Can a change in screening and prescribing practice reduce the risk of venous thromboembolism in women taking the combined oral contraceptive pill?

The risk of Venous thromboembolism (VTE) associated with low dose combined oral contraceptive pills (COCs) is low at between 15 and 30 cases per 100 000 women years of use. Screening the total population or even those women with a family history of VTE in a first degree relative is unlikely to have a major impact on the number of cases of VTE associated with COC. Women with a known family history of an inherited thrombophilia should have this defect excluded before taking COCs. Women with a known thrombophilia or a personal history of VTE should consider alternative methods of contraception to the COC.

PIP: The risk of venous thromboembolism (VTE) associated with low-dose combined oral contraceptive (OC) use has been estimated at 15-30 cases/100,000 women-years. This risk increases in women with thrombophilias associated with antithrombin III, protein deficiencies, and Factor V Leiden (FVL) mutation. Under debate has been whether all women, or at least those with a family history of VTE in a first-degree relative, should be screened for thrombophilia before OCs are prescribed. This article considers two assessment models salient to this debate. The first model considers family history and hereditary thrombophilia based on data from several epidemiologic studies. It suggests that screening 1 million women would result in the detection of 41,080 women with a hereditary thrombophilia; of these, 92 would experience VTE, and there would be 0.92 associated deaths. Screening of 1 million women with a family history of VTE would result in the identification of 672 VTE cases, with a fatality rate of 6.7/year. The second model, based on data concerning FVL mutation, also failed to provide support for the efficacy of a thrombophilia screening program. Women with a family history of thrombophilia, nonetheless, should be offered the option of screening and urged to use an alternative contraceptive method if a thrombophilia is detected.

Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy.

The concept of bioavailability is discussed with particular references to the sex steroids. Problems encountered in the measurement of bioavailability of these steroids and the various factors that may affect their bioavailability are briefly described. Information regarding the bioavailability of the estrogens and gestogens, some of which are prodrugs, used in oral contraception and hormone replacement therapy is summarized and the implications regarding the clinical use of these steroids are discussed.

PIP: This review examines the bioavailability of sex steroids used in oral contraceptives and hormone replacement therapy and the implications of the clinical use of these steroids. These steroids include the estrogens (estradiol, estrogen sulfates, ethinyl estradiol) and the gestogens (progesterone, norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate, and medroxyprogesterone acetate). The naturally occurring sex steroids are estradiol, estrogen sulfates, and progesterone or their derivatives. The synthetic sex steroids are ethinyl estradiol, norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate, and medroxyprogesterone acetate. Factors influencing bioavailability of these sex steroids revolve around drug formulation (dosage form, disintegration rate, and dissolution rate), drug characteristics (chemical properties and stability in the gastrointestinal tract), user's characteristics (gastrointestinal and hepatic functions), and possibly smoking, diet, and other drugs. A wide variation exists in the bioavailability values both within any study and between the different studies with the same steroid. Possible reasons for the variability include experimental error, a small number of subjects, the rate and extent of absorption of the compound, the compound's rate of metabolism and elimination (especially hepatic metabolism and elimination), differences in dose, and interaction between the estrogen and the gestogen. Some of the synthetic sex steroids are prodrugs.

Enlarged follicles in women using oral contraceptives.

Ultrasound examination of the ovaries was performed in the first and/or second half of three consecutive cycles in 3 groups of women; Group T who had been using a levonorgestrel triphasic oral contraceptive for at least 6 months, Group P who had been using a progestogen-only pill for at least 6 months, and Group C, a control group. Any follicles greater than 10 mm in diameter and any cysts were measured. Fifty-three scans were performed in Group T, 45 in Group P and 31 in Group C. Only 4 follicles were detected in 17 women in Group T compared to 10 follicles in 15 women in Group P and 7 follicles in the women in Group C; all follicles were 25 mm or less in diameter except for 3 follicles in 2 women. The differences between the groups were not statistically significant. Four enlarged follicles were detected in 3 women during 53 scans in Group T, 15 in 8 women (45 scans) in Group P, and only 1 in 31 scans in Group C. Based upon the proportions of scans with enlarged follicles, the difference between Groups T and P was statistically significant, indicating that the incidence of enlarged follicles was lower in women using a combined oral contraceptive than in those using a progestogen-only pill. Furthermore, the study shows that any enlarged follicles which occurred were transient.

PIP: In 1990, researchers in England enrolled 42 healthy women aged 21-46 attending the family planning clinic in Reading in a study designed to determine whether a triphasic oral contraceptive (OC) affected ovarian cyst formation any differently than did a progestogen-only pill (POP). They also wanted to ascertain the life span of any ovarian cysts detected. 17 women used the triphasic OC containing various doses of ethinyl estradiol and levonorgestrel (LNG). 15 women used either the POP Microval (30 mcg LNG) or Micronor (350 mcg norethisterone). The remaining 10 women had used neither a steroidal contraceptive nor an IUD for at least six months. The researchers depended on ultrasonography to detect enlarged ovarian follicles (10 mm and 30 mm in diameter) and cysts (30 mm detected in 2nd half of cycle that persisted for more than 2 cycles). The women in the OC group underwent 53 ultrasonic scans. Those in the POP group underwent 45 ultrasonic scans. Controls underwent 31 ultrasonic scans. Only four women in the OC group had ovarian follicles, while 10 women did in the POP group and 7 in the control group. Except for three follicles in two women, all the follicles were no more than 25 mm in diameter. The POP group had a significantly higher proportion of ultrasonic scans detecting the presence of enlarged follicles than did the OC group (14/45 vs. 4/53; p = 0.01). Since none of the enlarged follicles lasted for more than two cycles, there were no functional ovarian cysts. These findings show that women using the triphasic OC had a lower incidence of enlarged follicles than those using the POP and that the enlarged follicles were temporary.

New progestogens in oral contraception.

The major developments in combined oral contraceptives (COCs) have been a reduction in the total dose of both the oestrogen and progestogen administered per cycle and the introduction of new progestogens which are claimed to be more 'selective' than the older ones. This review examines in detail the clinical efficacy of the new COCs, where possible in comparison with those containing levonorgestrel or norethisterone, and their pharmacological effect on carbohydrate and lipid metabolism, haematological factors, pituitary-ovarian function and serum protein and androgen concentrations. Based mainly on the pharmacological evidence, the newer COCs are an improvement over the older low-dose formulations and are clearly preferable to the high-dose ones. However, the older low-dose COCs, despite many years of use, have not resulted in a high incidence of adverse effects. The increasing use of the new COCs, as evidenced by their increasing market share throughout Europe, does indicate that they have been well accepted in clinical practice.

PIP: European researchers have conducted most of the clinical tests of the 3 new progestogens used in low-dose, combined oral contraceptive (OC) formulations: desogestrel (DSG), gestodene (GSD), and norgestimate (NGM). Enough clinical trial data for GSD and DSG OCs exist to compare with those of other low-dose OCs. The newer OCs are at least as effective and have at least as good cycle control as other low-dose OCs. Minor side effects of the newer OCs correspond to those of other OCs. Various flaws in studies make it hard to compare major adverse side effects of the different OCs. To compare OCs, parameters must be accurately measured. Continuation rates, measurement of blood pressure, and incidence of specific side effects can be accurately measured, but only in large comparative trials using standardized assessment methods. Other possible comparative parameters are metabolic parameters, but trials must be well-designed and adequately controlled. Almost all studies show that the new OCs do not affect fasting levels of glucose and insulin. More research is needed on the validity of a glucose tolerance test to stimulate any changes in carbohydrate metabolism, however. Recent data show that lipid metabolism may vary among the new OCs, but the research is largely limited to assessing the serum levels of various lipids. Yet, assessment of various ratios or an assay of the apoproteins are better indicators of the risk of cardiovascular disease. An assay of just high density lipoprotein-cholesterol allows researchers to distinguish between OCs. Hematologic factors are not a good basis for comparison, due to a variety of problems with measurement. Accurate measurements of serum proteins (e.g., sex hormone binding globulin) can be made, however. New OC use has increased 2-fold in 4 years in some European countries, attesting to their popularity and acceptability.

Effects of different doses of norethisterone on ovarian function, serum sex hormone binding globulin and high density lipoprotein-cholesterol.

The ovarian effects of different doses of norethisterone (NET) were compared in 45 normally menstruating women in order to find the lowest effective dose of the Chinese NET "visiting pill". Subjects were randomly divided into 3 groups. Each subject in each group was taking 0.5, 1.5 or 3.0 mg per day from days 5 to day 18 of the cycle. Blood samples were taken on days 5, 8, 11, 14, 17, 20, 23, 26 and 29 of the cycle. Serum oestradiol (E2), progesterone (P), sex hormone binding globulin (SHBG), high density-lipoprotein cholesterol (HDL-C), and NET concentrations were measured. Ovulation, delayed ovulation, ovulation inhibition and follicular activity were classified by the analysis of the peripheral serum levels of sex hormones. Ovulation occurred in 7 women in the 0.5 mg group, in 2 women in the 1.5 mg group and in none of the 3.0 mg group. Mean serum SHBG levels were reduced progressively by 6.6% (Group 0.5), 15.5% (Group 1.5) and 23.4% (Group 3.0). There were no significant changes in HDL-C levels in any group. There was a significant correlation of mean serum NET concentrations with dose. The lack of complete inhibition of ovulation in most women in the 1.5 mg and 0.5 mg groups might suggest that the dose of NET required when used as a visiting pill could not be reduced below 3.0 mg.

PIP: In Shanghai, China, 45 25-35 year old women took a daily norethisterone (NET) "visiting pill" (vacation pills) on menstrual cycle days 5-18 as part of a clinical study comparing various doses of NET on ovarian function, sex hormone binding globulin (SHBG), and high density lipoprotein-cholesterol (HDL-C). The aim of the study was to determine the lowest effective dose of the NET visiting pill. Even though some ovarian activity occurred at all 3 doses (0.5, 1.5, and 3 mg), no woman experienced ovulation at 3 mg NET/day during days 5-18 of the cycle. It suppressed ovulation in 11 (73.3%) of the 15 women. Follicular activity occurred in the remaining 4 women. Ovulation occurred in 33% of women taking the 1.5 mg dose and in 66% of those taking the 0.5 mg dose. The higher the NET dose, the greater was the fall in mean serum SHBG levels from control levels (3 mg, 23.4%; 1.5 mg, 15.5%; and 0.5 mg, 6.6%). Both the regression equation and log dose regression equation showed a significant correlation between mean serum NET levels and dose (p .001). HDL-C levels remained basically the same as control levels. Since, at the 1.5 mg dose, ovulation occurred in 5 women and only 5 women experienced complete inhibition, a dose no lower than 3 mg should be used for the NET visiting pill.

Long-term use of depot-norethisterone enanthate: effect on blood lipid fractions.

This is the third report of a metabolic study on 56 long-term users (24 for 2-5 yr; 32 for over 5 yr) of the injectable contraceptive norethisterone enanthate (Net-En) and deals with the effects on the blood levels of lipoprotein fractions. There was no significant difference between this group and a group of 30 non-users in serum concentrations of triglycerides, total cholesterol, low density and very low density lipoproteins. There was a significant reduction in mean high density lipoprotein levels between the controls and the user groups (16% for the intermediate duration and 12% for the longer duration). Age, ethnic group, body-mass index and a close family history of cardiovascular disease were taken into account, as were various lifestyle factors: diet, exercise, alcohol consumption and smoking. In a smaller group, levels of apoproteins A and B were also assayed. There was a significant reduction in apoprotein A between controls and all users, but the significance was lost on adjusting for confounding variables. Consideration was given to the ratio of total cholesterol to high density lipoprotein cholesterol as an index of coronary risk. There were no significant differences in the total cholesterol:HDL-C ratio between controls and user groups. There was a significant interaction with ethnic group (Caucasian or Afro-Caribbean) in the response to duration of use.

Interactions with oral contraceptives.

The interaction of a range of different factors with the pharmacologic activity of oral contraceptives is reviewed. Pharmacokinetic interactions with oral contraceptives may occur (1) during absorption and extrahepatic circulation, (2) by interfering with protein binding, and (3) during hepatic metabolism. The hepatic mixed function oxidase system, which is mainly responsible for the metabolism of oral contraceptives, is affected by several different factors and is easily induced. Nutrition affects the activity of many drugs, but information regarding oral contraceptives is meager. Both pharmacokinetic and pharmacodynamic interactions, which may be synergistic or antagonistic, between the estrogen and gestagen components of oral contraceptives, are important, but there is no correlation between the rate of metabolism of the two components. Evidence suggests that some anticonvulsant, antibiotic, and antibacterial drugs may reduce the efficacy of oral contraceptives. Instances of interactions of other therapeutic agents are reported infrequently. The incidence of serious interactions is low and does not appear to have been reduced with low-dose oral contraceptives, probably because of large intersubject variability in the pharmacokinetics of oral contraceptives.

PIP: Pharmacokinetic interactions between oral contraceptives (OCs) and other drugs and nutrients may occur during absorption and extrahepatic circulation, through interference with protein binding, and during hepatic metabolism. However, the most significant locus of drug interaction is the mixed function oxidase system of the liver endoplasmic reticulum. Increased activity of the mixed function oxidase system produced by other drugs tends to reduce the half-life of elimination of sex steroids and consequently of their serum concentrations and biological effect. At the same time, OC administration generally has an inhibitory effect on the metabolism of other drugs and consequent reductions in their pharmacologic activity. The rate of drug metabolism will vary according to genetic and environmental factors such as diet, alcohol use, smoking, and pathologic conditions. Although the influence of nutrition on the absorption and bioavailability of contraceptive steroids has not yet researched adequately, high-protein diets appear to stimulate the activity of the hepatic drug-oxidizing system and increase the metabolism of other drugs. Pharmacokinetic and pharmacodynamic interactions between the estrogen and gestogen components of OCs may be synergistic or antagonistic, but no correlation has been found between the rate of metabolism of the 2 steroids as reflected in their elimination half-lives. Despite evidence that some anticonvulsant, antibiotic, and antibacterial drugs reduce the efficacy of OCs, this interaction is severe enough to lead to OC failure in less than 5% of cases. It can be postulated that women in whom drug interactions lead to contraceptive failure are fast metabolizers or have liver enzyme systems especially susceptible to induction.

A pharmacodynamic and pharmacokinetic study of the Chinese No. 1 pill.

A pharmacodynamic and pharmacokinetic study of the Chinese No. 1 pill, a combined oral contraceptive containing 35 micrograms ethynyloestradiol (EE) and 600 micrograms norethisterone (NET), was performed in 29 women over a period of six months. Blood samples for analysis were taken during a pretreatment cycle, the first and 6th treatment cycles and post-treatment. Minor changes in carbohydrate metabolism occurred and these were particularly noticeable when the incremental areas under the serum concentration-time curves for both glucose and insulin in response to a glucose tolerance test were calculated. No changes occurred in the serum glycosylated haemoglobin levels. The serum concentrations of all the lipids measured (total cholesterol, triglycerides, LDL-C, HDL-C and apolipoproteins AI, AII and B) were significantly increased on treatment as were levels of Factor X, SHBG and caeruloplasmin whereas antithrombin III decreased. In 38 of the 40 treatment cycles, ovulation was suppressed. In one cycle serum oestradiol and progesterone levels showed a typical ovulatory pattern and in another there was evidence of follicular activity without ovulation. Serum EE concentrations showed a similar pattern in both treatment cycles showing that co-administration of NET did not affect EE metabolism. Serum NET levels were higher in the 6th than in the first treatment cycles. On comparing pharmacodynamic and pharmacokinetic parameters, the only statistically significant correlations were between the percentage change in triglycerides and SHBG and serum NET, but not EE concentrations, and between apolipoproteins AI and serum EE.

Hemostatic changes in women using a monthly injectable contraceptive for one year.

The effect of consecutively injecting a one-a-month contraceptive (norethisterone enantate 50 mg with estradiol valerate 5 mg) for one year on haematological parameters was evaluated in 42 Chinese women. The healthy volunteers were randomly allocated to either the treatment group (22) or a control group (20). Blood samples were collected in the follicular and luteal phases of a pretreatment cycle, on days 28 +/- 3 after the 1st, 3rd, 6th, 12th injections and in the luteal phase of the post-treatment cycle. The results showed that in both groups, prothrombin time and fibrinogen fluctuated significantly, and leucocyte count was not significantly changed during the whole course. Factor VIII-related antigen and antithrombin III (AT-III) antigen showed minor changes, although in the 3rd treatment cycle, the differences between the two groups in both parameters reached statistical significance. A progressive and significant decrease in Factor X and AT-III functional activity occurred with the monthly injectable treatment, decreasing by about 14% and 20%, respectively, after 12 months of treatment. Haemoglobin levels were increased in the treatment group after the 3rd injection and remained at the higher level during the study period. It is doubtful whether these changes are likely to be of clinical relevance.

Oral contraceptives and lipids.

PIP: Many studies have demonstrated a correlation between serum lipid concentrations and the high risk of developing cardiovascular disease. Further, oral contraceptives (OCs) are known to change lipid metabolism. The extent of the change depends on the dose and structure of the estrogen and gestagen, however. Many researchers studying the effect of OCs on lipid metabolism have encountered numerous sources of variability in their studies, such as age of the subjects, smoking, daily variations in serum lipid concentration, and whether samples were stored before analysis and for how long. Since there are many sources of variability, the results of any study should not be accepted uncritically. Published studies of OCs with 30ug ethinyl-estradiol and 150 ug levonorgestrel, serum low density lipoprotein (LDL) cholesterol concentration was lowered in 12 and unchanged in 13. On the other hand, results of studies for the triphasic OC containing ethinyl-estradiol and levonorgestrel were more consistent--this triphasic OC produced no change in either serum LDL cholesterol or high density lipoprotein (HDL) cholesterol concentrations. As for ethinyl-estradiol combined with 150 ug desogestrel, 15 studies showed an increase in serum HDL cholesterol concentration and 4 with no change, and 9 reported no change in serum LDL cholesterol concentration and 2 with a decrease. Further, research shows that changes in lipid metabolism appear not to be progressive with continued use of OCs, and the lipids revert to their pretreatment concentrations after stopping OC use. Despite inconclusive evidence of increased cardiovascular risk with OC use, physicians should prescribe formulations containing the lowest dose consistent with efficacy and acceptability.^ieng

Pharmacokinetic study of levonorgestrel used as a postcoital agent.

The pharmacokinetics and pharmacodynamics of levonorgestrel (LNG) were studied in six women given 0.75 mg LNG orally for seven days during the periovulatory phase of the menstrual cycle. Steady-state concentrations of LNG were reached within three days and serum LNG concentrations at various times on day 7 were generally lower than on day 1, presumably due to a reduced serum level of SHBG. On day 7 the volume of distribution was significantly increased and Co significantly decreased and both the clearance and elimination half-life were higher on day 7 than on day 1. Half-lives varied from 5.6 to 25.1 hours. The day-to-day intra-subject variations in serum LNG concentrations ranged from 23% to 80%. Serum concentrations of pituitary and ovarian hormones suggested that ovulation was not inhibited in four of the six subjects and was delayed in the remaining two. No significant changes in serum prolactin levels were observed.

Interactions of contraceptive steroids with binding proteins and the clinical implications.

PIP: There are various complex interactions between combined oral contraceptives (COCs) containing the estrogen, ethinyl estradiol, and a synthetic gestagen and sex hormone binding globulin (SHBG). 1 interaction is that the magnitude of effect of the COC on hepatic synthesis, and thus serum concentration of SHBG, depends on the relative doses of the estrogen and gestagen and on the nature of the gestagen. Next, the interaction between the COC and the SHBG affects the biological activity of the synthetic steroids and influences the binding and the biological activity of the sex hormones produced by the body. The extent of this effect is based on the relative doses of the estrogen and gestagen, on the nature of the gestagen, and the concentration of endogenous sex hormones present. In addition, since women take the COC once/day, serum concentrations of the synthetic estrogen and gestagen fluctuate. Therefore the equilibrium between the synthetic hormones and the endogenous sex hormones also changes. Finally, a broad variation exists in serum concentrations of the synthetic estrogen and gestagen between females using the same COC. Therefore large intersubject variations between SHBG and the endogenous and exogenous hormones are expected.^ieng

A pharmacokinetic and pharmacodynamic study of a 'visiting pill' containing norethisterone.

The pharmacokinetics and pharmacodynamic effects of two doses of norethisterone (5mg and 3mg) used as a 'visiting pill' were investigated. There were no significant differences in the pharmacokinetics of the two doses except for the peak concentration achieved and the bioavailability as assessed by the area under the serum norethisterone concentration - time curve. Both doses were rapidly absorbed. Pharmacodynamic effects were minor. No change occurred in serum concentrations of total cholesterol, total triglycerides or HDL-cholesterol. The area under the serum glucose concentration--time curve and particularly the area under the serum insulin concentration--time curve were significantly increased as a result of treatment but no change occurred in the serum levels of glycosylated haemoglobin. SHBG concentrations in serum decreased on treatment whereas those of ceruloplasmin increased.

Indium-111 leucocyte scintigraphy in the investigation and management of inflammatory bowel disease.

The results of indium-111 tropolonate leucocyte scintigraphy in 105 patients with known inflammatory bowel disease are reviewed. Scintigraphy is as sensitive as radiology in detecting and assessing the extent of active colonic disease, and probably more sensitive in assessing small bowel disease. In a further 40 patients scintigraphy was successfully used as a screening test to identify, or exclude, bowel inflammation in patients with gastrointestinal symptoms. Scintigraphy has advantages over barium studies, being safe, non-invasive, more sensitive than small bowel radiology and giving additional information such as the bowel identification of intra-abdominal abscesses. The time required to label the leucocytes (about 2 hours) and the higher unit cost, unless many scintigrams are performed, are disadvantages.

Symptoms of food allergy.

Adverse reactions to foods can be due to many causes, but only those involving an immunological mechanism can be defined as food allergic disease. An increasing number of gastrointestinal and other diseases are being shown to involve food intolerances. Immediate reactions with symptoms within hours of eating a particular food are most readily shown to be due to food allergy and are often associated with the presence of food-specific IgE as shown by skin prick tests and RASTs. When reactions are delayed for 24 to 48 hours or more, underlying food intolerance is harder to recognize and much less often shown to be due to allergy. At present, diagnosis and management depends on dietary manipulation, showing that symptoms improve on food avoidance and are reproduced by food challenge (preferably double-blind). Further understanding of the mechanisms involved in food allergy, in Crohn's disease and irritable bowel syndrome may allow the development of simple tests to identify the foods concerned and perhaps, in the case of allergic disease, cure by the induction of tolerance.

Oral contraceptives, lipids and cardiovascular disease.

Evidence for the involvement of changes in lipid metabolism and oral contraceptive use in the development of cardiovascular disease is briefly reviewed with particular reference to the main object of the article, to assess the effect of different oral contraceptive formulations on serum lipid levels. The preferred formulations should contain a low dose of ethynyloestradiol and should not increase serum levels of cholesterol and LDL-C or reduce those of HDL-C. Such formulations appear to be the triphasic one containing ethynyloestradiol and levonorgestrel and the ethynyloestradiol-desogestrel combination, which appears to be unique in that it may actually increase HDL-C. However other determinants in addition to effects on lipid metabolism will be important in deciding the choice of an oral contraceptive. Any changes which do occur in serum lipid concentrations with OC use appear within the first three months and do not appear to be progressive with continued use after this time.

An evaluation of high-dose medroxyprogesterone acetate (MPA) therapy in women with advanced breast cancer.

The efficacy of high-dose intramuscular MPA therapy in controlling progressive measurable metastatic breast carcinoma was assessed in 32 women. In addition serial measurements of MPA blood levels were carried out in 20 of the patients and subjective effects of treatment were monitored in detail in 18 of the women. Overall 6 patients (19%) gained an objective response and a further 7 (22%) experienced disease stasis from 4-17 months whilst on treatment. Significant differences in serum MPA levels were seen between responders and non-responders, objective tumour shrinkage only being seen in those patients who rapidly attained, and sustained, blood levels in excess of 100 ng ml-1. Subjective assessment showed no evidence of a euphoriant effect of MPA therapy in the non-responders group.

Ovarian function following a single administration of depo-medroxyprogesterone acetate (DMPA) at different doses.

The effects of a single administration of depo-medroxyprogesterone acetate (DMPA) at different doses upon ovarian function was studied in a group of healthy ovulating Mexican women. Single doses of DMPA of 25, 50, 100, and 150 mg were intramuscularly administered. Ovarian function was assessed by the measurement of the serum levels of 17 beta-estradiol and progesterone in blood samples drawn twice weekly for 6 months after DMPA administration. The results disclosed that ovulation was inhibited in all cases for at least 3 months following DMPA administration even at the lowest dose, whereas the return of luteal function exhibited a significant positive correlation with the dose of DMPA administered. As expected, follicular activity preceded that of luteal function in all subjects. A correspondence between serum medroxyprogesterone concentrations and ovarian function was found. The overall data indicated that the currently used contraceptive formulation (150 mg) is well above the effective pharmacologic range, and suggested that the dose can be substantially reduced without losing its anovulatory potency.

Return of ovulation and fertility in women using norethisterone oenanthate.

The return of ovarian activity was studied in 20 women who had discontinued norethisterone oenanthate after using the injectable contraceptive for 6 months to 5 years. Follicular activity returned within 70 days of discontinuing in four women and within 90 days in a further seven. In only 4 women was the return of follicular activity associated with a rise in the serum progesterone level. The serum norethisterone concentration was usually less than 1 ng/ml at the time of return of ovarian activity and was lower in women in whom ovarian activity returned before day 90 than in those in whom it returned after day 90. Of 40 women who discontinued norethisterone oenanthate, pregnancy occurred in 14 women within 12 weeks of discontinuing and in 21 (52.5%) within 6 months. The findings suggest that there is no impairment of fertility in women using norethisterone oenanthate.

PIP: The return of ovarian activity was studied in 20 women who had discontinued norethisterone enanthate after using the injectable contraceptive for 6 months-5 years. Follicular activity returned within 70 days of discontinuance in 4 women and within 90 days in a further 7. In only 4 women was the return of follicular activity associated with a rise in serum progesterone level. The serum norethisterone concentration was usually less than 1 ng/ml at the time of return of ovarian activity and was lower in women in whom ovarian activity returned before day 90 than in those in whom it returned after day 90. Of 40 women who discontinued norethisterone enanthate, pregnancy occurred in 14 women within 12 weeks of discontinuing and in 21 (52.5%) within 6 months. Findings suggest that there is no impairment of fertility in women using norethisterone enanthate.

Pharmacokinetics of different doses of norethisterone oenanthate.

Doses of norethisterone oenanthate of 300, 150, 100 and 50 mg were administered to four groups of subjects. Due to wide intersubject variations there were no statistically significant differences in the pharmacokinetic parameters for the different groups but there were significant correlations between the dose and the mean values for these parameters. There was little difference between the groups in the duration for which ovarian function was suppressed due to the inter-subject variation being greater than the inter-dose effect. The duration of the antifertility action of norethisterone oenanthate cannot be increased by increasing the dose above the standard 200 mg; however, with an injection interval of 60 to 70 days, it seems likely that the dose could be reduced to 150 mg.

PIP: Doses of norethisterone enathate of 300, 150, 100, and 50 mg were administered to 4 groups of subjects. Due to wide intersubject variations, there were no statistically significant differences in the pharmacokinetic paraetmers for the different groups but there were significant correlations between the dose and the mean values for these parameters. There was little difference between the groups in duration for which ovarian function was suppressed due to the intersubject variation being greater than the interdose effect. The duration of the antifertility action of norethisterone enanthate cannot be increased by increasing the dose above the standard 200 mg; however, with an injection interval of 60-70 days, it seems likely that the dose could be reduced to 150 mg.