Existence of multiple peaks in plasma ethinyl estradiol and norethindrone after oral administration of a contraceptive pill.

Previous measurements of plasma ethinyl estradiol (EE2) and norethindrone (NE) over 24 h after oral administration of a contraceptive pill have demonstrated a single steroid peak occurring 1-2 h after pill ingestion, with a gradual decline over the next 22 h. In the present study plasma concentrations of EE2 and NE were measured 0, 0.5, 0.75, 1, 2, 4, 12, and 24 h after oral ingestion of a contraceptive pill containing 35 micrograms EE2 and 1 mg NE at 0, 3, 6, and 9 months of use in 58 normal healthy women. Contrary to previous reports, analysis of the 464 steroid curves (58 subjects x 4 time periods x 2 steroids) revealed the presence of multiple hormone peaks. Two peaks of EE2 were identified in 44.8% of women during the first pill cycle and in 75.9%, 55.2%, and 67.2% of women after 3, 6, and 9 months of pill use. Two hormone peaks of NE were observed in 29.3% of women during the first cycle and in 36.2%, 50%, and 44.8% at 3, 6, and 9 months, respectively. Existence of these multiple peaks at the frequency observed has not previously been reported. Further quantification of the frequency and magnitude of these peaks could be helpful in explaining differences in biological responses associated with pill use.

Prospective studies of insulin sensitivity in normal women receiving oral contraceptive agents.

Seven normal premenopausal women were studied before (control) and after 3 and 6 months of oral contraceptive agent (OCA) administration (30 micrograms ethinyl estradiol plus 150 micrograms levonorgestrel). The plasma glucose responses during 75-g oral glucose tolerance tests were not altered by the OCA, but the 3- and 6-month plasma insulin responses significantly exceeded control values (P less than 0.05). On a separate morning a constant iv infusion of [3H]3-glucose was given throughout a 2-h basal period and during two successive 2-h euglycemic clamp procedures at iv insulin delivery rates of 10 and 40 mU/m2.min, respectively. Endogenous glucose production rates (milligrams per kg/min) were not altered after 3 or 6 months of OCA administration. Peripheral glucose utilization rates were expressed as M (milligrams per kg/min) or the ratio of M over the prevailing plasma insulin concentration (M/I). One or both parameters were significantly reduced below control values at both insulin infusion rates after 3 months (P less than 0.05), but returned toward control values after 6 months. Serum androgen concentrations were reduced or not altered by OCA administration. We conclude that insulin resistance induced by OCA administration is manifested by reduced peripheral tissue insulin sensitivity and may ameliorate with time. This effect does not relate consistently to total plasma insulin responses during oral glucose tolerance tests or to elevated serum androgen concentrations.

Oral contraception and insulin sensitivity: in vivo assessment in normal women and women with previous gestational diabetes.

The sensitivity to insulin (euglycemic clamp technique) was assessed in previous gestational diabetic women (n = 6) and nondiabetic women (n = 6) before and twice during low-dose triphasic oral contraceptive administration (ethinyl estradiol and levonorgestrel) for 6 months. Both groups had normal plasma glucose and insulin levels during oral glucose tolerance tests before and during treatment. In vivo peripheral insulin action was measured during insulin infusion of 40 mU/m2 X min with plasma glucose clamped at fasting levels. Before treatment glucose infusion rates were identical in both groups [1.56 +/- 0.12 (SEM) mmol/m2 X min and 1.51 +/- 0.09 mmol/m2 X min, respectively]. After hormonal treatment for 6 months the amount of glucose infused decreased significantly in the previously gestational diabetic women (1.10 +/- 0.12 mmol/m2 X min, P = 0.01), whereas the decrease was less pronounced in the nondiabetic women (1.30 +/- 0.22 mmol/m2 X min, P = 0.09). The decrease in insulin sensitivity was not sufficient to alter glucose tolerance either in the previous gestational diabetic women nor in the nondiabetic women.

Comparative study on the efficacy and acceptability of two contraceptive pills administered by the vaginal route: an international multicenter clinical trial.

The efficacy and acceptability of two widely used oral contraceptive tablets, one containing 250 mg levonorgestrel and 50 micrograms ethinyl estradiol and the other containing 150 micrograms desogestrel and 30 micrograms ethinyl estradiol, administered by the vaginal route were compared in 1055 women studied over 12,630 woman-months of vaginal contraceptive pill use. This multicenter clinical trial was performed in nine countries of the developing world by the "South to South Cooperation in Reproductive Health," an organization founded by scientists from the Third World working in the area of reproductive health, and the study was developed and coordinated by one of these centers. The findings of this study confirm the efficacy of both these tablets when administered by the vaginal route. Involuntary pregnancy rates at 1 year of 2.78 for subjects in the levonorgestrel group and 4.54 for subjects the desogestrel group showed no statistically significant difference between the two groups. However, total discontinuation rates of 47.01 for subjects in the levonorgestrel group and 56.33 for subjects in the desogestrel group showed a statistically significant difference between the two groups, and discontinuation rates attributable to prolonged bleeding of 0.6 for subjects in the levonorgestrel group and 3.2 for subjects in the desogestrel group were also significantly higher in the group of subjects using the desogestrel vaginal contraceptive pill. Blood pressure remained at admission values throughout treatment. A statistically significant weight increase from admission values occurred in both groups of subjects.

PIP: Efficacy and acceptability of 2 combined oral contraceptive pills administered vaginally are summarized. This is the 1st collaborative trial published by the South to South Cooperation in Reproductive Health. 1055 women participated in 12,630 cycles, in 9 countries, from June 1988 to May 1991. The pills were commercially available tablets containing 50 mcg ethinyl estradiol and 250 mg levonorgestrel (Schering AG, Sao Paulo, Brazil), or 30 mcg ethinyl estradiol and 15 mcg desogestrel (Organon, Sao Paulo, Brazil). Subjects were aged 17-39 younger and of lower parity from Mexico and Dominican Republic and older from Egypt and China. All had at least 1 pregnancy. 675 participated for 6 months, 470 for 1 year, 364 for 18 months, and 210 for 2 years. The 1-year discontinuation rate averaged 47.01% for the levonorgestrel group and 56.33% for the desogestrel group (p = 0.0061); 2-year discontinuation rates were 48.01% and 69.36, respectively, explained in part by higher involuntary pregnancy rates and prolonged bleeding rates in the desogestrel group. The most common medical reasons for stopping contraception were unplanned pregnancy, vaginal or vulval irritation, nausea, vaginal discharge and headache. Vaginal irritation was reported by 1%, 9 in each group. There were 32 pregnancies, 14 in the levonorgestrel and 18 in the desogestrel group. 17 were in missed pill cycles and the rest were method failures, 6 in the levonorgestrel group and 9 in the desogestrel group. The Pearl index varied from 0 in Nigeria to 12.24 in Mexico, and was 2.45 for levonorgestrel vs. 3.74 for desogestrel. There was a wide variation in discontinuation rates by center: Brazil and China had few, while many women from Dominican Republic, Mexico and Zambia left the study. Bleeding problems were common complaints, more so in the desogestrel group. There were 363 women with intermenstrual bleeding (only once in 80%), 148 with spotting (only twice in 65%). Bleeding duration was significantly less in pill cycles than baseline, pressure. Women gained an average of 1 kg over 2 years, more in the desogestrel group. The pregnancy rate of 2.78 is within the range reported for levonorgestrel rings.

Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians.

Hepatic enzyme-inducing antiepileptic drugs (AEDs) lower oral contraceptive (OC) sex hormone levels approximately 40% and increase the risk of unplanned pregnancies in women with epilepsy. AEDs also increase the risk of birth defects in offspring of women with epilepsy. We performed a national survey to determine obstetricians' and neurologists' knowledge of OC and AED interactions and the risk of birth defects for women with epilepsy taking AEDs. We received responses to a mailed questionnaire from 160 of 1,000 neurologists (16%) and 147 of 1,000 obstetricians (15%) from 47 states. Practice demographics and ages of responders were typical for U.S. neurologists and obstetricians. Ninety-one percent of neurologists and 75% of obstetricians said they treat women with epilepsy of child-bearing age. Only 4% of the neurologists and none of the obstetricians, however, knew the effects of the six most common AEDs on OCs, even though 27% of neurologists and 21% of obstetricians reported OC failures in their patients taking AEDs. Although increasing OC doses can compensate for insufficient OC sex hormone levels due to AEDs, most physicians do not increase the doses. Even though the risk of birth defects for the offspring of women with epilepsy is 4 to 6%, up from the background level of 2%, 44% of neurologists thought the risk was lower (0 to 3%), and some of the respondents guessed that it was as high as 50%. Many neurologists and obstetricians do not have accurate information to counsel women with epilepsy properly about their contraceptive and pregnancy choices.

PIP: Responses from 160 of 1000 neurologists (16%) and 147 of 1000 obstetricians (15%), selected from an American Medical Association listing to receive a mailed questionnaire, revealed a disturbing lack of knowledge about the interactions between antiepileptic medications and oral contraceptives (OCs). Hepatic enzyme-inducing antiepileptic drugs lower OC estradiol levels by about 40% and may reduce free progestin levels, thereby increasing the risk of unplanned pregnancy; moreover, antiepileptics increase the risk of birth defects in their epileptic users, who already have a 4-6% increased risk of such defects. Physicians can reduce, but not prevent, the risk of unwanted pregnancy by increasing the OC estradiol dose to at least 50 mcg and prescribing valproic acid and gabapentin (non-enzyme-inducing antiepileptics). 91% of neurologists and 75% of obstetricians reported that they treated epileptic women of childbearing age, and 27% of the former and 21% of the latter physicians acknowledged cases of OC failure in these patients. Only 4% of the neurologists and none of the obstetricians knew the effects of the 6 most common antiepileptic drugs on OCs. Just 41% of neurologists and 43% of obstetricians routinely had patients adjust their OC doses if they were taking antiepileptics. Such adjustment was more likely among physicians who had an epileptic patient with an unintended pregnancy and those who had accurate knowledge of OC-antiepileptic drug interactions. 44% of neurologists and 23% of obstetricians underestimated the birth defects risk as 0-3%. Since the physicians who chose to respond to this survey were presumably more concerned and knowledgeable about the reproductive effects of antiepileptic drugs than those who chose not to respond, continuing education efforts are urged to enable health care providers to counsel epileptic women about contraception.

Ovulation suppression in women following vaginal administration of oral contraceptive tablets.

PIP: A preliminary trial was conducted to test the possibility of using intravaginally a contraceptive tablet manufactured for oral use to achieve ovulation suppression. 12 women who could not continue with oral contraceptives (OCs) because of gastrointestinal complaints and/or nausea volunteered to participate. All subjects discontinued oral use of tablets for at least 2 months prior to the vaginal administration. Condoms were provided for use during the interim period. Patients were instructed to manually place in the vagina either 1 (4 subjects) or 2 tablets (8 subjects) daily for 21 days. Progesterone blood levels remained at preovulatory levels, below 2 ng/ml, throughout the treatment period, indicating that ovulation was suppressed in all subjects. Levels of 17beta-estradiol (32) which showed considerable variation during the control cycle remained low during the treatment cycle. Withdrawal bleeding occurred 2-5 days following the last tablet and lasted 3-5 days, as in normal menstruation. In patients inserting 1 tablet, intermenstrual spotting was common, but in those inserting 2 tablets daily no spotting occurred. 5 of 6 subjects who complained of nausea during OC use reported no nausea during the period of vaginal administration. These patients requested vaginal administration as a regular contraceptive method.^ieng

Evaluation and therapy of breakthrough bleeding in women using a triphasic oral contraceptive.

This study was designed to investigate the incidence and pattern of breakthrough bleeding (BTB) in 1,259 women who were prescribed for the first time a triphasic oral contraceptive (OC, 7-7-7) and to evaluate a hypothesis of management for BTB persisting after three cycles. The new users were compared with a control group of 696 women who had used various OCs for at least 6 months. The incidence of BTB in the control group was 16.8% and in the new users was 24.9%, 17.5%, and 15.3% in the first 3 months, respectively. Breakthrough bleeding occurred late in the 7-7-7 package in 58% and early or midway through the package in 17% and 25%, respectively. We hypothesized that late-package BTB would improve if the patient was switched to a monophasic pill similar to the relatively estrogenic formulation of the beginning of the package and vice versa for early or midpackage BTB. Seventy women with BTB at 3 months were randomly given 0.5/35 or 1/35 for a further 3 months. Breakthrough bleeding was more likely (P less than 0.05) to improve in women switched to 1/35 compared with 0.5/35 regardless of where in the package BTB occurred.

PIP: this study was designed to investigate the incidence and pattern of breakthrough bleeding (BTB) in 1259 women who received a triphasic oral contraceptive (OCs; 7-7-7) for the 1st time and to evaluate a hypothesis of management for BTB persisting beyond 3 cycles. The new users were compared with a control group of 696 women who had used various OCs for at least 6 months. The incidence of BTB in the control group was 16.8% and in the new users was 24.9%, 17.5%, and 15.3% in the 1st 3 months, respectively. BTB occurred late in the 7-7-7 package in 58% and early or midway through the package in 17% and 25%, respectively. The authors hypothesized that late-package BTB would improve if the patient was switched to a monophasic pill similar to the relatively estrogenic formulation of the beginning of the package and vice versa for early or midpackage BTB. 70 women with BTB at 3 months were randomly given 0.5/35 or 1/35 for a further 3 months. BTB was more likely (p0.05) to improve in women switched to 1/35 compared with 0.5/35 regardless of where in the package BTB occurred.

Clinical use of oral contraceptives administered vaginally: a case report.

PIP: Effectiveness in cycle control and plasma steroid levels were monitored in a woman with promyelocytic leukemia being treated with chemotherapy, given 2 combined oral contraceptives given vaginally. The 18-year old woman had been taking an oral contraceptive containing 50 mcg mestranol and 1 mg norethindrone during the 3 months since she began treatment for leukemia. After recurrence of leukemia, she developed acute hemorrhagic mucocitis and inability to swallow while on cytosine arabinoside, daunorubicin and etoposide. She was administered 2 of the same oral contraceptives daily per vagina, and her withdrawal bleeding continued to be suppressed for 6 weeks while receiving transfusions for aplastic marrow. Compared to 10 normal women taking 30 mcg ethinyl estradiol and 100 mcg norethindrone, the patient's plasma level of radioimmunoassayed ethinyl estradiol was comparable as to concentration and peak time. Her level of norethindrone was lower, with the highest level measured at 12 hours, compared to a peak at 2 hours in women taking one pill orally.^ieng

Effect of oral contraceptives or dexamethasone on plasma beta-endorphin during the menstrual cycle.

Several studies have showed a significant increase of plasma beta-endorphin levels during the periovulatory days of the menstrual cycle. The aim of the present study was to investigate the origin of the periovulatory changes of plasma beta-endorphin, trying to discriminate between a possible ovarian and/or pituitary origin. Daily plasma beta-endorphin, luteinizing hormone (LH), and cortisol levels were measured from the 8th to the 20th day of the menstrual cycle in healthy normal-cycling women (10 cases) before and during dexamethasone (DEX; 6 cases) or estroprogestinic treatment with monophasic (5 cases) or triphasic (5 cases) pill. In the control menstrual cycle, during the preovulatory days, a significant increase of plasma beta-endorphin was found. While oral contraceptives abolished the midcycle increase of plasma beta-endorphin, the periovulatory plasma beta-endorphin peak was present during DEX treatment. Plasma cortisol levels did not show any significant change throughout the control menstrual cycle, while they were significantly lowered by the DEX administration and significantly increased during estroprogestinic treatment. These results suggest that the increase of plasma beta-endorphin during the periovulatory days is related to the ovulatory function, and suggest a possible ovarian origin.

Comparison of the effects of contraceptive steroid formulations containing two doses of estrogen on pituitary function.

A pituitary stimulation test with gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) was undertaken to determine (1) whether pituitary responses to GnRH vary in individual women taking oral contraceptive steroids over time, (2) whether a less suppressive pituitary gonadotropin effect is produced by formulations containing less than 50 microgram of estrogen, and (3) to obtain more information concerning prolactin secretion in users of oral contraceptive steroids. The same subjects who had had a suppressed luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response 6 to 9 months previously also had a suppressed response, indicating that this effect persists over time. Contraceptive formulations containing less than 50 microgram of estrogen have a lesser suppressive effect on LH release than do formulations containing 50 microgram of estrogen or more. The basal prolactin (PRL) response as well as the maximal PRL response to TRH were found to be significantly greater in subjects using oral contraceptives than in the control subjects. However, no difference in PRL response was found between the subjects using low or high doses of estrogen fomulations.

PIP: A comparison of the effects of contraceptive steroid formulations containing 2 doses of estrogen on pituitary function is reported. The gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) stimulation tests were carried out with 11 control women, 23-38 years of age, and 39 women receiving various oral contraceptive (OC) formulations. The responses to GnRH stimulation were similar in the same subjects who had been stimulated 6-9 months previously, indicating that the effect persists over time. OCs containing less than 50 mcg of estrogen showed a lesser suppressive effect on luteinizing hormone (LH) release than did OCs containing 50 mcg or more of estrogen (p .001). Peak serum follicle stimulating responses were significantly lower (p .01) than those of controls, but there was no marked difference between the 2 groups of OC users. Basal prolactin (PRL) response as well as the maximal PRL response to TRH were significantly greater (p .025 and p .05), respectively) in subjects using OCs than in the control subjects. It is concluded that OCs have a suppressive effect on pituitary gonadotropin release in most users, which is independent of the dose of estrogen.

Ingestions considered nontoxic.

The authors have compiled a list of common household products and drugs that are frequently ingested by children and may be considered nontoxic unless taken deliberately or in large amounts. An understanding of the nontoxic ingestion should prevent overtreatment and decrease emergency room visits.

PIP: In 1980, the National Clearinghouse for Poison Control Centers (NCPCC) received 126,000 reports from Poison Control Centers, but the true incidence of ingestions was actually much higher. Only 1 in 50 ingestions may be reported, indicating that the majority of ingestions are innocuous. 70% of reported episodes occurred in children under 5 years of age. Nontoxic ingestions occur when a victim consumes a nonedible product that usually does not produce symptoms. No product is entirely safe and all can produce symptoms if a large enough concentration is consumed. Knowledge of nontoxic ingestions helps avoid overtreatment and its risks and serves as a warning of inadequate supervision or an improper and unsafe environment. The designation of nontoxic ingestion has 6 criteria: 1) absolute identification of the product 2) absolute assurance that only 1 product was ingested 3) no signal word (danger, poison, warning, caution) on the container 4) a good approximation of the amount ingested 5) assurance that the victim is free of symptoms and 6) the ability to call back at intervals to determine that no symptoms have developed. A good rule of thumb for the average drug that 5 times the therapeutic dose may be a toxic dose; opiate narcotics are the exception and require medical observation because of their narrow margin of safety. There are several points to consider in deciding wheter to decontaminate the gastrointestinal tract, including the toxicity of the ingested agent, the amount ingested, the elapsed time since ingestion, and the presence of symptoms. Emergency room referral is mandatory in case of exposure to highly toxic agents, of a dose sufficient to lead to anticipation of servere symptoms, of manifestations of toxic exposure such as alterations in vital signs already present, or of a history of intentional ingestion. A detailed discussion of frequently ingested nontoxic household items and related items that may be toxic includes writing and art materials, toiletries and laundry agents, deordorizers and disinfectants, tobacco and matches, medicinals, pesticides and insecticides, miscellaneous substances, petroleum distillate hydrocarbons, and plants. Hormonal contraceptives have been reported to produce almost no toxicity. A 1962-65 report from the NCPCC of 962 ingestions listed only 40 producing nausea nd vomiting even after consumption of 21 pills. An iron additive could make the ingestion toxic for iron.

Potential value of plants as sources of new antifertility agents I.

PIP: A comprehensive review of plants that possess contraceptive or interceptive, abortifacient, ecbolic, oxytocic, or emmenagogue properties is presented. The plants reviewed are those which have a folkloric reputation of contraceptive effects and those which have been tested on laboratory animals for their antifertility effect. The preovulatory, preimplantation, and postimplantation antifertility mechanisms of plant substances affecting the hypothalamus-pituitary, ovary, oviduct, uterus, or vagina are discussed in terms of reproductive differences among laboratory animal species. Lithospermic acid, m-Xylohydroquinone, coronaridine, rutin, and rottlerin are among the few active antifertility principles to be identified in higher plants. Volatile oils, quinine and castor oil, and sparteine have been used as abortifacient agents, but not with consistent success, and often with toxic, if not fetal, side effects.^ieng

Use and acceptance of the "paper pill". A novel approach to oral contraception.

A randomized, crossover study comparing the acceptance of and attitudes towards two dosage forms of the same oral contraceptive product - a paper presentation and the conventional tablet, was carried out in a network of rural and suburban research centers in the State of Durango, México. The results failed to show any significant advantage (in terms of acceptability or continuation) of the paper formulation. Although two-thirds of the participants indicated a preference for the conventional tablet, there was a high degree of acceptance of the paper formulation among new oral contraceptive acceptors.

PIP: A randomized, crossover study comparing the acceptance of and attitude towards 2 dosage forms of the same oral contraceptive product -- a paper presentation and the conventional tablet -- was carried out in a network of rural and suburban research centers in the State of Durango, Mexico. 68 women used the paper pill for 3 months and then switched to the tablet for another 3, while 70 women took the tablet 1st and switched to the paper pill. The results failed to show any significant advantage in terms of acceptability or continuation for the paper formulation. Both formulations were perceived as effective and easy to use. 2/3 of the participants indicated a preference for the tablets at the end of the study, but there was a high degree of acceptance of the paper formulation among new oral contraceptive acceptors. The authors believe that an improved paper formulation could be successfully introduced into a national program, if there were substantial savings in cost associated with the "paper pill."

Vaginal administration of a combined oral contraceptive containing norethisterone acetate.

The effects of vaginal administration of an oral contraceptive pill containing 1 mg of norethisterone acetate and 0.05 mg of ethinyl oestradiol were studied in 20 subjects for a total of 57 cycles. The results show effective ovulation suppression in the two dose regimens used. The lower dose regimen was associated with fewer side effects and no breakthrough bleeding. No significant change was observed in the serum concentration of glucose, total proteins, albumin, cholesterol and HDL after several cycles of treatment in both dose regimens used. It is concluded that vaginal administration of this preparation of oral contraceptives is an effective alternative method of hormonal contraception.

Bone mass and long-term monophasic oral contraceptive treatment in young women.

A prospective study has been designed to investigate bone metabolism in young women taking an oral monophasic contraceptive formulation (ethinylestradiol 20 micrograms + desogestrel 0.150 mg) over 5 years. Healthy women (n = 200) between 19 and 22 years of age were divided into two groups. Group A received oral contraception, Group B did not receive any treatment. All the subjects underwent a bone mass density (BMD) evaluation at spinal level L2-L4 with Dexa (Norland XR-26) and a measurement of the serum alkaline phosphatase levels and urinary excretion of OH-proline at baseline and every 12 months over 5 years. Our results demonstrated that Group A did not show any significant BMD change after 5 years of oral contraceptive treatment, while Group B demonstrated a significant increase (p < 0.01) in the bone mass content at the end of the time of observation (+7.8% after 5 years). No significant changes were found in serum alkaline phosphatase levels and in urinary excretion of OH-proline at the end of the study in comparison with basal levels in both groups. Our data suggested that long-term treatment with an oral monophasic contraceptive formulation (ethinylestradiol 20 micrograms + desogestrel 0.150 mg) did not modify the BMD but prevented the occurrence of the physiologic peak of bone mass in young women.

PIP: Between June 1988 and March 1989 in Italy, health workers enrolled 200 women aged 19-23 attending obstetric-gynecology clinics in and around Pavia into a five-year study of the effects of an oral contraceptive (OC) with 20 mcg ethinyl estradiol and 0.15 mg desogestrel on bone mass. They were able to follow 76 of the 100 women using the OC and 71 of the 100 women using no OC for five years. Health workers conducted a bone mass density (BMD) evaluation at spinal level L2-L4 with Dexa (Norland XR-26). They measured serum alkaline phosphatase levels and urinary excretion of hydroxyproline (OH-proline) at baseline and every 12 months for five years. Neither urinary excretion of OH-proline levels nor alkaline phosphatase levels differed significantly in the two groups during the five years from baseline levels. Over the five years, the BMD of OC users did not change significantly while the BMD of the controls increased 7.8% from baseline (p 0.01). These findings suggest that this monophasic OC prevented or delayed the physiologic peak bone mass. Even though the low dosage of ethinyl estradiol (20 mcg) may have contributed to the prevention of bone mass loss, it could not achieve the peak bone mass. More studies are needed to understand the effect of long-term OC treatment on bone mineral content.

Systemic availability of levonorgestrel after single oral administration of a norgestimate-containing combination oral contraceptive to 12 young women.

Norgestimate is a novel progestin which undergoes both in vivo and in vitro metabolic conversions to a number of metabolites, of which the most important are levonorgestrel acetate, levonorgestrel oxime and levonorgestrel itself. It has been claimed that the progestogenic activity of norgestimate in clinical studies is almost exclusively based on the parent drug and its major metabolite, levonorgestrel oxime, and that levonorgestrel does not make an important contribution. However, to date, no data on the presence of levonorgestrel in the serum of women who have received oral doses of norgestimate have been presented. In the present study, 12 young female volunteers received single oral doses of 250 micrograms levonorgestrel in combination with 50 micrograms ethinylestradiol and 250 micrograms norgestimate in combination with 35 micrograms ethinylestradiol in an open, randomized, intraindividual comparison. Blood samples were taken at regular time intervals after each treatment, and the serum samples were analyzed for their content of levonorgestrel. Basic pharmacokinetic parameters of levonorgestrel were calculated and from the ratio of the AUC values obtained after both administrations, the bioavailability of norgestimate-derived levonorgestrel was calculated. About 22 +/- 6% of the dose of norgestimate administered became systemically available as levonorgestrel. Thus, it was concluded that levonorgestrel is a major metabolite of orally administered norgestimate, and that at least part of the pharmacologic activity of norgestimate in women is due to the presence of levonorgestrel.

Cardiovascular safety of oral contraceptives. What has changed in the last decade?

PIP: As a result of careful patient selection, the cardiovascular safety of oral contraceptives (OCs) has improved dramatically in the past decade. The incidence of stroke and myocardial infarction is exceedingly low among women who use OCs containing 35 mcg or less of ethinyl estradiol, and formulations containing under 50 mcg of estrogen account for almost all current use in the US. This article reviews the epidemiologic data on use of OCs of varying steroid dosages on the risks of myocardial infarction, hemorrhagic and ischemic stroke, and venous thromboembolism. Although four studies published since 1995 have suggested that OCs containing desogestrel or gestodene increase the risk of venous thromboembolism above that associated with levonorgestrel, these findings are likely due to prescribing bias and differences in the duration of use. The greatest risk of an arterial cardiovascular event comes from smoking while taking OCs.^ieng

The acceptance of a 7-week cycle with a modern low-dose oral contraceptive (Minulet).

Cycle control and tolerance were studied in a group of 55 female volunteers, who took during 42 consecutive days a modern low-dose oral contraceptive: gestodene 75 micrograms/ethinylestradiol 30 micrograms (Minulet). During these 42 days, 96% of the women experienced no breakthrough bleeding and 81% of the women experienced no spotting or breakthrough bleeding. When the findings of this study are compared with the findings of an earlier study with also a seven-week cycle but with other oral contraceptives, it can be concluded that Minulet offered an excellent cycle control.

PIP: 55 women took the combined oral contraceptive Minulet (30 mcg ethinyl estradiol and 75 mcg gestodene) for 42 consecutive days, using 2 active pill strips, to lengthen the interval between withdrawal bleeding and assess acceptability. The study was an open multi-center trial in which 38 general practitioners each supervised 1 or 2 women. The women averaged 27 years old (range 18-40), and had used Minulet without problems for the previous 6 months. 10 women noted spotting, and 2 had breakthrough bleeding, both after Day 21 of pill intake. There was 1 dropout for unrelated medical reasons. Other minor side effects were breast tenderness (7%), nausea (4%), abdominal bloating (4%), headache (2%), and dysmenorrhea (2%). 92% of the women reported extreme to moderate satisfaction, but 4% were not satisfied because of breakthrough bleeding. Nevertheless, these data on breakthrough bleeding were much lower than published data from trials with other combined pills, especially those containing levonorgestrel.

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.

Investigation of Danazol as a contraceptive agent.

PIP: An attempt to determine the efficacy of Danazol in producing an inadequate luteal phase either by inhibiting follicular development or by producing an insufficient luteinzing hormone (LH) surge at the time of ovulation is reported. Danazol is the 2,3-isoxasol derivative of 17alpha-ethinyl testosterone. Subjects were 17 healthy women treated during the first 7 days of their menstrual cycles. Daily blood samples were analyzed for plasma estradiol, progesterone, and serum follicle stimulating hormone (FSH) and LH. A group received Danazol 400 mg/day for 7 days. Another group was given 800 mg and a 3rd group 1600 mg/day for 7 days. The follicular span, from onset of menses to LH surge, was lengthened and ovulation delayed for at last 1 week, in all but 2 cases. Although delayed, the LH surge was normal, and a normal progesterone output occurred during the luteal phase. The luteal span was 12 days or more which was considered normal. Inhibition of gonadotropin output was noted during Danazol administration but prompt recovery followed. Serum chemistries showed no significant abnormalities. Hematologic and urinary parameters were normal. It is thought that FSH was inhibited more than expected resulting in the delayed ovulation with effects similar to those when estrogen is given during the proliferative phase. However, an inadequate luteal phase did not follow the inhibition of FSH-stimulted follicular development.^ieng