prolactin, which rose sporadically in some women, was not significantly changed. In contrast, the levels of sex hormone binding globulin, corticosteroid binding globulin, and cortisol were significantly elevated by 100%. During the hormone-free interval of 7 days, all parameters returned at least partly to baseline. There was no significant difference between the effects of both formulations. The results suggest the possibility of a direct inhibitory effect of contraceptive steroids on ovarian steroid synthesis.

PIP: A randomized crossover study involving 26 women in Germany investigated the effect of two triphasic oral contraceptives (OCs) on selected hormonal parameters. The first triphasic, Trisiston, contained 0.03 mg of ethinyl estradiol (EE) and 0.05 mg of levonorgestrel (LNG) (6 tablets), 0.04 mg EE and 0.075 mg LNG (6 tablets), and 0.03 mg EE and 0.15 mg LNG (9 tablets). The second, Triquilar, differed from the first in the second (5 tablets) and third (10 tablets) phases. Serum samples were collected on days 6, 11, 21, and 28 of the control and washout cycles and the third treatment cycle. There were no significant differences in the hormonal effects of the two formulations. Both triphasics inhibited ovulation reliably and decreased serum levels of gonadotropins, free testosterone, and dehydroepiandrosterone sulfate in a time-dependent manner. Estradiol and testosterone were already suppressed on day 6. Prolactin rose sporadically in some women, but was not significantly changed. In contrast, levels of sex hormone binding globulin, corticosteroid binding globulin, and cortisol were significantly elevated by 100%. During the 7-day hormone-free interval, all parameters returned at least partly to baseline. These findings suggest a direct inhibitory effect of OC steroids on ovarian steroid synthesis.

Omitting the first oral contraceptive pills of the cycle does not automatically lead to ovulation.

OBJECTIVE: Our purpose was to test the hypothesis that omitting the first three pills of the contraceptive cycle leads to ovulation. STUDY DESIGN: Ninety-nine women, randomly assigned to 1 of 3 treatments of combined oral contraceptives, completed the study. Treatments contained ethinyl estradiol and either monophasic gestodene, triphasic gestodene, or monophasic desogestrel. Pituitary-ovarian activity was monitored by ultrasonography of the ovaries and assay of serum concentrations of estradiol, progesterone, and follicle-stimulating hormone over 1 normal cycle (study period 1) and 1 cycle after an extended pill-free interval of 10 days (study period 2). RESULTS: None of the women experienced normal ovulation as evaluated by ultrasonography and serum progesterone concentrations. However, follicle-stimulating hormone reached a maximal serum concentration in most women during the first 7 pill-free days, indicating complete pituitary recovery, and increases in serum estradiol concentrations were seen in each woman although with marked interindividual variation. During study period 2 we found follicles of >18 mm in 24%, 24%, and 40% of the monophasic gestodene, triphasic gestodene, and monophasic desogestrel groups, respectively. CONCLUSIONS: Follicular growth up to preovulatory size is common in women missing the first one to three pills of their contraceptive cycle. Although this creates the prerequisite for ovulation, normal ovulation did not occur when pill omissions were limited to only 3 days.

PIP: The hypothesis that omission of the first three pills of the oral contraceptive (OC) cycle leads to ovulation by extending further the pill-free period was investigated in 107 healthy women 18-35 years of age recruited from family planning programs in Finland, the Netherlands, and Belgium. Study participants were randomly allocated to one of the following treatment groups: 1) monophasic gestodene--75 mcg of gestodene and 30 mcg of ethinyl estradiol; 2) triphasic gestodene--6 days of 50 mcg gestodene and 30 mcg ethinyl estradiol, 5 days of 70 mcg gestodene and 40 mcg ethinyl estradiol, and 10 days of 100 mcg gestodene and 30 mcg ethinyl estradiol; or 3) monophasic desogestrel--150 mcg desogestrel and 20 mcg ethinyl estradiol. Noncompliance with OC taking was simulated by extending the pill-free period from 7 to 10 days. During or after the extended pill-free interval, follicular growth exceeding 18 mm occurred in 24% of women in the monophasic gestodene group, 24% in the triphasic gestodene group, and 40% in the monophasic desogestrel group. Follicle-stimulating hormone reached a maximum serum concentration in most women during the first 7 pill-free days, indicating complete pituitary recovery. No normal ovulation was observed after either a 7- or 10-day pill-free period as evaluated by ultrasonography of follicles and serum progesterone assays. Since normal ovulation did not occur when pill omissions were limited to 3 days, OC users who forget to take these three tablets can be safely advised to start the pill cycle on day 11.

A regimen of oral contraceptives restricted to the periovulatory period may permit folliculogenesis but inhibit ovulation.

Increased safety of oral contraceptives (OC) has resulted from a reduction in the estrogen and progestin content per tablet. A reduction in the number of hormonally active pills and their placement at critical points within the cycle may provide a novel regimen for further reducing the hormonal content of OC per cycle and their attendant side effects without compromising efficacy. The objective of this study was to determine the effectiveness of two OC regimens that incorporate a delayed start and limited midcycle use of the combination of ethinyl estradiol and norethindrone, and limited use of norethindrone only during the second half of the cycle. Main outcome measures were defined as ovulation, serum concentrations of estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone (P), follicular diameters, and endometrial thickness. Volunteers were issued blister packs containing 28 pills and randomized to one of two groups. Group 1 used a combination of 50 micrograms ethinyl estradiol and 1 mg norethindrone per tablet day 6-10, and 0.70 mg norethindrone only day 11-19. Placebo tablets were used on days 1-5 and day 20-28. Group 2 used a combination of 50 micrograms ethinyl estradiol and 1 mg norethindrone per tablet on day 8-12, and 0.70 mg norethindrone only on day 13-21. Placebo tablets were used on day 1-7 and day 22-28. A total of 20 cycles were studied using 10 volunteers. To assess any possible carryover effect, two successive cycles were studied for each subject. Serum sampling for E2, FSH, LH, and P, and transvaginal ultrasound imaging to assess endometrial thickness and follicle diameter were carried out at 4 day intervals throughout the cycle. One ovulation occurred in 10 cycles in group 1. Five ovulations occurred in 10 cycles in group 2. All ovulations, regardless of group, occurred in the second cycle. Peak E2 concentrations were not significantly different between groups (152.04 +/- 107.1 pg/mL vs 162.1 +/- 56.1 pg/mL [mean +/- SD] for groups 1 and 2, respectively] but occurred earlier in the cycle in group 1. No differences were noted between the groups in serum concentrations of FSH or LH for any given cycle day. Maximum follicle diameters were not different between groups 1 and 2, regardless of ovulatory status (20.5 +/- 8.1 mm2 vs 20.6 +/- 14.2 mm2, respectively). Ultrasound imaging assessment of midcycle follicle growth revealed diameters ranging from 18.5 mm2 to 34.0 mm2 with gradual resolution through the second half of the cycle in anovulatory cycles, and 16.0 mm2 to 23.5 mm2 with abrupt disappearance in ovulatory cycles. Endometrial thickness did not exceed 10 mm for any anovulatory cycle regardless of group, but ranged from 6 to 9 and 6 to 11 during the luteal phase of ovulatory cycles of groups 1 and 2, respectively. Peak serum P concentrations at midluteal phase in ovulatory cycles ranged from 9.2 ng/ml to 18.2 ng/ml. Data from this preliminary study suggest that ovulation may be prevented with a combination of ethinyl estradiol and norethindrone started as late as cycle day 6 and limited to 5 days' duration using norethindrone only for 9 days during the second half of the cycle. Such a restricted regimen may offer both an effective method of contraception and a means of further reducing both estrogen and progestin content per cycle and the possible short and long term adverse side effects of these hormones.

PIP: A reduction in the number of hormonally active oral contraceptive (OC) pills and their placement at critical points within the cycle represents a novel potential regimen for further reducing the hormonal load of OCs per cycle and the attendant side effects without compromising efficacy. The present study evaluated the effectiveness of two such OC regimens: group 1--placebo tablet on days 1-5, 50 mcg of ethinyl estradiol and 1 mg of norethindrone per tablet on days 6-10, 0.70 mg of norethindrone only on days 11-19, and placebo tablets on days 20-28; and group 2--placebo tablet on days 1-7, 50 mcg of ethinyl estradiol and 1 mg of norethindrone per tablet on days 8-12, 0.70 mg of norethindrone only on days 13-21, and placebo on days 22-28. 10 volunteers were randomized to one of the two groups for two cycles. There was 1 ovulation in the 10 cycles completed in group 1 and 5 ovulations in the 10 cycles in group 2. All ovulations occurred in the second cycle. Peak estradiol concentrations occurred earlier in the cycle in group 1, but were not significantly different between groups. Serum concentrations of follicle-stimulating hormone or luteinizing hormone and mean follicle diameters were not different between groups. Folliculogenesis occurred in all 20 cycles. Mid-cycle follicular growth resolved gradually during the second half of the cycle in anovulatory cycles and abruptly in ovulatory cycles. The length of the luteal phase for ovulatory cycles was 7 days in group 1 and 8-12 days in group 2. These findings suggest ovulation may be prevented with a combination of ethinyl estradiol and norethindrone started as late as cycle day 6 and limited to 5 days' duration, using norethindrone only for 9 days during the second half of the cycle.

Effect of desogestrel-containing oral contraceptives on vascular reactivity and catecholamine levels.

The modifications induced by new oral contraceptives (OC) on blood pressure, great vessel vascular reactivity by color Doppler, and catecholamine levels were investigated. Young healthy women not taking OC (n = 22; controls) or receiving, for > or = 6 months, OC containing desogestrel with either 30 micrograms (n = 14) or 20 micrograms of EE (n = 8) were enrolled. Blood pressure measured at rest in supine position was similar between controls and OC users. The pulsatility index (PI), an indirect index of resistance to blood flow, of axillary artery was significantly higher (p < 0.05) in 30 micrograms than in 20 micrograms EE OC users or controls. A similar trend, albeit not significant, was observed for the internal carotid artery PI. Norepinephrine (p < 0.01) and dopamine (p < 0.05) but not epinephrine levels, were lower in 30 micrograms EE OC users than in 20 micrograms EE OC users or controls. Thus, both 20 micrograms and 30 micrograms EE OC had no negative effect on blood pressure, but the 30 micrograms EE OC tended to increase great vessel resistance to blood flow, independently of catecholamine levels.

PIP: The effects on blood pressure of oral contraceptives (OCs) containing desogestrel plus either 20 or 30 mcg of ethinyl estradiol were investigated in 22 women who had been using one of these formulations for 6 months or more and 22 matched controls. There were no significant differences between both groups of cases and controls in blood pressure measured at rest in supine position. However, subtle differences were recorded in vascular reactivity, as evaluated by color Doppler ultrasound investigation. Compared to controls and users of OCs containing 20 mcg of ethinyl estradiol, cases taking OCs consisting of 30 mcg of ethinyl estradiol had a significantly higher pulsatility index in the axillary artery, indicating increased vessel resistance to blood flow. A similar, although not significant, trend was found in the internal carotid artery pulsatility index. On the other hand, catecholamine (dopamine and norepinephrine) levels were reduced by both OCs in a dose-dependent manner. Overall, these findings suggest that third-generation OCs, especially those containing 20 mcg of ethinyl estradiol, exert minimal effects on circulatory parameters. It is hypothesized that the cardiovascular effects of catecholamine reduction are antagonized by other mechanisms, among them the stimulus on the renin-angiotensin system.

Short-term treatment with levonorgestrel does not antagonize the ethinyl estradiol-induced increase of uterine blood flow in postmenopausal women.

The aim of this study was to determine the effect of a short-term ethinyl estradiol/levonorgestrel medication on blood flow in the uterine arteries in postmenopausal women in a prospective placebo-controlled double-blind study. Twenty-one healthy postmenopausal woman at least 2 years after menopause received 60 micrograms ethinyl estradiol (EE) for 14 days followed by 40 micrograms EE plus 125 micrograms levonorgestrel (LNG) for 12 days (total treatment period 26 days). Sonographically, uterine volume, endometrial thickness, and blood flow in the uterine arteries [as reflected by pulsatility (PI) and resistance indices (RI)] were measured. Uterine size increased from 44 to 80 mL (day 14, p < 0.001) and 87 mL (day 26, p = NS). Endometrium grew from 3 to 8 mm (day 14, p < 0.001) and 11 mm (day 26, p = NS). Uterine arterial PI fell from 2.76 to 1.37 (day 14, p < 0.001) and 1.34 (day 26, p = NS), whereas RI fell from 0.9 to 0.68 (day 14 and day 26, p < 0.001). In conclusion, short-term treatment with LNG does not antagonize the vascular effect of EE on the uterine arteries as reflected by PI and RI. This result might have clinical significance in the selection of the progestin used in hormonal replacement therapy.

PIP: The aim of this study was to determine the effect of a short-term ethinyl estradiol (EE)/levonorgestrel (LNG) medication on blood flow in the uterine arteries in postmenopausal women in a prospective placebo-controlled double-blind study. 21 healthy postmenopausal women, at least 2 years after menopause, received 60 mcg EE for 14 days followed by 40 mcg EE plus 125 mcg LNG for 12 days (total treatment period: 26 days). Sonographically, uterine volume, endometrial thickness, and blood flow in the uterine arteries [as reflected by the pulsatility index (PI) and the resistance index (RI)] were measured. Uterine volume increased from 44 to 80 ml (day 14, p 0.001) and 87 ml (day 26, p = NS). Endometrial thickness increased from 3 to 8 mm (day 14, p 0.001) and 11 mm (day 26, p = NS). Uterine arterial PI fell from 2.76 to 1.37 (day 14, p 0.001) and 1.34 (day 26, p = NS), whereas RI fell from 0.9 to 0.68 (day 14 and day 26, p 0.001). In conclusion, short-term treatment with LNG does not antagonize the vascular effect of EE on the uterine arteries as reflected by PI and RI. This result might have clinical significance in the selection of the progestin used in hormonal replacement therapy.

Modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest.

Twenty-two healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.3 +/- 4.1), were included in a single-center, noncomparative study to investigate the modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest. At baseline, during three treatment cycles and post-treatment, serum levels of luteinizing hormone, follicle-stimulating hormone, 17 beta-estradiol, and progesterone were assayed and ultrasonography was used to measure follicular size and the thickness of the endometrium. The primary efficacy variable was inhibition of ovulation as measured by ovarian activity grading. All volunteers ovulated during the pretreatment cycle. During treatment, none of the subjects had ovulatory cycles, although there was still some ovarian activity in several subjects. During the first treatment cycle, only 4% (1 subject) of cycles showed active follicle-like structures. The frequency of follicle-like structures increased to 33% and 35% during treatment cycles 2 and 3. The frequency of presumptive luteinized unruptured follicle-like structures was 5% (1 subject) and 15% (3 subjects) in treatment cycles 2 and 3. The serum hormone concentrations were effectively suppressed in comparison to baseline. The ovarian activity returned to baseline during the post-treatment period. One subject was excluded from further study because of a medical problem believed unrelated to use of the oral contraceptive. No serious adverse events were recorded during the course of the study. The results of the present investigation indicate that the modulatory effects on ovarian function of the monophasic oral-contraceptive containing 30 micrograms ethinyl estradiol combined with 2.00 mg dienogest lead to adequate suppression of ovarian activity and effective inhibition of ovulation.

A comparative randomized trial on the impact of two low-dose oral contraceptives on ovarian activity, cervical permeability, and endometrial receptivity.

In a double-blind randomized study, the suppression of ovarian activity and anti-conceptive effects on the cervix and endometrium were assessed during administration of two low-dose monophasic oral contraceptives (20 micrograms ethinyl estradiol [EE], 500 micrograms norethisterone--Eve 20 [Grünenthal, Aachen, Germany]; 20 micrograms EE, 150 micrograms desogestrel --Lovelle [Organon, Munich, Germany]). One hundred eighteen healthy women (ages: 18-35 years) were studied in 10 investigation centers during medication with either Eve 20 (n = 59) or Lovelle (n = 59). During three treatment cycles, ovarian activity was evaluated by sonographic determination of follicle-like structures (FLS) and by simultaneous assessment of serum endocrine profiles (gonadotropins LH and FSH, ovarian steroids estradiol [E2] and progesterone [P]). While on either treatment, no ovarian activity (as judged by no FLS and/or reduced sex steroid levels) was found in 90.8% (Eve 20) and 97.2% (Lovelle) of all investigated cycles. Follicular activity or cyst formation were detected in 18 of 173 cycles (Eve 20) and in 5 of 175 cycles (Lovelle), respectively. Gonadotropin levels were suppressed (LH < 6 IU/L, FSH < 8 IU/L) in most treatment cycles (Eve 20 76.6% vs. Lovelle: 84.8%). Serum E2 concentrations exceeding 0.1 nmol/L indicated residual follicular activity in 19.3% (Eve 20) versus 12.2% (Lovelle) of all cycles. An estimated by serum P levels over 5 nmol/L, ovulation had presumably occurred in 4.1% (Eve 20) versus 2.9% (Lovelle) of treatment cycles. However, when the sonographical and endocrinological data were combined, no ovulation was documented in any pill cycle. The quality and quantity of the cervical mucus was found to be minimal in the majority of women. Moreover, the endometrial layer was determined to be low by ultrasound during most pill cycles, indicating equally strong suppressive effects on endometrial receptivity by the two contraceptives. These observations suggest that ovarian activity is suppressed in the majority of cycles during use of low-dose contraceptives. This effect may mainly be medicated by pronounced suppression of serum gonadotropin levels. Strong anti-conceptive effects of these formulations on both cervical permeability and endometrial receptivity are additional factors ensuring the contraceptive efficacy of these formulations.

PIP: The impact of two low-dose monophasic oral contraceptives (OCs) on suppression of ovarian activity, cervical permeability, and endometrial receptivity was investigated in a randomized double-blind study involving 118 healthy women 18-35 years of age recruited from 10 study centers in Germany. 59 women received Eve (20 mcg of ethinyl estradiol and 500 mcg of norethisterone) and 59 were given Lovelle (20 mcg of ethinyl estradiol and 150 mcg of desogestrel) for a total of 3 cycles. No ovarian activity, as assessed by sonographic determinations of follicle-like structures and serum endocrine profiles, was detected in 90.8% of cycles of Eve users and 97.2% of cycles in the Lovelle group. Follicular activity or cyst formation was found in 18 of 173 cycles of Eve users and 5 of 175 cycles of Lovelle users. Gonadotropin levels were suppressed (luteinizing hormone under 6 IU/L and follicle-stimulating hormone less than 8 IU/L) in 76.6% of treatment cycles in the Eve group and 84.8% of cycles in the Lovelle group. Serum estradiol concentrations exceeding 0.1 nmol/L, indicative of follicular activity, were recorded in 19.3% of cycles of Eve users and 12.2% of cycles in the Lovelle group. Although serum progesterone levels were over 5 nmol/L in 4.1% of cycles in the Eve group and 2.9% of those in the Lovelle group, consolidation of sonographic and endocrinologic data failed to document ovulation in any treatment cycles. The quantity and quality of cervical mucus was minimal in most women in both groups. Finally, the endometrial layer was determined to be low by ultrasonography during most pill cycles, confirming the OCs' equally strong suppressive effects on endometrial receptivity.

A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20 micrograms ethinylestradiol/75 micrograms gestodene and 30 micrograms ethinylestradiol/75 micrograms gestodene, with respect to efficacy, cycle control, and tolerance.

The aim of this study was to compare contraceptive reliability, cycle control, and tolerance of an oral contraceptive containing 20 micrograms ethinylestradiol (EE2) and 75 micrograms gestodene (GSD), with a reference preparation containing a similar dose of gestodene but in combination with 30 micrograms ethinylestradiol. A higher incidence of intermenstrual bleeding was apparent under the 20 micrograms EE2 oral contraceptive. For the 20 micrograms EE2 preparation, 47.4% of all women reported spotting at least once over a period of 12 treatment cycles, whereas this figure was 35.5% for the 30 micrograms EE2 pill (p < 0.05). However, the incidence was within a range that corresponds to that of other OCs. The cumulative breakthrough bleeding rates (at least once during the one year of treatment) of 14.5% (20 micrograms EE2) and 11.8% (30 micrograms EE2) of women were not significantly different. In relation to all cycles, the intermenstrual bleeding rates were remarkably lower, indicating that the majority of the volunteers experienced such events only in few cycles under treatment: the spotting rate was 11.5% (20 micrograms EE2) and 7.2% (30 micrograms EE2) of all cycles, and the breakthrough bleeding rate was 2.6% and 1.6% of all cycles, respectively. Three pregnancies were recorded during the study (one in the 20 micrograms EE2 + 75 micrograms GSD group, two in the 30 micrograms EE2 + 75 micrograms GSD group). All three could be explained either by intake irregularities or by circumstances impairing the contraceptive effect. The influence of both treatments on the blood pressure and body weight proved to be extremely slight. Adverse events in both groups were rare and differences in the frequency of adverse events were not apparent. The discontinuation rate due to adverse events, including intermenstrual bleeding, was low (9.8% for 20 micrograms EE2 + 75 micrograms GSD, and 7.2% for 30 micrograms EE2 + 75 micrograms GSD) and was in the lower range known for other oral contraceptives. Both preparations were well accepted by the volunteers. The data obtained demonstrate clinically acceptable cycle control, good tolerance, and a high standard of contraceptive reliability for both drugs. Prescription of the 20 micrograms EE2 preparation could be the first-line therapy in order to provide the lowest amount of EE2 possible. In case of persistent cycle control problems, a switch to the 30 micrograms EE2 drug should be considered.

PIP: A double-blind, comparative study of oral contraceptives (OCs) containing 75 mcg of gestodene and either 20 mcg or 30 mcg of ethinyl estradiol (EE2) indicates that the lower-dose formulation neither compromises contraceptive effectiveness nor produces unacceptable cycle control. Study subjects included 649 randomly selected healthy women requesting contraception from 10 family planning centers in Germany; the 20 mcg EE2 pill was evaluated in 428 women for a total of 4470 cycles, while the 30 mcg preparation was tested in 221 women for 2377 cycles. During the 12-month study period, the incidence of at least 1 episode of intermenstrual bleeding (generally in the first cycle) was significantly greater in the 20 mcg EE2 group (47.4%) than in the 30 mcg group (35.5%); however, the cumulative breakthrough bleeding rates (14.5% and 11.8%, respectively) were not dissimilar. In relation to the sum of all cycles, the spotting rates were 11.5% for the 20 mcg EE2 OC and 7.2% for the 30 mcg OC, and the breakthrough bleeding rates were 2.6% and 1.6%, respectively. The 3 pregnancies that occurred all involved user failure. The discontinuation rates due to side effects, including spotting, were 9.8% in the 20 mcg EE2 group and 7.2% in the 30 mcg group. 66.6% of women in the former group and 71.0% of those in the latter group never complained of an adverse effect during the study. The incidences of spotting and discontinuation were well within the range reported for other OCs. These findings indicate that the 20 mcg EE2 preparation should be prescribed first; if cycle control problems persist, a 30 mcg EE2 OC can be considered.

Multicenter, double-blind, comparative clinical study on the efficacy and acceptability of a monthly injectable contraceptive combination of 150 mg dihydroxyprogesterone acetophenide and 10 mg estradiol enanthate compared to a monthly injectable contraceptive combination of 90 mg dihydroxyprogesterone acetophenide and 6 mg estradiol enanthate.

Healthy, regularly menstruating women, aged 14-38 years, were enrolled in a comparative, double-blind, phase III, clinical trial to evaluate the contraceptive efficacy and acceptability of a combination of 90 mg dihydroxyprogesterone acetophenide with 6 mg estradiol enanthate compared to the commercially available contraceptive combination of 150 mg dihydroxyprogesterone acetophenide with 10 mg estradiol enanthate. Subjects received the contraceptive combination intramuscularly, between the 7th and 10th day of each menstrual cycle, during 12 consecutive menstrual cycles. Approximately 60% of the subjects in both groups completed the study. Principal reasons for discontinuation were personal, nonmedical reasons. Principal medical reasons for discontinuation were menstrual-related, irregular bleeding being the most frequent. Differences in menstrual patterns between the two groups did not lead to differences in discontinuation rates. Three contraceptive failures occurred during the trial, one in Group A (90/6 mg) and two in Group B (150/10 mg), indicating that the lower dose formulation is at least as efficient as the higher dose.

Clinical experience of a combined oral contraceptive with very low dose ethinyl estradiol.

BACKGROUND: The risk of thromboembolic events related to the ethinyl estradiol (EE) dose in oral contraceptive (OC) pills has led to a further dose reduction. METHODS: An OC pill with 150 micrograms desogestrel combined with only 20 micrograms EE was compared with a pill containing the same dose of desogestrel but 30 micrograms of EE in a Scandinavian multicentre study with follow-up visits after 3, 6 and 12 months. RESULTS: In almost 5,000 cycles with each pill the numbers of pregnancies due to method failure with the lower and higher EE dose pills were 0 and 2, respectively. Irregular bleedings were slightly more common with the lower EE dose, but tended to decrease over the year of study. Other side effects were uncommon. Regarding metabolic effects, both pills tended to raise the plasma HDL level and the lower EE dose pill also reduced LDL. Free testosterone was reduced by two-thirds with both pills, showing beneficial effects on acne. CONCLUSIONS: It is concluded that both these pills are reliable and safe, but that many women would accept a slightly greater risk of irregular bleeding with the 20 micrograms EE dose pill in exchange for a reduction in potential risk related to the estrogenic component of OC pills.

PIP: In response to concerns about a possible thromboembolism risk, the ethinyl estradiol dose in oral contraceptives (OCs) has been further decreased. This study compared the effectiveness and metabolic effects of combined OCs containing 150 mcg of desogestrel and either 20 or 30 mcg of ethinyl estradiol. 1000 Swedish women requesting an OC were randomly assigned to receive either the 150/20 or 150/30 formulation, with follow-up visits scheduled 3, 6, and 12 months after OC initiation. The only 2 pregnancies attributable to method failure occurred in the 150/30 group. Although bleeding irregularities were more common in the 150/20 group, this incidence steadily decreased over the 12-month study period. Overall, bleeding irregularities were experienced by 9.9% of the 500 women in the 150/20 group and 6.0% of the 500 in the 150/30 group. The total cholesterol level increased significantly in the 150/30 mcg group but not in the lower-dose group. Low density lipoprotein cholesterol decreased only among 150/20 OC users. Total triglycerides increased more in users of the 30 mcg pill. Both pills reduced free testosterone levels substantially, but to the same extent. The small percentage of women who experience irregular bleeding with the lowest-dose OC are likely to accept this discomfort in exchange for its potentially improved safety profile.

Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians.

Hepatic enzyme-inducing antiepileptic drugs (AEDs) lower oral contraceptive (OC) sex hormone levels approximately 40% and increase the risk of unplanned pregnancies in women with epilepsy. AEDs also increase the risk of birth defects in offspring of women with epilepsy. We performed a national survey to determine obstetricians' and neurologists' knowledge of OC and AED interactions and the risk of birth defects for women with epilepsy taking AEDs. We received responses to a mailed questionnaire from 160 of 1,000 neurologists (16%) and 147 of 1,000 obstetricians (15%) from 47 states. Practice demographics and ages of responders were typical for U.S. neurologists and obstetricians. Ninety-one percent of neurologists and 75% of obstetricians said they treat women with epilepsy of child-bearing age. Only 4% of the neurologists and none of the obstetricians, however, knew the effects of the six most common AEDs on OCs, even though 27% of neurologists and 21% of obstetricians reported OC failures in their patients taking AEDs. Although increasing OC doses can compensate for insufficient OC sex hormone levels due to AEDs, most physicians do not increase the doses. Even though the risk of birth defects for the offspring of women with epilepsy is 4 to 6%, up from the background level of 2%, 44% of neurologists thought the risk was lower (0 to 3%), and some of the respondents guessed that it was as high as 50%. Many neurologists and obstetricians do not have accurate information to counsel women with epilepsy properly about their contraceptive and pregnancy choices.

PIP: Responses from 160 of 1000 neurologists (16%) and 147 of 1000 obstetricians (15%), selected from an American Medical Association listing to receive a mailed questionnaire, revealed a disturbing lack of knowledge about the interactions between antiepileptic medications and oral contraceptives (OCs). Hepatic enzyme-inducing antiepileptic drugs lower OC estradiol levels by about 40% and may reduce free progestin levels, thereby increasing the risk of unplanned pregnancy; moreover, antiepileptics increase the risk of birth defects in their epileptic users, who already have a 4-6% increased risk of such defects. Physicians can reduce, but not prevent, the risk of unwanted pregnancy by increasing the OC estradiol dose to at least 50 mcg and prescribing valproic acid and gabapentin (non-enzyme-inducing antiepileptics). 91% of neurologists and 75% of obstetricians reported that they treated epileptic women of childbearing age, and 27% of the former and 21% of the latter physicians acknowledged cases of OC failure in these patients. Only 4% of the neurologists and none of the obstetricians knew the effects of the 6 most common antiepileptic drugs on OCs. Just 41% of neurologists and 43% of obstetricians routinely had patients adjust their OC doses if they were taking antiepileptics. Such adjustment was more likely among physicians who had an epileptic patient with an unintended pregnancy and those who had accurate knowledge of OC-antiepileptic drug interactions. 44% of neurologists and 23% of obstetricians underestimated the birth defects risk as 0-3%. Since the physicians who chose to respond to this survey were presumably more concerned and knowledgeable about the reproductive effects of antiepileptic drugs than those who chose not to respond, continuing education efforts are urged to enable health care providers to counsel epileptic women about contraception.

The effect of oestrogen dose and progestogen type on haemostatic changes in women taking low dose oral contraceptives.

OBJECTIVE: To determine the effect of oestrogen dose and progestogen type on the coagulation and fibrinolytic systems of a group of normal healthy women taking three different oral contraceptive combinations. DESIGN: Plasma levels of factor VII, X, antithrombin III, protein C, fibrinogen, tissue plasminogen activator activity, plasminogen activator inhibitor I antigen and fibrin (D-dimer) degradation products were measured at pretreatment, 6, 14, 22 weeks of treatment and at 6 weeks post-treatment in a group of 67 women taking either 30 micrograms ethinyloestradiol/150 micrograms desogestrel (n = 21), 20 micrograms ethinyloestradiol/150 micrograms desogestrel (n = 24), 30 micrograms ethinyloestradiol/75 micrograms gestodene (n = 22). PARTICIPANTS: Sixty-seven healthy normal women, 18 to 34 years, smoking fewer than 15 cigarettes per day. The subjects were within 10% of their normal body weight and had no history of thromboembolic disease. SETTING: Coombe Women's Hospital and St James's Hospital, Dublin, Ireland. RESULTS: Factor VII and X levels were significantly raised on treatment with both the 30 micrograms ethinyloestradiol/desogestrel and gestodene combinations. Higher levels of factor VII activity were observed in the 30 micrograms ethinyloestradiol/desogestrel combination compared with the gestodene combination. Factor VII and X were not significantly affected by the 20 micrograms ethinyloestradiol combination. Increased plasminogen, fibrinogen and D-dimer levels and decreased plasminogen activator inhibitor I antigen levels were observed during the treatment phases in all three groups. Antithrombin III and protein C activity did not change during treatment with any of the oral contraceptives studied. CONCLUSIONS: Low dose oral contraceptives cause an activation of the coagulation system which is balanced by an activation of the fibrinolytic system. Reducing the dose of ethinyloestradiol from 30 micrograms to 20 micrograms reduces the effect on factor VII and X. This effect can be modified by the progestogen. The lesser effect of the 20 micrograms combination may make this a safer option for some women than pills containing a higher dose of oestrogen.

PIP: At Coombe Women's Hospital and St. James's Hospital in Dublin, Ireland, health researchers randomly assigned 67 healthy women aged 18-34 years to receive one of three low-dose combined oral contraceptives (OCs) so they could investigate the effect of the estrogen and the progestogen on the activation and inhibition of the coagulation and fibrinolytic systems. Two of the OCs contained 150 mcg desogestrel (DES) and either 30 mcg or 20 mcg ethinyl estradiol (EE). The third OC contained 30 mcg EE and 75 mcg gestodene (GES). The women were followed for 28 weeks. The two OCs with 30 mcg E2 significantly increased factor VII and X levels (p 0.01). The 30-mcg EE/DES OC effected an even higher increase of factor VII activity (p 0.001). The 20-mcg EE/DES OC did not significantly affect factor VII and X activity. All three OCs increased plasminogen, fibrinogen, and D-dimer levels and reduced plasminogen activator inhibitor I antigen levels. None of the OCs changed antithrombin III and protein C activity. In conclusion, these OCs activated the blood coagulation system as well as the fibrinolytic system. Specifically, activation of the fibrinolytic system balances the activation of the coagulation system. The progestogen can reduce the effect of a lower EE dose on factor VII and X. The reduced effect of the 20-mcg EE combined OC suggests that it may be a safer option for some women than the higher EE dose OCs.

Changes in haemostatic variables induced by oral contraceptives containing 50 micrograms or 30 micrograms oestrogen: absence of dose-dependent effect on PAI-1 activity.

Several studies have suggested a dose-response relation between the oestrogen content of oral contraceptive (OC) and the risk of both venous thrombosis and arterial disease, when oestrogen doses were higher than 50 micrograms. However, there is no clear epidemiological evidence for a decrease in thrombotic risk with formulations containing less than 50 micrograms oestrogen. Therefore, we investigated haemostatic variables in users of OC containing either 30 micrograms (35 women) or 50 micrograms (29 women) ethinyl estradiol as compared with non users (64 women) matched for age and smoking status. Mean values of antithrombin activity were significantly lower in 30 micrograms or 50 micrograms oestrogen users than in non users (96% and 98% vs 105%, respectively, p < 0.001), but they were not significantly different between the two groups of OC users. There was a significant increase in mean values of factor VII antigen in women taking either 30 micrograms or 50 micrograms oestrogen as compared with non users (96% and 101% vs 85%, respectively, p < 0.005). Although the difference between both groups of OC users was not significant, a positive linear trend in factor VII levels was observed within the 0-50 micrograms oestrogen range (p < 0.001). Mean levels of fibrinogen were slightly higher in 30 micrograms or 50 micrograms oestrogen users than in non users (2.71, 2.66 g/l vs 2.55 g/l, respectively), but there was no significant difference between the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: In Paris, France, clinicians compared data on 64 women aged 19-40 who used combined oral contraceptives (OCs) for 6-200 months with data on 64 healthy women who did not use OCs for the last two months and who were matched for age and smoking status to investigate activity of plasminogen activator inhibitor 1 (PAI-1), factor VII antigen, fibrinogen concentration, and antithrombin activity in users of OCs containing either 30 mcg or 50 mcg estrogen and in nonusers. OC users exhibited lower mean values of PAI-1 activity than nonusers (4.63-4.89 vs. 6.47 AU/ml; p 0.02). There was no dose-dependent effect of estrogen on PAI-1 activity, however. Antithrombin activity values were much lower in OC users than nonusers (96-98% vs. 105%; p 0.001). The difference between the two groups of OC users was not significant, however. The mean values of factor VII antigen in women using either 30 mcg or 50 mcg estrogen were higher than those for nonusers (96% and 101% vs. 85%, respectively; p 0.005). The difference in factor VII antigen values between the two OC groups was not significant, yet there was a positive linear trend in factor VII levels within the 0-50 mcg estrogen range (p 0.001). No significant difference in the mean fibrinogen levels between the three groups (30 mcg estrogen OC group, 50 mcg estrogen OC group, and nonusers) was observed. Hemostatic variables were not significantly different between 30 mcg estrogen OCs containing 100 mcg, 150 mcg, or 200 mcg levonorgestrel. The researchers could not conduct a valid assessment of the progestogen effect in 50 mcg estrogen OCs due to the wide range of different types of progestogens. These findings suggest an alteration of blood coagulation and fibrinolysis in OC users within the 30-50 mcg estrogen range. Estrogen appears to have a dose-dependent effect on factor VII but no significant effect on PAI-1 activity and other markers of thrombogenic risk and arterial disease risk.

A changing pattern in the association of oral contraceptives and the different groups of congenital limb deficiencies.

A case-control study on different groups of isolated congenital limb deficiency was performed in a ten-year population-based and revised Hungarian data set. A higher rate of one contraceptive pill type with relatively high dose (ethynodiol diacetate 1.0 mg + ethinyloestradiol 0.05 mg) used in the periconceptional period was found in the mothers of cases with terminal transverse defect (adjusted relative odds 1.9 with 95% confidence interval of 1.1-3.4). This risk is minimised by the use of recent low-dose pills.

PIP: In Hungary, researchers analyzed 1975-1984 population-based and revised data on 537 children with isolated congenital limb deficiency (CLD) (i.e., cases with at least 1 affected limb) and data on 537 age-matched controls with no CLD. They wanted to determine the association between periconceptional use of oral contraceptives (OCs) and CLD. Personal examination and/or medical documents confirmed reported diagnoses. They separated the isolated CLD cases into terminal transverse CLD, amniogenic CLD, radial and tibial CLD, ulnar-fibular CLD, split hand and/or foot CLD, and intercalary CLD. Periconceptional use of Bisecurin (relatively high dose of 1 mg ethynodiol diacetate and 0.05 mg ethinyl estradiol) was significantly associated with terminal transverse CLD (adjusted odds ratio [AOR] = 1.9; p = 0.03). It was also significantly associated with monomelic CLD (AOR = 1.6; 9.6% vs. 2.9%; p = 0.0015). The monomelic cases comprised 19 terminal transverse cases, 6 amniogenic cases, 7 radial cases, 3 atypical split hand cases, and 2 ulnar cases. 19 of the 20 terminal transverse cases were monomelic. Periconceptional use of Continuin (0.5 mg ethynodiol diacetate alone) was associated, but not significantly so, with terminal transverse CLD (6 cases vs. 1 control; p = 0.06). These findings suggest that use of OCs with a high dose of ethynodiol diacetate increases the risk of terminal transverse defect. Use of low dose OCs likely minimizes this risk.

Effect of oestrogen dose on whole blood platelet activation in women taking new low dose oral contraceptives.

Oral contraceptive use is known to cause changes in the haemostatic system. These changes are thought to be related to oestrogen dose and to provide a possible link between the increased risk of thromboembolic disease known to occur in women taking oestrogen containing oral contraceptives. This study measured whole blood platelet activation, serially, in women taking oral contraceptives containing 20 micrograms and 30 micrograms ethinyloestradiol combined with desogestrel. Increased levels of ADP and arachidonic acid induced aggregation were observed in women taking the 30 micrograms ethinyloestradiol combination. Platelet release of beta-thromboglobulin (beta TG) was also significantly increased. Increased collagen induced aggregation was observed but this failed to reach statistical significance for the individual treatment groups. In women taking the 20 micrograms ethinyloestradiol combination, a significant increase was only observed when platelets were stimulated with arachidonic acid. Platelet factor 4 (PF4) levels were unchanged in both groups. Significantly higher levels of beta TG were observed in women taking the 30 micrograms ethinyloestradiol combination compared with women taking the 20 micrograms ethinyloestradiol combination. These results show that oral contraceptive use is associated with platelet activation. Women taking the 20 micrograms ethinyloestradiol combination show less changes in platelet activation than women taking the 30 micrograms ethinyloestradiol combination. This lower dose pill may therefore be particularly suitable for high risk women wishing to use oral contraception.

PIP: To evaluate the effects of low-dose oral contraceptives (OCs) on platelet function, hematologic measures were compared in 45 Irish women taking OCs containing 20 or 30 mcg of ethinyl estradiol as well as 150 mcg of desogestrel. Serum samples were collected before treatment and at 6, 14, and 22 weeks after OC use commenced. ADP induced whole blood platelet aggregation was significantly increased in users of OCs containing 30 mcg of ethinyl estradiol, reaching a maximum at 22 weeks, but not in users of the low-dose OC. A significant increase in collagen induced aggregation was observed when both groups of OC users were combined, but not when either was tabulated separately. Both groups showed significant increases in arachidonic acid induced aggregation. Platelet count, hematocrit, and platelet factor 4 levels were unaffected. Increased levels of beta-thromboglobulin were observed at 6, 14, and 22 weeks in the 30 mcg group; there was no significant change in the 20 mcg group. Since the low-dose 20 mcg ethinyl estradiol OC produced fewer changes in platelet activation, its use is recommended for women with risk factors for thromboembolic disease.

Haemostasis profile in smoking and nonsmoking women taking low-dose oral contraceptives.

The effects of oral contraceptives on coagulation in 258 nonsmoking and in 190 smoking women were determined. In smokers and in nonsmokers taking oral contraceptives, fibrinogen and fibrinopeptide A concentrations were higher than in oral contraceptive nonusers. In nonsmokers, oral contraceptives increased antithrombin III activity. The effects on coagulation of oral contraceptives with a different ethinylestradiol content (from 35 mcg to 20 mcg) were then evaluated in 333 of these women. The biggest changes in coagulation were observed in smokers taking the preparation with the highest estrogen content. Reduction of the ethinylestradiol dose caused a decrease of the changes in coagulation induced by oral contraceptives both in smokers and nonsmokers. These results might suggest that during oral contraception the coagulation system is affected mainly in smokers and that the decrease of the estrogen dose might lower the effects of the association of smoking and oral contraception on coagulation.

PIP: The synergistic effect of cigarette smoking and oral contraceptive (OC) use on hemostasis was investigated in 448 healthy volunteers aged 17-46 years of age recruited from a family planning clinic in Italy. 190 subjects were smokers and 77 were current OC users; 33 of the OC users were also smokers. To be eligible for study participation, OC users had to be on formulations that contained no more than 35 mcg of ethinyl estradiol and to have at least 6 months of use. The OC users were randomly assigned to one of the following regimens: a monophasic OC containing 35 mcg of ethinyl estradiol and 2 mg of cyproterone acetate, two monophasic pills with 30 mcg of ethinyl estradiol and 75 mcg of gestodene or 150 mcg of desogestrel, or one monophasic combination of 20 mcg of ethinyl estradiol and 150 mcg of desogestrel. Overall, the findings confirmed that OC-related changes in blood coagulation are evident mainly in smokers. OC users who smoked had significantly higher plasma levels of fibrinogen and fibrinopeptide A as well as prothrombin activity values than nonsmoking OC users. However, OC use did not increase antithrombin III activity in smokers. The effect of smoking on blood coagulation factors was not affected by age or number of cigarettes smoked per day (although there were no heavy smokers in the study). An ethinyl estradiol dose-response effect was evident on hemostasis in all OC groups, but the changes in coagulation factors at higher doses were more pronounced in smokers than in nonsmokers.

A prospective study of a monophasic oral contraceptive containing 30 mcg ethinyl oestradiol and 150 mcg desogestrel (Marvelon).

PIP: Marvelon, a monophasic oral contraceptive (OC) containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel, has been available to Malaysian women through the national family planning program since 1982. To assess the safety, effectiveness, and side effects associated with this OC, 247 women who requested the pill were enrolled in a multicenter prospective study that included follow-up after the first, third, and sixth cycles of use. 81% of participants had never used any form of contraception before Marvelon. 194 women (79%) completed the 6-month study. There were no pregnancies recorded. Although women reported a slightly increased incidence of nausea, breast tenderness, and headache in the first treatment cycle, these side effects had abated by the end of the third cycle. After six cycles, mean body weight had decreased by an average of 0.4 kg. Both systolic and diastolic blood pressure were unaffected. An unexpected finding was a decrease in the severity of acne with continuous use of Marvelon. Although both spotting and breakthrough bleeding increased slightly in the first two cycles, irregular bleeding returned to pretreatment levels by the third cycle. The length of the withdrawal bleed in the pill-free week was reduced. The incidence of irregular bleeding and other side effects was substantially lower in this sample of Malaysian women than in Asian and Caucasian Marvelon users surveyed in other studies.^ieng

Menstrual impact of contraception.

Persistent bleeding is a common reason for the discontinuation of contraception. Standard terminology for describing bleeding patterns by reference period is presented. Observed bleeding patterns with oral contraceptives, depot medroxyprogesterone acetate, the levonorgestrel subdermal implant, and intrauterine devices are described. Bleeding days are least with oral contraceptives that are highest in progestin and estrogen potency and dose, but the ratio of the two steroids is also important. Published studies suggest that oral contraceptives containing new nonandrogenic progestins have bleeding patterns as acceptable as older low estrogen formulations. Approaches to the evaluation and treatment of intermenstrual bleeding with contraceptive methods are reviewed. Patient education on expected bleeding patterns is essential to compliance and continuation.

PIP: Many women discontinue hormonal contraceptives because of persistent bleeding. Discontinuation can result in unwanted pregnancy. Hormonal contraceptives may have 2 effects on the menstrual cycle: continued cyclic bleeding or partial or complete suppression of the normal cycle. Oral contraceptives (OCs) suppress the normal ovarian cycle with an artificial cycle caused by withdrawal of the hormones on day 21. Progestin-only OCs, subdermal implants, injectable steroids, and the levonorgestrel-releasing IUD cause partial or complete suppression of the normal cycle. OCs with the highest progestin and estrogen potency and dose are associated with the least number of bleeding days. The ratio of the 2 steroids may affect bleeding. For example, an increase in either steroid appears to decrease breakthrough bleeding (BTB). In some women, BTB or spotting is associated with OC use. Clinical trials of OCs do not use standard terminology and definitions, making it difficult to analyze bleeding patterns. OCs with the new nonandrogenic progestins and low-estrogen doses tend to effect acceptable bleeding patterns similar to those of the older low-dose estrogen OCs. Among Norplant users experiencing persistent bleeding, levonorgestrel (0.03 mg 2 times/day for 20 days), ethinyl estradiol (0.05 mg/day for 20 days), and ibuprofen (800 mg 3 times/day for 5 days) reduce bleeding days and episodes of treatment. Some possible regimens to treat persistent bleeding in OC users include 7 day courses of estrogen (0.02 mg ethinyl estradiol or 2.5 mg conjugated equine estrogens). When BTB occurs in an OC user who has previously had normal menstrual cycles, providers should consider causes other than OCs, such as trauma-vaginal laceration, cervical lesion, endometrial lesion, fallopian tube cancer, and pregnancy. They should deliver good patient education on bleeding patterns to achieve good compliance and continuation.

Efficacy and safety of a monophasic and a triphasic oral contraceptive containing norgestimate.

Both monophasic and triphasic formulations of ethinyl estradiol plus norgestimate, a progestin with marked progesterone-receptor affinity and minimal androgen-receptor affinity, have been evaluated in numerous clinical studies designed to determine if norgestimate's receptor-binding profile provides enhanced safety without a reduction in efficacy. To date clinical trials have shown that both formulations of ethinyl estradiol/norgestimate offer contraceptive efficacy equivalent to that of other oral contraceptives. Monophasic ethinyl estradiol/norgestimate was associated with an incidence of breakthrough bleeding and spotting similar to that of monophasic ethinyl estradiol/norgestrel and an incidence of amenorrhea less than that of ethinyl estradiol/norgestrel. Cycle control with triphasic ethinyl estradiol/norgestimate was similar to that with monophasic ethinyl estradiol/norgestimate. Weight gain and elevated blood pressure were insignificant in clinical trials with both fixed-dose and phasic ethinyl estradiol/norgestimate formulations. Perhaps of greatest importance, both monophasic and triphasic ethinyl estradiol/norgestimate formulations consistently showed favorable impact on metabolic parameters, including elevations in serum high-density lipoprotein cholesterol, and reductions in the low-density lipoprotein/high-density lipoprotein ratio, the parameter considered most sensitive for atherosclerotic risk. Both monophasic and triphasic ethinyl estradiol/norgestimate formulations were associated with minimal and clinically neutral effects on carbohydrate metabolism.

Pharmacokinetics of once-a-month injectable contraceptives.

The addition of a short- or medium-acting estrogen ester to the long-acting progestins depot-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) to produce "combined" injectable formulations has proved a successful strategy in the development of once-a-month injectable contraceptives. Recent clinical pharmacokinetic studies undertaken on once-a-month injectable contraceptives in various WHO Collaborating Centers have guided the selection of the estrogen-progestogen combinations, ratios and dose schedules. At least three combined once-a-month injectable preparations exhibit acceptable pharmacokinetic and pharmacodynamic profiles; however, further improvement in the design of optimal estrogen/progestin injectables are expected during this decade.

PIP: The World Health Organization [WHO] Special Programme of Research, Development and Research Training in Human Reproduction has coordinated the developmental strategy of combined once-a-month injectable contraceptives. The strategy consists of the selection, based on pharmacokinetic data, of appropriate long-acting progestin-estrogen combinations to develop at least 2 sustained-release formulations; assessment of safety and effectiveness of these formulations in clinical research facilities; and their evaluation at field level through service facilities of national family planning programs. WHO Collaborating Centers were involved in selecting the estrogen-progestogen combinations, ratios, and dose schedules. Research has found at least 3 combined once-a-month injectable contraceptives that demonstrate acceptable pharmacokinetic and pharmacodynamic profiles. 2 safe and effective once-a-month contraceptive formulations (Cyclofem and Mesigyna) can join the existing choice of contraceptive methods. WHO expects more improvement in the design of optimal estrogen/progestin injectables in the 1990s.