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Effects of oral contraceptive and estrogen administration on plasma calcitonin in pre- and postmenopausal women.

Estrogen (E) therapy and administration of oral contraceptives (OC) reportedly increase plasma calcitonin (CT) concentrations in women, effects said to mediate in part the beneficial actions of E on bone. To further examine this theory, we tested the effects of three cycles of OC therapy in 12 young women, comparing them to 10 healthy women before and after three normal menstrual cycles. We also determined the effects of 3 months of E therapy (ethinyl estradiol, 20 micrograms/day, 25 of 30 days) in 14 healthy postmenopausal women, using a crossover design (studied after 3 months with and 3 months without E). We determined CT by radioimmunoassay (antiserum G-1701) in whole plasma (iCT) and silica cartridge extracts of plasma (exCT) after overnight fasting, after calcium (Ca) infusion (2 mg Ca/kg over 5 minutes), and during a normal day at 0800, 1200, 1700, and 2000 h. In no control study was there a significant diurnal change in iCT or exCT, and neither OC nor E therapy altered this. Similarly, OC administration did not affect basal CT levels or the normal iCT and exCT responses to Ca infusion. E therapy induced expected changes in serum Ca, phosphorus, and alkaline phosphatase and urinary Ca and cAMP excretion; basal and diurnal plasma exCT levels were decreased significantly, consonant with the decrement in serum Ca. E did not alter normal iCT and exCT responses to Ca infusion. Thus, administration of either OC or E has no stimulatory effect on CT secretion, which suggests that the beneficial actions of E on bone are not mediated through CT-induced inhibition of bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

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.

Absorption↗

Pregnancy interruption with RU 486 in combination with dl-15-methyl-prostaglandin-F2 alpha-methyl ester: the Chinese experience.

In a multicenter study taking place in four centers in Beijing (People's Republic of China), pregnancies up to 49 days of amenorrhea (DA) were interrupted with RU 486 (RU 38486, mifepristone, 600 mg orally once), followed 36-60 hours later by administration of dl-15-methyl-PGF 2 alpha-methyl ester (PG05, 1 mg vaginal suppository). One-hundred-and-sixty women were included in the study, three of whom being excluded from efficacy assessment because of non-compliance to the protocol. Complete pregnancy interruption without additional surgical procedure (success) was obtained in 136 women (86.6%, 95% confidence interval: 81.3-91.9%). The success rate was significantly (P = 0.013) higher for pregnancies below (91.3%), than for pregnancies above 42 days of amenorrhea (DA) (76.6%). The time elapsed between RU 486 intake and complete expulsion was 2.8 +/- 1.5 (sd) days (range: 1-12 days). Expulsion took place at the latest 4 days after RU 486 in 125 women (94.7%), and in 107 of these women, it occurred 3.1 +/- 1.7 (sd) hours after PG05 administration. Uterine bleeding occurred in all women after RU 486 intake whatever the outcome of treatment and lasted 11.5 +/- 4.8 (sd) days (range: 3-36 days). It was judged more or much more abundant than usual periods in 6.15% of the women. It led to a slight but significant decrease in hemoglobin as measured eight and 14 days after RU 486 intake. In five women, hemoglobin decreased by 4 g/dl or more, but no patient required a blood transfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Humoral immunity in oral contraceptive users. I. Plasma immunoglobulin levels.

The worldwide acceptance of steroid-based oral contraception makes it imperative that the effect of these agents on the immune system is understood. Nevertheless, information regarding the effect of steroid-based oral contraception on plasma immunoglobulin (Ig) levels is often conflicting. In this report immunoglobulin levels in the plasma of females taking steroid-based oral contraceptives are measured in a novel manner using an enzyme-linked immunosorbent assay (ELISA). No significant alterations in the levels of IgG or IgM are reported.

Antibody Formation↗

Humoral immunity in oral contraceptive users. II. In vitro immunoglobulin production.

The worldwide acceptance of steroid-based oral contraception makes it imperative that the effect of these agents on the immune system is understood. Nevertheless, information regarding the effect of steroid-based oral contraception on humoral immunoregulation is limited. In this report the in vitro production of IgG and IgM is measured following stimulation with either the T-dependent activator pokeweed mitogen (PWM) or the T-independent activator fixed/killed Staphylococcus aureus Cowan I (StaCw). No significant differences are observed between the in vitro IgG or IgM levels following stimulation with PWM or StaCw for females taking steroid-based oral contraceptives and females not taking steroid-based oral contraceptives. We conclude that humoral immunoregulation is unaltered in steroid-based oral contraceptive users.

Antibody Formation↗

A norgestimate-containing oral contraceptive: review of clinical studies.

Despite the well-documented efficacy and safety of low-dose oral contraceptives, the development of newer formulations containing highly selective progestins with minimal or no androgenic activity has been a goal of pharmaceutical research. The efficacy and safety of norgestimate, a progestin with inherently low androgenicity, in combination with ethinyl estradiol, has been examined in several phase II and phase III clinical studies, and these are reviewed. Norgestimate/ethinyl estradiol has proved to be a low-dose oral contraceptive with high selectivity that provides the cycle control of older oral contraceptive formulations with comparable efficacy. Results of comparison studies between norgestimate/ethinyl estradiol and formulations containing norgestrel, a progestin with relatively greater androgenic activity, in combination with ethinyl estradiol, are reported for effects on lipid and lipoprotein levels and carbohydrate metabolism. Norgestimate/ethinyl estradiol consistently produced statistically significant increases in high-density lipoprotein cholesterol and improvement in the ratio of low-density lipoprotein cholesterol to high-density lipoprotein. In contrast, norgestrel/ethinyl estradiol produced statistically significant decreases in high-density lipoprotein cholesterol and potentially adverse changes in the low-density/high-density lipoprotein ratio. Phase II studies have confirmed that norgestimate/ethinyl estradiol has low androgenic activity and causes minimal effect on coagulation factors and carbohydrate metabolism.

Blood Coagulation↗

Effects of diethylstilbestrol and estramustine phosphate on serum sex hormone binding globulin and testosterone levels in prostate cancer patients.

Serum testosterone-estradiol binding globulin and total testosterone were measured in 2 groups of male controls (less than 50 and more than 65 years old) and in 7 groups of prostatic cancer patients treated with various endocrine manipulation procedures, including orchiectomy, and estramustine phosphate and diethylstibestrol therapy. There were 133 individuals studied. Total serum testosterone levels were significantly higher in the younger versus the older control group and testosterone-estradiol binding globulin levels were significantly higher in the older men. Whereas orchiectomy reduced serum testosterone to low concentrations (72 plus or minus 11 ng. per 100 ml.) testosterone-estradiol binding globulin levels were not altered. In contrast, estramustine phosphate and diethylstilbestrol therapy, when administered to intact or castrated patients, resulted in depressed testosterone and markedly elevated testosterone-estradiol binding globulin serum levels, particularly in those patients receiving estramustine phosphate (less than 35 ng. per 100 ml. and more than 6 micrograms per 100 ml., respectively). These studies led to the conclusion that diethylstilbestrol or estramustine phosphate therapy is significantly more effective than orchiectomy in eliciting a concomitant elevation of testosterone-estradiol binding globulin and a depression of total testosterone. Even though free serum testosterone was not measured in the present study the law of mass action would indicate that in those patients with high testosterone-estradiol binding globulin (more than 5 microgram. per 100 ml.) and low total testosterone levels (less than 80 ng. per 100 ml.) the availability of biologically active (unbound steroid) testosterone would be negligible.

Adult↗

Circulating levels of placental protein 12 and chorionic gonadotrophin following RU 38486 and gemeprost for termination of first trimester pregnancy.

First trimester termination of pregnancy was successfully induced in ten patients with RU 38486 followed 2 days later by a prostaglandin (Gemeprost) pessary. Human chorionic gonadotrophin (HCG) values remained unaltered until after the abortion. The levels of placental protein 12 (PP12) showed an immediate and significant fall following RU 38486, then rose to values substantially higher than those at the initial visit after 2 days. These findings show that RU 38486 has a direct inhibitory effect on tissues producing PP12 and confirm the progesterone dependency of this protein.

Abortifacient Agents↗

Translation of the mRNA for rabbit uteroglobin in cell-free systems. Evidence for a precursor protein.

Uteroglobin, an hormonally induced protein composed of two similar subunits, represents around 50% of the proteins synthesized and secreted into the uterine lumen of rabbits treated sequentially with estradiol and progesterone. The endometrium of these animals was used as a source for the isolation of the mRNA for uteroglobin. Poly(A)-rich RNA, extracted from purified polysomes with phenol chloroform and isolated on oligo(dT)-cellulose columns, contains one fourth of the total protein coding activity of the endometrium. Between 20--25% of the polypeptides synthesized by this RNA in cell-free systems derived from Krebs II ascites cells or wheat germs react with a monospecific antiserum prepared in guinea pigs against uteroglobin. The material bound to the antibody was identified as a precursor of uteroglobin according to the following criteria. 1. The product synthesized in vitro can be displaced from the complex with the specific immunoglobulin by purified uteroglobin. 2. Analysis of the immunoprecipitate on polyacrylamide gels containing urea and dodecylsulfate demonstrate the existence of a single labelled polypeptide with an apparent molecular weight larger than the uteroglobin subunits. 3. The tryptic digest of this polypeptide, labelled in vitro with [3H]lysine, shares seven peptides with mature uteroglobin labelled with the same amino acid in perfused uteri, and exhibits and additional peptide not present in uteroglobin. 4. Injection of the same mRNA preparation into Xenopus oocytes results in the production of uteroglobin. The endometrium of intact animals treated with estradiol alone also contains the same mRNA bound to polysomes but in a smaller proportion, indicating that the progesterone-induced synthesis of uteroglobin is accompanied by an accumulation of the specific mRNA in the polysomes.

Animals↗

A prospective controlled study of the effect on blood pressure of contraceptive preparations containing different types and dosages of progestogen.

A prospective controlled study investigated the effects of oral contraceptives on blood pressure in 485 women who were between 17 and 46 years of age and had blood pressures of less than 140/90 mmHg at entry. The women were divided into seven groups depending on the chosen method of contraception: intrauterine device or barrier method (control group): ethinyl oestradiol 30 micrograms plus levonorgestrel 150 micrograms (Microgynon-30 or Ovranette); norethisterone 350 micrograms (Micronor); norgestrel 75 micrograms (Neogest); norethisterone oenanthate 200 mg intramuscularly every 2 months for the first 6 months, then every 3 months thereafter; ethinyl oestradiol 30 micrograms plus ethynodiol diacetate 2 mg (Conova-30); and ethynodiol diacetate 500 micrograms (Femulen). Blood pressures were measured every 3 months by the family planning clinic nurse under standardized conditions using an Elag-Köln automatic sphygmomanometer. After one year, blood pressure had risen significantly (P less than 0.05) in the 137 women taking ethinyl oestradiol plus levonorgestrel (mean systolic and diastolic rises 6.4 and 2.7 mmHg respectively) and in the 91 women taking ethinyl oestradiol plus ethynodiol diacetate (mean systolic and diastolic rises 6.2 and 3.0 mmHg respectively). The 94 women taking the progestogen-only preparations and the 143 women in the control group showed no increases in blood pressure. These data were confirmed after 2 years of follow-up.

Adolescent↗

Early abortion induction by a combination of mifepristone and oral misoprostol: a comparison between two dose regimens of misoprostol and their effect on blood pressure.

OBJECTIVES: 1. To investigate the efficacy of 800 micrograms misoprostol (a PGE1 analogue) when administered to women pretreated with mifepristone for early pregnancy termination. 2. To establish means of minimising gastrointestinal side effects by comparing two different misoprostol regimens. The impact of these regimens on blood pressure was investigated in a subgroup of patients. DESIGN: A randomised study of 150 women of 56 days gestation, or less, allocated to receive oral misoprostol either in a single dose of 800 micrograms or as two doses of 400 micrograms administered sequentially 2 h apart; in each case misoprostol was administered 36 to 48 h after receiving mifepristone 200 mg orally. MAIN OUTCOMES: Complete abortion rates, the frequency and severity (patients' perception) of gastrointestinal side effects, and blood pressure changes in response to prostaglandin administration. RESULTS: The overall success rate was 93%. Seventy-one (95%) women who received a single dose of misoprostol and sixty-nine (92%) who received the sequential dose aborted completely. There were two ongoing pregnancies in the first group (2.5%) and three (4%) in the second. The overall ongoing pregnancy rate was 3%. The incidence of diarrhoea was significantly lower for women receiving the sequential dose, and no significant differences were found in the incidence of the other gastrointestinal side effects. The only noted significant change in blood pressure was in diastolic pressure 4 h after the administration of the higher dose of prostaglandin, but this was slight. CONCLUSIONS: The combination of mifepristone and oral misoprostol provides an alternative method to inducing abortion of pregnancies of up to eight weeks gestation. Patients receiving the single dose of 800 micrograms were more troubled by diarrhoea than those on the sequential regimen. The ongoing pregnancy rate was higher than previously reported with vaginal or parenteral administration of prostaglandin.

Abortion, Induced↗

Influence of estrogens and progesterone on the venous system of the lower limbs in women.

Treatments with estrogens and progestogens are suspected of causing vascular complications either directly or by metabolic consequences. Although many studies have demonstrated an increased incidence of arterial and deep venous thrombosis, since 1970 the dose of estrogens and progesterones have been lowered with a proportional lowering of side effects. After classification of estrogens and progestogens, we studied their peripheral vascular effects. In our study, we demonstrated that the effects of estroprogestogen treatment on the superficial venous system depend on the dose of estrogen and progestogen.

Adult↗

Levels of protein S during the normal menstrual cycle and in women on oral contraceptives low in estrogen.

Total protein S, a coagulation regulating protein, was determined by an electroimmunoassay in samples of plasma collected during one menstrual or hormone-induced cycle in 15 young women and 11 women using oral contraceptives with 30 micrograms ethinyl estradiol and 150 micrograms levonorgestrel. Distinct individual levels caused the with-in-group variations of plasma total protein S to be larger than the individual variations. There was no statistically significant difference between the groups, but in the hormone group there was a slight but statistically significant decrease during the hormone-induced cycle.

Adult↗

Induction of abortion in early pregnancy with mifepristone in conjunction with gemeprost.

This study was performed to investigate the efficacy of oral mifepristone and vaginal gemeprost for termination of early pregnancy. Eighty women requesting first trimester abortion and with amenorrhea of less than 56 days were included. Gestational age was confirmed with ultrasonography. Mifepristone was administered as a single 600 mg dose followed after 48 hours by a vaginal pessary containing 1 mg gemeprost. One woman did not return for gemeprost and later had a vacuum aspiration performed. There was complete abortion in all remaining women. No serious side effects were registered and the number of women requiring opioid analgesia was low (8%). The conclusion is that this treatment is a genuine alternative to vacuum aspiration but medical supervision is necessary for some time after gemeprost administration.

Abortifacient Agents, Nonsteroidal↗