Incidence of pregnancy, changes in menstrual pattern, and recovery of endometrial function after discontinuation of medroxyprogesterone acetate therapy.

The incidence of pregnancy, recovery of endometrial function, and changes in menstrual pattern were studied in 62 women who had received two or more intramuscular injections (150 mg) of medroxyprogesterone acetate (Depo-Provera) every three months and oral diethylstilbestrol (1 mg) daily for seven days every month. Immediately after discontinuing this therapy, 71% of the patients had regular menstrual cycles, 10% had irregular cycles, and 19% had amenorrhea. All the patients had regular cycles by the end of one year except one women who was probably menopausal. The average time required to conceive after stopping therapy was 9.3 months, range, 3 to 21 months). Conception was definitely delayed as shown by endometrial biopsies and the incidence of pregnancy. Within six months, 25% of the patients conceived and within one year, 69% conceived. By two years, four had not conceived. The percentage of pregnancies seemed to decrease with increased patient age.

The effect of combination and low dose progestogen oral contraceptives on serum lipids.

Fasting serum triglyceride, free fatty acid, phospholipid, and cholesterol levels were determined in women who were taking either combination or low dose progestogen oral contraceptives. The contraceptives used were: ethynodiol diacetate and ethynyl estradiol; norgestrel and ethynyl estradiol; norgestrel; and megestrol acetate. Serum lipids significantly increased in women taking combination pills. They significantly decreased in patients taking norgestrel, while they remained almost unchanged in patients taking megestrol acetate. This decrease varied with the type of progestogen used in continuous low dosage therapy. The confusion when interpreting the results from different reports on the effects of oral contraceptives on serum lipids will be reduced if proper attention is given to the types of steroid used.

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.

Thyroid functions of women taking oral contraceptives.

PIP: A study to assess thyroid status and excessive weight gain among women taking oral contraceptives found a correlation between the percentage of free thyroxine and weight gain. Serum percentage of iodine uptake, total thyroxine, free thoraxine, and weight changes in 38 women taking combination oral contraceptives and 27 taking low dosage progestagens were studied. No change in the absolute free thyroxine levels were observed, although combination oral contraceptives caused an increase in total thyroxine and a decrease in the percentage of free thyroxine. Changes occurring in percentage of free and total thyroxine could be related to increases in thyroxine binding proteins. Low dosage progestogens showed no change in any of the thyroid tests studied. A lowering of the 24-hour uptake by the thyroid gland and weight gain with combination oral contraceptives were observed.^ieng

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

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.

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

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.

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.