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Determinants of menstrual bleeding patterns among women using natural and hormonal methods of contraception. I. Regional variations.

Records of the occurrence of vaginal bleeding were obtained from women using either a natural method of contraception or one of four types of hormonal contraceptive. The relationships between their bleeding patterns and a number of demographic variables were examined, with the aim of identifying subgroups of women who, if they used a particular hormonal method of contraception, would be likely to suffer more or less disruption to their bleeding pattern than the 'norm'. Within contraceptive method, bleeding patterns were more closely related to the women's geographical region of residence than to any other factor. Some of the differences between regions were consistent across contraceptive methods. European women tended to have more bleeding/spotting days than women in other regions; Latin American women had relatively short episodes and long bleeding-free intervals, whether they were using the ovulation method, combined pills or a vaginal ring. Other differences were method-specific. Women using combined pills in India or Pakistan had fewer spotting episodes than women using the same method elsewhere; those using progestogen-only pills had more. Regional variations in bleeding patterns were particularly marked among women using DMPA, and increased over time: by their fourth injection interval, 25% of European women had amenorrhea, as compared with 72% of subjects in North Africa. These findings need to be confirmed by carefully controlled studies of menstrual bleeding patterns and their acceptability in various ethnic groups. The results would be valuable in counselling new contraceptive acceptors, and could eventually guide the choice of methods for introduction into national family planning programmes.

Administration, Intravaginal↗

Hormonal contraception in diabetic women: acceptability and influence on diabetes control and ovarian function of a nonalkylated estrogen/progestogen compound.

The clinical acceptability and the influence on diabetes control were investigated in 50 women with insulin-dependent diabetes mellitus (IDDM) during intake of a combined nonalkylated estrogen/progestogen compound (4 mg 17-beta estradiol, 2 mg estriol and 1 mg norethindrone) for one year. In 6 IDDM women, the influence of the hormonal treatment on diabetes control and on ovarian function was investigated by measuring the concentration of glycosylated hemoglobin (Hb-Alc), fasting plasma glucose, serum estradiol, serum estrone, serum progesterone and sex hormone binding globulin (SHBG) capacity. No pregnancy occurred during the study and the overall continuation rate of 60% compare well with the continuation rate normally found in non-diabetic women after administration of conventional type oral contraceptives. No difficulties with diabetes control was registered and no significant changes in insulin requirements, 24-h urinary glucose excretion nd Hb-Alc were found. Ovulation was inhibited during the hormonal intake as judged by serum progesterone measurements. Serum estrone increased (p less than 0.05), but this had no influence on SHBG capacity, indicating that the estrogen/androgen balance was unchanged during treatment.

Adult↗

Pharmacodynamic assessment of dihydroxyprogesterone acetophenide plus estradiol enanthate as a monthly injectable contraceptive.

The pharmacodynamics of the combination of dihydroxyprogesterone acetophenide (DHPA) and estradiol enanthate (E2-EN) following its intramuscular administration at two doses were studied in 16 healthy women of reproductive age. Subjects were randomly allocated in two groups: group I (n = 9) received the combination DHPA 150 mg + E2-EN 10 mg on three consecutive monthly injections, while group II (n = 7) received half-dose of the same formulation. Ovarian function and endometrial bleeding patterns were investigated in all participants for one pre-treatment cycle, three treatment intervals and two post-treatment cycles. The results disclosed that ovulation was inhibited for at least 30 days following DHPA/E2-EN administration in all participants from both groups. The circulating estradiol levels 30 days after last injection were slightly elevated as compared with those observed in normal early follicular phase. Return to ovulatory cycles was documented within 90 days after treatment. The length of the bleeding-free intervals during treatment was shortened in both groups, particularly in group II. No significant changes in HDL-cholesterol levels were observed throughout the study. It is envisaged however, that large modification of the formulation and additional long-term safety studies will be required prior to its recommendation.

Adult↗

Somatic tissue responses of male rhesus monkeys treated with a contraceptive steroid formulation.

Rhesus monkeys (Macaca mulatta) were treated with testosterone (100 micrograms/kg/day) plus estradiol (0.5 micrograms/kg/day) via subcutaneous polydimethylsiloxane (PDS; Silastic) implants for thirteen months. This steroid regimen inhibited dramatically spermatogenesis. Gross and histopathological examination of the musculoskeletal, circulatory, endocrine (excluding the testis), central nervous, gastrointestinal and respiratory systems failed to uncover any untoward effects of the long-term exposure due to the contraceptive formulation. Similarly, no remarkable effects were observed in the ionic, chemical and formed elements of blood or secondary sex structures. Failure to detect secondary complications attributed to the steroid treatment offers further justification for evaluating a contraceptive strategy based on administering naturally occurring steroids at sustained rates approximating those at which they are produced endogenously in the human male.

Animals↗

Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel.

The oral administration of 150 micrograms desogestrel and 30 micrograms ethinyl estradiol (EE2) increases (P less than 0.001) serum concentrations of sex-hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG), whereas treatment with 150 micrograms levonorgestrel and 30 micrograms EE2 only increases serum CBG concentrations. No changes in serum albumin concentrations occurred during or after treatment with either preparation, and increases in SHBG and CBG returned to the pretreatment values 1 month after treatment ceased. The serum distribution of levonorgestrel was unchanged during treatment, whereas the increase in serum SHBG concentrations after treatment with the preparation containing desogestrel decreased (P less than 0.001) the percentage of non-protein-bound 3-keto- desogestrel and the percentage of albumin-bound 3-keto- desogestrel but increased (P less than 0.001) the SHBG-bound fraction. Oral contraceptives containing either progestogen decrease the mean serum non-protein-bound testosterone concentrations, especially during treatment with desogestrel (P less than 0.001), and desogestrel may therefore by the more appropriate progestogen for the treatment of women prone to androgenic side effects.

Adult↗

Return of fertility after discontinuation of depot medroxyprogesterone acetate and intra-uterine devices in Northern Thailand.

796 Thai women who stopped using the long-acting injectable contraceptive 'Depo-Provera' (medroxyprogesterone acetate) and 125 women who had an intra-uterine device removed to have a planned pregnancy were followed-up to ascertain the delay between conception and the end of contraception, and to determine the proportion of women who did not conceive in the 2 years after discontinuation. The median delay before conception was 5.5 months plus the estimated duration of the effect of the last injection of depo-provera and 4.5 months after discontinuing the IUD. Since depo-provera acts for approximately 15 weeks, women can except a median delay to conception of around 9 months after their last injection. The proportions of women who did not conceive within 1 year and within 2 years of stopping contraception by the two methods were similar. There was no evidence to suggest that prolonged use of depo-provera increases the delay before conception, and the return of fertility among never pregnant ex-users resembled that of ever pregnant ex-users.

Delayed-Action Preparations↗

Termination of early pregnancy by the 3 beta-hydroxysteroid dehydrogenase inhibitor epostane.

Progesterone is essential to sustain pregnancy in the first eight weeks. Its synthesis requires the enzyme 3 beta-hydroxysteroid dehydrogenase (3-HSD). We tested the efficacy of an orally administered 3-HSD inhibitor, epostane, in terminating unwanted early pregnancy. Fifty women in the fifth through eight weeks of pregnancy took epostane (200 mg orally every six hours) for seven days. By day 14, pregnancy had been terminated in 42 of the 50 patients (84 percent). Eight women (16 percent) did not abort and underwent dilation and curettage. Vaginal blood loss occurred on average on the third day of epostane treatment, and abortion on the fifth day. Two patients had incomplete abortions; one required a transfusion because of blood loss. Nausea was frequent (in 86 percent), but 76 percent of the participants concluded that epostane was preferable to dilation and curettage. The mean (+/- SD) pretreatment progesterone level (76 +/- 16 nmol per liter) decreased by day 7 (to 16 +/- 11 nmol per liter) and day 14 (to 10 +/- 9 nmol per liter) in those who aborted; levels of human chorionic gonadotropin also decreased from the mean at base line (73 +/- 72 kIU per liter) to 18 +/- 7 kIU per liter on day 7 and 9 +/- 5 kIU per liter on day 14. In those who did not abort after epostane treatment, progesterone levels decreased only slightly by day 7 (to 52 +/- 21 nmol per liter) and rose again (to 81 +/- 18 nmol per liter) by day 14. Among women who responded to epostane, normal menstrual periods had resumed by day 42 after the beginning of treatment in 72 percent. We conclude that epostane taken orally is an effective and safe method for the noninvasive termination of undesired early pregnancy.

3-Hydroxysteroid Dehydrogenases↗

Normal values for peripheral blood white cell counts in women of four different ethnic origins.

Total and differential white cell counts were studied in 399 women living in the same community in Britain but drawn from four different ethnic groups. The groups were white (northern European), Indian, black (African and West Indian), and Oriental. The total white cell count and absolute neutrophil count were significantly lower in the black group than in each of the other groups. The absolute monocyte count was higher in whites than in each of the other groups. Contrary to earlier reports, the absolute eosinophil count in blacks was no higher than in whites, suggesting that the high eosinophil counts previously found had an environmental rather than a genetic cause. The eosinophil count of Indians was only marginally higher than that of whites and the difference was not significant, again suggesting that high eosinophil counts previously reported had an environmental cause. No ethnic variation was found in the absolute lymphocyte count. The lower white cell count and neutrophil count found in blacks is of considerable practical importance, and blacks should not be assessed in relation to reference ranges derived for whites. Nevertheless, the eosinophil count in healthy blacks is no higher than that of whites and counts above reference ranges for whites should be considered clinically important. The differences between white cell counts of Indians and Orientals and those of whites are minor and for practical purposes they can be assessed in relation to reference ranges derived for whites.

Adolescent↗

The effect of levonorgestrel administered in large doses at different stages of the cycle on ovarian function and endometrial morphology.

In a pharmacokinetic study, levonorgestrel (L-NOG) 0.75 mg was administered orally to 10 swedish women in the early follicular phase of the menstrual cycle. L-NOG levels were measured after L-NOG administration. A peak level of 16 nmol/l was reached after 2 hours, T 1/2 was estimated to be 14.5 hours (8.5-18.5) in the 24-48-hour interval after dosing. Seventy-two women (in Stockholm, Bombay and Shanghai) were assigned to 4 treatment groups and studied during a control cycle, a treatment cycle and a posttreatment cycle when 0.75 mg L-NOG was administered orally for 4 days in the follicular phase, periovulatory period or luteal phase. Peripheral blood was drawn 3 times weekly during the entire study for the assay of estradiol and progesterone. In 22 women in Stockholm, an endometrial biopsy was obtained on cycle day 20-22 in all 3 cycles studied. When L-NOG was administered on periovulatory days 9, 11, 13, and 15, 3 women showed follicular activity only, 7 exhibited follicular activity followed by insufficient luteal function and 7 women ovulated normally. When L-NOG was administered on periovulatory days 11, 12, 16 and 19, 7 women ovulated during treatment, 6 women exhibited follicular activity followed by insufficient luteal function and 5 exhibited follicular activity only. When L-NOG was administered in the follicular or luteal phase, no effect on ovarian function was seen. No significant prolongation of the cycle lengths was seen when L-NOG was taken during the follicular phase. Only minor effects in the endometrium were observed during treatment.

Adult↗

The effect of a biodegradable contraceptive capsule (Capronor) containing levonorgestrel on gonadotropin, estrogen, and progesterone levels.

Eight ovulatory women participated in the preliminary evaluation of a new method of contraception. The technique consisted of subdermal implantation of a biodegradable capsule capable of controlled release of levonorgestrel. The study spanned five menstrual cycles: three observation cycles to confirm ovulation, a cycle with the capsule implanted, and a follow-up observation cycle after its removal. All subjects who were sexually active relied on barrier contraception during the study. Basal body temperature determinations were made throughout all five cycles, and the last three cycles included serum assays of luteinizing hormone, follicle-stimulating hormone, estradiol, progesterone, and levonorgestrel on days 5, 8 to 18, and 22. All subjects except one experienced suppression of ovulation while the capsule was in place. No serious adverse effects were encountered. These results would seem to justify a larger clinical trial to assess the actual efficacy of this contraceptive method.

Biodegradation, Environmental↗