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.

Effect of contraceptive steroids on human lactation.

Biochemical studies to detect changes occurring in the composition of mother's milk from the initiation of proper lactation to weaning were done in a group of 36 postpartum women, volunteers who were either using the conventional contraceptives or taking a low-dose combination pill, a low-dose progestational compound, or a 3 or 6 monthly injection as a mode of contraception. Apart from a significant increase in the protein content of milk and a slight increase in the quantity, the 3 monthly injection group behaved exactly like the control. On the other hand, the 6 monthly injection group showed a significant increase in quantity but with a significant decrease in protein, fats, and calcium. The low-dosage progestogens group showed a significant decrease in the quantity of fats and the calcium content of milk, but, surprisingly, the addition of 10 micrograms of estrogens to the low-dosage progestogen indicated a pattern almost similar to the control.

Carbohydrate metabolism of Indian women taking steroid contraceptives.

Three parameters, serum glucose, insulin, and growth hormone levels, were used to measure carbohydrate metabolism in 25 women not using steroid contraceptives, 48 women using combination oral contraceptives, and 27 women using low-dose progestogen oral contraceptives. Women in the combination contraceptives group had significant modifications in the responses of all three parameters studied. A bias toward modification was also seen in the normal tests of the combination group. The low-dose progestogen, megestrol acetate, did not cause similar changes in glucose, insulin, and growth hormone values.

PIP: A study was undertaken to report the responses of serum glucose, insulin, and growth hormone levels to iv glucose injections in 48 women using a combination oral contraceptive (OC) (OVral), in 27 women on dialy progestogen alone (megestrol acetate), and in 25 non-OC users. Women taking combination OCs had significant modifications in the responses of all 3 parameters ( p less than .05). The normal tests of the combination OC group also exhibited a tendency toward modification. Changes in serum glucose, insulin, and growth hormone values were absent in the low-dose progestogen group. These studies indicate that the mechanisms whereby OCs modify carbohydrate metabolism are unknown. More research is necessary to provide information concerning metabolic effects of hormonal contraceptives.

Effect of contraceptive steroids on serum lipids.

Serum triglycerides, free fatty acids, phospholipids, and cholesterol were estimated in groups of women who were taking either norgestrel, megestrol acetate, daily combination tablet, once-a-month pill, or once-a-month injection as a method of contraception. These estimations were done prior to and during therapy at specific times over a period of 2 years. A significant reduction in serum lipids was observed in women taking norgestrel. The women on megestrol acetate showed practically no changes. All the lipid fractions were significantly elevated in women taking combination pills. Raised serum cholesterol was observed in women receiving once-a-month injection.

Short-term effect of ovral and norgestrel on the vitamin B6 and B1 status of women.

PIP: An attempt was made to determine the effect of steroidal contraceptives on the utilization of Vitamins-B1 and B6. Subjects, aged 22-38 years, were not taking any external source of vitamins. A 24-hour urine sample was collected and a fasting blood sample drawn for the estimation of erythrocyte amino-transferases and transketolase. Then each subject was given 2 gm of L-tryptophan. Another 24-hour urine specimen was then collected. Xanthurenic acid values in urine specimens were compared. Ovral or norgestrel was then given for 3 cycles. After these 3 cycles, blood collections and tryptophan load tests were repeated. Erythrocyte alanine aminotransferase (EAIT) and aspartates aminotransferases (EAsT) were measured. Also, erythrocyte transketolase (ETK) was estimated and the "TPP" effect determined by adding 75 mcg of thiamine pyrophosphate. of 11 women taking Ovral, 7 showed an abnormal response to the tryptophan load as shown by the xanthurenic acid excretion. Responses of all 11 women on norgestrel to tryptophan loads were normal. EAIT and EAsT tests were normal with both drugs (p more than .05). Erythrocyte transketolase activity was not significantly changed by either preparation (p more than .05). The increased xanthurenic acid excretion with Ovral after tryptophan load is thought to indicate Vitamin-B6 deficiency. Basal levels of ETK decreased in 7 of 10 women on Ovral but increased in 5 of 8 women on norgestrel therapy. Also, in vitro stimulation with TPP was observed in 4 of these women. The relation of this finding to Vitamin-B1 is not clear. Urinary thiamine, blood pyruvic acid, and alpha-ketoglutaric acid and transketolase activity require study to assess the Vitamin-B1 status under contraceptive therapy.^ieng