A comparison of levonorgestrel implants with depo-medroxyprogesterone acetate injections for contraception.

PIP: The Norplant System of levonorgestrel implants and the Depo Provera contraceptive Injection of sterile medroxy progesterone acetate suspension (DMPA) are longterm, progestagen-based contraceptive delivery systems designed to overcome noncompliance which are under review for use in Canada. 150 mg of DMPA, a pregnane compound derived from progesterone, is injected every 3 months. Peak plasma concentrations are reached in 24 hours and plateau for 3-4 months before gradually declining. After termination, ovulation returns on average in 4.5 months, and conception occurs at a median time of 10 months. 90% conceive by 24 months. In the Norplant system, a steady daily supply of 50-80 mcg of levonorgestrel, a gonane progestin derived from the testosterone nucleus which has both progestogenic and androgenic receptor affinity, diffuses from 5 Silastic implants, which must be replaced every 5 years. Ovulation and fertility return rapidly after rod removal. The actual and lowest expected failure rates are equal for both systems. The failure rate for DMPA is .3 pregnancies per 100 women years, while that for levonorgestrel is .4% in 1 year. Although neither method affects blood pressure, DMPA appears to affect carbohydrate metabolism by impairing glucose tolerance and increasing insulin production. Lipid metabolism is also affected. 5% of those who use levonorgestrel discontinue it because of side effects, including headache, mastodynia, and acne; 19.1% of DMPA users did so, especially for weight gain and menstrual cycle abnormalities. Both methods have a higher frequency of menstrual abnormalities than normal. 27.7% of levonorgestrel users experienced prolonged bleeding, while 17% experienced spotting during the first 6 months. However, normal menses usually returned within a year, and only 7.9% discontinued use because of cycle abnormalities. In 1 study, less than 10% of DMPA users experienced normal cycles, and in another study 35% experienced amenorrhea (500/700 discontinued use). Amenorrhea replaced irregular bleeding with continued use, occurring in 68% of users by 2 years. There is also some concern about DMPA and breast cancer and bone loss. Based on 1 case-control study of 110 women with breast cancer who had taken DMPA, the relative risk is highest for those between ages 25 and 34 who use DMPA longer than 6 years. A WHO study concluded that the relative risk of developing breast cancer, because of DMPA, is inversely related to duration of use. A Phase IV study on DMPA and bone mineral density has been undertaken.^ieng

The new era in oral contraception: pills containing gestodene, norgestimate, and desogestrel.

The latest advance in the 30-year evolution of oral contraceptives (OCs) is the development of three new progestogens: desogestrel, norgestimate, and gestodene. These three new agents are derivatives of levonorgestrel, a gonane hormone, and have been used to develop pills that provide effective pregnancy prevention at lower doses than oral contraceptives using the older steroids. Desogestrel is a prohormone that must first be metabolized into its biologically active form. Norgestimate is already active, but it will be metabolized in part to levonorgestrel. Gestodene is biologically active in its native form. Among the improvements in metabolic parameters seen with this new generation of progestogens are a lack of impact on blood pressure, a balanced effect on coagulation, and a reduced impact on carbohydrate metabolism compared with earlier, higher-dose formulations. The new pills also seem to produce no negative effects on lipid and lipoprotein biosynthesis, and perhaps even improve the ratio of low-density lipoprotein to high-density lipoprotein. Cycle control with all three progestogens is improved, with much lower incidence of intermenstrual bleeding (IMB). Efficacy is as good as with other OCs. Another benefit of the new low-dose progestogens, however, is the low incidence of minor side effects observed in women using these contraceptives. Low incidences of weight gain, headache, and nausea were reported, and the dropout rate because of side effects was low in both international and US trials. Serious side effects are rarely seen with pills containing the new progestogens.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative contraceptive efficacy and mechanism of action of the norgestimate-containing triphasic oral contraceptive.

Norgestimate (NGM), a derivative of 19-nortestosterone with very specific affinity for the progesterone receptor, has been used in combination with ethinyl estradiol (EE) at low doses in both monophasic and triphasic oral contraceptives (OCs). An open-label comparative clinical trial was conducted with 4,234 healthy women using comparative clinical trial was conducted with 4,234 healthy women using triphasic levonorgestrel (LUG)/EE and NGM/EE through a total of 22,312 menstrual cycles. Contraceptive (LUG)/EE and NGM/EE through a total of 22,312 menstrual cycles. Contraceptive efficacy was excellent with both preparations, with no statistically significant between-regimen differences in pregnancy rates. The theoretical Pearl index was the NGM/EE triphasic, and 0.34 for the LNG/EE triphasic. Adverse experiences in groups were typical of those that may occur among women taking low-dose OC agents. was similar with the two preparations: 8.6% for the NGM/EE triphasic and 6.8% for the LNG/EE triphasic. In a separate mechanism of action study, specific endocrine parameters were investigated in 20 subjects using the NGM/EE triphasic for 4 cycles. Ovulation suppression was demonstrated in statistically significant decreases from pretreatment values in serum levels of luteinizing hormone, follicle-stimulating hormone, progesterone, and estradiol. Significant on-treatment increases in serum levels of sex hormone binding globulin evidenced minimal androgenicity. All hormonal values returned to or toward normal in the post-treatment cycle. The study results support those obtained in large noncomparative studies of the NGM/EE triphasic. This phased-dose combination suppresses ovulation and is a very effective, minimally androgenic contraceptive agent with a good safety profile.

PIP: Norgestimate (NGM), a derivative of 19-nortestosterone with very specific affinity for the progesterone receptor, has been used in combination with ethinyl estradiol (EE) in low doses in both monophasic and triphasic oral contraceptives (OCs). An open-label comparative clinical trial was conducted with 4234 healthy women using triphasic levonorgestrel (LNG)/EE and NGM/EE through a total of 22,312 menstrual cycles. Contraceptive efficacy was excellent with both preparations with no statistically significant between-regimen differences in pregnancy rates. The theoretical Pearl index was 0.12 for the NGM/EE triphasic, and 0.34 for the LNG/EE triphasic. Adverse experiences in both groups were typical of those which could occur among women taking low-dose OCs. The % of subjects who discontinued treatment due to use-related adverse experiences was similar among the 2 preparations; 8.6% for the NGM/EE triphasic and 6.8% for the LNG/EE triphasic. In a separate mechanism of action study, specific endocrine parameters were investigated in 20 subjects who used the NGM/EE triphasic for 4 cycles. Ovulation suppression was demonstrated in statistically significant decreases from pretreatment values in serum levels of luteinizing hormone, follicle stimulating hormone, progesterone, and estradiol. Significant on-treatment increases in serum levels of sex hormone binding globulin evidenced minimal androgenicity. All hormonal values returned to or toward normal in the posttreatment cycle. The study results support those obtained in large noncomparative studies of the NGM/EE triphasic. This phased-dose combination suppresses ovulation and is a very effective, minimally androgenic contraceptive with good safety profile.

Effect of a nutritional supplement on premenstrual symptomatology in women with premenstrual syndrome: a double-blind longitudinal study.

To assess the effectiveness of a vitamin/mineral supplement in controlling symptoms of premenstrual syndrome (PMS), we conducted a double-blind randomized study on 44 women with PMS. Subjects were carefully screened and excluded if underlying physical or psychopathological conditions were noted. Follicular and luteal testing with a menstrual symptom questionnaire, subdividing PMS into four subgroups, was completed for 1 month prior to treatment and for three menstrual cycles during treatment. Subjects were randomly assigned to receive either placebo or six or 12 tablets of the supplement a day for three menstrual cycles. All subjects had significant differences in severity of symptoms between the follicular and luteal phase of the control cycle. Comparing pre- vs posttreatment luteal phase scores, significant placebo effects were noted for two PMS subgroups. Significant treatment effects were noted in three subgroups for the six-tablet group and in all four subgroups for the 12-tablet group. These results suggest that this nutritional supplement may play a role in the management of women with PMS.

Evaluation of the clinical performance of three triphasic oral contraceptives: a multicenter, randomized comparative trial.

Three hundred thirteen women participated in an open, multicenter comparison of the incidence of intermenstrual bleeding (breakthrough bleeding and or spotting) associated with the use of three triphasic oral contraceptives. Triphasil (n = 107), containing levonorgestrel and ethinyl estradiol, and Ortho-Novum 7/7/7 (n = 97) and Tri-Norinyl (n = 109), both of which contain norethindrone and ethinyl estradiol, were administered over four cycles for a total of 1141 cycles. The total incidence of intermenstrual bleeding was significantly lower with Triphasil (17.2%) than with Ortho-Novum 7/7/7 (39.5%) or Tri-Norinyl (49.0%). The pattern remained the same when findings were analyzed cycle by cycle and for breakthrough bleeding and spotting separately. The incidence of other side effects was comparable for all regimens. Results of this study demonstrate superior cycle control with Triphasil compared with Ortho-Novum 7/7/7 and Tri-Norinyl during the first four cycles of use.

PIP: 313 women participated in an open, multicenter comparison of the incidence of intermenstrual bleeding (breakthrough bleeding or spotting) associated with the use of 3 triphasic oral contraceptives. Triphasil (n=107), containing levonorgestrel and ethinyl estradiol, and Ortho-Novum 7/7/7 (n=97) and Tri-Norinyl (n=109), both of which contain norethindrone and ethinyl estradiol, were administered over 4 cycles for a total of 1141 cycles. The total incidence of intermenstrual bleeding was significantly lower with Triphasil (17.2%) than with Ortho-Novum 7/7/7 (39.5%) or Tri-Norinyl (49.0%). The pattern remained the same when findings were analyzed cycle by cycle and for breakthrough bleeding and spotting separately. The incidence of other side effects was comparable for all regimes. Results of this study demonstrate superior cycle control with Triphasil compared with Ortho-Novum 7/7/7 and Tri-Norinyl during the first 4 cycles of use.

Saccharin and aspartame. Are they safe to consume during pregnancy?

Saccharin and aspartame are commonly used artificial sweeteners. Some of the currently available information on their safety in pregnancy was reviewed, with recommendations formulated on their use in the periconceptional period and pregnancy.

Efficacy of alpha-tocopherol in the treatment of the premenstrual syndrome.

In a preliminary study, alpha-tocopherol supplementation was effective in reducing specific symptoms of the premenstrual syndrome (PMS). To confirm these findings, we performed a randomized, double-blind study using d,alpha-tocopherol and placebo in a carefully screened population of women with PMS. Standardized PMS questionnaires were administered in the luteal phase of the menstrual cycle to all subjects, before and after daily treatment with 400 IU d,alpha-tocopherol or placebo for three cycles. Of the 46 subjects enrolled, 41 completed the clinical trial. A significant improvement in certain affective and physical symptoms was noted in subjects treated with d,alpha-tocopherol.

The effect of vitamin E on mammary dysplasia: a double-blind study.

Alpha-tocopherol (vitamin E) has been used to treat patients with benign breast disease. To evaluate the efficacy of this treatment, a randomized, double-blind placebo-controlled study was performed on 128 women with confirmed mammary dysplasia. Patients were treated with placebo or 150, 300, or 600 IU of d, 1 alpha-tocopherol per day for two months; breast examinations, sonography, and thermography were performed in the midluteal phase of the menstrual cycle before and after treatment. No significant objective effects to treatment were noted in any of the parameters monitored. In addition, serum concentrations of estradiol, progesterone, dehydroepiandrosterone sulfate, and testosterone were measured before and after treatment. There were no significant effects on concentrations of these hormones. From this study, d, 1 alpha-tocopherol does not seem to be beneficial in the treatment of patients with mammary dysplasia.

Reliability of contact-thermogram reading services.

Contact thermography has been advocated by some as a rapid, noninvasive diagnostic modality in evaluating patients at risk for breast cancer. In order to study the value of different criteria for interpreting thermograms, two sets of contact thermograms from 34 patients with benign breast disease were submitted to two different reading services. The results suggest that interrater agreement is enhanced when thermograms are classified as "normal" and "abnormal" rather than as class I-V.

The effect of alpha-tocopherol on premenstrual symptomatology: a double-blind study. II. Endocrine correlates.

In a randomized, double-blind, dose-response study, alpha-tocopherol significantly ameliorated symptoms in three of the four classes of the premenstrual syndrome (PMS). Alpha-tocopherol treatment had no significant effect on serum concentrations of testosterone, dehydroepiandrosterone sulfate (DHEA-S), estradiol, and progesterone. However, independent of treatment, a significant correlation emerged between temporal changes in one PMS category and changes in DHEA-S concentrations. These results suggest that improvement in PMS severity is not mediated through direct effects of alpha-tocopherol on serum steroids. Androgens, however, may play a role in some PMS symptomatology.

Evaluation and treatment of breast symptoms in patients with the premenstrual syndrome.

Breast symptoms are a common finding in women with the premenstrual syndrome (PMS). The underlying endocrine pathophysiology of PMS and benign breast disease may be similar and possibly related. Endocrine theories concerning both disorders have been developed, and nutritional intervention can be of aid. In a double-blind study, breast symptoms of PMS were recorded before and after vitamin E or placebo was administered. A significant decrease (p less than 0.05) in some of the symptoms was noted.

Aspirin in the treatment of episiotomy pain.

We studied 160 postpartum women having moderate to severe episiotomy pain to determine the efficacy of aspirin analgesia, with 5, 10, and 20 grain doses, as compared to placebo. Over a four-hour period, all groups treated with aspirin showed significantly more improvement in pain intensity scores than those given placebo. Only a small percentage of patients required additional analgesic medication. This study shows that aspirin alone is an effective treatment for relief of moderate to severe episiotomy pain.

The effect of alpha-tocopherol on premenstrual symptomatology: a double-blind study.

In a double-blind, randomized dose-response study, 75 women with benign breast disease were administered a written questionnaire in which they scored the severity of premenstrual syndrome (PMS) symptoms before and after two months of treatment with placebo or alpha-tocopherol (150, 300, or 600 IU/day). Controlling for age and pretreatment scores, alpha-tocopherol had a significantly greater effect than placebo, improving three of the four classes of PMS symptoms. These findings suggest that vitamin E supplementation may be of value in women with severe PMS symptoms.

Medical management of mammary dysplasia.

As a primary care physician for women, the gynecologist frequently is faced with management of patients who have benign breast disease. Mammary dysplasia, or fibrocystic disease, clinically presents a difficult management problem, both in terms of relieving the patients' symptomatology and of detecting occult malignancy. Traditionally, diuretics, salt restriction, and hormone therapies have been recommended. Recently, data concerning nutritional impact on this disease process, including methylxanthine restriction and tocopherol therapy, have been reported. New, effective pharmacologic agents also are now available. This article reviews the efficacy of these therapeutic regimens and recommends a rational approach for the management of patients with mammary dysplasia.

Endocrine parameters and alpha-tocopherol therapy of patients with mammary dysplasia.

Patients with mammary dysplasia (17 patients) and controls (6 patients) were treated in a double-blind study with alpha-tocopherol acetate (600 units/day). Determination of serum alpha-tocopherol, estradiol, estriol., and progesterone were made from blood samples collected on Day 21 of the menstrual cycle before and during therapy. Eight-eight % of patients showed clinical response to therapy. Serum alpha-tocopherol concentrations rose after therapy in patients and controls. Serum estradiol and progesterone concentration were not statistically different in patients or controls after therapy, although patients showed a trend toward increased serum progesterone concentration. However, the ratio of progesterone to estradiol, which is abnormal in mammary dysplasia patients, rose from 30 +/- 7 (S.E.) to 53 +/- 11 in patients after alpha-tocopherol therapy (p less than 0.05). Control patients showed no significant change in progesterone/estradiol ratio. Results of this study indicate that alpha-tocopherol therapy may correct an abnormal progesterone/estradiol ratio in patients with mammary dysplasia, with implications on reducing future risk for malignant breast disease.

Use of doxycycline in elective first trimester abortion.

Elective first trimester abortion was performed in 263 patients, including 86 control patients and 177 patients receiving doxycycline as prophylactic antibiotic coverage. Abortions were done by the same physicians, using a standard protocol. Control and study populations had similar courses, except that the incidence of major complications and total complications was significantly reduced in the group receiving doxycycline. No untoward reactions to the drug were noted, and patient compliance was excellent. The results suggest that the low morbidity of elective suction abortion is further reduced by prophylactic doxycycline.

Myasthenia gravis and preeclampsia.

Myasthenia gravis in pregnancy is rare, and its occurence in conjunction with preeclampsia has not been previously described. A case report of preeclampsia in a myasthenic patient is described with recommendations for management. The authors conclude that magnesium is a contraindicated pharmacologic agent in a myasthenic patient.