Impact of hormonal contraceptives vis-à-vis non-hormonal factors on the vitamin status of malnourished women in India and Thailand. World Health Organization: Special Programme of Research, Development and Research Training in Human Reproduction. Task Force on Oral Contraceptives.

The effects of combined oral contraceptives containing 30 or 50 micrograms ethinyl oestradiol and 150 micrograms levonorgestrel or a 3-monthly injectable preparation depo-medroxyprogesterone acetate (DMPA) on the vitamin status of low-income group women from two urban centres in India (Bombay and Hyderabad) and one rural centre in Thailand (Chiang Mai) were examined in a follow-up study over a period of 1 year. The magnitude of malnutrition in the study population vis-à-vis a middle-income reference group was assessed by comparing the baseline data on the two groups. Effects of time-related variables such as lactation and season were also examined by a cross-sectional analysis of the baseline data on the study population. In all three centres the majority of the study population suffered from biochemical riboflavin and/or pyridoxine deficiency even before initiating contraception. Lactation appeared to have an effect on the vitamin status, which varied among the different populations. Seasonal effects were seen, but showed inconsistent trends in the three centres. Both the oral contraceptive pills and DMPA tended to increase serum vitamin A and blood folate. The thiamin, riboflavin and pyridoxine status of the women who were already deficient did not deteriorate further with the use of hormonal contraception, as judged by enzyme saturation tests. Some deterioration in the riboflavin status of the normal women of Hyderabad was seen with the use of oral pills. Women who were biochemically deficient prior to the use of oral contraceptives tended to show some improvement in B-vitamin status, over the 1-year period of hormonal contraception.

Phase I comparative clinical trial with subdermal implants--bioabsorbable levonorgestrel or norethisterone pellet fused with cholesterol.

The potential for antifertility effect of two bioabsorable pellets, one containing norethisterone (NET) and the other containing levonorgestrel (LNG) fused with cholesterol, was studied in a group of healthy, menstruating but sterilised women. The pellets weighed approximately 30 mg and contain 85% steroid and 15% cholesterol. A single NET pellet was inserted in 4 subjects, out of which 2 were also studied for steroid pattern in blood. After reaching peak levels within 48 hours, the plasma NET levels declined gradually within a fortnight's time, and thereafter, ranged between 200 to 700 mg/ml up to 90 days post-insertion. After this period, occassional spurts of NET release were seen. Bleeding pattern was studied in 37 cycles; mid-luteal progesterone (P) estimation was done in 16 cycles, mid-cycle cervical mucus was studied in 27 cycles and post-coital test (PCT) in 7 cycles. Cycle length with pellet insertion was of 25 to 37 days duration except one cycle of 55 days duration. All cycles studied during the treatment were ovulatory (P greater than 5 ng/ml) and no consistent effect was observed on cervical mucus as well as on PCT. Thus, a single NET pellet does not seem to have a reliable contraceptive potential. A single LNG pellet was inserted in 8 subjects, and steroid patterns were studied in 6 women. Peak levels of LNG were reached within 24 hours of pellet insertion and the levels fell gradually in a week's time. Thereafter, LNG levels ranged between 100-400 pg/ml up to 8 months. In contrast to the observation with NET pellets, only one subject showed frequent spurts of LNG release until the 4th month of treatment. Bleeding pattern was studied in 90 cycles, P was estimated in 52 cycles, mid-cycle cervical mucus studied in 55 cycles and PCT done in 26 cycles. Breakthrough bleeding (BTB) occurred on 15 occasions, 11 episodes being in 2 subjects. Cycle length varied between 21 to 42 days. The LNG pellet did not exert a consistent effect either on ovulation inhibition or cervical mucus or PCT. In their present form, therefore, a single LNG pellet also does not appear to have a reliable contraceptive effect.

Release of 19-nor-testosterone type of contraceptive steroids through different drug delivery systems into serum and breast milk of lactating women.

The release of contraceptive steroids through different drug delivery systems into serum and breast milk was investigated in a group of lactating women. Four women in each group were taking either a low dosage progestogen compound like norethisterone (NET) 350 micrograms or d-norgestrel (d-Ng) 50 micrograms alone or low dosage combination pills containing NET 1 mg or d-Ng 150 micrograms with 30 micrograms ethinyl estradiol (EE2) or a biodegradable implant containing 25 mg NET or d-Ng. Peak levels in plasma and milk were seen in oral contraceptive users around 2 hours. Of the two low dosage progestogen compounds, d-Ng was below the detection limit in milk within 4 hours whereas NET was still detectable at the 24-hour interval. In contrast to this, because of the larger quantity of steroids in the combination pills, the NET/d-Ng levels in serum as well as in milk were high throughout the 24-hour period. With the subdermal route because of the sustained low release of the drug from the biodegradable implants, the levels in milk were below the detection limit within a day with d-Ng and within a week with NET.

PIP: Various drug delivery systems were tested and the release rates of steroids were measured in the serum and breast milk of a group of lactating women. 24 lactating women were divided into 3 groups: 1) low-dose combination (LDC) oral pill group; 2) low-dose progestin-only (LDP) oral pill group; and 3) biodegradable-cholesterol implants. Norethindrone (NET) or D-norgestrel (D-Ng) was the steroid released and it was assayed. LDC contained either 1 mg of NET or 150 mcg of D-Ng; LDP was 350 mcg of NET or 50 mcg of D-Ng; and the implants contained 25 mg of D-Ng or NET. By the oral route, peak levels of steroid were observed in both plasma and milk about 2 hours postdosing. In the LDP formulations, NET persisted within limits of detection for over 24 hours, whereas D-Ng was below the limit of detection in milk after 4 hours. In the LDC, however, detectable levels of both NET an D-Ng persisted for 24 hours. In the group implanted subcutaneously with progestin, levels of D-Ng were undetectable in milk within 1 day of insertion, and those of NET were undetectable within 1 week of implantation.

Presence of elevated circulating levels of LH during the pre-menstrual period in some copper IUD users and the possibility of their confusion with hCG.

A heterologous radioimmunoassay (RIA) capable of discriminating between LH and hCG was used to measure LH levels in sera obtained during the pre- and post-menstrual periods from 80 women bearing copper intrauterine contraceptive devices (IUD). hCG levels in these samples were also estimated by use of a homologous beta-hCG radioimmunoassay and a radioligand-receptor assay. Only two IUD users during the pre-menstrual period had detectable, but low hCG levels. However, LH levels, as estimated by specific RIA, in the serum of these two women were elevated to a level that would cause detection at low levels in the hCG assays. The data thus provide direct evidence to indicate that the positive hCG levels observed by others during the pre-menstrual period in some copper IUD users could be due to the interference in hCG assays by elevated LH.

Biochemical studies with once-a-month contraceptive pill containing quinestrol-quingestanol acetate.

PIP: Biochemical studies with a once-a-month contraceptive pill containing 2 mg quinestrol and 2.5 mg quingestanol acetate were undertaken during a period of 24 months. The 1st pill was given on the 2nd day of the menstrual cycle and the 2nd on the 22nd day of the same cycle; thereafter the pills were given every 28th day from the last pill. Blood samples were obtained before therapy and after 6, 12, 18, and 24 pills. Hemoglobin, packed cell volume, liver function tests, and serum proteins were not markedly altered. There was a significant (p less than .001) elevation in serum triglycerides, free fatty acids, phospholipids, and cholesterol after the ingestion of 6-12 pills in 17 women who were continuously followed for 2 years; however, serum triglycerides and phospholipids were less after the ingestion of 12 pills than after 6 pills. It appeared that these changes in serum lipids were similar to those reported in women taking daily combination pills. In no case did the serum lipids exceed the upper limit of normal. The drop-out rate was high after 12 pills. Th nonacceptability was of greater significance, therefore, than the metabolic effects in these trials.^ieng

Experience with oral contraceptives.

PIP: The Indian Contraceptive Testing Unit started making field trials with oral contraceptives in 1964. By June 1968, 958 women were taking oral contraceptives. Combination tablets used contained a minimum amount of progestogen (.5-3 mg) and a suitable amount of estrogen. The 21-tablet pack was found mot suitable. It was found that if a woman missed taking the tablets in the latter half of the cycle usually no harm resulted, but if she missed them at the beginning of the cycle pregnancy might follow as ovulation would not be inhibited. Main contraindications are liver damage, toxic hyperthyroidism, thromboembolic disease, and cancer of the genital tract or breast. Caution is advised for persons with chronic nephritis, a history of eclampsia, hypertension, varicose veins, ophthalmological disorders, or psychic depressive states. Side effects have been less with the smaller doses. The most serious side effect is thromboembolism. Those reported have been leg pain, giddiness, headache, breakthrough bleeding, nausea, vomiting, amenorrhea, abdominal pain, weakness, increased blood pressure, and skin rashes. Others have reported ocular disease and cranial nerve palsy. Sequential therapy has been reported to have a lower incidence of side effects but a higher rate of pregnancy. Low-dose progestogen therapy, the "minipill," does not inhibit ovulation but is effective by causing changes in the endometrium and in the mucus. The chlormadinone in the minipill does not affect lactation. However, the incidence of pregnancy is similar to that with an IUD (Lippes loop) which is 2.6/100 cases. Laboratory tests have been normal, except an increase in the thymol turbidity test. Vaginal cytology has revealed no case of malignancy. Results show that oral contraceptives are suitable for use on a mass scale as a method of population control.^ieng

Cytological studies of smears from removed loops.

PIP: Smears of adherent endometrial tissue were taken from 10 Lippes' Loops removed from women 19-40 years of age. The smears were stained according to the Papanicolaou method and classified as I-IV. There were large number of active histiocytes and multinucleated histiocytes, with frequent mitotic figures. In 9 smears the endometrial cells showed atypicality by presence of increased amount of chromatin clumps. All cells obtained from endometrial biopsy (done at the same time as removal of the loop) were normal.^ieng