Nomenclature of the gonane progestins.

PIP: The use of gonane nomenclature can be traced back to the early 1960s, when the first compound submitted for trial, the carbon-18 homologue of the anabolic agent Nilevar was named bisnortestosterone. However, the confusion about how this compound was named led scientists to introduce the gonane system for naming bisnortestosterones and structurally related compounds. Use of the terms gonane and estrane to classify the levonorgestrel and norethindrone families of progestins, respectively, originates from the systemic name of these compounds. Levonorgestrel is 17beta-hydroxy-17alpha-ethinyl-13beta-ethyl-4-gonen-3-one, while norethindrone is 17beta-hydroxy-17alpha-ethinyl-4-estren-3-one. The term gonane signifies that levonorgestrel and the related progestins are a separate class of steroids that differ from other steroids. Levonorgestrel and the related progestins form a structural category of 18-homologated 19-nortestosterones. Thus, it would be better to categorize levonorgestrel and the structurally related progestins such as desogestrel, norgestimate, gestodene as carbon-18-homologated 19-nortestosterones. Alternatively, it is simpler to refer to these compounds as the levonorgestrel family of progestins. In a similar manner, norethindrone and the related progestins can be referred to as the norethindrone (norethisterone) family of progestins.^ieng

Pain of endometriosis: effects of nafarelin and danazol therapy.

OBJECTIVE: To compare the efficacy of nafarelin acetate with danazol in the treatment of dysmenorrhea, dyspareunia, and pelvic pain associated with endometriosis. DESIGN: Prospective, randomized double-blind controlled study. PATIENTS, SETTING, TREATMENTS: Two hundred thirteen patients aged 18 to 48 with laparoscopically confirmed pelvic endometriosis and dysmenorrhea, dyspareunia or pelvic pain were randomly assigned to 6 months of treatment with either nafarelin acetate 800 micrograms per day or 400 micrograms per day, or danazol 800 micrograms per day. MAIN OUTCOME MEASURES: The percentage of patients with dysmenorrhea, dyspareunia or pelvic pain before treatment who still had these symptoms after 6 months of treatment and 6 months following completion of treatment. RESULTS [table: see text] CONCLUSIONS: Nafarelin acetate and danazol both provided significant relief of dysmenorrhea, dyspareunia, and pelvic pain during treatment and for 6 months following treatment in women with endometriosis.

Oral contraception: a review.

PIP: This review of the development of oral contraceptives (OCs) begins with a summary of research between 1920 and 1950 that led to the first highly effective, orally active progestogen for human use. Enovid by Searle, the first marketed OC, began being distributed in 1960; it was combination of 9.85 mg of norethynodrel and .150 mg of mestranol. Research on combination norethynodrel-containing products revealed that the dosage was too high. Discussion focuses on preparations containing norethisterone, norethisterone acetate, medroxyprogesterone diacetate, norgestrel, other Norgestrel products available outside the US, progestogen, as well as the sequentials and the multiphasics. The active phase of clinical development was during 1950s and 1960s. The Food and Drug Administration (FDA) had an active role in regulating OCs; OCs with more than .05 mg of estrogen were removed from the market; FDA permitted ethinyl estradiol as a substitute for mestranol. Pregnancy rates appear lower in clinical trials than among the general population. 3% during the first year is considered more characteristics of the failure rate among the general population. It appears that intermenstrual bleeding (IMB) has decreased as doses have been decreased, but strict comparison between studies and over time is not possible. There is valid documentation of the rate of IMB with low-dose OCs, or of differences between new OC users and prior OC users, or of the impact of the strength of OC components.^ieng

Oral contraceptives and cancer.

PIP: Concerns over the safety of oral contraceptives (OCs) have led to numerous empirical studies of the relationship of OC use to normal pregnancy outcomes, pituitary effects, cardiovascular accidents, and cancer. The article reviews some of the results of studies on the effects of OC use on ovarian, uterine, cervical, and breast cancer and on hepatic cancer and melanomas. Reference is made to direct study results rather than to reviews of studies, although it is noted that the critical reviews of Goldzieher and Realini reflect appropriate critiques of the validity of the methods employed in the analysis of cancers as well as cardiovascular risks. Concern is raised for meta-analysis of pooled data. In spite of the 30 years of research on OCs there is no definitive answer to the question of cause and effect. The epidemiological articles reviewed do not meet the standards of critical editorial review boards of experimental journals; confirmation of findings is also lacking. Studies suggesting increased risks as well as those showing positive benefits are questionable. The conclusion reached is that OCs protect against ovarian and uterine cancers and do not cause mammary, cervical, or liver cancer or melanoma. This conclusion is based on inconclusive data. The conclusion on hepatic cancer is that the 3 retrospective case control studies and anecdotal reports are flawed in design, and little confidence can be placed on such a limited number of cases. Malignant melanoma conclusions are that the data are inconsistent and hover around a risk of one for long-term OC-users. There is no increased risk related to OC-use. Ovarian cancer risk seems to be decreased in about 40% of OC-users. Endometrial cancer risk seems to be decreased, except for the sequential contraceptive Oracon which is associated with increased risk. Decreased risk is related to length of usage and continues after stoppage. Cervical carcinoma results appear to confirm the finding that prolonged OC use slightly increases the risk, but confounding factors may be present. Breast cancer shows no association with OC use, but inconsistent data among subgroups, particularly young women who used OCs before their first birth, some increased risks show.^ieng

Pharmacokinetics of norethindrone: effect of particle size.

In 24 healthy women between the ages of 19 and 35 years who had not used oral contraceptive preparations for at least 60 days, it was found that the smaller the particle size of norethindrone (NET) administered, the higher was the plasma NET level obtained. Three different preparations having particle sizes of NET smaller than 250 microns, 44 microns or 10 microns were tested in a crossover pattern. The time required to reach maximum plasma concentration (Tmax) became shorter with decreasing particle size, 1.69 hr, 1.52 hr and 1.06 hr, respectively. As particle size was reduced, the maximum NET plasma concentration (Cmax) increased for the 3 different 1 mg NET preparations, i.e. 8.66 ng/ml, 10.53 ng/ml and 15.73 ng/ml. A trial with a 2 mg NET preparation made with NET utilizing the 44 microns same material displayed a Tmax similar to the 1 mg NET preparation having the same particle size while the Cmax reached a level of 17.56 ng/ml. The area under the plasma concentration versus time curve from 0-24 hrs and the extrapolated total area under the curve, increased with decreasing particle size. The use of a smaller particle size allows for more rapid dissolution or oral contraceptive tablets when measured in vitro; however, there is no evidence that such faster dissolution leads to a significant difference in efficacy. Oral contraceptive tablets have, since their inception, utilized both large and small NET particle size material in various preparations.

Bioequivalence of two oral contraceptive drugs containing norethindrone and ethinyl estradiol.

Two oral contraceptive drugs, Formulation A and Formulation B, both of similar hormonal content, were compared with each other to determine if they were bioequivalent. Both drugs contain 1 mg of norethindrone (NET) and 0.035 mg of ethinyl estradiol (EE). Application of an interval test for the ratio of the computed parameter means demonstrated equivalence for the two formulations with respect to the 0-24 hour area under the plasma level versus time curve (AUC24), the total area under the curve (AUCtot) and for the maximum plasma concentration (Cmax) for both ethinyl estradiol and norethindrone. The data support the hypothesis for bioequivalence of the two formulations with respect to total absorption.

Bleeding patterns with low-dose, monophasic oral contraceptives.

Cycle control over 12 months with low-dose oral contraceptives (OCs) was analyzed using calendars of bleeding on pill-taking days 1 through 21 (intermenstrual bleeding; IMB). One preparation contained 0.5 mg norethindrone and 0.035 mg ethinyl estradiol (NET + EE), the other 0.3 mg norgestrel and 0.03 mg ethinyl estradiol (Ng + EE). Half the subjects had previously used OCs containing greater than or equal to 0.05 mg estrogen (switch-over); the others had not previously used OCs for 2 months or more (fresh). Fresh subjects reported more IMB than switch-over subjects, especially during the first three cycles; IMB decreased over time for both groups. Ng + EE subjects had fewer IMB episodes during the early cycles than NET + EE subjects. Daily incidence of IMB formed a characteristic W-shaped curve in the NET + EE subjects that was most apparent in early cycles.

Drug interactions with oral contraceptives: compilation and analysis of an adverse experience report database.

Over 700 alleged OC/drug interactions were reported for antituberculous drugs, other antibiotics, anticonvulsants, antidepressants, and analgesics. Fewer than ten reports of OC/drug interactions were found involving antihistamines, thyroid hormone, vitamin C, antacids, ulcer medication, or diuretics. These may represent a set of OC/drug interaction problems that need to brought into medical awareness. Pregnancy is the first event reported when OCs appear to interact with another drug. However, menstrual disturbances are reported more often. BTB is the most frequently reported menstrual disturbance: it has been considered a warning signal that OC efficacy may be compromised. In such circumstances, contraceptive backup may be warranted. Reports of interference with OC efficacy have been most common for drugs used to treat tuberculosis, epilepsy, and depression, so patients and their physicians should be aware of potential problems. However, the average woman is more likely to encounter antibiotics, analgesics, and antihistamines, and current package inserts contain appropriate warnings. In recent years, prescriptions for low-estrogen OCs have outnumbered those for high-dose preparations. Many physicians became concerned that there was an increased risk of OC drug failure with the low-dose products. The database does not seem to suggest that this has happened. The dose of estrogen is not correlated with total adverse experience reports, time of appearances of the first adverse experience reports, or rate of reporting of the interactions. Likewise, reports of potential interactions with menstrual disturbances are not correlated with lower estrogen doses in OCs. There is, however, an association between low-estrogen OCs and recently reported pregnancies attributed to OC/drug interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Given the large numbers of oral contraceptive (OC) users, coupled with the prevalence of use of antibiotics, antidepressants, anticonvulsants, and anticoagulants, there is a need for a comprehensive analysis of potential OC/drug interactions. This review includes a compilation of a database of all the adverse experience reports contained in the literature, results voluntarily reported to Syntex, and a survey of clinical and animal studies in this field. Over 700 alleged OC/drug interactions were reported for antituberculous drugs, other antibiotics, anticonvulsants, antidepressants, and analgesics. Fewer than 10 reports of OC/drug interactions were found involving antihistamines, thyroid hormones, vitamin C, antacids, ulcer medication, or diuretics. The greatest number of incidents (256) involved antibiotics; of these, antituberculous drugs accounted for 76% of the total. Of the 713 cases involving possible interference with the efficacy of OCs, only 21% resulted in pregnancies; 41% reported menstrual disturbances and 38% reported no problems at all. 94% of the cases of adverse OC/drug interactions involved higher-dose (50 mcg or more) estrogen OCs. Likewise, reports of potential interactions with menstrual disturbances are not correlated with lower estrogen doses in OCs. There is, however, an association between low-estrogen OCs and recently reported pregnancies attributable to OC/drug interactions. Breakthrough bleeding was the most commonly reported menstrual disturbance and may constitute a warning sign of adverse OC/drug interactions.

Bioequivalence of norethindrone and ethinyl estradiol for two different weight tablets with the same hormonal content.

Two tablets of differing weights, 100 mg (A) and 50 mg (B), of an oral contraceptive drug (OC) were compared with each other and to a solution (C) of the same components. The composition of the OC consisted of 1 mg of norethindrone (NET) and 0.035 mg of ethinyl estradiol (EE2). Both tablets were shown to differ from the solution, which was more rapidly absorbed, but were not significantly different from each other. Formulation means for NET and EE2, for each of the two products, were similar. Application of an interval test for the ratio of computed parameters demonstrated equivalence of the two formulations with respect to 0-24 hr area under the curve (AUC24) and total area under the curve (AUC+o+) for both NET and EE2 and with respect to concentration maximum (Cmax) for EE2. The data support the hypothesis for bioequivalence of the two formulations with respect to total absorption.

Naproxen sodium for OB/GYN use, with special reference to pain states: a review.

The effectiveness of naproxen sodium and its parent compound, naproxen, has been assessed in the treatment of a variety of obstetric and gynecologic problems, particularly pain states. This article summarizes the literature on the efficacy of the naproxen compounds in treatment of the following conditions: primary and secondary dysmenorrhea, insertion of a contraceptive intrauterine device, suction curettage, postpartum pain, pelvic inflammatory disease, gynecologic surgery, menorrhagia, premature labor and menopause. The data from the studies compiled demonstrate the usefulness of naproxen sodium or naproxen as an effective analgesic in treating pain and inflammation associated with these conditions.

PIP: Naproxen sodium, a nonsteroidal anti-inflammatory drug that blocks prostaglandin synthesis, has been shown to be effective for relief of mild to moderate pain. This article summarizes the literature on the efficacy of the naproxen compounds in the treatment of the following conditions: primary and secondary dysmenorrhea, IUD insertion, suction curettage, postpartum pain, pelvic inflammatory disease, gynecologic surgery, menorrhagia, premature labor, and menopause. Since naproxen does not affect the reproductive cycle, it appears to be ideal for obstetrics-gynecology use. Pediatricians, family practitioners, internists, surgeons, and geriatric specialists will also encounter patients requiring relief from pain caused by gynecologic pathology. The combined therapeutic use of nonsteroidal anti-inflammatory drugs and antibiotics for infections of the female reproductive tract appears indicated. The literature has established therapeutic success with naproxen and naproxen sodium as compared to a placebo in the treatment of dysmenorrhea and pain associated with IUD insertion, suction curettage, and postpartum conditions; joint pain in menopausal women; pain and inflammation associated with pelvic infections; and gynecologic surgery.

[Oral contraceptives: recent safety studies (author's transl)]. / Contraceptifs oraux: recentes etudes de tolerance.

PIP: Considerable research evidence now exists to suggest that the risks of oral contraceptive (OC) use were seriously overestimated in earlier work. Because experimentation in medicine is never possible in the rigorous sense in which it is employed in basic sciences, other sources of information must be substituted. Information on the dangers of OC use has come from anecdotal reports, retrospective case control studies, prospective cohort studies, and statistical analyses of deaths, each source being associated with specific problems of interpretation. Recent findings of the Royal College of General Practitioners, the Walnut Creek Study, and the Oxford Study have suggested a lowered incidence of malignant neoplasms in OC than in IUD or diaphragm users; a reduced incidence of breast cancer although the relationship did not consistently achieve statistical significance, and a reduced incidence of ovarian and endometrial cancer. The risks of cervical cancer among OC users appeared slightly higher but disappeared when sexual behavior was controlled. Despite much concern with the possibility of postpill amenorrhea and perhaps sterility among women discontinuing OC use, it now appears that after 2 years there is no difference in the fertility of women who have discontinued use of OCs, IUDs, or diaphragms. Use of OCs as a contraceptive before pregnancy does not appear to be associated with fetal malformations, spontaneous abortion, or perinatal mortality, and the inadvertent use of OCs in early pregnancy is apparently associated with only a very slight risk of anomalies. Recent studies of cardiovascular disease risks indicate that the relative risks of cardiovascular disease among OC users have been greatly exaggerated, especially when smoking is taken into account. Various studies of mortality data have failed to establish a link between OC use and excess mortality from cardiovascular disease.^ieng