Development of a low-dose monthly injectable contraceptive system: II. Pharmacokinetic and pharmacodynamic studies

A drug delivery system which provides a sustained release of norethindrone (NET) and mestranol (ME) for one month after a single intramuscular injection was assessed as a long-acting injectable contraceptive. The system is based upon well defined particle size crystals of the synthetic steroids maintained in suspension with saline solution. Eight healthy ovulating women volunteered for the study; they received a combination of 10 mg of NET plus 1 mg of ME in 1 ml of vehicle by intramuscular injection on day five of their menstrual cycle. Blood samples were drawn at 0, 1, 5, 10, 13, 17 and 21 days after drug administration. The immunoreactive serum levels of estradiol, progesterone, NET and ethinylestradiol were measured by specific radioimmunoassay procedures to assess ovarian function and the kinetic parameters of the synthetic steroids. This newly developed contraceptive system proved to be both effective, and long-lasting as well as devoid of side effects.     

Pharmacokinetics,pharmacodynamic and endometrial effects of a single dose of 200 mg norethisterone enanthate

Ovulation was confirmed by daily analyses of the peripheral plasma levels of estradiol (E₂)⁴) and progesterone (P) in a pre-treatment cycle of 14 subjects. An endometrial biopsy was taken either in the proliferative or in the secretory phase of the cycle. On the 5th day of a subsequent cycle 200 mg norethisterone enanthate (NET-EN) was administered intramuscularly. The levels of E₂, P and those of NET were analyzed during the next 19 days and again during 44–60 days following the injection. The endometrial biopsy was repeated on the 23rd and 59th day of the treated cycle. The levels of NET reached a peak of 34.3 nmol/1 on the sixth post-injection day and decreased to below detectable limits in 3 of 12 subjects by the end of the observation. Ovarian activity was completely suppressed in all women during the first period, but returned to different levels in 11 subjects during the second. Four of them exhibited ovulatory steroid pattern. The morphologic changes of the endometrium reflected the progestogen effect in the first post-injection period but were characteristic of the ovarian reaction in the second.     

In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women

Previous studies with postmenopausal women receiving oral doses of norethisterone-containing preparations have shown that a small fraction of the dose is converted metabolically to ethinyl estradiol and may be detected in the peripheral blood. To investigate the extent and the dose dependence of this conversion in more detail, we performed a study with 24 postmenopausal women who received single oral doses of 5 mg norethisterone as well as 5 and 10 mg norethisterone acetate with a washout phase of 2 weeks between each treatment. After each treatment, blood was collected at regular intervals and the concentrations of norethisterone and ethinyl estradiol were analyzed in the serum samples by a specific radioimmunoassay and by gas chromatography/mass spectrometry, respectively. Ethinyl estradiol was present in the serum samples of all women following treatment with norethisterone acetate and, except for four cases, also after treatment with norethisterone. The conversion ratio of norethisterone acetate to ethinyl estradiol was 0.7 ± 0.2% and 1.0 ± 0.4% at doses of 5 and 10 mg, respectively. This corresponded to an oral dose equivalent of about 6 μg ethinyl estradiol per milligram of norethisterone acetate. For norethisterone, a conversion ratio of 0.4 ± 0.4% was found at a dose of 5 mg, which corresponded to an oral dose equivalent of about 4 μg ethinyl estradiol per milligram of norethisterone. Although it cannot be excluded that in individual cases, even higher doses of ethinyl estradiol may be produced by conversion, it is concluded that at therapeutic doses of the progestogens, the exposure to metabolically derived ethinyl estradiol is probably of little clinical significance not only in fertile women using oral contraceptive combination preparations containing norethisterone and ethinyl estradiol, but also in postmenopausal women who receive oral doses of estradiol for estrogen replacement. The estrogenic effects of metabolically derived ethinyl estradiol on the liver (eg, synthesis of transport proteins) are very likely more than compensated due to the androgenic activity of norethisterone.     

Pharmacokinetics of norethisterone oenanthate in humans

The pharmacokinetics of a dose of 200 mg NET-OEN were studied after intramuscular injection into nine subjects. Blood levels of NET and NET-OEN increased rapidly, reaching peaks in most subjects within seven days. At all times after injection, serum levels of NET exceeded those of NET-OEN. The half-life of absorption varied from 5.4 to 22.3 days and the half-life of elimination varied from 7.5 to 22.5 days; there was a significant correlation (R = 0.78) between these two half-lives. There were significant correlations between the absorption half-lives and the peak values of NET and NET-OEN, the time to reach peak values and the time for which NET was detectable in serum. In all subjects NET was detectable in the circulation for a longer time after injection (mean value 74 days) than NET-OEN (mean value 43 days). The time for which the two steroids were detectable in the circulation showed a significant correlation with the elimination half-lives but there was no correlation with the peak values attained, the time taken to reach peak values and bioavailability. There was a two-fold variation between the subjects in the bioavailability of NET, less than 5% of the bioavailable NET was released after day 60.     

Assessment of a new low-dose once-a-month injectable contraceptive

Norethisterone (NET) in combination with mestranol (ME), in a macrocrystalline aqueous suspension that provides sustained release of steroids, was assessed as a once-a-month injectable contraceptive in ten healthy women of reproductive age. The ovarian function was studied before and after the intramuscular administration of 12mg NET plus 1.2mg ME, delivered as crystals of 150 micron average size. Serial blood samples were taken throughout the injection intervals in all women to measure serum progesterone (P), estradiol (E2), and NET. The NET/ME preparation effectively inhibited ovulation in 23 out of the 25 injection intervals studied. The administration of this formulation induced in some women a small degree of follicular maturation not followed by luteal activity. The endometrial bleeding patterns after each injection showed a bleeding-free period of two to three weeks. The overall data demonstrate that the parenteral administration of a macrocrystalline steroid preparation of NET/ME can bring about a sustained release contraceptive system at a substantially lower dose than those currently employed in once-a-month injectable contraception.     

Demonstration of an early abortifacient effect of norethisterone (NET) in the primate (baboon)

A long-acting injectable contraceptive which provides continuous controlled release of norethisterone (NET) for three months following a single intramuscular injection was tested for antifertility effects in baboons using a low dose of microcapsules (total NET dose 2.5 mg; daily dose approximately 0.03 mg/day) which has no effect on ovarian function or ovulation. The continuous administration of NET during the cycle of conception had no effect on ovulation, fertilization or implantation as evidenced by the occurrence of nine pregnancies following 23 test matings. Pregnancy was diagnosed by the measurement of baboon chorionic gonadotropin hormone and the maintenance of elevated serum progesterone levels past the normal time of menstruation. Six of the nine pregnancies, however, ended in abortion between days 27 and 35 of pregnancy. The remaining three pregnancies continued to term and normal, healthy babies were delivered. Five control baboons included in this study became pregnant and all delivered normal, healthy infants. The results of this study demonstrate that early abortion should be considered as a mechanism of antifertility action for NET when administered continuously in low doses. These findings are contrary to the generally accepted explanation that low-dose synthetic progestins exert their contraceptive effect by inhibiting sperm transport and/or preventing implantation.     

Pharmacokinetic and pharmacodynamic studies with vaginal devices releasing norethisterone at a constant,near zero order

The pharmacokinetic and pharmacodynamic effects of norethisterone (NET) released continuously from vaginal devices at a constant rate of 50 μg/24 h and 200 μg/24 h, respectively, were studied during a period of 90 days of continuous exposure in two groups of 15 normally menstruating women each. Peripheral blood samples were withdrawn 3 times weekly (on Mondays, Wednesdays and Fridays) during a pretreatment (control) cycle and during the treatment period, and the levels of NET, estradiol and progesterone were analyzed by radioimmunoassay techniques. Furthermore, in 8 subjects of each group, blood samples were also withdrawn at frequent intervals during 72 hours following the removal of the devices, in order to assess the removal half-life of NET. In another group of 8 women with the devices releasing NET at a rate of 200 μg/24 h, an additional pharmacokinetic study was conducted on the initial absorption rate and removal half-life of NET following a short exposure of 8 days.The initial plasma levels of NET did not indicate any “burst” effect; the maximum “plateau” level was reached within 24 hours, and 50% of that level in approximately two hours. After the first few days, the plasma levels declined very slowly, with an average of 12 and 18%, respectively, after 90 days, corresponding to a daily decline of 0.1 to 0.2 percent. Following eight days of exposure, the half-life times were 6.4 hours (first compartment) and 11.2 hours (second compartment). After 90 days of exposure, the half-lives appeared to be somewhat shorter. Whether this is a reflection of a change in the metabolism of the drug, remains to be ascertained.Of the 44 cycles studied with the devices releasing NET at a rate of 50 μg/24 h, complete lack of luteal activity was found only in 7%, whereas of the 46 cycles studied in the same way with 200 μg/24 h-releasing devices, 74% did not show any signs of luteal function. Since the corresponding figure in 43 women taking the 300 μg NET minipill, who were studied simultaneously during 64 cycles, was only 36%, it appears that the ovulation-inhibiting potency of 200 μg NET released continuously from vaginal devices is considerably stronger than that of the 300 μg NET minipill taken daily.     

Serum norethindrone (NET) concentrations following intramuscular NET enanthate injection. Effect upon serum LH, FSH, estradiol and progesterone

Serum norethindrone (NET), estradiol-17 beta (E), progesterone (P), and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were radioimmunoassayed in 15 women after injection of 300 mg norethindrone enanthate (NET-EN) in 2 ml of oil (5 women), 200 mg NET-EN in 2 ml of oil (5 women), and 200 mg NET-EN in 1 ml of oil (5 women). These values were measured twice a week for 4-6 months to determine 1) the effect of various serum NET concentrations upon hypothalamic/pituitary-ovarian function; 2) intersubject variability of this effect; 3) between-subject variability of serum NET values; 4) the effect of an increase in NET-EN dosage or in the volume of the vehicle; and 5) the correlation between uterine bleeding and serum NET, E and P patterns. Peak serum NET levels were reached 4-15 days (median 7 days) postinjection. These high levels lasted about 20 days postinjection and then decreased, quickly at first and then gradually. Serum NET averaged 1.0 and .38 ng/ml 60 and 120 days postinjection and continued to be measurable in some of the subjects for up to a year. Calculations of day levels of serum NET revealed 63% in the 1st 20 days, 26% in the 2nd, and 11% in the 3rd. Follicle development occurred between 33-116 days postinjection (median 43 days) and was followed by ovulation in only 1 subject (45 days postinjection) with the 2nd earliest ovulation at 80 days postinjection. Uterine bleeding patterns were independent of dosage of NET-EN. The higher dose of NET-EN provides no contraceptive advantage, and the larger vehicle has no effect. A variability of positive feedback inhibition among subjects is thought to be responsible for differing patterns of return to ovulation, suggesting that for contraceptive purposes a regimen of 150 mg or less NET-EN every 6 weeks may be appropriate.     

A prospective, partially randomized study of pregnancy outcomes and hematologic responses to oral and intramuscular iron treatment in moderately anemic pregnant women

BACKGROUND: Daily oral iron supplementation during pregnancy fails to reduce the prevalence of anemia. However, 2 or 3 intramuscular doses of iron given at monthly intervals were recently found to be effective. OBJECTIVE: We compared the safety and efficacy in treating pregnancy anemia of 3 intramuscular doses of iron given at monthly intervals with those of daily oral iron supplementation. DESIGN: In a prospective, partially randomized study, 148 pregnant women received daily oral doses of 100 mg elemental Fe and 500 micro g folic acid, and 106 pregnant women received 3 intramuscular doses of 250 mg elemental Fe as iron dextran at 1-mo intervals and oral doses of 5 mg folic acid twice weekly. One hundred women in each group completed the study. Changes in hemoglobin, iron indicators, pregnancy outcomes, and birth weight were compared between the 2 groups. RESULTS: Hemoglobin and iron indicators improved significantly with both treatments. The increase in serum ferritin concentration after parenteral iron treatment was significantly higher than that after oral iron treatment. No significant differences between the 2 groups in pregnancy outcomes and birth weight were observed. Systemic side effects were more common in the parenteral iron group, whereas gastrointestinal side effects were more common in the oral iron group. CONCLUSIONS: The intramuscular administration of 3 doses of 250 mg Fe at monthly intervals appears to have good compliance and efficacy and may be used in women who cannot tolerate oral administration of iron. However, intramuscular administration of iron is appropriate only in hospital settings well equipped to treat anaphylactic crises.     

The acute behavioral effects of diisopropyl fluorophosphate in the chicken, pigeon, and rhesus monkey

The effects following oral and intramuscular injection of diisopropyl fluorophosphate (DEP) were studied in chickens and pigeons responding under a multiple fixed-ratio, fixed-interval schedule of food presentation. The effects for both routes for DFP were also studied in chickens responding on a multiple fixed-ratio, time-out schedule of food presentation. In addition, the effects of intramuscular DFP were also studied in a rhesus monkey responding under a chain fixed-ratio, fixed-ratio schedule of sucrose presentation. The effects of DFP were to cause a general depression of fixed-ratio, fixed-interval, and time-out responding with no mean response rate increases. Doses producing behavioral effects also produced acute cholinergic effects in the chicken and the rhesus monkey but not in the pigeon. The potency and duration of DFP effects depended on the species and route of administration. The monkey was the most sensitive animal with the lowest active intramuscular dose (0.1 mg/kg) disrupting responding for 5 days. A higher dose (0.125 mg/kg) disrupted responding for 8 days. Intramuscular DFP disrupted responding in the chicken in a dose-related manner and with 0.25 mg/kg being the lowest active dose. Higher doses (0.5 and 0.75 mg/kg) disrupted responding for 2 days after administration. Oral DFP was much less potent than the intramuscular route in both chickens and pigeons, with a marginally active dose being 1 mg/kg. Effects following oral administration lasted less than 1 day. Potency was the same in the pigeon by both the oral and intramuscular routes.     

A randomized study of metabolic effects of four low-estrogen oral contraceptives: I. Results after 6 cycles

Healthy, non-smoking, normotensive, well-motivated young women were assigned at random to one of four different, commercial, low-estrogen, oral contraceptive products. Measurements of biochemical parameters were made on blood specimens collected from fasting subjects twice during the late pretreatment cycle, then again during each late treatment cycle for six months. All women assigned to one product (0.5mg NET + 35 microgram EE) dropped out of the study before the end of the fifth cycle, but discontinuations with the other three products were few. While numbers of subjects are small, the groups are closely matched and most metabolic differences are statistically significant. Products containing EDA and NET were associated with increases in serum total cholesterol and triglycerides, but decreases in HDL-cholesterol. In contrast, the LNG-containing preparation produced significantly less effect on these tests. A similar pattern was seen with a range of blood coagulation and fibrinolytic factors, Minimal alterations were seen with the LNG preparation, while those containing NET or EDA showed marked increases in factors I. VII, VIII, X and plasminogen, associated with a decrease in antithrombin III. It is suggested that differences in the metabolic impact of the various commercially available low-estrogen preparations, combined with effects on intermenstrual bleeding, allow a choice of the progestogen component most suitable for general use.     

Plasma levels of norethindrone in indian women receiving norethindrone enanthate (20 mg) injectable

Plasma norethindrone (NET) and progesterone were estimated by radioimmunoassay in seven Indian women after intramuscular administration of 20 mg NET enanthate. One subject had intermenstrual bleeding throughout the cycle. Out of the six subjects considered for analysis, three subjects showed ovulation suppression, two had delayed ovulation and the remaining one exhibited normal ovulatory pattern. Post-peak average plasma NET values ranged from 1.0 to 2.1 ng/ml. These values showed a significant positive correlation with the anthropometric indices such as body weight and mid-arm-circumference. The subjects with lower anthropometry showed exponential decline of plasma NET. A possible role for nutritional status of an individual in drug disposition is indicated from this study.     

A randomized, double-blind study of two combined and two progestogen-only oral contraceptives

A randomized double-blind study of two combined oral contraceptives and two progestogen-only oral contraceptives was conducted using the same protocol at WHO Collaborating Centres for Clinical Research in Human Reproduction in Bombay and Ljubljana of the 518 women admitted to the trial, 123 received mestranol 50 micrograms + norethisterone 1mg (MES 50 + NET 1); 137 received ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms (EE 30 + LNG 150); 130 received norethisterone 350 micrograms/NET 350); and 128 received levonorgestrel 30 micrograms (LNG 30). At one year, between 52.6 and 61.0 percent of those recruited had discontinued oral contraceptive use for all reasons, and by two years, between 70.5 and 76.5 percent had discontinued the treatment. These rates did not differ between the four treatment groups. However, discontinuation rates for all medical reasons at one and two years, and at two years pregnancy rates and discontinuation rates for bleeding disturbances, were significantly lower in the EE/LNG preparation. The groups receiving the MES/NET, LNG and NET had similar pregnancy rates, discontinuation rates for all medical reasons and all bleeding disturbances. There were two ectopic pregnancies among the 22 pregnancies in the progestogen-only groups. Discontinuation because of headache, dizziness and other central nervous system symptoms were significantly more common in those receiving MES/NET compared to EE/LNG. In contrast, discontinuation for gastro-intestinal disturbances were significantly higher in the EE/LNG combined preparation. Bleeding disturbances in the first few cycles tended to be higher in NET than in the LNG group. The data suggest that greater consideration be given to the benefits and risks of including progestogen-only oral contraceptives in the family planning programmes of some countries.     

Pharmacokinetics of norethindrone in Indian Women.

Pharmacokinetics of norethindrone (NET) was evaluated in eleven women belonging to a low socio-economic group and in five womem belonging to the high socio-economic group after the administration of an oral dose of 0.35 mg NET minipill on an empty stomach. Blood samples were collected at different intervals of time over a period of 24 hours. Plasma NET was estimated by radioimmunoassay. In all women, peak levels of NET occurred within 1-2 hours and a semi-log plot of plasma NET levels showed a biexponential decline. The half-life of plasma NET clearance was relatively shorter in women of low socio-economic group with poor nutritional status as indicated by anthropometric indices, as compared to that in well nourished women of high socio-economic group. There was a significant positive correlation between weight/(height) 2x 100 index on the one hand and t1/2 (beta) on the other in all the women studied, thereby suggesting a role for nutritional status in the metabolic handling of NET.     

A radioimmunoassay for norethindrone (NET): Measurement of serum net concentrations following ingestion of net-containing oral contraceptive steroids

A sensitive and reliable radioimmunoassay (RIA) for the measurement of norethindrone (NET) in serum has been established employing anti-11,-hydroxynorethindrone 11-hemisuccinyl-bovine serum albumin serum in conjunction with norethindrone-3-(O-carboxymethyl)oximino-[¹²⁵I]-iodohistamine. of a number of ring A reduced NET metabolites, only 17β-hydroxy-17-ethinyl-5β-estran-3-one (43%) and 17-ethinyl-5-estrane-3β,17β-diol (15.7%) cross-reacted appreciably in this RIA. Ethinyl estradiol (EE₂) and mestranol (MEE₂) exhibited cross-reactions of only 1.1 and 0.4%, respectively. Serum NET levels were measured in four groups of 3 women, each ingesting either 1 mg NET plus 0.05 mg MEE₂ (Norinyl 1 + 50 ® or Ortho Novum 1/50 ® ), 0.5 mg NET plus 0.035 mg EE₂ (Brevicon ® ) or only 0.35 mg NET (Micronor ® ) daily for 5 consecutive days. Peak serum NET levels were observed within 1/2 to 4 hours after oral intake and fell precipitously thereafter. After reaching a maximum, serum NET concentrations declined in a manner consistent with at least two disposition phases. The average half-life for the first disposition phase was 2.3. 3.4, 3.9 and 4.4 hours in subjects ingesting Norinyl 1 + 50 ®, Ortho Novum 1/50 ®, Brevicon ® and Micronor ®, respectively. Peak and 3-hour post-ingestion serum NET concentrations were dose-related but showed considerable subject-to-subject variations. Following discontinuation of tablet intake, serum NET levels remained detectable ( > 0.05 ng/ml) for at least 5 days in all 3 women who had taken Ortho Novum 1/50 ®, but in none of the other 9 volunteers. These results suggest that different preparations of identical doses and combinations of oral contraceptive steroids may yield different serum NET profiles. However, due to considerable subject-to-subject variations, larger numbers of subjects are required for a conclusive investigation.     

Comparative safety, efficacy, and cycle control of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and Ortho-Novum 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic). Lunelle Study Group

An open-label, nonrandomized, parallel, controlled study compared the efficacy, safety, and cycle control of a new monthly injectable contraceptive containing 25 mg of medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) with that of a norethindrone 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic oral contraceptive (Ortho-Novum 7/7/7). At study enrollment, women chose either the injections or the oral contraceptive. A higher proportion of women in the NET/EE group (65.1%) than in the MPA/E2C group (48.7%) had used hormonal contraception during the month before the study (p < 0.01). Overall, 55.5% (434/782) of MPA/E2C users and 67.6% (217/321) of NET/EE users completed the 60-week trial. One-year contraceptive efficacy (13 cycles of 28 days) for MPA/E2C and NET/EE was based on 8008 and 3434 woman-cycles of use, respectively. During the first year, one pregnancy occurred in an NET/EE user for a life table rate of 0.3; no pregnancies occurred in users of MPA/E2C. One additional pregnancy in the NET/EE group occurred during the 15th treatment cycle. After the first treatment cycle, women in both groups experienced regular menses, with an average cycle length of 28 days in MPA/E2C users and 27 days in NET/EE users. Although MPA/E2C users were more likely to experience bleeding irregularities, only 2.5% (19/775) cited metrorrhagia as a reason for discontinuing treatment. The adverse events reported in both treatment groups are consistent with those expected with the use of combined hormonal contraceptives. Overall, the results of this first Phase III US clinical trial of MPA/E2C confirm this method's high contraceptive efficacy and safety, as shown in previous studies by the World Health Organization. These results suggest that a monthly combination injectable would represent a welcome new contraceptive option for women in the US.     

Endometrial morphology and peripheral steroid levels in women with and without intermenstrual bleeding during contraception with the 300 μg norethisterone (NET) minipill

The peripheral levels of estradiol and progesterone were analyzed in blood samples withdrawn three times a week (Mondays, Wednesdays and Fridays) from 24 normally menstruating volunteers during a pretreatment (control) cycle and then every day during the second month of administration of daily oral doses of 300 μg norethisterone (NET). An endometrial biopsy was also taken on days 23–25 of the control cycle for morphometric, microfluorometric and ultramicroscopic quantitation.Intermenstrual bleeding occurred in 12 subjects during the second month of NET administration; the number of days with bleeding and spotting (13.4 ± 5.1 days) in this group significantly exceeded that found in their control cycle (6.3 ± 1.2), or in the group of “non-bleeders” (6.0 ± 1.2) taking the same dose of NET.Within 6 hours after the onset of intermenstrual bleeding, another endometrial biopsy was taken, after which the subjects were allocated at random to two types of treatment:6 subjects were given daily oral doses of 50 μg of ethinylestradiol for 7 days and 6 subjects received placebo for the same period of time. Daily blood samples were withdrawn during this period.Daily blood samples were also withdrawn from “non-bleeders” during the second month of NET administration and an endometrial biopsy was taken between days 23 and 25 of this month.     

Iodine supplementation with oral or intramuscular iodized oil. A two-year follow-up of a comparative trial

A controlled trial of iodine supplementation comparing oral with intramuscular iodized oil has been carried out in an iodine deficient area of Zaire. Two years after the administration of 2 ml of oral iodized oil to the population of four villages the overall goitre prevalence had fallen from 64 to 54%. In a further two villages given 2 ml of intramuscular oil the prevalence fell from 65 to 50%. The effectiveness of supplementation was also assessed by measuring changes in thyroid function in women of reproductive age. Among women in the villages given oral iodized oil, the geometric mean thyroxine concentration, measured in dried bloodspots, rose from 27.2 to 52.6 nmol/L at the two-year follow-up. This was similar to the response of the intramuscularly treated villages in which thyroxine levels rose from 32.1 to 65.4 nmol/L. There was no change in goitre prevalence or thyroid function in two control villages. Oral iodized oil is a cheaper and simpler alternative to the injected form providing effective iodine prophylaxis for up to two years after a single dose.     

Iodine supplementation: comparison of oral or intramuscular iodized oil with oral potassium iodide. A controlled trial in Zaire

A community-based controlled trial of iodine supplementation comparing oral or intramuscular iodized oil with oral potassium iodide has been carried out in 23 severely iodine-deficient villages in Eastern Zaire. The overall goitre prevalence in the population (n = 5999) was 61% and mean urinary iodine excretion in sample of 57 women 10.9 (SD 6.8) micrograms/g creatinine. All adults in three groups of four villages were given single doses of potassium iodide of 0.5 g, 1.0 g, and 2.0 g respectively. A fourth group was given oral iodized oil (2 ml) and a fifth placebo-treated. A further three villages were given intramuscular iodized oil (2 ml). The effectiveness of supplementation was assessed by measurements of bloodspot thyroxine (T4) concentration in women of reproductive age in the villages. The effects of iodide were small and inconsistent. Eight months after supplementation with oral iodized oil the distribution of T4 concentrations was similar to that seen with intramuscular oil. We conclude that oral iodized oil is an effective alternative to injected oil and would be feasible for iodine supplementation in remote areas with untrained people.     

Reduction of the oral contraceptive estrogen burden by alternate day estrogen administration.

Reduction of the oral contraceptive estrogen burden by alternate-day estrogen administration was studied. 3 regimens: 1) 1 mg norethindrone acetate (NET-Ac) plus .05 mg ethinyl estradiol (EE) on alternate days, 2) .05 mg NET plus .03 mg EE daily, and 3) .05 mg NET daily plus .06 EE on alternate days, were compared. Studies with the 1st regimen were prematurely terminated due to gross cycle irregularities; the 2nd regimen provided better cycle control but inadequate pregnancy protection apparently because of inconsistent inhibition of ovulation. Studies with the last regimen, expanded to include 1090 women for 12,942 patient-months, had clinically acceptable bleeding patterns with a bleeding discontinuation rate after the 1st year of 10.5 and after the 2nd year of 11.9. 2 of 8 pregnancies which occurred were attributed to method failure.