A comparison of cycle control and effect on well-being of monophasic gestodene-, triphasic gestodene- and monophasic desogestrel-containing oral contraceptives. Gestodene Study Group.

This was an open-label multicenter study to compare the cycle control and effect on well-being of two oral contraceptives containing gestodene and one containing desogestrel. A total of 2419 healthy women < or = 41 years of age were randomized to receive oral contraceptives containing monophasic gestodene (Minulet; n = 806, mean age 24.5 years), triphasic gestodene (Tri-Minulet; n = 808, mean age 24.6 years) or monophasic desogestrel (Mercilon; n = 805, mean age 24.6 years). Subjects were to participate in the study for up to 13 treatment cycles. A modified Moos Menstrual Distress Questionnaire was used to evaluate menstrual symptoms and to assess overall well-being. A total of 698 women were withdrawn from the study, 154 due to adverse events. Cycle control with gestodene was superior to that with desogestrel at almost all time points, particularly for breakthrough bleeding and/or spotting, which occurred significantly less frequently with gestodene than with desogestrel at cycles 1-7 and 9-11 (p < 0.05). Generally, the proportion of subjects with breakthrough bleeding and/or spotting was almost twice as great with desogestrel as with gestodene. The duration of bleeding was not consistently different between the gestodene and desogestrel groups; however, the intensity of bleeding was greater with gestodene at all time points (p < 0.05). The latent period before withdrawal bleeding was significantly longer for monophasic gestodene at cycles 1-5 and 8-10 (p < 0.05). Treatment significantly improved overall well-being at cycles 6 and 9 with triphasic gestodene and at cycle 13 with desogestrel; however, no statistically significant differences among treatment groups in overall well-being scores or individual factors of well-being could be identified. All three treatments were well tolerated. The most common drug-related adverse events were headache (14.2%), breast pain (6.2%), nausea (4.1%), metrorrhagia (3.9%) and abdominal pain (3.5%). The incidence of adverse events in all treatment groups was similar, with the exception of metrorrhagia, which occurred in more patients in the desogestrel group than in the gestodene treatment groups (p < 0.05).     

Influence of pituitary suppression with triphasic or monophasic oral contraceptives on the outcome of in vitro fertilization and embryo transfer

Purpose: To compare the clinical outcome of IVF treatment after pituitary suppression with two different oral contraceptives (OCs). Methods: 65 patients who received IVF treatment was classified into 2 groups based on the difference of OCs they used for pituitary suppression before ovarian hyperstimulation. Group 1 included 36 patients who received monophasic OCs. Group 2 included 29 patients who received triphastic OCs. Both groups received the OCs from the 5th day of the cycle for consecutive 21 days. The hormone profiles after OCs and clinical outcome of IVF treatment were compared between two groups. Two-sample t-tests and X2 tests were used for statistical analyses. P < 0.05 was considered statistically significant. Results: The mean age and basal hormone profiles were comparable between two groups. After ovulation suppression with different OCs, the day 2 FSH and LH value revealed statistically significant difference between two groups(4.2±1.8 vs 6.0±2.6; 2.7±2.0 vs 4.2±3.3 respectively). The numbers of oocyte per retrieval and fertilization rate were comparable between two groups, but higher quality embryos as revealed by the cleavage speed were noted in the triphastic OCs group. Although statistically not significant, higher implantation rate and pregnancy rate were also noted in the triphastic OCs group. Conclusions: Different OCs for pituitary suppression can result in different hormone profiles. Ovulation induction in IVF treatment should be individualized according to these hormone changes to achieve the optimal clinical outcome. Triphastic OCs exceeds monophastic OCs in producing good quality embryo in IVF-ET treatment.     

Functional ovarian cysts and the need to remove them.

OBJECTIVE: To review the need for the removal of functional ovarian cysts. MATERIALS AND METHODS: Over a 5-year period, between July 1994 and June 1999, all functional ovarian cysts files were reviewed in order to determine the main surgical indication. RESULTS: Thirty-four functional ovarian cysts (11.45%) were removed during that period. In 14 cases, the surgical operation was considered justified. In 32 cases, the cysts were not organic as supposed to be and had no reason to be removed. DISCUSSION: Reported functional ovarian cyst removal rates range from 15 to 30%. Present exploration means (particularly ultrasound-guided needle aspiration) does not permit to discriminate functional from organic cysts in more than 70% of the cases. CONCLUSION: It is impossible to reduce functional cyst removal rate to 0% but we should all evaluate our activity yearly and be able to limit this rate to less than 30%.     

Contraceptive compliance with a levonorgestrel triphasic and a norethindrone monophasic oral contraceptive in adolescent patients.

OBJECTIVE: This study was undertaken to assess the impact of two low-dose oral contraceptive pills on compliance and side effects in adolescent patients. STUDY DESIGN: The use of a levonorgestrel-containing triphasic pill (N = 114) was compared with that of a monophasic (1 + 35) norethindrone-containing pill (N = 110) at two different sociodemographic sites. RESULTS: No significant difference in compliance or pill satisfaction was observed between the pills. Socioeconomic factors were the overriding predictors of compliance. At 3 and 12 months of follow-up, there were significantly fewer complaints of overall side effects (p less than 0.001 and p = 0.004, respectively), breakthrough bleeding (p = 0.017 and p = 0.018), and pill amenorrhea (p = 0.002 and p less than 0.001) among users of the triphasic pill. Mean weight change at 12 months was +1.1 kg for the monophasic pill and -0.1 kg for the triphasic pill. All known pregnancies occurred among noncompliant city clinic patients. CONCLUSIONS: Adolescents experienced fewer side effects with the triphasic pill than with the monophasic one, but compliance was the same.     

Evaluating triphasic oral contraceptives: the rationale for a randomized trial

The randomized clinical trial is one of the major achievements of our times. Randomized trials set the standard for scientific rigor. They are medicine's closest approximation to the controlled experiments of the laboratory scientist. These studies prevent selection bias and minimize ascertainment bias. In addition, they are statistically efficient. There have been few randomized clinical trials comparing the metabolic effects and adverse drug experiences of low-dose oral contraceptives. Previous studies conducted with oral contraceptives containing higher doses of estrogen (equivalent to greater than 50 micrograms of ethinyl estradiol) may not be relevant today when low-dose preparations are more widely used. For this reason a randomized trial was conducted to compare three multiphasic oral contraceptives marketed in the United States.     

Use of multiphasic oral contraceptives and hospitalizations of women with functional ovarian cysts in the United States

A case-series report of seven women who developed functional ovarian cysts while taking multiphasic oral contraceptives has raised the possibility of an association between these two events. To address this question, we calculated the nationwide rates of hospitalization of women diagnosed with such cysts and examined the use of multiphasic oral contraceptives from 1979-1986. Whereas the use of multiphasic oral contraceptives grew from zero to three million users during the study interval, the hospitalization rate for functional ovarian cysts fluctuated between 472-522 per 100,000 women aged 15-44 years. Thus, there was no discernible association between taking these contraceptives and being hospitalized for functional ovarian cysts. Although this indirect assessment can neither confirm nor refute the postulated association, it suggests that if such an association does exist, its net public health impact has not been great.     

The effect of triphasic oral contraceptives on plasma lipids and lipoproteins

To determine the effect of triphasic oral contraceptives on plasma lipid transport, 150 nonsmoking women with normolipidemia, ages 18 to 35 years, were randomly assigned to receive one of three contraceptive formulations: (1) ethinyl estradiol, 30, 40, and 30 micrograms/day, each for 6, 5, and 10 days per menstrual cycle, and levonorgestrel, 50, 75, and 125 micrograms/day, each for 6, 5, and 10 days; (2) ethinyl estradiol, 35 micrograms/day for 21 days, and phased norethindrone, 500, 750, and 1000 micrograms/day each for 7 consecutive days; and (3) ethinyl estradiol, 35 micrograms/day for 21 consecutive days, and norethindrone, 500, 1000, and 500 micrograms/day for 7, 9, and 5 days, respectively. A control group consisting of 49 women taking a nonhormonal form of contraception was also included. After 6 months of oral contraceptive treatment, significant increases in plasma triglyceride (28% to 52%) and plasma apolipoprotein B levels (20% to 23%) were observed in each treatment group. The changes in total plasma cholesterol (3% to 10%) and low-density lipoprotein cholesterol values (0% to 11%) were less striking. Changes in total high-density lipoprotein cholesterol levels were statistically insignificant (-2% to -4%); however, high-density lipoprotein2 cholesterol levels decreased by 29% to 33% and high-density lipoprotein3 cholesterol levels increased by 20% to 23%. Concomitantly, plasma apoliporprotein A-1 values increased by 5% to 12%. No consistent significant differences among analyses were observed between and of the groups receiving different oral contraceptives for 6 months.     

The effects of two triphasic oral contraceptives on carbohydrate metabolism in women during 1 year of use

Sixty-one women were randomly assigned to use one of two different triphasic oral contraceptives (OCs), for one year's time (Ortho Novum 777, Ortho Pharmaceutical Corp., Raritan, NJ, and Triphasil, Wyeth Laboratories, Philadelphia, PA), containing the progestins norethindrone and levonorgestrel, respectively. The carbohydrate metabolism was evaluated using the oral glucose tolerance test before OC use and at the end of the 12th month. Both plasma glucose and insulin levels were measured. The fasting glucose value in the norethindrone-containing OC group (777) was significantly lower at the 1-year testing. All other values were unchanged. These data demonstrate that the triphasic oral contraceptive preparations currently in use have minimal effects on carbohydrate metabolism.     

Over-the-counter use of oral contraceptives in Kuwait.

Oral contraceptive pills (OCPs) are available over-the-counter (OTC) in Kuwait, and constitute a leading method for spacing and limiting children. Data from a nationally representative survey of Kuwaiti women are used to examine OTC use of OCPs. One-fourth of the women initiated use without consulting a doctor, and 50% bought OCPs from the pharmacy. No socioeconomic or demographic differences were found between those who consulted a physician, implying that women of different background have similar accessibility to the physician. Using multivariate analysis, the odds of consulting a physician were found to be significantly lower for women who first bought OCPs directly from the commercial pharmacy. The duration of first time OCP use did not differ according to physician consultation. It is concluded that OTC availability of OCPs has many advantages and prevents unwanted pregnancy. However, there is a need for better packaging and instructions that would enable high-risk women to identify themselves and to use OCPs under physician supervision.     

Potential advantages of triphasic combined oral contraceptives in the light of recent epidemiological and endocrinometabolic data

New epidemiologic data on the vascular risks of oral contraceptives (OCs) were assessed to determine whether the recently introduced low dose triphasic pills offer greater potential safety for OC users than previous formulations. Epidemiologic studies have demonstrated that vascular accidents are less frequent with OCs containing lower doses of both estrogens and progestins. The new triphasic pills have the lowest steroid content of any pills yet developed and less of a progestin climate than low dose monophasic pills. The gradual increases in the progestin dose, from 50 mcg on days 1-6 to 75 mcg on days 7-11 and 125 mcg on days 12-21 and of ethinyl estradiol from 30 mcg on days 1-6 to 40 on days 7-11 and back to 30 on days 12-21 reflect the natural cycle of steroid secretion. The endometrial mucus is better developed than under low dose monophasic pills, permitting better cycle control. Triphasic pills have been shown in all studies to block secretion by the hypothalamus and pituitary of the gonadotropins follicle stimulating hormone and luteinizing hormone, resulting in absence of follicular maturation and of ovulation. Even with the small dose of levonorgestrel, the cervical mucus is rendered inhospitable to capacitation and passage of sperm. The impact on glucose tolerance of low doses of ethinyl estradiol, even after long use, is minimal, but the 19 norsteroids used in most combined pills have a more significant impact. To the directly stimulating effect of progestins on pancreatic insulin secretion is added the development of increased peripheral resistence apparently due to a decrease in the number of insulin receptors in the target tissue. The decrease appears to be dose dependent and proportional to the androgenicity of the progestin. A recent study indicated that triphasic pills caused less of a deterioration in glucose tolerance than standard or low-dose combined OCs or a biphasic formulation. This finding was significant because of the possibility that disturbances in carbohydrate metabolism can favor development of vascular diseases. Triphasic OCs have a slight estrogen dominance, which allows them to maintain favorable levels of high density lipoprotein cholesterol, the fraction believed to provide cardiovascular protection. Similarly, they caused minimal variation on the order of 10-15% in the levels of fibrinogen, factors VII, VIII, and X, plasminogen, and antithrombine III. It has not yet been established with certainty however that changes in the levels of these coagulation factors correspond to changes in actual risk of thromboembolic accidents. Triphasics cause a minimal increase in renin substrate and activity of 12-30% compared to the 30-40% at higher estrogen doses. No significant variation in blood pressure has been observed in triphasic OC users.     

Functional ovarian cysts in patients cured of ovarian neoplasms

Twenty-seven patients with ovarian cancer underwent unilateral salpingo-oophorectomy and were followed for 12-215 months (mean 80) after completion of therapy. Of these, nine patients who received pelvic irradiation subsequently developed ovarian failure. Of the remaining 18 patients who maintained ovarian function, 13 (72%) developed a functional ovarian cyst during the follow-up period. Of these 13 patients, eight were observed until the functional cyst regressed, four were treated with oral contraceptives (OCs) to suppress ovarian function, and one underwent oophorectomy for a large corpus luteum cyst. We recommend that OC pills be considered for suppression of ovarian function in postmenarcheal girls after completion of therapy for ovarian neoplasms. Routine use of OCs may simplify the follow-up of these patients by preventing the formation of functional ovarian cysts. In postmenarcheal patients not treated with OCs, the finding of a unilocular ovarian cyst should be considered to represent a functional cyst, and a trial of OCs for 3 months may result in spontaneous regression. Persistent cysts must be operatively removed.     

Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomized trial

OBJECTIVE: We sought to evaluate the efficacy of postoperative administration of monophasic, combined, low-dose oral contraceptives on endometrioma recurrence and on persistence-recurrence of associated pain symptoms after laparoscopic treatment of moderate-to-severe endometriosis. STUDY DESIGN: In a prospective, randomized trial 70 patients who were not attempting to conceive, aged 20 to 35 years, underwent laparoscopic excision of ovarian endometriomas, followed by either postoperative administration of low-dose cyclic oral contraceptives for 6 months or no treatment on the basis of a computer-generated sequence. At 3 and 6 months after surgery and then at 6-month intervals, both groups underwent ultrasonographic examination for possible evidence of endometrioma recurrence and for evaluation of the absence, persistence, or recurrence of pain symptoms. RESULTS: Two patients in the oral contraceptive group did not complete the study. After a mean follow-up of 22 months (range, 12-48 months), there were 2 (6.1%) endometrioma recurrences in the 33 patients who received postoperative oral contraceptives versus 1 (2.9%) recurrence in the 35 patients in the control group (not significant). The moderate-to-severe pain recurrence rate was 9.1% in the oral contraceptive group versus 17.1% in the control group (not significant). The mean time to recurrence of either symptoms or endometriomas was 18.2 months in the oral contraceptive group versus 12.7 months in the control group. The 12-month cumulative recurrence rate at life-table analysis was significantly lower for patients receiving oral contraceptives versus control subjects, whereas no significant difference was evident at 24 and 36 months. CONCLUSION: Postoperative administration of low-dose cyclic oral contraceptives does not significantly affect the long-term recurrence rate of endometriosis after surgical treatment. A delay in recurrence is evident at life-table analysis.     

Alkaline phosphatase activity of polymorphonulcear leukocytes in relation to oral contraceptives

25 fertile women aged 25-36 with an average of 3 children were tested over 93 cycles to observe the effects of synthetic steroids on the neutrophil alkaline phosphatase. The women were using 3 different types of oral contraceptives: Anovlar, Lyndiol, and Enovid-E. 14 women using Anovlar were analyzed for 50 cycles and showed fluctuation in alkaline phosphatase activity with higher levels as compared to normal cycles before the use of Anovlar. 8 women receiving Lyndiol over 18 cycles indicated a low-rise, while 3 women on Enovid-E over 10 cycles showed a rise in alkaline phosphatase activity, but not as much as with the Anovlar. After a 5-cycle follow-up, 5 women who discontinued the pill showed a drop in alkaline scores. After pill discontinuation, there was a gradual return to the neutrophil alkaline phosphatase activity, but these levels did not indicate a correlation with the total leukocyte or absolute neutrophil count.     

Cyclic use of combination oral contraceptives and the severity of endometriosis.

The author reports on 206 cases of endometriosis examined between 1970-1977. 172 patients had used OC (oral contraception) for a varying period of time prior to diagnosis of endometriosis; of these, 122 had taken only combined OCs containing 50 mg. or more of estrogen. These data neither support nor contradict the contention that the cyclic use of the combination pill will alter the progression of endometriosis. The only difference within the groups with mild, moderate, or severe endometriosis was the length of treatment. Endometriosis can cause infertility as well as other problems; if the dose of estrogen plays a role in the etiology of endometriosis, low-dose combination pill should be considered.     

The use of oral contraceptives to regulate oocyte retrieval

This study was designed to determine the efficacy of using OCs prior to ovulation induction in an IVF-ET program. A total of 26 cycles were initiated after gonadotropin suppression with OCs and 22 laparoscopies (84.6%) were performed. A pregnancy rate of 22.7% per laparoscopy and 23.8% per ET was achieved. The results suggest that the use of OCs to regulate oocyte retrieval can result in acceptable pregnancy rates and facilitate efficient time use of IVF-ET personnel.     

A randomized, double-blind, placebo-controlled comparison of the impact of low-dose and triphasic oral contraceptives on follicular development.

OBJECTIVE: This investigation tests the hypothesis that triphasic oral contraceptives are associated with the development of large, persistent ovarian cysts. STUDY DESIGN: Weekly vaginal ultrasonography was used in a randomized, double-blind, placebo-controlled, parallel-group, single-center study that compared the incidence, risk, size, and time to resolution of ovarian follicles in healthy women who took Estrostep or Loestrin oral contraceptives (manufactured by Parke-Davis) or a placebo during three consecutive menstrual cycles. RESULTS: Sixty-three percent of placebo-treated subjects developed follicles greater than 18 mm, compared with 39% and 23% in the Estrostep and Loestrin groups. The risks for each group of developing a large follicle during a single cycle were not different. No dominant follicle persisted for greater than 2 weeks for any subject. CONCLUSION: These results demonstrate that follicular development continues during treatment with oral contraceptives. In addition, the findings fail to support the hypothesis that triphasic oral contraceptives result in persistent ovarian cysts.     

Androgenic progestins in oral contraceptives and the risk of epithelial ovarian cancer

OBJECTIVE: Oral contraceptives (OCs) have been consistently linked to reduced risk of ovarian cancer. Oral contraceptive formulations display varying degrees of androgenicity. Data linking androgens to ovarian cancer suggest that OC androgenicity may impact efficacy in preventing ovarian cancer. The authors investigated whether OC efficacy might differ according to androgenicity by using data from a large, population-based, case-control study (the Steroid Hormones and Reproductions [SHARE] Study). METHODS: Detailed data on OC formulation was obtained by an in-person interview for 568 cases and 1,026 controls. Multivariable logistic regression was used to assess the association of OC androgenicity with ovarian cancer while controlling for the known potential confounders of age, parity, family history of ovarian cancer, and tubal ligation. RESULTS: Androgenic and nonandrogenic OCs conferred a similar and significant reduction in ovarian cancer risk (odds ratio 0.52, 95% confidence interval 0.35-0.76 and odds ratio 0.59, 95% confidence interval 0.45-0.78, respectively). No differences in duration of use, age at first use, and time since last use were found between androgenic and nonandrogenic formulations. CONCLUSION: In general, the androgenicity of an OC does not alter chemopreventive efficacy. LEVEL OF EVIDENCE: II-2.     

Serum concentrations of markers of type I collagen metabolism in women taking monophasic oral contraceptives

OBJECTIVES: To investigate serum concentrations of the carboxy-terminal propeptide of type I procollagen (PICP) and cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), reflecting the rate of synthesis and degradation of the parent collagen respectively, in women using monophasic oral contraceptives. STUDY DESIGN: PICP and ICTP were estimated in 60 women taking 20 micrograms of ethinyl estradiol (EE) + 150 micrograms of desogestrel (DSG) or 30 micrograms of EE + 150 micrograms DSG over six months. RESULTS: Mean PICP concentration decreased in women receiving 20 micrograms of EE + 150 infinity g of DSG after three cycles of administration. However, after six months this value returned to a level comparable to the initial one. In women taking 30 micrograms of EE + 150 micrograms of DSG the mean concentrations of PICP did not change significantly throughout the period studied. None of the oral contraceptives noticeably influenced the concentrations of ICTP. CONCLUSION: Investigated oral contraceptives do not significantly affect the metabolism of type I collagen, however a transient decrease in its biosynthesis may be expected during the use of formulations containing 20 micrograms of EE.