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.

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.

Relationships between blood pressure, oral contraceptive use and metabolic risk markers for cardiovascular disease.

Data from a previous study, designed to compare metabolic risk markers for cardiovascular disease in non-users and oral contraceptive (OC) users, were analysed to evaluate the influence of OC composition on blood pressure. Healthy, female volunteers (1189 women) either not using OC (non-users) or currently using one of six different combined formulations (users) were compared. Combinations studied contained 30-40 micrograms ethinyl estradiol combined with the progestins levonorgestrel, norethindrone (at two and three different doses, respectively) or desogestrel. After statistical standardisation to account for the significantly greater age of the non-users and longer duration of OC use amongst the levonorgestrel combination users, mean blood pressure was higher, compared with non-users, in users of monophasic or triphasic levonorgestrel combinations (systolic: +4.3 mmHg (p < 0.001) and +2.7 mmHg (p < 0.001), respectively; diastolic: +2.6 mmHg (p < 0.001) and +2.3 mmHg (p < 0.05), respectively). Blood pressures in users of monophasic norethindrone and desogestrel combinations were not significantly raised and there was no increase in the proportion of women with abnormal values. Diastolic and systolic blood pressures were positively associated with oral glucose tolerance test insulin response (r = 0.11 (p < 0.01) and r = 0.15 (p < 0.001), respectively) in users but not in non-users. Currently used OC containing norethindrone or desogestrel progestins have little impact on blood pressure. Their correlated reduction in impact on insulin concentrations, though small, suggests common mechanisms through which OC affect blood pressure and insulin.

PIP: The influence of oral contraceptive (OC) composition on blood pressure was investigated in 1189 healthy volunteers recruited from centers in London and southeast England. The mean age of the non-users was 32.5 years compared with 28.0 years among OC users. The OC users were currently taking one of six types of combined OCs containing 30-40 mcg of ethinyl estradiol combined with the progestins levonorgestrel (150 mcg or a 50-125 mcg triphasic), norethindrone (500 mcg, 1000 mcg, or a 500-1000 mcg triphasic), and desogestrel (150 mcg). After adjustment for age and duration of OC use, mean blood pressure was significantly higher compared to non-users in users of monophasic or triphasic levonorgestrel combinations (systolic, +4.3 and +2.7 mm Hg, respectively; diastolic, +2.6 and +2.3 mm Hg, respectively). There was no significant increase in blood pressure levels in users of monophasic norethindrone and desogestrel combinations. Diastolic and systolic blood pressures were significantly positively associated with oral glucose tolerance test insulin responses (r = 0.11 and -0.15, respectively) in OC users but not in non-users. These findings suggest that currently used low-estrogen dose OCs containing norethindrone or desogestrel have little effect on blood pressure. They further indicate that the typical profile recorded in OC users--elevated blood pressure, increased triglycerides, decreased high density lipoprotein cholesterol, increased insulin concentrations, and reduced insulin sensitivity--mainly reflect the independent effects of the contraceptive steroids rather than a single coordinated disturbance.

Insulin sensitivity is decreased in normal women by doses of ethinyl estradiol used in oral contraceptives.

OBJECTIVE: We determined the independent effects of various doses of ethinyl estradiol used in oral contraceptives or norethindrone acetate, as well as their combination, on insulin sensitivity in normal women. STUDY DESIGN: Thirty-three normal ovulatory female volunteers were recruited for this study. Insulin tolerance tests were performed after carbohydrate loading to determine the kinetic disappearance of glucose and insulin. After initial testing the women were randomized into four groups: ethinyl estradiol 20 micrograms, 35 micrograms, and 50 micrograms and norethindrone 1 mg. Insulin tolerance tests were repeated after 1 month of treatment and again after a second month, when all ethinyl estradiol groups received the addition of norethindrone 1 mg to their doses of ethinyl estradiol. Plasma glucose and insulin were measured, and insulin sensitivity (K(itt) glucose) and the disappearance of insulin (K(itt) insulin) were calculated. RESULTS: All groups were comparable at baseline, and no significant changes in fasting glucose and insulin were evident with treatment. After ingestion of 50 micrograms ethinyl estradiol the K(itt) glucose value decreased significantly (p < 0.03) and ingestion of 20 micrograms and 35 micrograms showed individual changes, but as groups the changes were not statistically significant. All ethinyl estradiol groups combined had a significant decrease in K(itt) glucose (p < 0.01). Norethindrone 1 mg alone did not change K(itt) glucose values, and after the addition of norethindrone to ethinyl estradiol, K(itt) glucose values normalized. K(itt) insulin values were also lower with treatment but were lower with ethinyl estradiol plus norethindrone compared with ethinyl estradiol alone (p < 0.04), suggesting an attenuation of insulin clearance with the progestin. CONCLUSION: Ethinyl estradiol alone decreases insulin sensitivity, and this may occur at lower doses, but norethindrone 1 mg does not appear to do so. However, progestins may alter insulin clearance.

PIP: In southern California, reproductive endocrinologists compared data on 3 normal ovulatory 19-42 year old women blindly randomized into 4 groups to determine the independent effect of ethinyl estradiol and norethindrone acetate, both of which are in oral contraceptives, on glucose tolerance and insulin sensitivity. They used the most simple and rapid of the alternatives to the oral glucose tolerance test--the insulin tolerance test. Women received either 20 mcg/day, 35 mcg/day, or 50 mcg/day of ethinyl estradiol or 1 mg/day of norethindrone acetate. For the 2nd month, all women using ethinyl estradiol also received 1 mg/day of norethindrone acetate. The women in all 4 groups had comparable plasma glucose and insulin values while fasting. Estrogen in the 3 contraceptive doses reduced insulin sensitivity (p 0.03). The effect was not significant at 20 mcg and 35 mcg ethinyl estradiol, but 22.2% and 14.3% of the women receiving 20 mcg and 35 mcg ethinyl estradiol, respectively, did experience some reduction in insulin sensitivity. One mg norethindrone acetate alone did not affect insulin sensitivity, but when it was administered with 50 mcg ethinyl estradiol, insulin sensitivity values returned close to normal. 35 mcg of ethinyl estradiol lowered insulin clearance values (19.17% min vs. 9.53%/min; p 0.03). Addition of 1 mg norethindrone acetate to all ethinyl estradiol groups resulted in even more of a reduction (10.58%/min vs. 8/81%/min; p 0.04), indicating that a progestin reduces insulin clearance. In conclusion, ethinyl estradiol, even at low doses, appears to decrease insulin sensitivity while progestins do not. Yet, progestin appear to affect insulin clearance.

Effects of different doses of norethisterone on ovarian function, serum sex hormone binding globulin and high density lipoprotein-cholesterol.

The ovarian effects of different doses of norethisterone (NET) were compared in 45 normally menstruating women in order to find the lowest effective dose of the Chinese NET "visiting pill". Subjects were randomly divided into 3 groups. Each subject in each group was taking 0.5, 1.5 or 3.0 mg per day from days 5 to day 18 of the cycle. Blood samples were taken on days 5, 8, 11, 14, 17, 20, 23, 26 and 29 of the cycle. Serum oestradiol (E2), progesterone (P), sex hormone binding globulin (SHBG), high density-lipoprotein cholesterol (HDL-C), and NET concentrations were measured. Ovulation, delayed ovulation, ovulation inhibition and follicular activity were classified by the analysis of the peripheral serum levels of sex hormones. Ovulation occurred in 7 women in the 0.5 mg group, in 2 women in the 1.5 mg group and in none of the 3.0 mg group. Mean serum SHBG levels were reduced progressively by 6.6% (Group 0.5), 15.5% (Group 1.5) and 23.4% (Group 3.0). There were no significant changes in HDL-C levels in any group. There was a significant correlation of mean serum NET concentrations with dose. The lack of complete inhibition of ovulation in most women in the 1.5 mg and 0.5 mg groups might suggest that the dose of NET required when used as a visiting pill could not be reduced below 3.0 mg.

PIP: In Shanghai, China, 45 25-35 year old women took a daily norethisterone (NET) "visiting pill" (vacation pills) on menstrual cycle days 5-18 as part of a clinical study comparing various doses of NET on ovarian function, sex hormone binding globulin (SHBG), and high density lipoprotein-cholesterol (HDL-C). The aim of the study was to determine the lowest effective dose of the NET visiting pill. Even though some ovarian activity occurred at all 3 doses (0.5, 1.5, and 3 mg), no woman experienced ovulation at 3 mg NET/day during days 5-18 of the cycle. It suppressed ovulation in 11 (73.3%) of the 15 women. Follicular activity occurred in the remaining 4 women. Ovulation occurred in 33% of women taking the 1.5 mg dose and in 66% of those taking the 0.5 mg dose. The higher the NET dose, the greater was the fall in mean serum SHBG levels from control levels (3 mg, 23.4%; 1.5 mg, 15.5%; and 0.5 mg, 6.6%). Both the regression equation and log dose regression equation showed a significant correlation between mean serum NET levels and dose (p .001). HDL-C levels remained basically the same as control levels. Since, at the 1.5 mg dose, ovulation occurred in 5 women and only 5 women experienced complete inhibition, a dose no lower than 3 mg should be used for the NET visiting pill.

Hormone levels and anogenital swelling of female chimpanzees as a function of estrogen dosage in a combined oral contraceptive.

A combined oral contraceptive consisting of ethinyl estradiol (EE2) in three dosages (50, 100, and 400 micrograms) and norethindrone (0.5 mg) was given to female chimpanzees to determine the effect on endogenous sex hormone levels and anogenital swelling. Serum levels of EE2 increased with increasing dosages of EE2, estradiol decreased, and luteinizing hormone, progesterone and testosterone were maintained at approximately midfollicular phase levels. Urinary levels of EE2 glucuronide increased with the increasing dosages of EE2, whereas estrone and pregnanediol glucuronide were essentially undetectable. The cyclic increase in female anogenital swelling was abolished when the norethindrone was combined with 50 micrograms of EE2 and relatively constant and low levels of swelling were recorded. Relatively constant but successively higher levels of swelling were recorded when the norethindrone was combined with the higher dosages of EE2. These effects of oral contraceptives on female genital tissues are relevant to our laboratory studies of sexual behavior in chimpanzees given oral contraceptives and could also have implications for women taking oral contraceptives.

Long-term use of depot-norethisterone enanthate: effect on blood coagulation factors and menstrual bleeding patterns.

Fifty-six women using depot-norethisterone enanthate injections for contraception for 2 years or more were compared with a control group of 48 women not using hormonal contraception. No significant difference was found between the study group and controls for Factors VIIc and Antithrombin III. Factor Xc was reduced in women who had used the injections for over two but less than five years [controls: mean 90.3% SD31.2 vs users for 2-5 yr: 78.7% SD17.1, 95%CI difference in means -0.3, -22.9]. In the group using Net-En for five years or more, Factor Xc was significantly higher than in the control group, but only by 14% of the mean control value [users for over 5 yr: 103.2% SD15.2, 95%CI difference in means 3.1, 22.7]. Haemoglobin levels, red cell count and packed cell volume were higher in those using the injections than in the control group. Changes in the platelet count were not statistically significant. Twenty-three women using the injection agreed to keep menstrual diaries. Of these, 20 experienced amenorrhoea for more than two consecutive injection intervals (112 days). It is concluded that long-term use of norethisterone enanthate is not associated with any markedly deleterious effects on Factor VIIc, Xc, or antithrombin III or haemoglobin levels. Amenorrhoea of 4 months or more can be expected after two years of continuous use.

Effect of long-acting progestagen-only injectable contraceptives on carbohydrate metabolism and its hormonal profile.

Two groups, each composed of 20 women, who used depomedroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) injectable contraceptives were investigated for changes in 75-g OGTT and in the fasting and two-hour post oral glucose load (2-hours) levels of serum insulin, growth hormone, glucagon, cortisol and blood pyruvate. Samples were taken before and 3, 6 and 12 months after use of injectables. DMPA and NET-EN caused significant changes in mean blood glucose and pyruvate and in mean serum insulin, growth hormone and glucagon, but not in mean fasting cortisol. Changes with NET-EN started after 3 months, became maximal after 6 months and reverted to normal after 12 months of use, due to more frequent administration during the first 6 months of use (every 60 +/- 5 days) and to more spacing of the injections (every 84 +/- 5 days) after that. Changes with DMPA started after 3 months, and increased with the duration of use to become maximal after 12 months. Maximal changes were similar with DMPA and NET-EN and consisted of: a significant increase in fasting blood glucose and pyruvate and serum insulin; a significant increase in 2-hour blood glucose and pyruvate, serum insulin, growth hormone and glucagon. Although significant changes in blood glucose levels occurred with both DMPA and NET-EN, yet they did not reach the lower cut-off levels for impaired glucose tolerance in any user. With the same spacing of injections, i.e. every 84 +/- 5 days for NET-EN and every 90 +/- 5 days for DMPA, the effects on various parameters studied were less with NET-EN.

Hirsutism: metabolic effects of two commonly used oral contraceptives and spironolactone.

Fifty-one hirsute women were randomly treated for nine months with ethinyl estradiol 35 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with spironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin levels were higher as opposed to either low-dose oral contraceptive preparation. Ethinyl estradiol 30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradiol 35 ug plus norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.

PIP: 51 hirsute women were randomly treated for 9 months with ethinyl estradiol (EE) 35 mcg + norethindrone 0.4 mg or 30 mcg EE + 1.5 mg norethindrone acetate if contraception was necessary or spironolactone 200 mg daily if it was not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the 2 oral contraceptives (OCs) but not with spironolactone. While systolic blood pressure was lower with it, fasting insulin levels were higher as opposed to either low-dose OC preparation. EE 30 mcg + 1.5 mg norethindrone acetate lowered 3-alpha-diol-glucuronide levels; however, E 35 mcg + norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.

[The effects and mechanism of norethisterone and megestrol on lipoprotein metabolism in rats].

PIP: The authors studied rat lipoprotein metabolism treated by norethisterone on megestrol (2 mg/rat/day) for 15 days). The results were as follows. Female SD rats treated with norethisterone had lower plasma TC, LDL-C, and HDL-C. Those treated with megestrol showed opposite results. To explain this outcome, the authors measured the concentration of HDL-C and VLDL-C turnover by injecting 125 I-labelled human LDL into rats. These results showed that megestrol could increase the synthesis and/or secretion of HDL-C and VLDL-C from rat liver and decrease the binding and degradation of rat 125 I-HDL in rat hepatocytes, while the uptake and degradation of human 125 I-LDL was unchanged. Norethisterone could inhibit the synthesis and secretion of HDL-C and VLDL-C from rat liver; it could also inhibit the uptake and degradation of LDL but the former inhibition was dominant. If norethisterone and megestrol were not used continuously, the changed metabolism would return to normal. (author's modified)^ieng

Effect of norethisterone enanthate on endometrial bleeding and changes in coagulation function, ovarian hormones and endometrial histology in Thai women.

Endometrial bleeding and alteration in blood coagulation, fibrinolysis, ovarian function and endometrial morphology were studied in twelve normally menstruating women who received the injectable contraceptive norethisterone enanthate (NET-EN) 200mg at 60-day intervals. Levels of clotting factor VII declined significantly during episodes of irregular bleeding compared to those during both normal pretreatment menstruation and the bleeding-free period during treatment. Antithrombin III and fibrinolytic activity, expressed by euglobulin lysis time, showed no marked change. The average level of progesterone during the bleeding-free period was slightly but significantly lower than that during the bleeding period. There were no significant alterations in the mean levels of estradiol and the ratio of estradiol to progesterone. The endometrial biopsies showed considerable individual variation and seem to be independent of the effects of NET-EN on ovarian function.

Oral contraceptives and antithrombin III: variations by dosage and ABO blood group.

A randomized clinical trial of oral contraceptives evaluated 67 women on a regimen of 50 micrograms ethinyl estradiol and 1.0 mg norethindrone, 61 women on a regimen of 35 micrograms ethinyl estradiol and 1.0 mg norethindrone, and 64 women on a regimen of 35 micrograms ethinyl estradiol and 0.5 mg norethindrone. ABO blood group type was determined in all women. At baseline and at 3, 6, and 9 months, plasma antithrombin III levels, by both an immunologic and an activity method, and selected plasma levels of the contraceptive steroids were measured. Antithrombin III levels for all oral contraceptive groups combined decreased from baseline by 19.7% and 28.8% for the immunologic and activity methods, respectively. Analysis of interrelationships among antithrombin III by activity method, oral contraceptive type, and ABO blood group showed larger declines in antithrombin III for type O women using the highest estrogen dose preparation (31.6%) and for non-type O women using the lowest progestin dose preparation (38.9%). Plasma levels of contraceptive steroids also were related to changes in the most extreme levels of antithrombin III.

Ovarian response in superovulated cycles after suppression with oral contraceptive steroids.

The endocrine response to controlled ovarian hyperstimulation was reviewed in 94 women undergoing in vitro fertilization during 114 cycles. The purpose of this review was to evaluate the effect of short-term oral contraceptive suppression on the recovery of pituitary gonadotropin function and subsequent controlled ovarian hyperstimulation. Seventy-three cycles (64%) were adequate for oocyte retrieval. In 41 cycles (36%) hyperstimulation was discontinued. The serum 17 beta-estradiol value in women with a poor response was 57 +/- 50 pg/ml on day 8 compared with 376 +/- 334 pg/ml in the women who completed in vitro fertilization (p less than 0.05). The majority of women (84.2%) had a prompt response to controlled ovarian hyperstimulation after short-term oral contraceptive suppression. Most discontinuations were due to dominant follicle selection or luteinizing hormone surge and not to oversuppression by short-term oral contraceptives. Clinical pregnancies occurred in 15 women (20.5% of harvests).

Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes.

A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE2) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or "suicide" inactivation of cytochrome P-450. We have compared the effects of the different progestogens on EE2 2-hydroxylation (a reaction catalyzed by enzymes from the P-450IIC, P-450IIIA and P-450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE2 as substrate, GSD, 3-keto desogestrel (3-KD, the active metabolite of desogestrel) and LNG produced some concentration-dependent inhibition of EE2 2-hydroxylation (maximum 32% inhibition at 100 microM 3-keto desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3 microM (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 microliters) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 microM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD greater than 3-KD greater than NET greater than LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

Effect of oral contraception on water-suppressed proton NMR spectra of plasma.

Lipid linewidths were measured in the plasma proton spectra of young women. The individuals taking a contraceptive pill associating ethinyloestradiol and levonorgestrel or norethisterone were found with an average linewidth 2.5 Hz narrower than controls. As this drug regimen systematically induces an increase in plasma VLDL and a decrease in HDL/LDL ratio, our observation supports the theory that the Fossel test reflects plasma lipids abnormalities in cancer patients.

PIP: Physicians enrolled at least 140 female soldiers and military employees in a screening program to detect breast and gynecologic cancers at the outpatient clinic of the military hospital in Liege, Belgium using the Fossel test, a magnetic resonance (NMR) spectroscopy of plasma. They also underwent a clinical examination, including a pap smear. Only 1 patient had a grade I cervical lesion and the remaining women had no disease. The plasma lipid average linewidths were distributed normally. The values ranged from 20-48.5Hz with a mean of 33.4Hz + or - .5Hz. 26.9Hz represented the 10th percentile and 41Hz the 90th percentile. The only correlation between test results and clinical parameters was chronic intake of sex steroids (p=.03). A significant association between chronic intake of sex steroids and a decrease in plasma lipids proton NMR linewidths existed (p=.04). Specifically, the association was only significant with oral contraceptives (OCs) containing levonorgestrel or norethisterone (p=.02) which produce androgenic activity. Moreover those who used the higher dose estrogen OCs (50ug ethinyl estradiol) had lower results than the lower dose estrogen OCs or the controls (p=.06). In fact, the OCs with ethinyl estradiol combined to levonorgestrel or norethisterone narrowed plasma lipids linewidths on average 2.5Hz. Such Ocs increase very low density lipids (VLDL) and the low density level-cholesterol to high density level-cholesterol ratio. Continuous administration of sex steroid hormones to cancer patients also increases lipid metabolism and narrows the plasma methyl and methylene resonances. In conclusion, the Fossel test does detect abnormal distribution of plasma lipoproteins in cancer patients, particularly in the proportion of VLDL.

Oral contraceptives stimulate the excretion of clofibric acid glucuronide in women and female rats.

1. Glucuronidation of clofibric acid, the pharmacologically active form of the hypolipidemic drug clofibrate was investigated in a human population, either in vitro with liver homogenates from biopsies, or after ingestion of the drug and determination of the urinary metabolite. No difference in the glucuronidation rate according to age of the patients was observed. Bilirubin but not clofibric acid glucuronidation was significantly higher in women (106% increase), when expressed per gram of tissue. 2. The excretion of clofibryl glucuronide in women who took oral contraceptives was significantly enhanced by 25%. 3. In female rats, treatment with the contraceptive agent norethindrone also stimulated by 48% the formation of clofibrylglucuronide in liver microsomes.

PIP: The effect of oral contraceptive (OC) intake on the glucuronidation of clofibric acid was investigated both in vivo, by measuring the excretion of urinary clofibrylglucuronide in female Wistar rats, or in vitro, with liver biopsy homogenates from 69 health female volunteers. In both study groups norethindrone markedly enhanced glucuronidation of clofibric acid while the situation was modulated by the administration of ethinyl estradiol. Excretion of clofibric acid into urine averaged 142.1 + or - 38.4 mg in OC users compared to only 105.8 + or - 31.5 mg in non-users. When expressed per gram of tissue, bilirubin but not clofibric acid glucuronidation was significantly greater in human liver biopsies from OC users compared to non-users. In rats treated with norethindrone, the liver microsomal protein content was increased 28% over the average control value and formation of clofibylglucoride was stimulated by 48%. It is hypothesized that the stimulation of clofibylglucuronide in OC users results from the selective stimulation in the liver of the isoenzyme involved in the process of the glucuronidation of clofibric acid.

Long-acting hormonal contraceptives for women.

Following the development and widespread use of oral hormonal contraceptives, it became evident that alternative long-acting delivery systems would be required to improve contraceptive practice in some cultural settings where injectable or subdermal routes of administration are preferred. Nowadays, long-acting contraceptives constitute an important option in family planning services in many parts of the world. Indeed, two long-acting injectable contraceptives containing just a synthetic progestogen (depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN)) have been in clinical practice for more than 20 years. The World Health Organization's (WHO) Special Programme of Research in Human Reproduction, in collaboration with the U.S. National Institute of Child Health and Human Development (NICHD) and universities primarily in developing countries undertook a synthesis programme aimed at producing an improved injectable preparation by developing new derivatives of known steroids. One such compound (levonorgestrel 17-butanoate) is now at the stage of Phase II clinical testing. In addition, the Special Programme has developed and improved once-a-month injectable formulations and assessed their safety and efficacy in different countries worldwide. After large scale clinical testing, at least two progestogen-estrogen combinations have reached the point of introductory trials.

PIP: A survey of recent trials of new injectable hormonal contraceptives, progestogen-only, levonorgestrel esters, and once monthly injectables, follows a brief review of all the experimental long-acting contraceptive modalities, injectables, implants, vaginal rings, and hormone-releasing IUDs. Currently medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) are being used by 7 million women. WHO is conducting dose reduction trials and studies of bioavailability in various national populations. Even though a dose of 100 mg DMPA every 3 months has been satisfactory for contraception, 150 mg is still recommended until further pharmacodynamic data are available. Some populations, notably Thais and Mexican women, have higher peaks and more rapid elimination rates of DMPA, while Chinese women show slower elimination and higher blood levels of NET-EN. Extensive studies of new synthetic esters of levonorgestrel have proceeded to Phase II clinical trials with levonorgestrel butanoate. This ester is an effective contraceptive for 3 months at 12.5 mg, or 5-6 months at a dose of 25 or 50 mg. Trials of combined estrogen and progestogen injectables once-monthly have been ongoing for 10 years. The ratio of the 2 components is as important as the amounts. 2328 women from 12 countries participated in trials of DMPA 25 mg-estradiol cypionate 5 mg, and NET-EN 50 mg-estradiol valerate 5 mg. The continuation rate was better than that for 3-monthly progestogen-only injectables, because of less irregular bleeding. A combined injectable called Cyclofem, DMPA 25 mg-estradiol cypionate is being introduced in several countries. The steadily increasing demand for long-acting injectables prompts development of better formulations.

Clinical experience with the progestogen-only pill.

Experience with the progestogen-only pill (POP) in a family planning clinic is presented. From the clinic records, 408 women were identified who had opted to use a POP. Of these, 50 women had used the POP during lactation and these were excluded from the analysis. The remaining 358 women used the POP for up to 150 months, giving a total of 18,125 women-months of use. Three pregnancies occurred, giving a Pearl Index of 0.2 per 100 women-years. Non-menstrual side effects were minor and were reported by 77 women. For the women who discontinued the POP, the main reason was menstrual irregularity (47.5%). However, despite the long-term use by most of the women, almost 40% maintained a mostly regular menstrual pattern. Our findings suggest that the POP provides a very acceptable method of oral contraception for many women and that it should be more actively promoted.

Contraceptive efficacy of norethindrone encapsulated in injectable biodegradable poly-dl-lactide-co-glycolide microspheres: phase II clinical study.

Contraceptive efficacy of injectable norethindrone (NET) microspheres of 90 day duration was evaluated for 6 months: nine women received two injections of 65 mg each and eight received two injections of 100 mg each with 90 days between each injection. Average serum NET levels were 5 to 9 ng/mL on the day after injection and subsequently remained at 1 to 3 ng/mL. With 65 and 100 mg doses, respectively, 36% and 25% of cycles had normal bleeding patterns, 36% and 48% were amenorrheic, and the remaining 28% and 27% had prolonged bleeding. Also, 56% and 40% of cycles showed increased spotting for the 65 mg and 100 mg dose, respectively. There was no incidence of pregnancy or serious side effects. The mean serum NET concentration returned to RIA nonspecific basal levels 100 days after the second injection. Women returned to ovulatory cycles between days 100 to 115 after the second injection.

A clinical overview of a new triphasic contraceptive containing gestodene.

In three ongoing open studies conducted by 50 investigators in Europe, South America, and New Zealand, 639 subjects followed a new triphasic regimen of gestodene (GTD) and ethinyl estradiol (EE) for 3,020 cycles. One study used GTD + EE only, but in each of the other two studies a comparator oral contraceptive (OC) also was given: norethisterone (NET) + EE in one and desogestrel (DSG) + EE in the other. The objective of all three studies was to assess the efficacy, cycle control, and safety of the triphasic GTD + EE. The following is a report of the interim results. Statistical analysis was performed only on differences between groups in the incidences of bleeding irregularities. During six treatment cycles, subjects either followed the GTD + EE regimen (50 micrograms GTD + 30 micrograms EE for 6 days, 70 micrograms GTD + 40 micrograms EE for 5 days, and 100 micrograms GTD + 30 micrograms EE for 10 days) or took triphasic NET + EE or monophasic DSG + EE. Each cycle concluded with a seven-day hiatus in study medication. No pregnancies occurred with any of the contraceptive preparations (Pearl Index = 0). Compliance was good in all studies and a majority of subjects were still participants at cycle 6. Normal bleeding was reported during 92% of the total evaluable cycles of GTD + EE use. Cycle control with GTD + EE was superior to that with NET + EE or DSG + EE: Breakthrough bleeding occurred in 1.5% of the pooled GTD + EE cycles versus 6.6% of the NET + EE cycles and 2.6% of the DSG + EE cycles; spotting occurred in 4.5% of the GTD + EE cycles versus 9.7% of the NET + EE cycles and 10.3% of the DSG + EE cycles; and breakthrough bleeding plus spotting occurred in 2.1% of the GTD + EE cycles versus 8.1% of the NET + EE cycles and 4.6% of the DSG + EE cycles. Amenorrhea occurred in 2.0% of the cycles with NET + EE, but was reported by only 0.3% of all the subjects given GTD + EE and 0.7% of those given DSG + EE. Cycle length and intensity of bleeding changed little during the use of any of the study preparations. Mean length of withdrawal bleeding during the GTD + EE regimen shortened from 4.5 days (prestudy) to 4.0 days. With each OC, the subjects' mean weight during cycles 3 and 6 differed less than 0.5 kg from baseline values.(ABSTRACT TRUNCATED AT 400 WORDS)