Menstrual data of 13 control subjects and 88 subjects immunized with three beta-hCG-based vaccine formulations were analysed. Immunization did not change the menstrual regularity; bleeding days were normal (3-7 days) and 89% of the menstrual cycles were within the normal range of 22-35 days. Irregular (short or long) cycles were observed in both immunized and control groups. These were, however, unrelated to prevailing anti-hCG antibody titres or to cross-reactivity of antibodies with hLH.

Comparative phase I clinical trials were carried out in 5 centres with three formulations of beta-hCG-based vaccines inducing antibodies against human chorionic gonadotropin. The objectives of these trials were to determine their relative immunogenicity, duration, reversibility and safety. A total of 116 tubal ligated women volunteers were enrolled in the study and 101 subjects were followed-up for one year or more until the antibody titres declined to near zero levels. Every woman receiving the vaccine produced anti-hCG and anti-tetanus antibodies. Clinical examination carried out at intervals of 4–6 weeks revealed no abnormality. No serious side effects or adverse reactions were reported with any of the formulations during primary immunization with three monthly injections of the vaccine. Eleven women, however, demonstrated hypersensitivity to test dose at the time of the booster injection. The reaction was to tetanus toxoid; gonadotropin subunits conjugated to another carrier did not evoke any such reaction. Progesterone in bleeds taken at midluteal phase, as well as complete progesterone and estradiol done in two immunized women, indicated normal ovulatory cycles. Immunization with these formulations had no significant effect on haematological, clinical chemistry and other metabolic parameters. In summary, the results indicate that none of the three beta-hCG-based contraceptive vaccines had any adverse effects clinically, on endocrine status and metabolic parameters. Formulations A and B induced comparatively higher anti-hCG titres than M. Thus, further work can be undertaken to study the efficacy of these vaccines in humans for preventing pregnancy.

A non‐surgical, preferably self‐administered, procedure would be an attractive alternative to vacuum for the termination of early pregnancy. 20 patients with 49 days of amenorrhea and confirmation of pregnancy by ultrasound, urine testing and human chorionic gonadotrophin (β‐hCG) analysis, were administered RU 486, 25 mg twice daily for 4 days, (Group I). A further 20 patients received the same dose of RU 486 for 3 days (Group II). All patients received an intramuscular injection of the prostaglandin derivative sulprostone, 0.25 mg, on the last day of RU 486 treatment. Outcome of therapy was assessed on the second follow up visit (day 15) on the basis of clinical course, ultrasound findings and hCG levels. In Group I, all patients had a complete abortion with a success rate of 100%. In Group II, a success rate of 95% was achieved. Side effects were minimal and did not require any medication. A dramatic fall was observed in the plasma β‐hCG and progesterone levels on days 8 and 14, correlating with the clinical course of abortion. Plasma cortisol levels remained within the normal range. It is concluded that sequential therapy with RU 486 and prostaglandin is a highly safe, simple and effective non‐surgical method for termination of early pregnancy.

Fetuses with intrauterine growth retardation (IUGR) are of two types—symmetrical and asymmetrical, and it is important to differentiate between the two types antenatally. Ultrasound studies on 22 patients with IUGR were done after 28 weeks of gestation. The fetuses were distinguished as symmetrical and asymmetrical on the basis of ratio of head to abdominal circumference. It was found that the ratio of head to abdominal circumference differentiated well between the two types of IUGR after 36 weeks of gestation. The etiology and perinatal behaviour in the two groups were also different. A single head: abdominal circumference ratio may be useful in differentiating between symmetrical and asymmetrical IUGR after 36 weeks.

In an eleven-centre study, 627 nulliparous subjects in the 8th to 12th week of gestation admitted for termination of pregnancy were allocated to one of five treatments to induce pre-operatlve cervical dilatation. The treatments were: 0.5 mg PGE2 methyl sulphonylamide; 1.0 mg PGE1 methyl ester; 30 mg 9-methylene PGE2 free acid, 0.5 mg 15-methyl PGF2α; a single medium sized laminaria tent.

In an eleven-centre study, 627 nulliparous subjects in the 8th to 12th week of gestation admitted for termination of pregnancy were allocated to one of five treatments to induce pre-operative cervical dilatation. The treatments were: 0.5 mg PGE2 methyl sulphonylamide; 1.0 mg PGE1 methyl ester; 30 mg 9-methylene PGE2 free acid, 0.5 mg 15-methyl PGF2 alpha; a single medium-sized laminaria tent. The results indicate that the three PGE analogues are at least equally effective as one medium sized laminaria tent and more effective than 0.5 mg 15-methyl PGF2 alpha in producing adequate pre-operative cervical dilatation prior to vacuum aspiration. It is concluded that both pre-treatment with prostaglandin analogues and laminaria tent are effective methods for preoperative cervical dilatation and both types of treatment are associated with a low incidence of side effects. Prostaglandin analogue treatment can be administered by paramedical personnel but laminaria tent insertion has to be performed by medical staff.

The results of a comparative study of the efficacy and acceptability of sulprostone administered intramuscularly and vacuum aspiration for termination of very early pregnancy is reported. The period of amenorrhoea varied from 35 to 45 days with a positive pregnancy test. Group A (20 cases) received intramuscular sulprostone in doses of 500 micrograms and 1000 micrograms 4 hours apart without any pre-treatment. The success rate was 85%. Group B (20 cases) underwent vacuum aspiration with 100% success rate. Incidence of vomiting was comparable in both groups. Severe abdominal cramps/pain occurred in 11% following sulprostone administration. No immediate serious complication occurred. Estimation of serum HCG was done before sulprostone administration and 2 weeks later. A decline was noted 2 weeks post-treatment in successful cases, thus confirming the effectiveness of the therapy.

A total of 2388 subjects, 1181 for 60 +/- 5-day and 1207 for 90 +/- 5-day treatment regimen with norethisterone oenanthate (NET OEN) 200 mg injection, were observed for 24 months, constituting 28,513 woman-months. This clinical trial represents the largest clinical trial undertaken on NET OEN. The observations indicated that NET OEN given at 60 +/- 5-day intervals provides adequate contraceptive protection. However, as compared to the published studies elsewhere, higher method failures were seen during the first six months of NET OEN usage, when all women were receiving the drug at 60 +/- 5-day intervals. The reasons for this discrepant observation in the present study cannot be explained. The higher method failures reported with 90 +/- 5-day regimen were mainly during the third month following the injection, suggesting reduced contraceptive efficacy of the drug during this period. Thin build women (body weight less than or equal to 40 kg) were at higher risk of involuntary pregnancy. Disrupted menstrual pattern was the major reason for discontinuation ranging between 42-43 per 100 users at the end of 24 months. Amongst these, amenorrhoea was the commonest reason for discontinuation. No change in blood pressure was observed during contraceptive usage. The majority of NET OEN users did not show any change in body weight. The overall continuation rates with NET OEN were lower than those observed in similar conditions with Cu-T 200 mm2 IUCD.

A total of 2388 subjects, 1181 for 60 +/- 5-day and 1207 for 90 +/- 5-day treatment regimen with norethisterone oenanthate (NET OEN) 200 mg injection, were observed for 24 months, constituting 28,513 woman-months. This clinical trial represents the largest clinical trial undertaken on NET OEN. The observations indicated that NET OEN given at 60 +/- 5-day intervals provides adequate contraceptive protection. However, as compared to the published studies elsewhere, higher method failures were seen during the first six months of NET OEN usage, when all women were receiving the drug at 60 +/- 5-day intervals. The reasons for this discrepant observation in the present study cannot be explained. The higher method failures reported with 90 +/- 5-day regimen were mainly during the third month following the injection, suggesting reduced contraceptive efficacy of the drug during this period. Thin build women (body weight less than or equal to 40 kg) were at higher risk of involuntary pregnancy. Disrupted menstrual pattern was the major reason for discontinuation ranging between 42-43 per 100 users at the end of 24 months. Amongst these, amenorrhoea was the commonest reason for discontinuation. No change in blood pressure was observed during contraceptive usage. The majority of NET OEN users did not show any change in body weight. The overall continuation rates with NET OEN were lower than those observed in similar conditions with Cu-T 200 mm2 IUCD.

Sixty healthy women at 8 to 12 weeks of gestation were divided into three groups of 20 women each to evaluate three methods for gradual cervical dilatation prior to vacuum aspiration — Group I: Laminaria tent; Group II: Isaptent, and Group III: 250 ug 15-methyl-PGF2 alpha intramuscular injection. The three methods showed comparable cervical dilatation (10.46 mm) over a mean period of 3 hours 40 minutes. Administration of 15-methyl-PGF2 alpha, though relatively simple, had significant gastrointestinal side effects and bleeding per vaginum (P < 0.001) prior to vacuum aspiration and greater blood loss (P < 0.01) during vacuum aspiration as compared with the other two groups. No sequelae, immediate or delayed, were encountered. Isaptent indigenously made and relatively inexpensive is a reliable, safe and effective method for gradual dilatation of cervix for 8 to 12 weeks of gestation prior to vacuum aspiration and is the cervical dilator of choice.

The availability of norethindrone (NET) in serum was studied in 8 women after daily administration of a combination oral contraceptive pill (MinovlarR) containing 1 mg norethindrone acetate (NETA) and 50 micrograms ethinyl estradiol (EE2) from day 5 to day 25 of the menstrual cycle. The pill was taken daily at 9:30 a.m. after a light breakfast and blood samples were collected at 3 hr on alternate days and at 24 hr on other days after ingestion of the pill. On day 12 or day 15 of the first treatment cycle, serial blood samples were also collected at 1/2, 1, 2, 4, 6, 8 and 24 hr after taking the pill. Serum NET levels were estimated by the radioimmunoassay (RIA) technique. The plot of serum NET concentration versus time (0-24 hr) profile showed a rapid absorption of steroid and a peak NET concentration (18.3 +/- 4.8 ng/ml) reached at 2 hr after ingestion of the pill. By linear regression analysis of data (y = 0.27 + 0.12x; r = 0.95), it was observed that the serum NET level was initially about 1 ng/ml. Thereafter, it increased by 0.12 ng/ml per day up to 3.5 ng/ml by the end of 21 days' treatment with oral pills. The serum NET concentration decay slope fitted a two-compartment open model with an initial rapid decay (half-life of 1.2 +/- 0.1 hr) followed by a slower beta-phase with a half-life of 8.5 +/- 1.5 hr. The study revealed that there was an accumulation of norethindrone in plasma during the treatment period and this suggests the possibility of exploring a reduction in the dose of this preparation so as to achieve the optimum NET concentration for contraception, and thereby avoiding unwanted steroid accumulation in the plasma of women.

Two doses of the prostaglandin analogue 16-phenoxy-ω-17,18,19,20-tetranor-PGE2 methyl sulphonylamide were compared in a randomized multicentre trial in 6 centres for the termination of second trimester pregnancy. A total of 295 patients were treated with either 0.5 mg or 1.0 mg given by intramuscular injection every 4 h or 8 h, respectively. The 1-mg dose was more effective in inducing an abortion than the lower dose but the difference was not statistically significant. Eighty-four per cent of the patients aborted within 30 h from the onset of treatment. The induction-abortion interval was approximately 15 h in both groups. The incidence of incomplete abortion, heavy blood loss and blood transfusion was similar for both treatments. Cervical lacerations occurred in 1.3% of patients given the smaller dose and 2.1% of the larger dose. In one patient belonging to the latter group an anterior rupture of the lower uterine segment was diagnosed necessitating hysterectomy. Fifty per cent of the patients had no vomiting and 90% no diarrhea. The frequency of gastrointestinal side effects was slightly higher with the 1-mg dose. The major advantages of this treatment are the simplicity of administration and the low frequency of gastrointestinal side effects in comparison with prostaglandin F analogues.

Sulprostone was given intramuscularly in two dose schedules of 0.5 mg at 4 hourly intervals for 8 doses and 1.0 mg at 8-hour intervals for 4 doses to 56 women in the 12th–20th week of gestation coming for termination of pregnancy. Forty-nine of them aborted within the 30-hour observation period, giving a success rate of 87.5%. Within the observation period, the induction-abortion interval with the 0.5-mg schedule was 16.6 hours while the interval with the 1.0-mg schedule was 15.4 hours. Side effects caused by the drug were minimal and it was observed that patients receiving 1.0 mg Sulprostone had slightly more side effects per person than in those cases receiving 0.5 mg Sulprostone. Serum parameters assessing liver and kidney functions were carried out in 48 patients prior to, 24 hours later and two weeks after the abortion. There were significant changes in the levels of uric acid, potassium, serum proteins and SGOT, though these changes were within the normal range.

The levels of available norethindrone were found to be similar in women and rabbits after s.c. administration of crystalline and amorphous, norethindrone acetate respectively, and this study indicates that the rabbit may be used as an animal model for further investigation with this contraceptive steroid.

The metabolic clearance rate (MCR) of norethindrone acetate (NETA) and norethindrone (NET) levels in plasma were studied after an iv injection of [3H]NETA in three women before and at 1 week, 1, 2 and 6 months following the insertion of a single silastic subdermal implant releasing microquantities of NETA. No significant change in the MCR of NETA was observed at 1 week (459 +/- 72 1/day), 1 month (489 +/- 113 1/day) and 2 months (522 +/- 144 1/day) compared with that of control (525 +/- 108 1/day). However, MCR of NETA showed significant increase in women exposed to continuous presence of NETA for a period of 6 months (608 +/- 121 1/day; P less than 0.025). NETA was rapidly and extensively metabolized into NET. At 1 week, 1, 2 and 6 months of study, NET was observed to be present in higher amounts compared with NETA. The production rate (PR) of progesterone decreased significantly at 2 and 6 months of NETA implant insertion compared with the PR before the insertion of implant.

Six normally menstruating women were inserted each with a single silastic implant-D releasing norethindrone acetate (NETA). The levels of endogenous hormones, FSH, LH, E2 and progesterone, were estimated by radioimmunoassay (RIA) procedures in the control and treatment cycles. In addition, the levels of drug in the serum as norethindrone (NET) which is a major metabolite of NETA were also estimated by RIA procedures in the treatment cycles. In all, 12 treatment cycles were studied. In the initial treatment cycles (1st/2nd or 3rd), the serum NET levels were either 1 ng/ml or above. The LH and FSH showed either normal or suppressed mid-cycle peaks, but the progesterone levels were completely suppressed. In the sixth treatment cycles, the serum NET levels were either 0.5 ng/ ml or below. The FSH and LH mid-cycle peaks were lower but distinct while the luteal progesterone levels were of normal ovulatory type. These studies lead us to the conclusion that a serum level of NET of the order of 1 ng/ml is required to bring about suppression of luteal progesterone, either as a result of direct action on the ovary or through suppression of pituitary gonadotropins. When the serum level falls to 0.5 ng/ml or below, the suppressive effect is removed and ovulatory pattern of progesterone returns.