Reciprocal coordination of a combination oral contraceptive containing desogestrel+ethinyl estradiol on the expression of LOX-1 and LDLR in placental trophoblast cells

BackgroundThe aim of this study was to assess the consistency of antiatherosclerotic potential of a combination oral contraceptive steroid (ethinyl estradiol+desogestrel) by rating its effect on the differential expression of the low-density lipoprotein receptor (LDLR) and lectin-like oxidized LDL (LOX-1) receptor.Study DesignCells from placental trophoblast cell line (JAR) and differentiated primary placental trophoblast cells isolated from term human placentae were used for this study. Expressions of LOX-1 and LDLR were assessed by immunoblot and immunocytochemistry assays. Differential effects of the constituent steroids in the combination of ethinyl estradiol and desogestrel were verified on the expression profile of the receptors.ResultsDesogestrel opposed the effect of ethinyl estradiol on LOX-1 expression, and when used in combination, the combination oral contraceptive reduced the expression of LOX-1 in contrast to LDLR. The characteristic change in the expressions of LOX-1 and LDLR showed an antiatherosclerotic improvisation at the unique combination of ethinyl estradiol (10 ng/mL) and desogestrel (20 ng/mL).ConclusionThe aforesaid combination of ethinyl estradiol and desogestrel keeps LOX-1 and LDLR reciprocally expressed in antiatherosclerotic mode.     

Reciprocal coordination of a combination oral contraceptive containing desogestrel+ethinyl estradiol on the expression of LOX-1 and LDLR in placental trophoblast cells

Background

The aim of this study was to assess the consistency of antiatherosclerotic potential of a combination oral contraceptive steroid (ethinyl estradiol+desogestrel) by rating its effect on the differential expression of the low-density lipoprotein receptor (LDLR) and lectin-like oxidized LDL (LOX-1) receptor.

Study Design

Cells from placental trophoblast cell line (JAR) and differentiated primary placental trophoblast cells isolated from term human placentae were used for this study. Expressions of LOX-1 and LDLR were assessed by immunoblot and immunocytochemistry assays. Differential effects of the constituent steroids in the combination of ethinyl estradiol and desogestrel were verified on the expression profile of the receptors.

Results

Desogestrel opposed the effect of ethinyl estradiol on LOX-1 expression, and when used in combination, the combination oral contraceptive reduced the expression of LOX-1 in contrast to LDLR. The characteristic change in the expressions of LOX-1 and LDLR showed an antiatherosclerotic improvisation at the unique combination of ethinyl estradiol (10 ng/mL) and desogestrel (20 ng/mL).

Conclusion

The aforesaid combination of ethinyl estradiol and desogestrel keeps LOX-1 and LDLR reciprocally expressed in antiatherosclerotic mode.     

Efficacy of second versus third generation oral contraceptives in the treatment of hirsutism

OBJECTIVE: To compare second versus third generation combination oral contraceptives (OCs) in the treatment of hirsutism. METHODS: Women with hirsutism, as defined by a minimum Ferriman-Gallwey score of 10, were randomized in a double-blind fashion to receive an OC containing either ethinyl estradiol/desogestrel or ethinyl estradiol/levonorgestrel for 9 months of treatment. Ferriman-Gallwey scores, androgen levels and sex hormone-binding globulin were measured at baseline and every 3 months for the duration of the study. Hormones were measured in duplicate by radioimmunoassay. RESULTS: Of the 47 women enrolled, 24 were randomized to ethinyl estradiol/desogestrel and 23 were randomized to ethinyl estradiol/levonorgestrel. Mean sex hormone-binding globulin increased significantly in subjects using the desogestrel-containing contraceptive compared with the levonorgestrel-containing contraceptive. Ten subjects completed the 9 months of treatment in the levonorgestrel group and 11 completed the study in the desogestrel group. Mean free testosterone and 3alpha-androstanediol glucuronide decreased significantly in the group receiving ethinyl estradiol/desogestrel but not in the ethinyl estradiol/levonorgestrel group. Mean Ferriman-Gallwey scores decreased significantly in both treatment groups. Improvement in mean Ferriman-Gallwey score was 35.7 +/- 38.1% (p < 0.001) for the ethinyl estradiol/desogestrel arm and 33.4 +/- 27.3% (p < 0.001) for the ethinyl estradiol/levonorgestrel arm. There were no statistically significant differences found in the improvement of Ferriman-Gallwey scores between the two treatment arms, although the power to detect a difference was limited by the small sample size. CONCLUSIONS: Treatment of hirsute women with third generation OCs containing desogestrel results in a significant increase in sex hormone-binding globulin and decrease in free testosterone and 3alpha-androstanediol glucuronide. Both second and third generation OCs were clinically effective in treating hirsutism.     

Comparison of a transdermal contraceptive patch vs. oral contraceptives on hemostasis variables

PURPOSE: The aim of this study was to compare effects of the transdermal contraceptive patch, a desogestrel/ethinyl estradiol (EE)-containing, monophasic combination oral contraceptive (COC) and a levonorgestrel/EE-containing, triphasic COC on hemostasis variables. STUDY DESIGN: This was a randomized, open-label study of 104 young women who received six cycles of treatment. Blood was collected at baseline and on treatment; changes by Day 20/Cycle 6 in baseline hemostasis markers [prothrombin fragment 1+2 (F 1+2), plasmin-plasmin inhibitor complex (PAP) and fibrin degradation products (D-dimer)] were assessed. RESULTS: All contraceptives induced similar increases in F 1+2 and D-dimer. Patch-induced PAP increases were less than with the monophasic and similar to the triphasic COC. Decreases in protein S and increases in sex hormone-binding globulin were greater with the patch than with either COC. Patch-induced increases in activated protein C resistance were greater than with the triphasic and similar to the monophasic COC. CONCLUSION: These contraceptives appeared to accelerate baseline procoagulation processes to a similar extent and to change coagulation potency variables differently.     

Randomized controlled study of the influence of two low estrogen dose oral contraceptives containing gestodene or desogestrel on carbohydrate metabolism

This study compared the impact on carbohydrate metabolism of two combinedoral contraceptives (COCs). This open-label, single-center trial enrolled participants for a total of 15 cycles. Thirty-six women were randomized to receive either 20 μg ethinyl estradiol (EE) and 75 μg gestodene (GSD) or 20 μg ethinyl estradiol and 150 μg desogestrel (DSG) daily for 21 days out of 28. A glucose tolerance test was performed at baseline and cycles 6 and 13. The area under the curve (AUC) for glucose increased in both study groups. The change was statistically significant (p = 0.036) for the 20 EE/75 GSD group at cycle 6 versus baseline. Fasting blood glucose at cycle 13 was significantly (p < 0.01) higher for both treatment groups compared to baseline. No changes were found for fasting insulin and fasting C-peptide levels or for the AUCs of insulin or C-peptide. Both regimens were well tolerated. Gestodene and desogestrel in combination with 20-μg ethinyl estradiol induce similar changes in carbohydrate metabolism which are smaller than those described earlier for COCs containing higher estrogen doses or more androgenic progestins such as levonorgestrel.     

Hormonal contraception: a comparison between patients of the private and public health network

The aim of this paper is to assess the profile of patients using hormonal contraceptives in the public health network and a comparison with the private health service, as well as the frequency of side effects and adherence to treatment. A cross-sectional study was conducted with 240 patients, namely 120 patients from the private health service and 120 patients from the public health network. The most commonly prescribed hormonal dosage on the private group (36.7%) was 15 or 20 micrograms of ethinyl estradiol (EE), associated with gestodene, desogestrel or levonorgestrel. On the other hand, the prescribed hormonal dosage in the public group was a combination of 30 micrograms of EE associated with gestodene, levonorgestrel or desogestrel (48.3%). There was no difference between the frequency of side effects in both groups surveyed (p>0.05). Meanwhile, adherence to treatment was higher in patients of the private group. The authors concluded that the most widely used contraceptive method was a low oral dose of ethinyl estradiol and there is no difference between the frequency of side effects. However, adherence to treatment was higher in the private group, which may be associated with social and cultural aspects of the patients surveyed.     

Desogestrel and ethinyloestradiol

The effectiveness and side effects of Marvelon (0.150 mg desogestrel and 30 mcg ethinyl estradiol) were evaluated in a multicenter study of 1570 women for a total of 22,158 menstrual cycles. Half the women in the study were under age 25. Only 1 pregnancy was reported, and this was due to patient failure. The frequency of spotting and breakthrough bleeding decreased steadily from 22.3% in the 1st treatment cycle, 14.9% in the 2nd, 8.4% in the 6th, 5.6% in the 12th, to 2.8% in the 21st and then rose slightly from 3.6% in the 24th cycle. This pattern of irregular bleeding during the early cycles is common to all oral contraceptive preparations. Changes in body weight were almost negligible and restricted to women under age 20. There was no change in average blood pressure when compared with pretreatment values. Superficial thrombophlebitis occurred in 7 women. Side effects, including nausea, headache, nervousness, depression, and breast tenderness, declined to negligible levels as treatment progressed. Levels of plasma protein sex-hormone-binding globulin (SHBG) appear to be higher with Marvelon than with a similar preparation containing levonorgestrel and ethinyl estradiol. Other studies have noted significantly higher serum high density lipoprotein (HDL) cholesterol levels with Marvelon than with combined levonorgestrel and ethinyl estradiol. This is attributed to the lack of androgenicity of desogestrel in the clinical dosage used in this study. SHBG and serum HDL levels are increased by estrogens and decreased by androgens.     

Bioavailability of the Yuzpe and levonorgestrel regimens of emergency contraception: vaginal vs. oral administration

Separate crossover studies compared the bioavailability of oral vs. vaginal routes of administration for the Yuzpe (n=5) and levonorgestrel regimens (n=4) of emergency contraception. Twice the standard dose of the Yuzpe regimen (200 microg of ethinyl estradiol, 1000 microg of levonorgestrel) or the levonorgestrel regimen (1500 microg of levonorgestrel) was self-administered vaginally. One week later, each subject received orally the standard dose of the assigned medication. Serial blood samples were collected over 24 h and assayed for levonorgestrel and ethinyl estradiol (for the Yuzpe regimen only). Paired t tests were used to compare oral vs. vaginal administration for maximum concentration (Cmax), time to maximum concentration (Tmax) and area under the curve over 24 h (AUC0-24). Relative bioavailability (vaginal/oral) was derived from AUC0-24. Vaginal administration of double the standard dose of the Yuzpe regimen resulted in a lower Cmax (vaginal=5.4 vs. oral=14.6 ng/mL, p=.038) and a later Tmax (5.9 vs. 2.0 h, p=.066) for levonorgestrel, compared to oral administration. Corresponding ethinyl estradiol concentrations were higher (786 vs. 391 pg/mL, p=.039) and peaked later (4.0 vs. 1.9 hr, p=.154) with vaginal administration. Relative bioavailabilities for levonorgestrel and ethinyl estradiol were 58% and 175%, respectively. Similarly, vaginal administration of the levonorgestrel regimen resulted in a lower Cmax (vaginal=5.4 vs. oral=15.2 ng/mL, p=.006) and a later Tmax (7.4 vs. 1.3 h, p=.037) for levonorgestel, compared to oral administration. The relative bioavailability was 62%. Our preliminary data suggest that vaginal administration of these emergency contraception regimens appears to require at least three times the standard oral dose to achieve equivalent systemic levonorgestrel concentrations.     

Serum lipids in Chinese patients using oral contraceptive pills

Eighty-four Chinese patients attending the Family Planning Association of Hong Kong for contraception with oral contraceptive pills were randomized into 2 groups. The first group received pills containing 0.15 mg levonorgestrel and 0.03 mg ethinyl oestradiol. The second group received pills containing 0.15 mg desogestrel and 0.03 mg ethinyl oestradiol. Blood was taken after overnight fast before the use of pills for assay of serum total lipids, triglycerides, total cholesterol and high density lipoprotein cholesterol (HDL-C). The tests were repeated at 1 month, 3 months and 6 months after the use of pills. There was a significant increase in the serum total lipids in the levonorgestrel group but not in the desogestrel group. The serum triglycerides showed a significant increase in the desogestrel group but not in the levonorgestrel group. There was no significant change in the serum total cholesterol levels in both groups. There was a significant decrease in the HDL-C in the levonorgestrel group but there was no significant change in the desogestrel group.     

Ovarian follicular development is initiated during the hormone-free interval of oral contraceptive use

We evaluated ovarian follicular development in women during compliant use of oral contraceptives (OC). Thirty-six healthy women received: [35 microg ethinyl estradiol (21)/180 microg norgestimate (7), 215 microg norgestimate (7), 250 microg norgestimate (7)]; [30 microg ethinyl estradiol (21)/150 microg desogestrel (21)]; or [20 microg ethinyl estradiol (21)/100 microg levonorgestrel (21)] for 3 consecutive 28-day cycles. Transvaginal ultrasonography was performed every third day to monitor follicular development. If a follicle reached > or = 14 mm, ultrasonography was performed daily and blood drawn every other day to determine estradiol-17beta concentrations. Seventeen of 36 women (47%) grew follicles > or = 10 mm. Nine of the 17 women (53%) grew follicles > or = 14 mm, in association with increased serum concentrations of estradiol-17beta. Thirty-seven of 43 follicles > or = 10 mm (86%) emerged during the hormone-free interval (HFI). No ovulations were observed. Our results supported the hypothesis that follicular development to an ostensibly ovulatory diameter occurs during compliant OC use, in association with loss of endocrine suppression during the HFI.     

Extended regimens of the contraceptive vaginal ring versus hormonal oral contraceptives: effects on lipid metabolism

BackgroundCombined oral contraceptives used in an extended regimen have been studied because of their potential benefits; however, there have been few publications on extended regimens of contraceptive vaginal rings. The aim of this study was to assess the effects of these two extended regimens on the lipid metabolism of women using these contraceptive methods during 1 year.Study DesignThis prospective study enrolled 150 women: 75 used a vaginal contraceptive ring (11.7 mg etonogestrel and 2.7 mg ethinyl estradiol), and 75 used oral contraceptives (30 mcg ethinyl estradiol and 150 mg desogestrel). Both groups used their respective method for 84 days followed by a 7-day pause during 1 year. At baseline and every 3 months during the study period, blood was collected to assess total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and apolipoprotein (apo) A-I and B. The analysis of variance test was used to analyze differences in the results of these exams over time.ResultsA total of 62 vaginal ring and 61 oral contraceptive users completed the study. There were no significant differences in the discontinuation rate, mean total cholesterol and fraction levels, apo B concentration or apo A-I/apo B ratio. Vaginal ring users had significantly higher apo A-1 levels than oral contraceptive users.ConclusionDespite the vaginal route of administration, the steroids released by the ring had the same effects on the lipid metabolism and lipoprotein levels typically seen with ethinyl estradiol given either by oral or parenteral routes.     

A multicentre comparative study of serum lipids and lipoproteins in four groups of oral combined contraceptive users and a control group of IUD users

A prospective clinical trial was conducted in three centres to assess the effects of the type and dose of progestogen, the dose of estrogen and the progestogen-to-estrogen ratio of oral contraceptives on lipid metabolism. The preparations selected contained levonorgestrel 250μg + ethinyl estradiol 50μg (Neogynon), levonorgestrel 250μg + ethinyl estradiol 30μg (Eugynon 30), levonorgestrel 150μg + ethinyl estradiol 30μg (Microgynon) or norethisterone acetate 1mg + ethinyl estradiol 50μg (Minovlar).

Four-hundred-and-seven premenopausal women were randomly assigned to one of the four pill groups and compared to a control group of 119 users of a CuT220c intrauterine device. Total cholesterol, HDL-cholesterol, LDL-cholesterol and total triglycerides were monitored and the analysis includes the data of those who were followed over 48 weeks, 241 OC users and 87 IUD users.

250μg of levonorgestrel were found to induce more unfavourable lipid changes in terms of atherosclerotic risk than 1mg of norethisterone acetate. Levonorgestrel was found to have a dose-effect on HDL-cholesterol and LDL-cholesterol serum levels, while ethinyl estradiol had a dose-effect on serum triglycerides. HDL-cholesterol was related to the progestogen-to-estrogen ratio. Most of these findings were consistent across centres. Finally, some comments are made on the implications of the study results on the design of future lipid studies.     

Effects of two combined oral contraceptives containing ethinyl estradiol 20 microg combined with either drospirenone or desogestrel on lipids, hemostatic parameters and carbohydrate metabolism

OBJECTIVE: To compare the effect of ethinyl estradiol 20 microg/drospirenone 3 mg (EE 20 microg/DRSP 3 mg) administered according to a 24/4 regimen with ethinyl estradiol 20 microg/desogestrel 150 microg (EE 20 microg/DSG 150 microg) administered according to the conventional 21/7 regimen on lipid, carbohydrate and hemostatic parameters. STUDY DESIGN: In this open-label study, healthy women were randomized to EE 20 microg/DRSP 3 mg or EE 20 microg/DSG 150 microg for seven cycles. Mean differences in high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol levels at cycle 7 compared to baseline were assessed. Secondary variables included changes in other lipid, hemostatic and carbohydrate parameters. RESULTS: Both treatments increased HDL-cholesterol, but decreased LDL-cholesterol by a comparable extent. Although slightly elevated in both groups, blood glucose and C-peptide levels measured during oral glucose tolerance tests were within normal reference ranges at cycle 7. Overall, the differences in lipid, hemostatic or carbohydrate parameters were not significant between the two treatments. CONCLUSION: EE 20 microg/DRSP 3 mg has a good safety profile comparable with EE 20 microg/DSG 150 microg.     

Influence of oral contraceptives on integrated secretion of gonadotropins.

The mechanism of action of various oral contraceptives has not yet been satisfactorily resolved, as to how gonadotropins affect ovarian function. Alterations of the pulsatile release of LH might be a common denominator. As methodological difficulties for the evaluation of LH pulse pattern with low basal levels exist, we elected to determine the area under the curve (AUC) for LH and FSH for 6 hours before and during treatment with oral contraceptives. LH and FSH were determined every 15 min for 6 hours on day 4 and day 20 of a control cycle and a treatment cycle in 22 women with ovulatory cycles. They received either a combined preparation containing 150 micrograms desogestrel and 30 micrograms ethinyl estradiol, a sequential preparation containing 50 micrograms of ethinyl estradiol and 125 g of desogestrel or only 125 micrograms desogestrel. There was no difference between the sum of LH pulses on day 4 and day 20 of the control cycle. The AUC for FSH was lower on day 20. When the combined preparation was taken, FSH was suppressed on day 4, and FSH and LH on day 20 of treatment. The degree of suppression was even more pronounced when the sequential OC was taken. Ethinyl estradiol alone was as effective as the combination with desogestrel. Desogestrel alone inhibited ovulation without affecting serum LH and FSH in a comparable manner, suggesting a direct effect on the ovary. The determination of the AUC seems to be a sensitive tool for the evaluation of OC-induced changes in gonadotropin output.     

Lipid and biochemical changes after low-dose oral contraception.

A randomized double-blind study of the metabolic effects of 2 low-dose combined oral contraceptives was carried out in Singaporean women. The subjects comprised 58 women randomly allocated to two treatment groups (29 each): norethisterone 1 mg/ethinyl estradiol 35 micrograms (NET/EE) or levonorgestrel 150 micrograms/ethinyl estradiol 30 micrograms (LNG/EE) and a control group of 23 women using intra-uterine devices (IUD). Blood samples were taken on admission and at 3 and 12 months after pills or insertion of IUDs. Fasting glucose levels were decreased while 2h glucose and triglyceride were increased throughout the treatment period in NET/EE group [corrected]. LNG/EE group only showed significant increase of 2h glucose at 12 months and decrease of LDL cholesterol at 3 months while total cholesterol was significantly suppressed at 3 and 12 months [corrected]. The atherogenic index, LDL/HDL cholesterol was significantly reduced by 12 months. Both groups had no change in hemoglobin, hematocrit and total protein levels but alkaline phosphatase, bilirubin and aspartate transaminase (SGOT) were suppressed. While NET/EE suppressed albumin significantly, this was not observed with LNG/EE group. However, these differences observed with use of each pill preparations, were not so obvious between treatment groups and control. Changes in total, HDL and LDL cholesterol and SGOT were not significantly different than the IUD group. Furthermore, except for 2h glucose, there was no increase in the number of abnormal parameters after treatment. On the contrary, there was a reduction of abnormal values in most liver function parameters. Thus, except for glucose intolerance, the observed changes in metabolic parameters may not constitute any clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of desogestrel and levonorgestrel in low-dose oestrogen oral contraceptives on serum lipoproteins

Serum HDL-cholesterol and total cholesterol levels were analyzed in 54 women before and after 3, 6 and 12 months of treatment with oral contraceptives containing 0.030 mg ethinyloestradiol (EE) plus 0.150 mg desogestrel or levonorgestrel. The combination of 0.150 mg desogestrel + 0.030 mg EE induced a small increase in HDL-cholesterol and in the ratio HDL-cholesterol/total cholesterol, whereas 0.150 mg levonorgestrel + 0.030 mg EE induced a small decrease; the differences between the effects of the two combination on these parameters were statistically significant after 6 and 12 months of treatment and can be best explained by the higher androgenicity of levonorgestrel.     

An open label, randomized study to evaluate the effects of seven monophasic oral contraceptive regimens on hemostatic variables: Outline of the protocol

Complementary to the epidemiological knowledge on the association between oral contraceptive use and the occurrence of venous thromboembolism, a study was designed to obtain more conclusive data regarding the effect of estrogen dose and progestogen type of oral contraceptives on risk markers for the occurrence of venous thromboembolism. The protocol for this multicenter, randomized, open label, parallel group, comparative study is outlined in the present article. A total of 730 healthy, nonsmoking, nulliparous women were treated for six cycles with one of the seven monophasic oral contraceptives tested in this study. The effects of progestogen type (desogestrel, gestodene, levonorgestrel, and norgestimate) and the effects of ethinyl estradiol dose (50, 30, and 20 μg) on various hemostatic variables was assessed, including the key components of the anticoagulant and fibrinolytic system, as well as the coagulation system. The primary outcome variables in the study were prothrombin fragment 1+2 and -dimer.     

Effects of two low-dose oral contraceptives containing ethinylestradiol and either desogestrel or levonorgestrel on serum lipids and lipoproteins with particular regard to LDL size

This study was designed to determine the effects of two low-dose oral contraceptives, most frequently given in our area, monophasic desogestrel/ethinylestradiol (DG/EE) and triphasic levonorgestrel/ethinylestradiol (LNG/EE), on lipoprotein parameters, especially LDL particle size and HDL subclass distribution (determined by lipid-stained 2%-20% polyacrylamide gradient gel electrophoresis) in 37 healthy normolipidemic women aged 19 to 27 years. Lipid and lipoprotein parameters were measured before the start of treatment and in the third month of oral contraceptive use. Results reflected the estrogen-progestin balance. As compared with baseline values, with both formulations, plasma total cholesterol, phospholipids, and HDL3 cholesterol increased, and LDL-predominant peak size decreased, with a translation of LDL pattern A towards pattern I. With DG/EE, plasma triglycerides, apolipoproteins AI and B increased. With LNG/EE, LDL cholesterol increased, and HDL2 cholesterol decreased. All these modifications were moderate, within threshold limits. Estrogen-dominant monophasic DG/EE appears to be more favorable than progestin-dominant triphasic LNG/EE, since the reduction in LDL-predominant peak size is not associated with an increase in LDL cholesterol or with a decrease in HDL2 cholesterol.     

Effects of low dose oral contraceptives containing norethindrone and ethinyl estradiol on serum levels of progesterone and pituitary gonadotropins

Serum gonadotropin and progesterone levels were studied in longterm (>18 months) patients receiving oral contraceptives containing either 1.0 mg or 0.5 mg norethindrone in combination with 35 μg of ethinyl estradiol. In ten patients treated with 1.0 mg norethindrone and 35 μg ethinyl estradiol, no mid-cycle surges of LH were noted and LH levels never exceeded 225 ng/ml. FSH levels were generally elevated during the first half of the cycle. Serum progesterone concentrations in these patients and in fourteen additional women whose blood was sampled intermittently were generally less than 1 ng/ml, and no characteristic luteal phase elevation of this hormone was detected. Of six patients treated with 0.5 mg norethindrone and 35 μg ethinyl estradiol, five clearly had no mid-cycle surge of LH, and levels of this hormone never exceeded 250 ng/ml. The concentrations of FSH and progesterone in these patients and serum progesterone levels in two additional women whose blood was sampled intermittently were similar to those found in patients treated with 1 mg norethindrone and 35 μ ethinyl estradiol. In the sixth patient, hormonal levels did not follow the same pattern, but they were not characteristic of ovulation. It is concluded that there is no evidence of cyclic fluctuations in FSH, LH and progesterone characteristic of ovulation in patients treated longer than eighteen months with either 1.0 mg or 0.5 mg norethindrone in combination with 35 μg ethinyl estradiol.