This study was conducted to examine whether small doses of ethinylestradiol (EE, 0.02 mg) and chlormadinone acetate (CMA, 2 mg) administered in a novel 24/4-day regimen during six cycles would suffice to suppress proliferation and to cause secretory changes in the endometrium.
This Phase II, randomized (two assessment groups), single-center, open, uncontrolled, multiple-dosing study treated 59 female subjects. The subjects underwent three endometrial biopsies: one pretreatment, one during medication (either at Cycle 3 or Cycle 6) and one during the first post-treatment cycle.
The study revealed that 0.02 mg EE/2 mg CMA effectively transformed the endometrium from a proliferative state into a secretory or inactive state after three (90% of subjects) and six (76% of subjects) medication cycles. The mean endometrial thickness decreased markedly from 10.2 (SD±3.0) mm (pretreatment) to an unfavorable level for the nidation of a blastocyst [5.3 (SD±2.1) and 4.1 (SD±2.2) mm in Medication Cycles 3 and 6, respectively]. Correspondingly, estradiol and progesterone levels decreased during treatment. In the post-treatment cycle, endometrial biopsy and ultrasound evaluation as well as sex hormone levels suggested a quick return to fertility. There were no signs of hyperplasia, endometrial polyps, neoplasia or other detrimental histopathological changes at any time during the trial. Treatment-related adverse events (AEs) were reported by 22 (37%) of 59 subjects and were reported most commonly in Cycle 1, decreasing continuously thereafter. No AEs led to discontinuation of the trial medication and there were no serious AEs.
The 24/4-day regimen of 0.02 mg EE/2 mg CMA provided effective and reversible endometrial effects with secretory transformation or suppression without inducing pathological changes.
This study was conducted to assess the long-term efficacy and safety of a low-dose monophasic combined oral contraceptive (COC) containing 0.02 mg ethinylestradiol (EE) and 2 mg chlormadinone acetate (CMA) in a novel regimen administered daily for 24 days followed by a 4-day placebo interval.
In this multicenter, uncontrolled, Phase III trial, 1665 subjects took the COC 0.02 mg EE/2 mg CMA for up to 21 cycles. The overall Pearl Index was the primary end point; cycle control, safety, effect on acne and seborrhea, and changes in body weight and libido were secondary end points.
Contraceptive efficacy was analyzed for 1653 subjects completing 21,495 cycles. Six pregnancies occurred during trial duration with one attributable to method failure. The overall Pearl Index for the first year of use was 0.33 (95% confidence interval, 0.09-0.85). The mean number of bleeding/spotting days during six 90-day reference periods (RPs) decreased from 17.0 (RP 1) to 11.7 (RP 6), and the number of bleeding episodes per RP decreased from 3.8 (RP 1) to 2.7 (RP 6). Among subjects who presented with acne at the baseline visit, a decrease of papules/pustules and comedones was observed during the course of the trial. The most common "at least possibly related" adverse events were headache, breast discomfort and nausea. The tolerability and well-being was reported as being excellent or good in the majority of trial subjects (84.6% and 80.2%, respectively).
The low-dose COC 0.02 mg EE/2 mg CMA administered daily for 24 days followed by a 4-day placebo interval provides high contraceptive efficacy combined with an adequate cycle control and safety profile, beneficial effects on acne, and is well tolerated.
The study was conducted to compare the effects of 0.02 mg ethinylestradiol (EE)/2 mg chlormadinone acetate (CMA), given for 24 days each cycle, with those of 0.02 mg EE/0.15 mg desogestrel (DSG) and 0.03 mg EE/0.15 mg levonorgestrel (LNG), given for 21 days each cycle, on hemostatic, lipid, and carbohydrate metabolism parameters in healthy subjects, over six medication cycles.
A randomized, multicentre, open-label, Phase II trial measured markers of hemostasis, and of lipid and carbohydrate metabolism in 165 subjects randomly assigned to treatment with one of three combined oral contraceptives (COCs).
EE/CMA and EE/DSG had a similar effect on hemostatic parameters, the EE/LNG group showed comparatively smaller increases in the activity of factor VII [8.1% vs. 36.6% (EE/CMA) and 28.2% (EE/DSG)], protein C [5.9% vs. 32.9% (EE/CMA) and 21% (EE/DSG)] and endogenous thrombin potential-based activated protein C resistance [44.1% vs. 93.5% (EE/CMA) and 108.1% (EE/DSG)], and in contrast, free protein S levels decreased in the EE/CMA and EE/DSG groups (-12.7% and -4.3%, respectively) but rose in the EE/LNG group (20.4%). In all treatments, total cholesterol, total triglyceride and apolipoproteins increased. Levels of very low-density lipoprotein cholesterol particularly rose across all groups. Slight increases in high-density lipoprotein (HDL) cholesterol were observed for EE/CMA (14.6%) and EE/DSG (8.5%), with a rise above the upper limit of normal in 30% of the subjects taking EE/CMA. Conversely, for EE/LNG slight decreases in HDL cholesterol were observed (-12.4%) lipoprotein (a) levels decreased in the EE/CMA (-6.6%) and EE/LNG (-16.9%) groups and were unchanged in the EE/DSG group.
The changes observed were typical of those seen across low-dose COCs that differ according to commonly-used progestogens.
In a multicenter prospective trial, 58 healthy women aged between 35 and 49 years were studied for one year (639 cycles) while taking an oral contraceptive (OC) containing desogestrel 0.150 mg and ethinylestradiol (EE) 0.020 mg. Efficacy, control of the cycle, side effects, complaints, and climacteric symptoms were monitored after 3, 6, 9 and 12 cycles. No pregnancies occurred during the study period. Spotting gradually decreased from 29.3% in cycle 1 to 4.2% in cycle 12, while breakthrough bleeding (BTB) disappeared after cycle 7. One case of superficial thrombophlebitis and 3 cases of minor side effects were registered. With regard to the complaints, breast tenderness, headache, and depression gradually decreased during the study (basal vs. 12-month data: 50.9% vs. 31.2%, 48.3% vs. 18.7%, 39.6% vs. 20.8%, respectively), while nausea disappeared after three months. A significant treatment-dependent reduction of climacteric symptoms was obtained after cycle 3 and this tendency was maintained up to cycle 12. No changes were registered in body mass index (BMI) or blood pressure.
This study was a non-randomized clinical trial which compared the breast-feeding experience of 250 Argentine women taking levonorgestrel 0.03 mg daily (begun one week after delivery) with that of 250 women using non-hormonal contraceptives. Weight gain of unsupplemented infants, the most important of the several criteria used to assess breast-feeding performance, was similar for the two contraceptive groups. Levonorgestrel users began supplementary feeding of their infants significantly later than did non-hormonal users; levonorgestrel users were also somewhat less likely to discontinue breast-feeding during the study period. The two contraceptive groups were similar with regard to several other measures of breast-feeding performance: growth of all infants (regardless of supplementation), patterns of contraceptive discontinuation, mothers' subjective impressions of breast-milk sufficiency, and comparison of supplementation initiation with previous experience.
This study was a non-randomized clinical trial which compared the breast-feeding experience of 250 Argentine women taking levonorgestrel 0.03mg daily (begun one week after delivery) with that of 250 women using non-hormonal contraceptives. Weight gain of unsupplemented infants, the most important of the several criteria used to assess breast-feeding performance, was similar for the 2 contraceptive groups. Levonorgestrel users began supplementary feeding of their infants significantly later than did non-hormonal users; levonorgestrel users were also somewhat less likely to discontinue breast-feeding during the study period. The 2 contraceptive groups were similar with regard to several other measures of breast-feeding performance; growth of all infants (regardless of supplementation), patterns of contraceptive discontinuation, mothers' subjective impressions of breast-milk sufficiency, and comparison of supplementation initiation with previous experience.
This prospective noninterventional study assessed the contraceptive efficacy, safety and the effects on signs of androgenization of the generic oral contraceptive containing 2 mg chlormadinone acetate/0.03 mg ethinylestradiol (CMA/EE) in a real-world setting.
A total of 1440 women were investigated during a six-cycle period by 229 gynecological practices throughout Germany.
The adjusted Pearl index was 0.136 (unadjusted: 0.271). Of 463 patients with cycle irregularities at baseline, 83.4% had regular cycles after six cycles. Likewise, 74.1% of 162 patients with spotting or breakthrough bleeding at baseline were free from these symptoms at the end of study. The percentage of patients with dysmenorrhea decreased significantly from baseline (36.5%) to visit 3 after six cycles (12.3%; p=.0001), with a significant reduction in the use of pain medication (p<.0001). Additionally, the number of patients with skin and hair problems was significantly reduced (skin: 56.3% at baseline, 19.6% after six cycles; hair: 45.7% at baseline, 13.4% after six cycles; p=.001). CMA/EE was well tolerated by the patients, and 89.44% of the gynecologists were satisfied with the treatment.
Generic CMA/EE exhibits very good contraceptive efficacy, cycle control and dysmenorrhea reduction. Furthermore, treatment with generic CMA/EE led to a favorable reduction of skin and hair problems in our study.
Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z)).
Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography-mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose.
Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of approximately 400-500 pg/mL for CMA and 20-40 pg/mL for EE. Mass balance factors were 1.2-1.4 for CMA and 1.6-1.7 for EE, and accumulation factors were 1.7-2 for CMA and 1.7-1.8 for EE. Mean t(1/2,z) of CMA was approximately 25 h after single dosing and 36-39 h at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3+/-6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively.
The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t(1/2,z) of CMA was 36-39 h after multiple dosing, which is considerably shorter than the 80 h often quoted in the literature.
The study was conducted to assess the effects of the monophasic combined oral contraceptive containing ethinyl estradiol (EE) 0.03 mg and chlormadinone acetate (CMA) 2 mg (EE/CMA) on papulopustular acne of the face, décolleté (low neck) and back; on moderate comedonal acne of the face; and on seborrhea, alopecia and hirsutism.
Three hundred seventy-seven women were randomized (2:1) to receive EE/CMA (n=251) or placebo (n=126) for six medication cycles. Due to the placebo-controlled, double-blind design of the trial, condoms were supplied for contraception. The primary efficacy end point was defined as a reduction of at least 50% in the number of papules and/or pustules of the face from admission to Medication Cycle 6.
In total, 64.1% (161/251) of subjects treated with EE/CMA responded compared with 43.7% (55/126) of those taking placebo (p=.0001). The median reduction in papules/pustules on the face at Cycle 6 compared with admission was 63.6% (EE/CMA) compared with 45.3% (placebo group). For comedonal lesions of the face, the reduction in lesion numbers was 54.8% (EE/CMA) compared with 32.4% (placebo). Moderate papulopustular acne of the décolleté decreased by 92.9% (EE/CMA) vs. 50% (placebo group) and of the back by 86.0% and 58.3%, respectively. For these skin conditions, the p values for the relative difference between groups vs. baseline were <.05 at Cycles 3 and 6, in favor of EE/CMA. As part of a self-assessment rating, at least 70.5% (EE/CMA) vs. 41.3% (placebo) reported an at least satisfactory improvement of their moderate acne. Even 39.8% of women taking EE/CMA reported an "excellent improvement" or "complete resolution" of moderate acne compared with 12.7% taking placebo.
In addition to its contraceptive efficacy described elsewhere, EE/CMA is an effective treatment for moderate papulopustular acne and other androgen-related skin disorders.
An open, randomized cross-over study, comparing the effects of the oral contraceptive combinations 0.150 mg desogestrel (Org 2969) + 0.030 mg EE∗ and 0.150 mg levonorgestrel + 0.030 mg EE on lipid and lipoprotein metabolism, was carried out in healthy female volunteers. The study covered 9 cycles; a pretreatment cycle was followed by 6 treatment cycles (3 with one combination and 3 with the other combination), which in turn were followed by 2 post-treatment cycles. Eight volunteers received desogestrel + EE followed by levonorgestrel + EE and 7 volunteers received levonorgestrel + EE followed by desogestrel + EE. Each treatment cycle consisted of 21 days of tablet administration followed by a 7-day tablet-free period. Free and total cholesterol, phospholipids, triglycerides, lipoprotein-lipids, lecithinfatty acids and cholesterol ester-fatty acids were determined in serum samples obtained once before treatment, after both contraceptive periods and two months after the last treatment cycle. The effects of desogestrel + EE and levonorgestrel + EE on the above parameters, and on body weight and blood pressure were compared statistically, using an analysis of variance.
Acne is a multifactorial disease characterized by androgenic stimulation of sebaceous glands. Therefore, combined oral contraceptives (COCs) containing anti-androgenic progestogens are suitable candidates for acne treatment. This study aimed to show that a COC containing the anti-androgen dienogest (DNG) is superior to placebo and not inferior to a COC containing the potent anti-androgen cyproterone acetate (CPA) in improving mild to moderate acne.
Healthy women between 16 and 45 years old with mild to moderate facial acne were randomly assigned to receive ethinylestradiol (EE)/DNG (n=525), EE/CPA (n=537) or placebo (n=264) for six cycles in a multinational, multicenter, three-arm, double-blind and randomized trial. The primary efficacy variables were the percentages of change (from baseline to cycle 6) in inflammatory and total lesion count and the percentage of patients with acne improvement according to the Investigator Global Assessment.
All primary analyses proved that EE/DNG was superior to placebo and non-inferior to EE/CPA (p<.05). For inflammatory lesions, the reduction (+/-SD) rates were -65.6+/-29.9% for EE/DNG, -64.6+/-31.2% for EE/CPA and -49.4+/-41.0% for placebo. For total lesions, the reduction rates were -54.7+/-26.3% for EE/DNG, -53.6+/-27.5% for EE/CPA and -39.4+/-33.6% for placebo. The percentages of patients with improvement of facial acne were 91.9% for EE/DNG, 90.2% for EE/CPA and 76.2% for placebo.
EE/DNG was superior to placebo, in spite of the prominent placebo effects, and as effective as EE/CPA in the treatment of mild to moderate acne, thus proving a valid option for the treatment of acne in women seeking oral contraception.
During oral treatment with 3 mg micronized 17 beta-estradiol and 0.150 mg desogestrel for 21 days followed by 0.030 mg (A) desogestrel (15 women) or placebo (B) (14 women) for 7 days, ovarian function, bleeding pattern and estradiol levels were evaluated. The study was performed in a group-comparative, double-blind fashion. During a pre-treatment control cycle, using ultrasound scan, follicular diameter was measured on cycle days 10-16 and endometrial thickness on one of cycle days 22-26. Estradiol was measured at the time of ultrasound scan and progesterone three times in the luteal phase. During three treatment cycles, follicular diameter and endometrial thickness were monitored three times weekly and at the same time, estradiol and progesterone were measured. Treatment resulted in anovulation in all women. Maximum and mean estradiol levels were approximately 900 pmol/l and 550 pmol/l during treatment, respectively, and approximately 200 pmol/l during the estradiol-free weeks in both groups. Ten women showed ovarian activity (follicle size > or = 15 mm) during treatment, seven in group A and three in group B. Endometrial thickness decreased approximately 3 mm during treatment in both groups. The incidence of breakthrough bleeding and spotting was higher in group A when compared to group B. The study indicates that the combination of 3.0 mg micronized estradiol and 0.150 mg desogestrel is an effective and safe contraceptive, offering an acceptable cycle control. The addition of a low dose of desogestrel during the pill-free period did not further suppress ovarian activity nor improve the bleeding pattern. The results of this study should be interpreted with great care, since the number of women studied is relatively small.
The pharmacokinetics of gestodene (GEST) was determined in 12 healthy women (age 22 to 34 years), following single dose administration of 0.075 mg GEST. The same preparation was also administered during one treatment cycle after a wash-out phase of 1 week. After single dose administration, maximum concentrations of GEST in the serum were 4.9 +/- 2.5 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.2 +/- 0.2 h and 14.9 +/- 6.7 h, respectively. The apparent clearance was calculated to be 0.8 +/- 0.4 ml x min-1 x kg-1. The free fraction of GEST was 1.3 +/- 0.3% and the fractions bound to SHBG and albumin were 64.3 +/- 10.7% and 34.4 +/- 10.4%, respectively. The results showed that there was a gradual decrease in serum trough levels of GEST during the cycle, due to a concomitant and equally high decrease in SHBG concentrations in the serum of about 26%. At the end of one treatment cycle, the free fraction of GEST increased to 1.8 +/- 0.5%, the SHBG-bound fraction decreased to 57.0 +/- 10.2% and the albumin-bound fraction increased to 41.3 +/- 9.9%. Total serum clearance increased during the same time period from a mean value of 0.8 to about 1.2 ml x min-1 x kg-1. The clearance of unbound GEST, however, remained unchanged. An examination of the free GEST concentrations revealed the same time course of GEST trough levels during the cycle as the simulated curve. This was derived from the pharmacokinetic parameters which were obtained after single dose administration. Thus, the present study showed that the pharmacokinetics of GEST can be fully explained on the basis of single dose pharmacokinetics and the changes in serum protein binding which were caused by a reduction of SHBG levels in the serum during chronic treatment with GEST. There was no evidence of GEST inhibiting its own metabolism.
This study was conducted to compare the effects of two monophasic oral contraceptives (OCs) containing ethinyl estradiol (EE) 30 mcg+either chlormadinone acetate (CMA) 2 mg (Belara) or 0.15 mg desogestrel (Marvelon) on lipid, hormone and other relevant metabolic parameters.
Markers of lipid and carbohydrate metabolism, and reproductive hormone levels, were measured in 45 subjects randomly assigned to 6 months of treatment with one of the two OCs. The cortisol response to adrenocorticotrophic hormone (ACTH) stimulation was also evaluated.
In both treatment groups, triglycerides, high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) AI and Apo AII levels increased; low-density lipoprotein cholesterol (LDL-C) and the LDL-C/HDL-C ratio decreased; and total cholesterol and lipoprotein(a) were unchanged during treatment. Effects on HDL-C, Apo AI, LDL-C and the LDL-C/HDL-C ratio were more evident in the EE 30 mcg+CMA 2 mg group. Follicle-stimulating hormone, luteinizing hormone and androgen levels decreased and sex hormone-binding globulin levels increased in both groups. Both OCs increased basal cortisol levels and cortisol response to ACTH. Oral contraceptive did not have a clinically significant impact on carbohydrate metabolism.
Both low-dose monophasic OCs had comparable effects on lipid, hormone and metabolic parameters during six cycles of treatment in healthy female subjects. There was some evidence of a beneficial effect on atherogenic cardiovascular risk markers, which was slightly more pronounced with EE 30 mcg+CMA 2 mg.
The pharmacokinetics of levonorgestrel (LNG) was determined in 12 healthy women (age 21 to 33 years), following single dose administration of 0.15 mg LNG. The same preparation was also administered during one treatment cycle after a washout phase of 1 week. After single dose administration, maximum concentrations of LNG in the serum were 4.3 +/- 1.3 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.6 +/- 0.2 h and 13.9 +/- 3.2 h, respectively. The clearance was calculated to be 1.5 +/- 0.6 ml x min-1 x kg-1. The free fraction of LNG was 1.1 +/- 0.1% and the fractions bound to SHBG and albumin were 61.8 +/- 6.7% and 37.1 +/- 6.7%, respectively. There was a gradual decrease in serum trough levels of LNG from about 0.5 to 0.3 ng/ml during the cycle, and a concomitant decrease in SHBG concentrations in the serum by about 50%. Serum protein binding of LNG changed markedly during the treatment cycle. The free fraction increased to a value of 1.7 +/- 0.3%, the SHBG-bound fraction decreased to 42.0 +/- 11.4% and the albumin-bound fraction increased to 56.4 +/- 11.2%. Total serum clearance increased during the same time period from a mean value of 1.5 to about 2.5 ml x min-1 x kg-1. The clearance of unbound LNG, however, remained unchanged. An examination of the free LNG concentrations revealed the same time course of LNG trough levels during the cycle as the simulated curve. This was derived from the pharmacokinetic parameters which were obtained after single dose administration. Thus, the present study showed that the pharmacokinetics of LNG can be fully explained on the basis of single dose pharmacokinetics and the changes in serum protein binding which were caused by a reduction of SHBG levels in the serum during chronic treatment with LNG.
The clinical and metabolic effects of a short-term treatment with a combination contraceptive pill containing 0.150 mg desogestrel and 20 mcg ethinylestradiol were evaluated in a group of 17 healthy women. In spite of the low estrogen content, the pill exerted a good cycle control and the incidence of irregular bleedings was low. The minor side effects commonly associated with oral contraceptive (OC) use rarely occurred, and an improvement of premenstrual symptoms was reported during pill intake. As for the different biochemical parameters tested, the formulation induced a significant increase of fibrinopeptide A (FPA) plasma levels. However, the resulting increase of peptide was lower than that induced by pills containing 30 mcg ethinylestradiol. No significant modifications of plasma total cholesterol (T-CH) and low-density lipoprotein cholesterol (LDL-CH) were observed, while triglycerides (TG), high-density lipoprotein cholesterol (HDL-CH) concentrations and the HDL-CH/LDL-CH ratio significantly increased. A significant increase of apolipoproteins AI (Apo AI) and apolipoproteins AII (Apo AII) concentrations was also observed. Moreover, the pill did not alter fasting insulin and glucose levels and their response to an oral glucose tolerance test (OGTT). It may be concluded that this new formulation can be considered acceptable for clinical use, mainly in consideration of the minor or no changes in the biochemical parameters regarded as risk factors for venous and arterial diseases.
Nine women thought to be 15-16 weeks pregnant were treated with a vaginally inserted silastic device containing a 0.25% concentration of 15(S)-15 methyl prostaglandin F2α methyl ester for elective termination of pregnancy. All aborted before 22 hours. Mean time to fetal abortion was 12.7 ± 4.2 hours. All patients experienced some vomíting and diarrhea initially. Ease of administration and excellent abortifacient efficacy justify a wider trial of this promising approach to pregnancy termination.
Quingestanol acetate, an oral progestin, was administered in a continuous daily dose of 0.3 mg to 382 healthy women for a total of 3,208 woman-months, for contraceptive purposes. There was a cumulative pregnancy rate of 2.9 percent and a cumulative continuation rate of only 50 percent at the end of 12 months.The predominant cause for discontinuation — 33 percent of all terminations — was menstrual cycle disruption, experienced by 86 percent of all users. The most frequent disturbance of this type was intermenstrual bleeding (63.6 percent of all users), although patients were more intolerant of amenorrhea and of menorrhagia, which occurred less frequently (19.8 percent and 2.9 percent, respectively).The incidence of systemic complaints was small, occurring in only 9.4 percent of the total acceptors for 15.7 percent of the terminations.The high incidence of menstrual cycle disturbances appears to be the major disadvantage of this oral contraceptive. The anticipated advantage of contraceptive protection without ovulation inhibition was not borne out by this study.
Femulen, a progestogen only oral contraceptive (ethynodiol diacetate 0.5mg), was evaluated for its contraceptive efficacy and safety in 425 women aged between 16 and 47 years. This was a multicentre open study carried out in General Practice and Family Planning clinics. Five pregnancies were reported, three of which were a result of patient failure. The net pregnancy rate at one year for method failure was 0.5%. No ectopic pregnancy was reported. The median length of the menstrual period was between four and five days and the average length of the non-bleeding interval remained between 24 and 25 days throughout the study. Blood pressure on the whole remained within normal limits. However, there was a small decrease in both systolic and diastolic blood pressure which did not reach significant levels. Body weight was unaltered and no abnormality was found in cervical smears. Femulen was shown to be an effective and acceptable contraceptive in women of varying ages.
Femulen, a progestogen only oral contraceptive (ethynodiol diacetate 0.5mg), was evaluated for its contraceptive efficacy and safety in 425 women aged between 16 and 47 years. This was a multicenter open study carried out in General Practice and Family Planning clinics. 5 pregnancies were reported, 3 of which were a result of patient failure. The net pregnancy rate at 1 year for method failure was 0.5%. No ectopic pregnancy was reported. The median length of the menstrual period was between 4 and 5 days and the average length of the non-bleeding interval remained between 24 and 25 days throughout the study. Blood pressure on the whole remained within normal limits. However, there was a small increase in both systolic and diastolic blood pressure which did not reach significant levels. Body weight was unaltered and no abnormality was found in cervical smears. Femulen was shown to be an effective and acceptable contraceptive in women of varying ages.
Abortion was successfully induced in 15 of 20 patients from the 6th to the 12th week of gestation by intravaginal insertion of a newly developed silastic device containing an 0.5% concentration of 15(S)-15-methyl-prostaglandin F2α methyl ester. The mean abortion time for the 15 successful abortions was 11.33 hours, and multiparous patients aborted in a significantly faster mean time 7.33 hours, as compared to nulliparous patients, mean time 15.90 hours. The five patients who failed to abort with the prostaglandin all developed uterine activity and experienced cervical changes in conjunction with the prostaglandin administration. Abortion was achieved in these 5 patients by suction aspiration without the need for mechanical dilatation of the cervix or anesthesia. Fourteen patients in the study were premedicated with antiemetic and antidiarrheal drugs and 4 of the 14 experienced gastro-intestinal side effects. Six patients were not premedicated and all 6 developed gastro-intestinal side effects related to the prostaglandin administration. This technique of abortion induction was well tolerated and had good patient acceptance. Induction of abortion during the first trimester by intravaginal administration of a silastic device containing 15-ME-PGF2α could offer a valid alternative to the surgical interruption of pregnancy. The prostaglandin silastic device could also be employed along with surgical techniques to provide for a gradual softening and dilatation of the cervix thus eliminating the need for mechanical cervical dilatation with its potential of cervical damage leading to cervical incompetence and prematurity.
The study was conducted to assess the impact of depot medroxyprogesterone acetate subcutaneous injection 104 mg/0.65 mL (DMPA-SC 104) on body weight.
Changes in weight from pretreatment were analyzed using data from two 1-year, noncomparative trials of DMPA-SC 104 (North/South American, N=722; European/Asian, N=1065) and a 3-year, randomized study (SC/IM) comparing DMPA-SC 104 (N=266) with the DMPA intramuscular injection 150 mg/mL (DMPA-IM 150). For each study, additional analyses were conducted for changes in body weight by age (<25, 25 to 35 and >35 years) and body mass index (BMI) (<or=25, >25 to <or=30 and >30 kg/m2) subgroups.
In both 1-year trials, the mean (+/-SD) weight gain at month 12 was <2 kg [1.7 kg (+/-4.5 SD) in the Americas trial and 1.4 kg (+/-3.6 SD) in the Europe/Asia trial]. In the SC/IM trial, mean weight changes were similar between DMPA-SC 104 and DMPA-IM 150 groups, with mean (+/-SD) gains at month 36 of 4.5+/-8.5 and 5.8+/-8.7 kg, respectively. Similar differences in weight gain were observed by age or baseline BMI in all studies.
DMPA-SC 104 was associated with modest weight gain in most women.
The Population Council studied a pre-coital contraceptive microbicide vaginal product containing levonorgestrel (LNG) as active component and Carraguard gel as a vehicle (Carra/LNG gel) for couples who engage in occasional unplanned intercourse. The objective of this study was to evaluate the effect of sexual intercourse after vaginal application of Carra/LNG gel on serum levels of LNG in women and to assess LNG absorption by the male partner.
This was a randomized, cross-over, pharmacokinetic study including an abstinence arm and an arm in which couples engaged in sexual intercourse between 2 and 4 h after gel application. In each study arm, each woman received a single application of Carra/LNG gel (0.75 mg in 4 mL gel) followed by serial blood samples taken at 0, 1, 2, 4, 8, 24 and 48 h after gel application for LNG measurements. In the intercourse arm, LNG was measured in blood samples taken from the male partner before intercourse and at 4, 8 and 24 h after gel application in the female partner.
Time concentration curves for serum LNG levels showed a mean C(max) of 7.8+/-5.5 and 8.3+/-5.7 nmol/L, a mean T(max) of 6.2+/-5.9 and 7.5+/-5.7, and comparable area under the curve for the intercourse and abstinence arm, respectively. Pharmacokinetic parameters presented large variability between subjects, but excellent reproducibility within each subject. LNG was undetectable in 10 out of 12 male partners.
Sexual intercourse does not appear to interfere with vaginal absorption of LNG after application of a Carra/LNG gel. A vaginal pre-coital contraceptive gel is feasible.
This study examined plasma levonorgestrel (LNG) concentrations and pharmacokinetics following oral administration of a single LNG 0.75 mg tablet. Sixteen healthy female volunteers 19-44 years old enrolled in the study. Serial blood samples were drawn over 72 h after dosing in a fasting state. A gas chromatographic, negative ionization mass spectrometric detection analytical method was used to determine plasma LNG concentrations. The observed mean peak plasma LNG concentration was 14.1 +/- 7.9 ng/mL (range 6.7-39.0 ng/mL). The mean time of peak concentration was 1.63 +/- 0.74 h (range 1-4 h). The plasma LNG concentration versus time profiles were subjected to noncompartmental pharmacokinetic analysis for the purposes of determining half-lives, apparent oral clearances (Cl/F), apparent volumes of distribution after oral administration (V/F), and mean residence time (MRT). Half-lives calculated from the terminal decline in plasma LNG concentrations ranged from 16.2 h to 32.3 h (mean = 24.4 +/- 5.3 h). The Cl/F was 7.06 +/- 2.69 L/h, V/F was 260 +/- 129 L, and MRT was 27.8 +/- 5.2 h. LNG was well tolerated; there were no serious adverse events during the study.
We assessed to what extent the standard dose of levonorgestrel (LNG), used for emergency contraception, or a single dose (half dose), given in the follicular phase, affects the ovulatory process during the ensuing 5-day period. Fifty-eight women were divided into three groups according to timing of treatment. Each woman contributed with three treatment cycles separated by resting cycles. All received placebo in one cycle, and standard or single dose in two other cycles, in a randomized order. The diameter of the dominant follicle determined the time of treatment. Each woman had the same diameter assigned for all her treatments. Diameters were grouped into 33 categories: 12-14, 15-17 or 18-20 mm. Follicular rupture failed to occur during the 5-day period in 44%, 50% and 36% of cycles with the standard, half dose and placebo, respectively. Ovulatory dysfunction, characterized by follicular rupture associated with absent, blunted or mistimed gonadotropin surge, occurred in 35%, 36% and 5% of standard, single dose or placebo cycles, respectively. In conclusion, LNG can disrupt the ovulatory process in 93% of cycles treated when the diameter of the dominant follicle is between 12 and 17 mm. It is highly probable that this mode of action fully accounts for the contraceptive efficacy as well as the failure rate of this method. The present data suggest that half the dose may be as effective as the standard dose.
Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the United States. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel phenyl phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine) which exhibit potent anti-HIV and spermicidal activities. This study reports the preliminary preclinical study of our lead compound WHI-05, 5-bromo-6-methoxy-5, 6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl) methoxyalaninyl phosphate, for use as a dual-function topical microbicide. Acute toxicity studies have shown that WHI-05 has no detectable adverse effects on laboratory animals. The 13-week subchronic and reproductive toxicity potential of intravaginal gel-microemulsion formulation of WHI-05 were studied in mice to support its further development as a virucidal spermicide. Groups of 10 female B(6)C(3)F(1) mice were exposed intravaginally to a gel-microemulsion formulation containing 0%, 0.5%, 1.0%, or 2.0% WHI-05, 5 days/week for 13 consecutive weeks. On a molar basis, these concentrations represent 300 to 1200 times their in vitro spermicidal potency, and 1.5x10(4) to 6.1x 10(4) times their in vitro anti-HIV activity. After 13 weeks of intravaginal treatment, one half of treated mice were evaluated for toxicity, and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. Repetitive intravaginal application of WHI-05 to yield a local concentration 6.1x10(4) times higher than its in vitro HIV IC(50) value and 1200 times higher than its spermicidal EC(50)96%), or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent, WHI-05, did not cause significant acute or subchronic and reproductive toxicity under the test conditions.
Heterosexual transmission of HIV to women is the fastest-growing mode of transmission. In a systematic effort to develop a microbicide capable of preventing HIV transmission as well as providing fertility control, novel phenyl phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) have been identified that exhibit potent anti-HIV and spermicidal activities. This study reports the synthesis, characterization, and preclinical formulation of compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl) methoxyalaninyl phosphate. The anti-HIV activities of WHI-05 and ZDV were compared by measuring p24 antigen production and reverse transcriptase activity as markers of viral replication using human peripheral blood mononuclear cells (PBMC) infected with both ZDV-sensitive and ZDV-resistant strains of HIV. The sperm immobilizing activity (SIA) of WHI-05 was compared with that of ZDV and nonoxynol-9 (N-9) by computer-assisted sperm analysis (CASA). The effect of WHI-05 on sperm membrane integrity was examined by high resolution, low voltage scanning electron microscopy (HR-LVSEM). The in vitro cytotoxicity profile of WHI-05 versus N-9 were compared using normal human vaginal, ectocervical, and endocervical epithelial cells. The in vivo vaginal tolerance, absorption, and toxicity of a 2% WHI-05 gel-microemulsion was tested in the rabbit. Whereas ZDV displayed potent anti-HIV activity but lacked SIA, WHI-05 elicited both potent anti-HIV activity and SIA. WHI-05 inhibited the replication of ZDV-sensitive as well as ZDV-resistant strains of HIV in PBMC. CASA combined with HR-LVSEM demonstrated that WHI-05-induced SIA was not associated with membrane damage. Unlike, N-9, the spermicidal activity of WHI-05 was not associated with cytotoxicity to reproductive tract epithelial cells. Repetitive intravaginal application of a 2% WHI-05 gel-microemulsion did not damage the vaginal epithelium or cause local inflammation in the rabbit model. As a potent anti-HIV agent that has spermicidal activity and is devoid of mucosal toxicity, WHI-05 shows a unique clinical potential to become the active ingredient for a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.
This study presents the synthesis, characterization, and preclinical formulation of WHI-05, a novel bromo-methoxy substituted phenyl phosphate derivative of zidovudine (ZDV) and a dual-action spermicide with potent anti-HIV activity. The p24 antigen production and reverse transcriptase activity were measured to determine the anti-HIV activities of WHI-05 and ZDV with the use of human peripheral blood mononuclear cells (PBMC) infected with both ZDV-sensitive and ZDV-resistant strains of HIV. Computer-assisted sperm analysis (CASA) compared the sperm immobilizing activity (SIA) of WHI-05 with that of ZDV and nonoxynol-9 (N-9). High-resolution, low-voltage scanning electron microscopy (HR-LVSEM) examined the effect of WHI-05 on sperm membrane integrity. Using normal human vaginal, ectocervical and endocervical epithelial cells, the in vitro cytotoxity profiles of WHI-05 and N-9 were compared. WHI-05 exhibited both potent anti-HIV activity and SIA, while ZDV showed only potent anti-HIV activity. WHI-05 blocked the replication of ZDV-sensitive as well as ZDV-resistant strains of HIV in PBMC. SIA induced by WHI-05 was not associated with membrane damage, as demonstrated by CASA combined with HR-LVSEM. Repetitive intravaginal application of a 2% WHI-05 gel-microemulsion did not injure the vaginal epithelium or stimulate local inflammation in the rabbit model. This study indicated that WHI-05 qualified as an active ingredient for a vaginal contraceptive for women who were at high risk for acquiring heterosexual vaginal transmitted HIV.
Contraceptive efficacy and side effects are primary concerns of women when choosing a contraceptive method.
This cross-sectional multicenter study was designed to assess the reasons for selecting the contraceptive pill, the skin patch or the vaginal ring in 9700 women, aged 18-49 years, who consulted their doctors for starting or re-initiating combined hormonal contraception. A self-administered questionnaire regarding the reasons for the selection made and for the refusal of the remaining two methods was completed.
The vaginal ring showed the highest acceptance (46%) compared with the pill (39%) and the skin patch (15%), particularly in women aged 35-39 years. The ring and the skin patch were mainly preferred because of the lower probability of inadvertent omission (62% of cases), convenience, and monthly or weekly frequency of use. The pill was preferred because of its proven efficacy (60% of cases) and ease of use. The acceptance of the skin patch increased with age and the pill was mostly accepted only by women in the youngest age groups.
Convenience, frequency of use and lower probability of inadvertent omission were the primary determinants of contraceptive choice rather than the women's profile.
The five-year experience of 1,092 laparoscopic tubal sterilizations performed in a free-standing clinic in the U.S. with no anesthesiologist under local anesthesia is reviewed. The current technique of the Hasson "open" method and bipolar cauterization is felt to minimize major mishaps and is acceptably comfortable to the patient.
The experience of performing a conseceutive series of 1092 tubal sterilizations, using a local anesthesia, at a free standing outpatient clinic in the US between 1976-81 is reported. The clinic's experience demonstrated that low cost sterilizations could be performed safely in a facility lacking a general anesthesiologist, a blood bank, and a laporatomy set-up. Initially, unipolar forceps and closed laporscope tocar insertion was used, but in 1977 clinic personnel began using Kleppinger bipolar forceps to reduce the risk of ectopic burns and Hasson's open laparoscopy method to reduce the risk of extraperitoneal gas insufflation and vascular injury. Patient were initially screened over the telephone for cardiopulmonary disorders and other contraindications. 72 hours before the operation, they were counseled and informed of the risks. Preliminary laboratory examinations included blood counts, urinalyses, Papanicolaou smears, and gonorrhea cultures. In performing the sterilizations the local anesthestic, Xylocaine, was used. Surgical procedures included 1) administering a tranquilizing agent and an analgesic intravenously, 2) performing a paracervical block using a local anesthestic; 3) achieving uterine elevation; 4) infiltrating the subumbilical layers of the anterior abdominal wall with local anesthestic; 5) making a 1.5 cm incision; 6) inserting a 10 mm operating laparoscope; 6) creating pneumoperitoneum with nitrous oxide; 7) spraying and infiltrating the isthmic portion of the fallopian tubes with the local anesthestic; 8) cauterizing the tubes at 3 sites; and 9) releasing the pneumoperitoneum and closing up. Operating time is 15 minutes. The patient is observed for an hour and then discharged. The 1092 patient treated at the clinic had a median age of 31.7, a mean gravidity of 2.9, and a mean parity of 2.0. 17% had never delivered, 12.1% had never married, and 36% used no previous method of contraception. At the time of sterilization, 87 of the patients had IUDs removed, and 100 had abortions performed. Between 1976-81, complications associated with the sterilizations included 1) 2 cases of pelvic infection; 2) 7 cases of abdominal pain; 3) 6 cases each of incision bleeding, incision hematoma, and dysmenorrhea; and 4) 1 case each of vaginocervical laceration, vaginal bleeding, and paralytic ileus. 4 pregnancies were reported following sterilization, and 2 of these were ectopic pregnancies. 3 of the pregnancies occurred during the 1st 2 years of clinic operation, and only 1 during the last 3 years.
This study examines the effects of intratesticular injection of aqueous 1,2,3-trihydroxypropane (THP; glycerol) solution on male reproductive biology. In a series of experiments, Sprague-Dawley rats of various ages (48-101 days) were injected with 50-200 microliters per testis and various parameters were studied for up to 21 weeks later. While an injection of THP resulted in testicular weight reduction of 45-60% within 2 weeks, the weights of prostate and seminal vesicles were not affected for the duration of the experiments. The number of sperm per epididymis in the THP-treated rats declined rapidly and was reduced by 99.99% (of controls) after the 3rd mating. THP-treated males mated with virgin females at the same frequency as control rats but all were infertile after the 3rd mating and remained infertile for the duration of the tests (21 weeks after treatment). In vitro studies showed that metabolism of 14C-progesterone by testicular homogenates was not altered quantitatively or qualitatively by THP treatment. Serum levels of androgens, LH and FSH of THP-treated rats did not differ significantly from the controls. Histologically and histochemically, the Leydig cells appeared to be normal, but the seminiferous tubules of THP-treated testes were devoid of spermatogenic cells within 2 weeks of a single treatment. It is concluded that direct injection of THP acts as a potent inhibitor of spermatogenesis resulting in long-term infertility without affecting steroidogenesis, libido, secondary sex characteristics, mating behaviour or serum hormone levels.
3,5-Bis(dimethylarmino)-1,2,4-dithiazolium chloride [ORF 5513] is considered to be a prototype for a new class of female antifertility agents. When orally administered to rats at dose levels between 0.01 and 0.1 mg/kg/day for 3 days prior to expected ovulation, treatment resulted in a dose-dependent inhibition of ovulation. However, when the compound was administered to animals for 2 days prior to ovulation, ORF 5513 had little or no effect on ovulation at doses as high as 10 mg/kg/day. ORF 5513 also interrupted pregnancy at several stages of gestation, including implantation, placentation and late pregnancy. The minimum effective dose (MED) in the rat for inhibiting implantation (Days 1–6) and interrupting pregnancy immediately after implantation (Days 7–10) appears to be ≤ 10 mg/kg. The MED varies between ≤ 5 mg/kg for days 10–13 or 13–16 to ≤ 20 mg/kg for days 16–19 of gestation. Endocrine bioassays and studies revealed that ORF 5513 lacks hormonal activity. Histological studies indicated that the corpora lutea in all animals appeared uninvolved. When the treatment was initiated on day 16 of gestation, the earliest detectable cellular changes occurred in the chorionic villi and chorionic fetal vessels which effectively interfere with fetal circulation. Degeneration of the fetus occurred by day 19 of gestation while maternal placental circulation remained intact.
Compound 84-182 prevented pregnancy when administered subcutaneously at 10 mg/kg dose on days 3-8 post-coitum in hamsters and on days 6-10 post-coitum in guinea pigs. At lower doses, while in hamsters there was a marked reduction in implantation number, majority of implantations in guinea pigs showed signs of resorption. The compound was ineffective when administered at 10 mg/kg dose on days 1-3 or 6-7 post-coitum in hamsters and on days 1-5 or 4-8 post-coitum in rats. In rhesus monkeys, treatment with the compound at 5 and 10 mg/kg doses on days 16-21 of the menstrual cycle induced frank vaginal bleeding between days 21 and 24. Treatment on days 21-30 or after confirmation of pregnancy on days 32-36 was ineffective. In conventional bioassays, the compound was devoid of any estrogenic, antiestrogenic, progestational, antiprogestational, androgenic or antiandrogenic properties at the contraceptive dose. In competitive protein binding assay, the compound showed relative binding affinity (RBA) of less than 0.1% and 0.28% of progesterone, respectively, for rabbit and hamster uterine cytosol progesterone receptors. Its RBA for rat uterine cytosol estrogen receptors was less than 0.1% of estradiol-17 beta.
The disposition of the retro-steroid progestogen, 6-chloro-9β, 10α-pregna-1, 4, 6-triene-3, 20-dione [Ro 4-8347, I] was studied in man. Following oral administration of 4 to 8 mg of C-7 tritium labelled I to two women and one man, 41-46% of the radioactive dose was excreted in the urine within 3 days. None of the intact drug could be detected in plasma or urine indicating complete biotransformation and/or alternate routes of excretion. However, a metabolite, tentatively identified as 6-chloro-20α-hydroxy-9β, 10α-pregna-1,4-6-trien-3-one, accounted for up to 88% of the total unconjugated (ether extractable) radioactivity in the plasma and had an "apparent" halflife of 8-14 hours.
Acute toxicity studies of [Ac-D-NAL(2)1,4FD-Phe2,D-Trp3,D-Arg6]-LHRH (LHRH-A), a potent antagonist of LHRH were performed. Subcutaneous administration of this peptide to rats induced transient edema of the face and extremities. This effect was maximal 3-5 h after peptide administration and subsided by 24 h. These effects were not seen with an LHRH agonist or two other antagonists. This side effects of LHRH-A was peculiar to rats and not observed in mice, rabbits and rhesus monkeys. Intravenous administration led within minutes to depression of spontaneous activity in rats and monkeys. We conclude that some LHRH antagonists produce species specific effects on vascular permeability and spontaneous activity.
C31G (Savvy) has been developed as a topical vaginal microbicide with broad-spectrum antibacterial and antiviral properties. The objective of this study was to evaluate the distribution of a 1.0% concentration of (3.5 mL) C31G vaginal gel in the human pelvis using magnetic resonance imaging (MRI). Gel delivery with a standard applicator was primarily to the upper vagina and was well tolerated. Vaginal mucosal coverage at 18 min was excellent with 92% linear coverage and 75% surface contact coverage of the vagina. The upper vagina was almost completely covered and gel was also noted in the lower vagina. Coverage 6 h after application was substantially decreased, with 60% of maximal linear coverage and 41% surface contact. There was a very minimal coverage of the vaginal mucosa noted 24 h following insertion. Simulated intercourse resulted in relatively little change in overall distribution at all three time points. Repeat application of the gel may be necessary if intercourse has not occurred within the first few hours after initial insertion.
Based on interview data from 10841 Danish women aged 20 to 29 years, determinants for non-use of contraception at first intercourse (NU) were studied. One-fourth of the women (n = 2704) reported NU, whereas condoms and oral contraceptives were used by, respectively, 59% and 15%. NU decreased with the birth year of the first male partner (OR = 3.6; 95% CI: 2.8-4.8 for <or=1954 vs. 1968-1974) mainly in favor of condom use. Other determinants were the birth cohort of the woman (OR = 1.4; 95% CI: 1.0-1.9 for 1961-1962 vs. 1970-1972) and the calendar year of the first intercourse (OR = 1.4; 95% CI: 1.2-1.7 for 1985-1986 vs. 1987-1992), both initially in favor of oral contraception and later in favor of condom use, whereas young age at first intercourse was associated with a high prevalence of NU (OR = 1.8; 95% CI: 1.4-2.1 for <or=14 years vs. >or=17 years) at the expense of both oral contraception and condom use. Finally, NU was found to predict high-risk sexual behavior in terms of subsequent multiple sex partners, non-use of condoms, and induced abortion.
Immunocytochemical localization of inhibin was carried out in paraffin embedded tissue sections of the control and antiprogestin (ZK 98.299)-treated bonnet monkey endometrium using polyclonal antibodies generated against human seminal plasma inhibin (10.5 kDa). The study shows that administration of low doses (5 mg/week) of antiprogestin results in an increase in the expression of inhibin by the endometrium. Treatment with higher doses (20 mg/week) caused a decrease in the expression. Since treatment with higher doses also caused atropic changes in the endometrium, the decrease in inhibin could be the result of morphological damage to the endometrium rather than the effects of antiprogestin on the expression of inhibin. The potential involvement of endometrial inhibin in the process of nidation is speculated.
Efficacy, cycle control, tolerance, and adverse events were studied in a clinical Phase IV study using a new progestogen, gestodene, in an amount of 75 micrograms combined with 30 micrograms ethinylestradiol. The study was performed as a multicenter trial in 96,000 patients over a period of 6 cycles. Half of the patients taking the new preparation were first-time OC users, the other half switched from another OC. With regard to contraceptive efficacy, the life-table analysis showed a value of 0.032% for method failure and 0.114% for patient failure. The correspondent Pearl-Index is 0.062 and 0.22. The new drug was found acceptable by more than 90% of the women involved in the trial. Dysmenorrhea present in the "switchers" mostly disappeared on the new OC, while body weight and blood pressure remained virtually unchanged. Thus, it can be concluded that blood pressure and body weight behaviour is similar to that seen with other low-dose OCs. The new combined pill offers excellent cycle stability and has a very favourable effect on dysmenorrhea. The number of clinically diagnosed thrombotic events documented in this study was 0.65 per 1000 woman-years (TWY) and does not exceed the range of events seen in groups of women using non-hormonal methods of contraception (Oxford-FPA study 0.4/TWY and RCGP study 0.8/TWY).
The objective of this study was to evaluate the safety and efficacy of 1000 microg misoprostol vaginally (Cytotec) self-administered into the vagina for medical abortion. Three-hundred women with gestations between 42 and 63 days, with previous written consent, received vaginal misoprostol every 24 h up to a maximum of three doses for abortion. Outcome measures assessed included: successful abortion (complete abortion without surgery), side effects, decrease in hemoglobin, mean time of vaginal bleeding, mean expulsion time and mean time of returning of menses. Complete abortion occurred in 279/300 (93.0%, 95% CI 90, 96) patients. Medication to relieve symptoms was administered to all subjects after every misoprostol dose. Vaginal bleeding lasted 14.7 +/- 5.4 days. Mean expulsion time was 8.1 +/- 3.0 h for those who aborted after the first misoprostol dose. The mean drop in hemoglobin was statistically significant (p = 0.0001) but without clinical relevance. The frequencies of nausea and diarrhea were high. According to the observed outcomes, 1000-microg misoprostol vaginally could be a valid method to terminate pregnancies up to nine weeks gestation.
A randomized, open-label, multicenter study was undertaken to compare the effects of oral contraceptives (OC) containing 100 micrograms levonorgestrel (LNG)/20 micrograms ethinyl estradiol (EE) (Aless/Loette) and 1000 micrograms norethindrone acetate (NETA)/20 micrograms EE (Loestrin Fe 1/20) on menstrual cycle control over four cycles of use. A total of 84 evaluable women provided 274 cycles of exposure in the LNG/EE group, and 89 women provided 289 cycles of exposure in the NETA/EE group. Overall, the LNG/EE group achieved a consistently higher percentage of normal menstrual cycles as well as a lower rate of intermenstrual bleeding and amenorrhea than the NETA/EE group. In cycle 4, 63.8% of cycles were normal in the LNG/EE group compared with 41.9% in the NETA/EE group (p < 0.005). Of the total cycles in the NETA/EE group, 10% were amenorrheic, compared with 1.1% in the LNG/EE group. The occurrence of bleeding and/or spotting was significantly lower in cycles 2 and 3 in the LNG/EE group (41.7% and 34.8%, respectively) compared with the NETA/EE group (62.3% and 56.3%; p < 0.05). Other cycle variables were generally similar between groups, as was the incidence of adverse events. These results demonstrate that good cycle control was achieved with an OC containing 20 micrograms EE and that 100 micrograms LNG/20 micrograms EE produces better cycle control than 1000 micrograms NETA/20 micrograms EE.
We assessed the effectiveness, safety and factors that affected the outcome of midtrimester medical termination of pregnancy at 13-21 weeks gestation. Of the 1002 women, 3 took mifepristone and decided to continue with the pregnancy, with 999 women being compliant with the regimen. Of these, 2 women aborted prior to administration of misoprostol and 970 (97.1%) aborted successfully within five doses of misoprostol. Surgical intervention was necessary to complete the abortion process in 81 (8.1%) women. Women with no previous pregnancy (p = 0.02), no previous live birth (p = 0.0001) and gestations 17-21 weeks (p = 0.001) required more prostaglandin. Younger women (p = 0.0001) and women with a previous live birth (p = 0.001) were more likely to have a successful abortion. The induction abortion interval was significantly longer with increasing gestation [95% confidence interval (CI) difference in means: -2.52 to -0.89, p = 0.0001], increasing age (p = 0.0001) and no previous live birth (95% CI difference in means: -0.25 to -1.01, p = 0.0001). Surgical intervention was more likely to be required with increasing age (p = 0.008). Mifepristone in combination with misoprostol is a safe and effective regimen for midtrimester medical abortion with younger women and those with a previous live birth more likely to have a successful abortion.
The effects of the antiestrogenic antifertility agents MER-25 and U-11,100A (nafoxidine), on the uterus of the spayed rat have been studied and compared with those produced by estradiol-17β. In the Allen-Doisy test, all agents were estrogenic. At doses roughly equiactive in this test, the antiestrogens produced marked hypertrophy of the luminal epithelium similar to estradiol-17β but did not increase the mitotic activity in contrast to estradiol-17β. The response to the antiestrogens also appeared to be self-inhibitory with time. The conclusion is made that the complexity of these responses invalidates terms such as estrogenic or antiestrogenic and suggests a need for a more precise terminology.
Mature female rats were treated orally with U11, 100A and U11,555A on Day 2 of pregnancy and plasma levels of oestradiol-17β and progesterone were determined. Also examined were the mitotic patterns in the stromal, luminal epithelial and glandular cells of the uterus. Both compounds, at doses completely inhibiting implantation, eliminated the plasma oestradiol peak normally occurring about 22.00 hrs on Day 3 and also totally suppressed stromal mitoses but had little effect on epithelial and glandular mitoses. Lower doses of U11,555A permitting approximately 40% implantation did not lower the oestradiol peak but reduced stromal mitoses. A similar physiologically active dose of U11, 100A eliminated the oestradiol peak but did not completely suppress stromal mitoses. Progesterone levels in animals treated with these lower doses did not rise after Day 9 of pregnancy. Synthesis of oestradiol-17β from testosterone by ovaries of treated animals was significantly decreased and addition of the anti-oestrogens to ovarian tissue also decreased oestradiol synthesis. The results show that both compounds have a primary effect on ovarian oestradiol synthesis and probably exert a secondary effect on the development of the placenta.
This study aims to assess changes in bleeding patterns with the use of depot medroxyprogesterone acetate (DMPA) 104 mg/0.65 ml subcutaneous injection (DMPA-SC 104).
An analysis was conducted using data from two 1-year, noncomparative clinical trials (N=1787) and a 2-year randomized study comparing DMPA-SC 104 (N=266) with DMPA intramuscular injection (DMPA-IM). Bleeding was analyzed per 30-day interval by category and number of days. Analyses also were performed for age and body mass index (BMI) subgroups and for the percentages of women shifting from bleeding/spotting to amenorrhea after each injection.
Each study showed decreased incidence of irregular bleeding and increased amenorrhea with continued use of DMPA-SC 104. Rates of amenorrhea at Month 12 (52-64% across studies) and Month 24 (71% in the 2-year trial) were comparable with those originally reported for DMPA-IM. Changes in bleeding patterns showed no consistent differences according to age or BMI. The percentages of subjects shifting from bleeding and/or spotting to amenorrhea increased with each subsequent injection.
Clinical data show that the incidence of amenorrhea increases over time with the use of DMPA-SC 104.
The aim of the study was to assess the use, efficacy and factors influencing the outcome of medical abortion at 9-13 weeks' gestation.
Retrospective chart review of consecutive women undergoing medical abortion at 9-13 weeks' gestation was done.
A total of 1927 abortions were carried out at 9-13 weeks' gestation, of which 1076 (55.8%) were undertaken medically. Efficacy decreased with increasing gestation (p=.02). Surgical evacuation was carried out in 45 (4.2%) women including 10 (2.7%) at 64-70 days, 11 (3.3%) at 71-77 days, 10 (5.1%) at 78-84 days and 14 (8.0%) at 85-91 days of gestation (p=.02). Indications for surgery included continuing pregnancy [16 (1.5%) women], retained sac [5 (0.5%)], incomplete abortion [20 (1.9%)] and emergency curettage for bleeding [4 (0.4%)]. The number of misoprostol doses used and the induction-to-abortion interval both significantly increased with gestation (p<.001), while analgesia requirements did not vary with increasing gestation (p=.18).
Medical abortion at 9-13 weeks' gestation is an effective alternative to surgery. Medical methods should be offered routinely at these gestations, thus increasing women's choice.
Attempts to prevent conception without ovulation inhibition have failed so far. The daily use of progestins interferes with the hormonal pattern and disrupts the cycle. Since the anti-progesterone, 13-ethyl-17-hydroxy-18, 19-dinor-17α-pregna-4,9,11-trien-20-yn-3-one (R 2323), competes for the progesterone/progestin binding sites of the uterine cytosol receptor in various species, we have postulated that blockage by R 2323 of progesterone binding to the estrogen-induced receptor at the beginning of the luteal phase could upset progesterone-dependent changes and thus exert a contraceptive effect. In a two-year clinical trial in Haiti (1362 cycles), R 2323 (50 mg) has been administered orally, once a day for three consecutive days, exactly two weeks after the first day of menstrual bleeding (15, 16, 17th days). Results indicate that: Cycle length varies from 21 to 35 days (93%), but is perfectly regular for each woman; there is no incidence of amenorrhea, menstrual bleeding lasts 3 to 5 days (83%) with hardly any spotting or breakthrough bleeding (9%). The main side-effect is vomiting. Pregnancy rate expressed as the Pearl Index is 4.6% for drug-failure and 5.5% for patient failure. Since four pregnancies are due to omissions, it appears that R 2323 does not affect return to fertility.
Understanding practice models and provider costs for medication abortion (MAB) provision may elucidate ways to facilitate MAB integration into a larger arena of health care services. This study provides descriptive data on the diverse MAB practice models currently being utilized by US health care providers and the costs associated with the components of those models.
Data were gathered from a sample of 11 abortion care settings, using clinic administrative records and patient satisfaction surveys.
Practice models varied dramatically, with a wide range in the type of staff employed to provide MAB. The total episode cost for providing MAB ranged from 252 to 460 US Dollars, and patient satisfaction was high across all practices.
Information from this study can be used to guide decisions regarding MAB integration into practices not currently providing abortion or which provide only aspiration abortions. The information may also be useful for providers wishing to refine their MAB services.
A study of pituitary gonadotropins and ovarian steroids in 11 healthy women during 17alpha-acetoxy-11 beta-methyl-19-norprogesterone (sc-21009) therapy is presented. 4 women received 40 mcg/day starting on Cycle Day 5 through Day 26 while 3 women received 200 mcg and 4 women received 1 mg/day also on Days 5-26. Daily blood and 24-hour urine samples were obtained for follicle stimulating hormone (FSH), luteinizing hormone (LH), estrogens, progesterone, and pregnanediol assays. 40 mcg SC-21009 significantly increased plasma LH levels (p less than .001) through the follicular phase with only a slight increase in FSH. Higher doses of SC-21009 did not markedly change the plasma gonadotropin profile. Estrogen and progesterone levels were similar to control cycle levels at all 3 doses. These results were interpreted as demonstrating LH-FSH positive feedback mechanisms at the follicular phase during low-dose SC-21009 therapy and a lack of ovulation inhibitory activity at the doses of 40 mcg through 1 mg/day.
Coagulation factors, 11-dehydro-TxB2 (metabolite of TxA2) and 6-keto-PGF1 alpha (metabolite of PGI2) levels in 87 women who were treated for 9 months with oral contraceptives (OC) containing low doses of oestrogens and progestogens (Triquilar, Trinovum or Cilest) were investigated. In plasma, increases in F I, II, VII, VIII-c and 11-dehydro-TxB2 levels, but no modification of 6-keto-PGF1 alpha were observed. In urine, FPA concentration rose, but no change occurred in 11-dehydro-TxB2 and 6-keto-PGF1 alpha levels. No marked difference between the 3 OC preparations were noted. These data, and particularly the large increase of 11-dehydro-TxB2 (p < 0.01) suggest that a hypercoagulable state persists in low dosage OC users.
The Bioself 110 is a hand-held electronic device that combines the BBT and calendar methods of fertility regulation for planning or preventing pregnancy. A pilot study was undertaken in three centers in the United Kingdom to evaluate the Bioself 110 as a contraceptive aid. This paper deals with 1238 cycles from 131 women. Only one unplanned pregnancy occurred where a volunteer correctly used the Bioself 110 and had intercourse on a supposedly "safe" day. A second pregnancy was experienced by a volunteer who incorrectly used the device and had intercourse on what she though was a "safe" day. Another 11 unplanned pregnancies occurred due to barrier method failures, as well as 11 pregnancies where the volunteers knowingly had unprotected intercourse during the fertile phase. There were five planned pregnancies. The Bioself 110 was correctly used in 71% of the cycles studied. Eighty-four percent of the volunteers indicated that they were satisfied with the Bioself 110 after six to twelve cycles of use. It was concluded that the Bioself 110 can serve as an effective family planning aid and should be added to the menu of contraceptive methods available to women today.
The BIOSELF 110 is a hand-held, non-invasive electronic instrument that measures basal body temperature and cycle length, and automatically identifies the fertile and infertile phases of the menstrual cycle with flashing red light and green light signals, respectively. The device was evaluated in 77 cycles from 33 ovulatory women in Kuala Lumpur, Malaysia. Ultrasound monitoring of maximum follicular diameter (MFD) and urinary LH measurements with Ovustick were used as reference methods to estimate the time of ovulation and the fertile period. Based on the MFD day, the BIOSELF correctly identified the entire fertile period, and at least four fertile days, in 89% and 94% of the cycles studied, respectively. The mean duration of the fertile period as determined by the number of flashing red light days was 11.0 days (SD 2.9). The device correctly identified the onset of the postovulatory infertile phase in 94% of cycles, with a mean duration of about 10 (green light) days. The results were similar using the LH peak day as the reference method. The mean interval from the onset of the fertile period (first flashing red light day) to the MFD day was 6.9 days (SD 2.6), and from the MFD day to the end of the fertile period, 3.1 days (SD 2.2). The BIOSELF 110 showed itself to be a reliable device for identifying the fertile and infertile phases of the menstrual cycle and, thus, should be a useful aid for couples seeking pregnancy. Prospective clinical trials are underway to assess the contraceptive effectiveness of the device.