LH excretion during the ovulatory cycle and during therapy with various estrogen-gestagen combinations

Immunochemical determination of urinary LH was carried out in 7 normally ovulating women and in 25 women treated with various combined, sequential, and depot hormonal contraceptives. In ovulatory cycles without hormone treatment an LH peak was always observed at midcycle. During treatment with Ovosiston, OZN, and Quinestrol-norethisterone acetate, no LH peak was seen. In women receiving sequential preparations (mestranol-chlormadinone acetate, estrone cyanate-chlormadinone acetate), elevated LH levels were observed during estrogen medication. LH excretion was suppressed after administration of chlormadinone acetate. LH levels were also slightly elevated before and after medication with Quinestrol-chlormadinone acatate (1 pill per month).     

Influence of chlormadinone acetate on hypothalamic differentiation in male rats

The effect of chlormadinone acetate on adult male rats during the hypothalamic differentiation phase was studied. Psychic intersexuality with increased male and increased female sexual behavior was observed both before and after postpuberal castration and sex hormone replacement. Organ weights of testes, seminal vesicles, and ventral prostrates were normal, but penis and adrenal gland weights were significantly smaller. Body growth was also significantly reduced compared with control animals. The effects of chlormadinone acetate on androgen-dependent brain differentiation are discussed and compared with analogous effects of cyproterone acetate and orchidectomy.     

Disappearance of [1alpha-3H]-chlormadinone acetate in the plasma and red cells of rhesus monkey.

The half-life and metabolic clearance rate of chlormadinone acetate in 4 rhesus monkeys was computed after iv injection. Chlormadinone was analyzed as total, free, and conjugated radioactivity, and as recrystallized chlormadinone acetate. 55.0 mc Ci, 222 mc Ci/mg was injected iv in 5 ml ethanolic saline. There was an initial rapid disappearance, half-life 68 minutes, and a slower disappearance, half-life 35.1 hours. These half-lives are much longer than those of estradiol and progesterone, but are shorter in monkeys than in women. The metabolic clearance rate of chlormadinone acetate was 102.6 liters/day. The half-life in red cells of 1 monkey was similar to those seen in plasma, but the amount of chlormadinone acetate was much less.     

The metabolism of 4-14C-pregnenolone in tissue sections of human ovaries and their modification by chlormadinone acetate]

In vitro incubations with slices of two normal human ovaries and 4-14C-pregnenolone as precursor were carried out to study the possibility of a direct influence of chlormadinone acetate on the metabolism of pregnenolone. In agreement with our previous studies the incubations of the ovary from the follicle phase of the cycle yields a profile of steroids different from that of the ovary from the corpus luteum phase of the cycle. Under the experimental condition chosen, the presence of enzymes of the steroidogenic pathway responsible for the synthesis of 17alpha-hydroxy-pregnenolone, DHA, androstenediol (basic metabolites) and androstenedione represents a characteristic profile of steroids of the ovaries from the follicle phase. After the addition of chlormadinone acetate to the incubation medium, the formation of androstenedione was inhibited, whereas the basic metabolites increased. The biosynthesis of progesterone, 17alpha-hydroxyprogesterone, estrone and estradiol represents a characteristic profile of steroids of the ovaries from the corpus luteum phase. After a addition of chlormadinone acetate to the incubation medium, the formation of this characteristic profile of steroids was inhibited. The influence of chlormadinone acetate on the two different profiles of steroids indicated, that chlormadinone acetate exerts an inhibitory effect on the 3beta-hydroxysteroid-dehydrogenase-delta5-4-isome     

Contraceptive treatment with chlormadinone and its effect on the endometrium. A histological investigation

To study the effectiveness of chlormadinone acetate as an oral contraceptive and its effect on the endometrium, 42 women took .5 mg of chlormadinone acetate daily for a total of 424 cycles. 19 patients became pregnant and represent Group 1, while 18 patients with constant cycles were identified as Group 2. Histological investigations of Group 1 revealed abnormal decidual and placental structures in 17 of the 19 women in this group. Group 2 was studied for the effect of luteal supplementation on the endometrium. Mucosa patterns showed numerous deviations from the normal pattern. Investigations into the endometrium showed chlormadinone to be a cause of disturbance in the endometrium, whereby normal placentation is checked to a greater extent than nidation. This would appear to be supported by a number of pathological findings in the fetal membranes of Group 1.     

Platelet aggregation during oral contraception

Platelet aggregation has been found to be significantly accelerated with the coagulation-induced Chandler''s tube technique in women taking combined oestrogen-progestin oral contraceptives, though this was less than in the third trimester of pregnancy. Women taking the pure progestogen, chlormadinone acetate, have not shown this change up to the sixth month of study. In contrast the accelerated platelet aggregation resulting from conventional oral contraception became normal one month after changing to the progestogen. There was no change in the platelet aggregation response to adenosine diphosphate (A.D.P.) during oral contraception.     

Effect of some progestational steroids on lactation in Egyptian women. I. Milk yield during the first year of lactation.

The effect of monthly injectios of 300 mg Depo-Provera or 150 mg Deladroxone, and of daily oral administration of .5 mg chlormadinone acetate or .3 mg quingestanol acetate on lactation was studied in Egyptian women during the 1st year of lactation. Women receiving Depo-Provera had the highest milk yield, followed by those taking Deladroxone and quingestanol acetate. The milk yields while taking these hormonal preparations were higher than in untreated controls. However, those women taking chlormadinone acetate had lower milk yields than untreated controls. The increased milk yield is probably due to the progestagenic activity, and minimal estrogenicity, of these drugs.     

In vitro effect of synthetic progestogens on estrone sulfatase activity in human breast carcinoma

The effect of progesterone and nine synthetic progestogens on the activity rate of microsome estrone sulfatase obtained from human breast carcinoma tissues was studied. The progestogens were classified into three groups: group I with a strict inhibitor effect: demegestone and chlormadinone acetate; group II with a strict activator effect: medroxyprogesterone acetate, quingestanol acetate, lynestrenol and progesterone and group III with a nonsignificant effect: dydrogesterone, promegestone, norgestrel and danazol. Demegestone was the most potent inhibitor and medroxyprogesterone acetate and quingestanol acetate had the highest activator effect. The effect of Triton X-100, a nonionic detergent, was also tested. This detergent consistently increased the microsome estrone sulfatase activity. A comparison was made between the effects of demegestone, medroxyprogesterone acetate and danazol on estrone sulfatase activity measured with or without Triton X-100 in the incubation medium. The presence of the detergent modified the progestogen action. Our results suggest that synthetic progestogens can influence the estrone sulfatase activity measured in human breast carcinoma tissues. However, the effect of progestogens was dependent on experimental conditions. Progestogens such as demegestone and chlormadinone acetate which inhibited estrone sulfatase activity in intact preparations, can reduce the intracellular production of biological active estrogen via the sulfatase pathway.     

Preliminary Evaluation of Four Oral Contraceptives Containing only Progestogens

One hundred and seventy-five women took part in a comparative clinical trial of four progestogen-only oral contraceptives and were followed for either a year or until treatment was discontinued. Megestrol acetate 0·25 mg. was found to be a very ineffective contraceptive, 21 out of 43 women becoming pregnant. One, three, and four pregnancies occurred during treatment with norethisterone acetate 0·3 mg., norgestrel 0·05 mg., and chlormadinone 0·5 mg., respectively, corresponding to pregnancy rates of 4, 9, and 12 per 100 woman-years of use.All three effective progestogens were very much less acceptable than modern low-dose combined oral contraceptives. Discontinuation of treatment for medical reasons (particularly menstrual disturbances) during the course of only one year affected 24% receiving norethisterone acetate, 38% receiving norgestrel, and 46% receiving chlormadinone.     

Effect of quinestrol-chlormadinone acetate on the endometrium, cervix uteri and vaginal epithelium

The effects of a combination of 4 or 5 mg quinestrol and 10 mg chlormadinone acetate on the female genitalia were studied in 15 women on the 14th, 21st, and 28th days of the cycle. The cervicotropic effect of quinestrol was stronger (studied by cervical mucus, Fern test, and opening of the os uteri) than its endometrial effect. Hormone withdrawal bleeding occurred overwhelmingly from proliferated endometrium. The chlormadinone acetate dose of 10 mg was sufficient to provoke an endometrial secretion in only 4 cases. Cervical, vaginal, and endometrial findings were functionally consistent.     

Contraception with Chlormadinone Acetate in Woman with Previous Contraceptive Jaundice

The oral contraceptive chlormadinone acetate has been given for eight months to a woman who had developed jaundice during four pregnancies, and twice while taking a combined contraceptive pill. No side-effects or changes in liver function were observed. This is further evidence that progestogens used for contraception, and in particular those derived from hydroxyprogesterone, are less hepatotoxic than the oestrogenic components.     

Desmopressin and bleeding time in patients with cirrhosis.

Desmopressin acetate 0.3 microgram/kg was given intravenously to nine patients with chronic liver disease and to a further six such patients in a double blind controlled study versus placebo. Desmopressin acetate significantly shortened the bleeding time compared with basal values in both groups and compared with placebo. There was also a significant decrease in partial thromboplastin time (but not prothrombin time) and significant increases in factor VIII and its components, von Willebrand factor and ristocetin cofactor activity, but not in factors VII, IX, X, XI, or XII. Increased fibrinolysis could be blocked by concomitant administration of tranexamic acid. No important side effects were seen. The multimer pattern of von Willebrand factor was studied for the first time in chronic liver disease. It was normal, but after administration of desmopressin acetate the percentage of multimers of higher molecular weight increased significantly. This may be an important mechanism in the shortening of the bleeding time in cirrhosis, as has been shown in uraemia and other conditions after administration of desmopressin acetate. Desmopressin acetate may be useful in correcting defects in primary haemostasis in chronic liver disease.     

The feedback effects of sex steroid hormones on pituitary gonadotropin release in Turner's syndrome and Klinefelter's syndrome.

The present study was designed to elucidate the feedback relationship between the release of pituitary gonadotropins and sex steroid hormones in Turner's syndrome and Klinefelter's syndrome. LH-RH stimulation test was employed to evaluate the effects of sex steroids on the release of gonadotropins. The release of gonadotropins in response to LH-RH as well as in baseline level was suppressed after the treatment with estrogen (mestranol 0.08 mg/day) for 10 days, followed by the treatment of the same period with estrogen (mestranol 0.08 mg/day) and progesterone (chlormadinone acetate 2.0 mg/day) in combination in both syndromes. The inhibitory effect of the combined treatment was greater than that of the treatment with estrogen alone. Administration of testosterone propionate (25 mg/day) for 3 days resulted in suppression of the release of both gonadotropins in baseline level and in response to LH-RH in both syndromes, but the suppressive effect appeared to be less complete as compared with that of estrogen or estrogen-progesterone. It was thus verified that the feedback interaction between the pituitary gonadotropin release and sex steroids such as estrogen, estrogen-progesterone or testosterone was operative in the same fashion in the patients with Turner's syndrome and Klinefelter's syndrome.     

Characterization of the stimulatory effect of medroxyprogesterone acetate and chlormadinone acetate on growth factor treated normal human breast epithelial cells

OBJECTIVE: Evidence is increasing that adding progestogens to hormone replacement therapy may be more harmful than beneficial, however it is debatable whether all progestogens act equally on breast cells. Mitogenic growth factors from stromal breast tissue are important in growth-regulation of breast cells, and may modify responses to progestogens. We investigated the effect of two C-21 derivatives, medroxyprogesterone acetate (MPA) and chlormadinone acetate (CMA) on growth-factor treated normal breast epithelial cells and tried to explore the underlying mechanisms of proliferation. METHOD: MCF10A (human epithelial, estrogen- and progesterone-receptor negative normal breast cells) were incubated with MPA or CMA at 0.1 and 1 microM for 7 days with the growth factors (GFs) EGF, bFGF and IGF-I at 1pM. The same combinations, as well as growth factors alone, were also incubated with the proliferation inhibitors PD98059 and LY294002 at 1 microM for 4 days. Cell proliferation rate was measured by the ATP-assay. RESULTS: MPA 0.1 and 1 microM, and CMA 1 microM in combination with GFs both significantly increased cell proliferation rate, with MPA having the greatest effect. MPA- and CMA-induced proliferation of GF stimulated cells was blocked by both PD98059 (selective inhibitor of MAP kinases) and LY294002 (phosphatidylinositol 3-kinase inhibitor); GF stimulated cells could not be significantly reduced by any of the inhibitors used. CONCLUSION: MPA and CMA have a stimulatory effect on benign growth factor stimulated MCF10A cells, possibly via activation of MAP kinase and subsequent substrates and activation of PI3-kinase. GF induced proliferation appear to be mediated by pathways other than those investigated here. Growth factors and progestogens therefore have an additive, synergistic effect on cell proliferation, eliciting their effects via different pathways.     

Excretion of 17-hydroxycorticosteroids under the effect of combined preparations containing separate progestagens: ethynodiol diacetate and chlormadinone

28 women were treated with .1 mg of mestranol + 3 mg of chlormadinone and 25 were treated with .1 mg of mestranol + 1 mg of ethynodiol diacetate. Examinations of the excretion of 17-corticosteroids in the urine were made and compared between the 2 groups. In the group treated with mestranol + chlormadinone here was no change in the excretion of 17-OHCS. The group of women treated with mestranol + ethynodiol diacetate showed a significant decrease of approximately 37%. The difference in the effects of these preparations is thought to be caused by their different chemical structure.     

Comparison of two synthetic progesterones on ventilation in normal males: CMA vs. MPA

We administered chlormadinone acetate (CMA), medroxyprogesterone acetate (MPA), and placebo to 16 normal male subjects using a randomized double-blind crossover study. After CMA administration, minute alveolar ventilation increased by +1.04 +/- 0.22 (SE) 1/min (P less than 0.05) accompanied by decrements of arterial PCO2 (-4.0 +/- 1.0 Torr) (P less than 0.01) and [HCO3-] (-2.1 +/- 0.05 mM/l) (P less than 0.01). On the other hand, in the MPA runs the corresponding changes of the above parameters were +0.71 +/- 0.21 l/min (P less than 0.05), -2.9 +/- 0.6 Torr (P less than 0.01), and -1.3 +/- 0.3 mM/l (P less than 0.01), respectively. The slopes of hypoxic ventilatory and occlusion pressure response lines remained unchanged in hypocapnia after CMA or MPA ingestion, but they increased when entidal PCO2 was adjusted to the predrug level. The hypercapnic ventilatory and occlusion pressure response lines merely shifted to the left without changing their slopes with these agents. No significant differences in all the above parameters were found between CMA and MPA runs. We concluded that in the normal males the effect of CMA on ventilation was similar to that of MPA, despite the fact that the luteinizing activity of CMA was reported to be approximately 10 times higher than the latter.     

Chlormadinone acetate, a progesterone derivative that binds to the digitalis receptor, inhibits the sodium pump in the isolated rat diaphragm

Rb+ uptake, intracellular Na+ and K+ levels, and the tissue-medium distribution of the nonmetabolized glucose analog, 3-O-methyl-D-glucose (3-MG) were measured in rat diaphragms incubated with chlormadinone acetate, 6-chloro-4,6-pregnadien-17-ol-3,20-dione 17-acetate (CMA), in the presence and absence of ouabain. CMA in concentrations of 5 X 10(-7) M or higher significantly depressed 86Rb uptake, and promoted an increase in internal Na+ and a decrease in internal K+, indicating inhibition of the sodium pump. Sugar transport in resting muscle parallels the changes in internal Na+ levels and is an additional indicator of sodium pump activity. Equilibration of 3-MG between tissue and medium was accelerated by CMA, in parallel to the rise in internal Na+ level. Effects of CMA on Na+ levels and sugar transport, but not on Rb+ uptake, were additive to those of various concentrations of ouabain, suggesting interaction with sites not affected by ouabain. These results on diaphragm muscle confirm our previous studies on isolated cardiac muscle preparations showing that CMA, added to the aqueous bathing medium, inhibits the sodium pump in intact muscle tissues.     

Effects of Progestogen Oral Contraception with Norethisterone on Blood Clotting and Platelets

The effects on clotting tests and platelet function of six months'' continuous administration of the 19-norsteroid, progestogen-only contraceptive, norethisterone, have been studied in four groups of women. In a group of women who have not previously taken oral contraceptive no acceleration of clotting or platelet factors was found, but in contrast a tendency to reduced coagulability was observed. Women who had previously been taking combined oestrogen-progestogen preparations showed reduced clotting and platelet parameters when norethisterone was substituted. No changes in clotting or platelets were found in women who changed from 17-acetoxysteroid progestogen chloramadinone acetate or in a group of women started postpartum.     

Protective role of allicin and L-ascorbic acid against the genotoxic damage induced by chlormadinone acetate in cultured human lymphocytes

In our present study, different doses of allicin and L-ascorbic acid were tested against the genotoxic damage induced by chlormadinone acetate (CMA; 40 microM) using chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs) as the parameters. Treatment with allicin and L-ascorbic acid resulted in reduction of CAs and SCEs. The results suggested a protective role of allicin and L-ascorbic acid against CMA induced genotoxic damage.     

Steroid metabolism in primates. XVIII. Return to higher levels of 17-ketosteroid excretion in urine after ending a long-term treatment with mestranol/chlormadinone acetate in the baboon]

6 weeks after terminating a long-time application of the ovulation inhibitor Ovosiston (mestranol/chlormadinone acetate) in female baboons, excretion of 17-ketosteroids in urine is still decreased. 6 months after ceasing the preparation, urinary 17-ketosteroid excretion resembles that of the control group.