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PubMed1987

Regulation of prolactin production and cell growth by estradiol: difference in sensitivity to estradiol occurs at level of messenger ribonucleic acid accumulation.

17 beta-Estradiol increases the growth rate of GH4C1 cells with a half-maximally effective concentration (EC50) that is about 10-fold less than the EC50 for the stimulation of PRL production. We have examined the effects of five other estrogens: estriol, estrone, 17 alpha-estradiol, and the metabolism-resistant analogs ethynyl estradiol and moxestrol. All were full agonists for both effects, and all were more potent for the stimulation of cell growth than for stimulation of PRL production. The order of analog potency for both biological effects was the same as the order of potency for inhibiting saturable [3H]estradiol binding to intact cells. Therefore, both biological effects appear to be mediated through the same receptor, and metabolism of 17 beta-estradiol is unlikely to account for the difference in the concentrations required to elicit the two effects. We selected two estrogen-responsive clones from a cDNA library made from GH4C1 cells. The clones were chosen because they were induced at the estrogen concentrations that stimulate growth. Estradiol caused maximal stimulation of the mRNAs corresponding to the two recombinant clones at 10(-10) M, a concentration over 10-fold lower than that required for maximal stimulation of PRL mRNA. These data indicate that a difference in sensitivity to estrogen occurs at the level of mRNA accumulation as well as at the level of the biological responses.

Animals↗
PubMed2001

Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls.

The objective of pubertal induction in children with hypogonadism is to mimic spontaneous puberty in terms of physical and psychological development. In a clinical observation study, we induced puberty in 15 girls with hyper- or hypogonadotropic hypogonadism using low doses of transdermal estradiol patches attached only during the night and compared the estradiol concentrations obtained with those in healthy girls. Pubertal induction was started between the ages of 12.3 and 18.1 yr. A transdermal matrix patch of 17beta-estradiol (25 microg/24 h; Evorel, Janssen Pharmaceuticals-Cilag) was cut into pieces corresponding to 3.1, 4.2, or 6.2 microg/24 h initially and attached to the buttock. After 4-14 months, the dose was increased gradually. Serum 17beta-estradiol concentrations were measured every 2 h by RIA (detection limit, 6.0 pmol/L; 1.6 pg/mL). The results show that it is possible to mimic the spontaneous levels as well as the diurnal pattern of serum 17beta-estradiol in early puberty, by cutting a transdermal 17beta-estradiol matrix patch and attaching a part of it, corresponding to 0.08-0.12 microg estradiol/kg BW, to the buttock nocturnally. In most of the girls, breast development occurred within 3-6 months of the start of treatment.

Administration, Cutaneous↗
PubMed2002

17Alpha-estradiol and 17beta-estradiol treatments are effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice.

Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17beta-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid beta (Abeta) levels and amyloid beta-protein precursor (AbetaPP) processing in vivo, Swedish mutant AbetaPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17beta- or 17alpha-estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Abeta levels; however, the levels of Abeta were decreased by 27% and 38% in mice treated with 17beta- and 17alpha- estradiol, respectively, with no change in AbetaPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAbetaPPalpha, the secreted form of AbetaPP. The ratio of Abeta/sAbetaPPalpha, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Abeta lowering effect of 17beta- and 17alpha-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17alpha-estradiol versus 17beta-estradiol may help to develop safe and effective therapeutics.

Alzheimer Disease↗
PubMed2003

Comparison of a novel vaginal ring delivering estradiol acetate versus oral estradiol for relief of vasomotor menopausal symptoms.

OBJECTIVE: To compare a novel vaginal ring releasing estradiol acetate (Menoring; Galen Holdings) with oral estradiol for relief of moderate to severe vasomotor symptoms in healthy postmenopausal women. DESIGN: This was a prospective, double-blind, multicenter, randomized, parallel-group study. METHOD: Women (n = 159) aged < 65 years experiencing >or= 20 hot flushes/night sweats per week received either a vaginal ring releasing estradiol acetate at a rate equivalent to 50 microg/day estradiol plus placebo tablets or oral estradiol 1 mg/day plus a placebo vaginal ring for 24 weeks. For patients with inadequate control of symptoms, the dosage was doubled at 12 weeks. A 24-week, open-label extension of the vaginal ring treatment followed double-blind treatment. RESULTS: The frequency of hot flushes/night sweats was significantly reduced (p < 0.001) in both groups at 12 and 24 weeks from baseline, by 84% and 94% for the vaginal ring group and by 73% and 83% for the oral group, respectively. The mean intensity of urogenital symptoms decreased from screening to the end of treatment in both groups. The incidence of adverse events was similar for both groups. No clinically relevant local effects of the vaginal ring were observed. CONCLUSIONS: The vaginal ring relieved both systemic and urogenital symptoms and was well tolerated and accepted. Overall, the efficacy, safety and acceptability of the vaginal ring were comparable with those of oral estradiol therapy.

Administration, Intravaginal↗
PubMedDate not supplied

The presence of 17-beta estradiol in Mytilus edulis gonadal tissues: evidence for estradiol isoforms.

OBJECTIVES: In earlier studies, we demonstrate that 17-beta -estradiol and an estrogen cell surface receptor can be found on various human cells, i.e., vascular endothelial, monocytes, and granulocytes, where they are coupled to nitric oxide release. We further demonstrated this phenomenon in the marine mussel Mytilus edulis ganglionic tissues. In the present report we sought to determine if estrogen can be found in M. edulis reproductive tissues. MATERIAL & METHODS: We determined the presence of 17-beta -estradiol via high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA) in the animals gonads. This substance was further identified via nanoelectro-spray ionization quadrupole time of flight mass spectrometry (Q-TOF-MS). RESULTS: 17-beta -estradiol was identified and quantified in Mytilus gonads. Interestingly, we also determined that estradiol isoforms also were present in this tissue. CONCLUSION: These data demonstrate that 17-beta-estradiol and an estradiol isoform is present in M. edulis gonadal tissues, suggesting that they have functions related to reproduction. This further suggests that estrogen's association with reproductive activities has a long evolutionary history and that this association began in invertebrates.

Animals↗
PubMed1990

Progesterone and estradiol concentrations in nonpregnant and pregnant human myometrium. Effect of progesterone and estradiol on cyclic adenosine monophosphate-phosphodiesterase activity.

We measured the concentration of progesterone and estradiol and calculated the progesterone:estradiol ratio in nonpregnant and pregnant human myometrium. Progesterone, estradiol and the progesterone:estradiol ratio were higher in pregnant than in nonpregnant myometrium. There was no difference in the concentration in the presence of labor. The progesterone:estradiol ratio showed a similar pattern. We also investigated the effect of the ovarian steroids on the activity of cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE). Progesterone in pharmacologic doses inhibited the activity of the high-affinity enzyme as much as 72% and the low-affinity form as much as 34%. High-affinity phosphodiesterase from nonpregnant myometrium was the least sensitive to inhibition, and the enzyme from pregnant myometrium obtained from laboring women was the most sensitive. Low-affinity phosphodiesterase from nonpregnant myometrium was less sensitive to inhibition than enzyme from pregnant women with or without labor. The degree of inhibition of the low-affinity enzyme in the two pregnant groups was not different. The type of inhibition was competitive in both the high- and low-affinity forms. Estradiol at similar concentrations did not have any effect on the activity of the enzyme. Progesterone in part may exert its effect on the human myometrium by its effect on cyclic adenosine monophosphate-PDE activity and the metabolism of cAMP.

Adenosine Monophosphate↗
PubMed1983

Plasma levels of estrone, estrone sulfate, and estradiol and the percentage of unbound estradiol in postmenopausal women with and without breast disease.

To investigate the possibility of increased tissue exposure to estrogen in breast cancer patients, plasma levels of estrogens and the percentage of unbound estradiol were measured in postmenopausal women with benign or malignant breast disease and compared with levels in normal postmenopausal women. The percentage of unbound estradiol in breast cancer patients [1.85 +/- 0.35% (S.D.)] was significantly higher (p less than 0.001) than in normal postmenopausal women [1.52 +/- 0.33%] and was still significantly higher when patients were matched with control subjects for weight (p less than 0.001) or ideal body weight (p less than 0.001). The binding capacity of sex hormone binding globulin was similar in both groups of women. No significant differences in the plasma levels of estrone, estradiol, or estrone sulfate were detected between breast cancer and normal subjects. It is concluded that, given similar concentrations of estradiol in plasma of normal and breast cancer subjects, the significant increase found in the unbound estradiol fraction may result in a very small increment in tissue exposure to estrogens in breast cancer subjects. However, even such a small increase in tissue exposure to estradiol may be significant, given the length of time required for breast tumor development.

Aged↗
PubMed1980

Estradiol-induced biochemical changes in human neoplastic cells: estradiol-mediated protease.

One human skin fibroblast (HSF), three normal mammary epithelial (HNMEC), four mammary carcinoma (HMCC) and three malignant melanoma (HMMC) cell lines were examined for responsiveness to 17 alpha- and 17 beta-estradiol. Responsiveness was monitored by changes in 3H-thymidine uptake (DNA synthesis), 3H-leucine uptake (protein synthesis), extranuclear protease activities and resistance to complement-dependent serum cytotoxicity (CDSC). 17 alpha-estradiol had no effect on any of the examined cell lines. 17 beta-estradiol had no effect on the extranuclear protease activities, or resistance to CDSC, but it increased DNA and protein synthesis in HSF and HNMEC cell lines. 17 beta-estradiol increased sensitivity to CDSC cellular lysis, DNA and protein synthesis. It induced qualitative and quantitative changes in the extranuclear protease activities suggesting an estradiol-dependent enzyme. Extracts of estradiol-treated human mammary carcinoma and human malignant melanoma cells yielded concentrated protease activities. Fractionation of the extracts gave enzymically active protein which differed in their catalytic properties.

Breast Neoplasms↗
PubMed1982

Estradiol fatty acid esters. The isolation and identification of the lipoidal derivative of estradiol synthesized in the bovine uterus.

The bovine uterus, like other estrogen-responsive organs of man and rat, synthesizes an unusual nonpolar metabolite of estradiol (Schatz, F., and Hochberg, R. B. (1981) Endocrinology 109, 697-703). This compound, the lipoidal derivative of estradiol (LE2), was synthesized from estradiol by bovine endometrial tissue in vitro, and it was purified by extensive chromatography on two adsorption columns, a reversed phase partition celite column and three different high pressure liquid chromatography columns. LE2 was separated into nine fractions which were analyzed by direct probe mass spectroscopy and by gas chromatography mass spectroscopy after cleavage of the lipoidal moieties. In this manner, 10 fatty acid esters of estradiol, exclusively esterified at C-17 of the steroid nucleus, were identified. The unsaturated fatty acid esters of estradiol comprise more than 85% of the total LE2 and estradiol 17 beta-arachidonate is the most abundant component. The cholesterol esters and phospholipids of the bovine endometrium were also purified and it was found that the distribution of fatty acids in these lipids is far different from that of LE2.

Animals↗
PubMedDate not supplied

Use of a biotinyl-estradiol derivative to demonstrate estradiol-membrane binding sites on adherent human breast cancer MCF-7 cells.

A biotinyl-derivative of 17 beta-estradiol has been used to demonstrate a site of recognition and binding of estradiol located on the plasma membrane of human breast cancer MCF-7 cells by using the biotin/avidin-FITC system. The specificity of this binding has been shown by a displacement of the fluorescent label by 17 beta-estradiol. No displacement was observed when testosterone was added. Quantification of this phenomenon has been shown by laser scanning cytometry while preserving the cells adhesiveness to their growth support as well as their membrane integrity. An analysis by confocal laser scanning microscopy suggested that the fluorescence distribution on MCF-7 cells treated with estradiol-biotin was on the cell periphery. The results obtained are in favour of the recognition and binding site of 17 beta-estradiol located on the plasma membrane of MCF-7 cells and they would indicate that the biological activity of estradiol, among others, could be initiated by an interaction with the membrane.

Binding Sites↗
PubMedDate not supplied

Relationship between serum estradiol concentration and IGF-I, IGF-II and IGF-binding proteins in patients with premature ovarian failure on short-term estradiol therapy.

OBJECTIVE: Insulin-like growth factors (IGFs) exert stimulatory effects on follicular growth and development, and early embryogenesis. In view of this, we studied the effect of short-term estradiol treatment, as used in preparing the uterus for embryo implantation, on the serum concentrations of IGFs and their binding proteins (IGFBP) in patients with premature ovarian failure (POF). PATIENTS AND METHODS: Twenty-four patients with POF, enrolled in an assisted reproduction program, were treated with increasing doses of estradiol up to 8 mg daily for 6 weeks. Blood was sampled for measurement of serum estradiol, IGF-I, IGF-II, and IGFBP 1, 2 and 3 at various times during estradiol treatment. RESULTS: There was no significant correlation between serum estradiol concentrations and the serum concentrations of IGF-I and IGF-II. As expected, IGF-I and IGF-II concentrations in serum correlated positively with the serum concentration of IGFBP-3, the major IGF-binding protein in serum. CONCLUSION: The results of this study suggest that estradiol therapy as used to prepare the uterus for implantation has no significant effect on serum IGF-I and IGF-II concentrations, and therefore probably does not influence, via an IGF-mediated mechanism, the success of implantation and early embryonic development.

Adult↗
PubMedDate not supplied

Estradiol induces DNA fragmentation in a human endometrial adenocarcinoma with estradiol-inhibited growth phenotype.

A moderately differentiated human endometrial adenocarcinoma heterotransplanted into nude mice was investigated for morphological and molecular changes in the tumours after treating the animals with estradiol. The tumour growth was previously characterised as estradiol-independent but responsive (inhibited) without any changes in cell proliferation. In response to hormonal treatment rather the cell loss factor increased. In this experiment tumours influenced by estradiol were investigated at different time-points after treatment by an in situ labelling technique to detect cells undergoing DNA fragmentation as a sign of apoptosis. Expression of the apoptosis related protein bcl-2 was evaluated by Western blotting. Tumours from animals treated with estradiol showed an increase in tumour volume doubling time from 5.4 days to 16 days compared to control tumours. Histologically, tumours influenced by estradiol were better differentiated than control tumours and showed a significant increase in cells staining positively with the in situ apoptosis detection technique. A parallel time dependent decreased expression of bcl-2 protein was observed. These results confirm our previous findings where estradiol influenced the cell loss factor without changes in the growth fraction, indicating increased apoptotic activity in response to hormonal treatment.

Adenocarcinoma↗
PubMed1998

Pharmacokinetics of estradiol and of estrone during application of a new 7-day estradiol transdermal patch with active matrix.

The pharmacokinetic patterns of estradiol (CAS 50-28-2) and of estrone (CAS 53-16-7) were investigated in 18 women in natural or surgical menopause during the application of a new estradiol transdermal patch with active matrix and without absorption enhancers designed for epicutaneous applications of 7 days (hereinafter called "patch 7D"). The study was made with randomized and balanced sequences of applications in cross-over of either patch 7D or of an authorized estradiol transdermal patch with a nominal release rate of 50 micrograms/day estradiol designed for a twice-a-week epicutaneous application (hereinafter called "patch 50"). The sequences consisted of applications for 3 weeks either of 3 patches 7D or of 6 patches 50. The patches were applied on the skin of the hips or upper buttocks. The serum samples were obtained during the 1st and during the last week of application of the patches. Estradiol (E2) was assayed in serum by a double-antibody RIA method selective for free estradiol. Estrone (E1) was assayed in serum using a 3H-estrone RIA method. The steady state with regard to E2 and E1 was achieved already during the application of the 2nd patch. Patch 7D provided within 6 h an increase of the E2 concentrations in serum from the basal postmenopausal level of less than 3 pg/ml to therapeutically effective concentrations. The Cmax of E2 of 45 pg/ml was reached on average after 25 h, the concentrations of E2 remaining at sustained and therapeutically effective levels during the whole application of patch 7D. At steady state, during the 3rd week of application, the Cav was on average 31 pg/ml. With a small delay, E1 also increased from the basal 15 pg/ml to a Cmax of 41 pg/ml after 44 h. At steady state, during the 3rd week of application, the Cav was on average 38 pg/ml. Patch 7D provided a similar bioavailability as patch 50 with regard to the rate and the extent of absorption of E2, as shown by the AUCs during the 7-day applications of one patch 7D compared to those during the 7-day applications of 2 patches 50. The release of E2 from patch 7D is therefore similar to that of patch 50, i.e. on an average of 50 micrograms/day over a 7-day period of application. The E2/E1 ratio increased from the postmenopausal values lower than 0.2 found before the application of patch 7D to average values of 0.67, i.e., to values that are normally found during the fertile life of the woman. The improvement of the E2/E1 ratio occurred already in the first 6-12 h of application of patch 7D. The E2/E1 ratio returned rapidly to the initial low postmenopausal levels after removal of the patch. Patch 7D was well tolerated by the skin, probably because it does not contain absorption enhancers. It provoked, however, some systemic adverse reactions typical of E2 overdosing. In the therapeutic practice these adverse reactions can easily be avoided using patches 7D of lower strength. No drop-out due to systemic or local intolerance occurred. The adhesion of patch 7D on the skin was good. During the application of a total of 54 patches, only in one occasion one patch became partially detached (about 40% of the total area) from the 3rd to the 7th day during the first 7-day period of application.

Administration, Cutaneous↗
PubMed1979

Ovulation inhibition with a combined oral contraceptive containing 20 micrograms ethinyl estradiol and 250 micrograms levonorgestrel. Serum levels of the active ingredients and FSH, LH, estradiol 17-beta and progesterone.

In order to investigate the possible ovulation inhibitory effect of a new oral contraceptive containing a combination of 20 micrograms ethinyl estradiol and 250 micrograms levonorgestrel peripheral serum from five healthy women between 17 and 24 years were analysed for FSH, LH, estradiol 17-beta and progesterone. The measurements were carried out during a control cycle before the treatment, during two treatment cycles and during a subsequent control cycle. In addition, serum levels of ethinyl estradiol and norgestrel were determined during the treatment periods. Radioimmunological methods were utilized for all the measurements. In all five women studied there was a complete inhibition of ovulation during treatment as indicated by a lack of mid-cycle LH peaks and by suppression of normal luteal phase levels of progesterone. Four out of the five women showed no biphasic estradiol pattern. During treatment the serum levels of levonorgestrel varied between 1 and 10 nmol/l while the levels of ethinyl estradiol usually were below the limit of detection for the method used (below 85 pmol/l). Post-treatment control cycles revealed a re-establishment of the ovulatory pattern in four of the five subjects.

Adolescent↗
PubMed1984

[Estradiol receptors in the cytosol of nitrosomethylurea-induced mammary tumors of the rat. Influence of cell nuclei on the cytoplasmic estradiol receptor].

The cytoplasmic estradiol receptor (ERc) in N-nitrosomethylurea induced mammary tumors of the rat was described and its binding properties were characterized. We found an estradiol receptor incidence of 100% and an ERc content of 40 +/- 10 fmol/mg cytosol protein (n = 18) 3-4 days after ovariectomy. A dissociation constant (KD) of 2,2 +/- 1,1 X 10(-10) M was measured. The optimal incubation time for the determination of the ERc was found to be c.18 h (0-4 degrees C). The occupied ERc was relatively stable (we observed only a c. 20% degradation of the estradiol receptor after an incubation time of 66 h (0-4 degrees C) in comparison with the value found during an incubation time of 18 h (0-4 degrees C), the unoccupied ERC is more instable. We found an inactivation of ERc after freezing of tumor tissue in dry ice for longer times (in this paper for 18 d). The occupied estradiol receptor was stable for at least 30 min at 30 degrees C, if an excess of steroid is available in the assay system (in this paper 4 X 10(-9) M). A distinct degradation was observed if occupied cytosol was incubated at 37 degrees C. We found a fast inactivation of the ERc if cytosol and nuclei were incubated together at 30 degrees C. At temperatures of 0-4 degrees C (incubation of cytosol plus nuclei) a slight degradation of the ERc could be seen. This degradation was not significant in every case. Nuclei of N-nitrosomethylurea-induced mammary tumors of the rat possess apparently a "factor" which is able to inactivate the cytoplasmic estradiol receptor and is highly active at elevated temperatures. It is possible that this "factor" also acts at temperatures of 0-4 degrees C but with diminished activity.

Animals↗
PubMed1984

Enhancement of hepatocarcinogenesis in female rats by ethinyl estradiol and mestranol but not estradiol.

The effect of dietary exposure to synthetic estrogens on hepatocarcinogenesis was evaluated. Diethylnitrosamine-initiated and 0.85% NaCl solution-treated noninitiated female Sprague-Dawley rats were transferred to semisynthetic diets containing mestranol (0, 0.1, or 0.5 ppm), ethinyl estradiol (0.5 ppm), estradiol (0.6 ppm), or mestranol plus beta-methasone (0.5 and 0.2 ppm, respectively). gamma-Glutamyl transferase (GGT)-positive transections and hematoxylin and eosin-detectable nodules and carcinomas were scored at 9 and 12 months. Quantitative stereological calculations were performed to determine GGT lesion number and size. At 9 months, in diethylnitrosamine-initiated rats, ethinyl estradiol and mestranol caused 3.5- and 4.4-fold increases, respectively, in the number of GGT lesions per liver and an increased incidence of hepatocellular carcinomas while estradiol had no enhancing effect. Addition of beta-methasone to the mestranol-containing diet caused a significant decrease in GGT lesion number but not carcinoma incidence compared to mestranol alone. At 12 months, in diethylnitrosamine-initiated rats, mestranol caused a dose-dependent increase in GGT lesion number. The hepatocellular carcinoma incidence was significantly increased at the high mestranol dose. Small increases in the numbers of larger GGT lesions were also observed in noninitiated animals treated with mestranol and ethinyl estradiol and are most probably due to promotion of spontaneously initiated hepatocytes. These results indicated that the synthetic estrogens cause dramatic increases in the number of presumptive preneoplastic GGT lesions. Carcinoma incidence is also enhanced. Thus, these results confirm and extend our previous studies which together with the results of others have shown that synthetic estrogens can act as promoters of hepatocarcinogenesis.

Animals↗
PubMed1993

Short term treatment of tamoxifen and estradiol on estradiol and progesterone receptors in rabbit uterus.

Effects of tamoxifen (Tam) on cytosolic estradiol (E2) receptors (ERc), progesterone (P4) receptors (PRc), nuclear estradiol (ERn) and progesterone receptors (PRn) were studied in adult normal rabbit uterine tissue. The ratio of cytosol: nuclear estradiol receptors (ER) was greater in rabbits treated with Tam than E2 or control uterine tissues. Rabbit uterine progesterone receptors (PR) in E2 treated animal were greater than Tam-treated animals. Tam caused nuclear accumulation of estradiol receptor, and simultaneous administration of E2 + Tam 500, estradiol could not revert Tam mediated accumulation of ER. The results suggest that Tam has an essentially antagonist action in the rabbit uterine tissue.

Animals↗
PubMed1976

[Liver function tests under the influence of sequential treatment using ethinyl estradiol-norethisterone acetate and ethinyl estradiol-chlormadinone acetate].

30 young healthy women were investigated during the first therapy cycle with ethinyl-estradiol-norethisterone acetate and ethinyl-estradiol-chlormadinone acetate as a sequential regime. The following laboratory data were achieved by each of the investigated group of young women: serum aminotransferase (GOT and GPT), serum alkaline phosphatase and alpha-amylase-activity in serum, serum proteins, serum cholesterol, serum bilirubin, serum ZST, serum TTT and the indocyaningreen-clearance of the liver. The serum protein pattern was determined by the paper electrophoretic method. A significant decrease of the aminotransferase GPT was viable during the sequential therapy with ethinyl-estradiol and norethisterone acetate. This viable decrease of the GPT was induced through the application of norethisterone acetate to estrogen. The alkaline phosphatase was significant lightly lower and the beta-globuline lightly elevated at the end of the therapy cycle. The sequential therapy with ethinyl-estradiol and chlormadinone acetate induced only a significant increase of the ZST in serum.

Adolescent↗