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H Kuhl

Publications and source records attributed to H Kuhl.

At least 19 recordsLinked to original sources
PubMed1992

[Hormonal contraception and substitution therapy: the importance of progestogen for cardiovascular diseases].

Epidemiological data have demonstrated, that the progestogen component of oral contraceptives is involved in the development of hypertension, ischaemic heart diseases and stroke. It had been suggested, that atherosclerotic lesions due to the unfavourable effect on lipid metabolism of progestogens with androgenic properties, play a causal role. It has, however, been shown, that there is no development of atherosclerosis despite reduced HDL and elevated LDL, presumably because of the induction of hepatic LDL- and remnant-receptors by the strong effect of ethinyl-oestradiol upon the liver. A series of experimental and clinical findings indicates that vasospasms caused by the vasoconstrictory effect of progestogens are involved in the development of arterial thromboses. In postmenopausal women, the additional administration of progestogens to the oestrogen treatment may trigger ischaemic diseases, particularly in the presence of vascular lesions. Oestrogens exercise a pronounced vasodilatory effect and stabilize the vascular tonus--through changes in the responsiveness of endothelium and smooth muscle cells to vasoactive compounds, through modulation of neurotransmitter release from nerve endings, and through direct blocking of calcium channels. The effects depend essentially on an intact endothelium. By a direct action on the vascular wall, progestogens increase the sensitivity of arteries to vasoconstrictory compounds and reduce blood flow. As aldosterone increases the number of beta-adrenergic receptors in the arterial smooth muscle cells and thus act vasodilatorily, it cannot be excluded, that progestogens with high affinity to the aldosterone receptor and antimineralocorticoid properties, may exert a strong vasoconstrictory effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiovascular Diseases↗
PubMed1992

Serum concentrations of ethinylestradiol, 3-keto-desogestrel, SHBG, CBG and gonadotropins during treatment with a biphasic oral contraceptive containing desogestrel.

During a cross-over study, the pharmacokinetics of ethinylestradiol (EE) and 3-keto-desogestrel (KDG) were investigated on days 7 and 22 of one cycle of treatment with two biphasic formulations containing 50 micrograms EE (7 tablets) and 50 micrograms EE + 125 micrograms desogestrel (DG) (15 tablets) (50/50 EE) or 40 micrograms EE + 25 micrograms DG (7 tablets) and 30 micrograms EE + 125 micrograms DG (15 tablets) (40/30 EE). Peak serum levels and areas under the curve of EE increased significantly by 50% between days 7 and 22 of those taking 50/50 EE, while during treatment with 40/30 EE, no difference was found between days 7 and 22. Both formulations caused identical KDG levels on day 22. There were only slight differences in the effects of both preparations on sex-hormone-binding globulin (SHBG; +150 to +160%) and on corticosteroid-binding globulin (CBG; +130 to +150%) on day 7. On day 22, the changes were more pronounced with 50/50 EE (SHBG, +310%; CBG, +240%) than with 40/30 EE (SHBG, +250%; CBG, +180%). On day 22 after discontinuation of treatment, the SHBG and CBG levels were still significantly above the control values. Using both formulations, LH and FSH levels were significantly suppressed on day 22, while on day 7 no significant reduction was observed. The rise in the EE levels between days 7 and 22 of 50/50 EE intake and the time course of the EE concentrations during treatment with 40/30 EE appear to be due to an inhibition of hepatic metabolism by the contraceptive steroids, as EE is nearly exclusively bound to albumin which does not change.

Adult↗
PubMed1992

Is 3 alpha, 17 beta-androstanediol-glucuronide a diagnostic marker in women with androgenic manifestations?

3 alpha, 17 beta-androstanediol-glucuronide (Adiol-G) has been described as a marker of local androgen excess due to the increased activity of 5 alpha-reductase in the cells of the hair follicles. In order to test the diagnostic value of Adiol-G, the serum level was compared to that of testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione and to the body mass index in 44 women with androgenic symptoms (Group I), 27 women with menstrual disturbances but no androgenic symptoms (Group II), and 48 healthy women (Group III) who served as controls. Adiol-G was significantly higher (7.8 +/- 5.1 nmol/l) in women with androgenic symptoms than in the other groups, but there was a considerable overlap. Serum testosterone was also found to be higher in Group I than in Groups II and III, respectively. There was a significant correlation between Adiol-G and testosterone, and Adiol-G and DHEA-S. No significant correlation could be shown to exist between androstenedione and Adiol-G. When Adiol-G and testosterone were simply classified as 'normal' or 'increased' (Adiol-G 9.4 nmol/l; testosterone greater than 2.4 nmol/l), higher than normal values of the former were found in the presence of normal testosterone in only 4% of the cases. It is concluded that the level of Adiol-G generally parallels that of testosterone. Consequently, it does not seem to be an effective marker of peripheral androgen excess.

Acne Vulgaris↗
PubMed1991

[Contraception with cyclic administration of buserelin and gestagens: increase in testosterone and free testosterone serum concentration].

During contraception with the LH-RH analogue buserelin, some women developed mild androgenic symptoms. Therefore, we investigated in 10 women various hormonal serum parameters during one cycle of treatment with daily 300 micrograms buserelin intranasally (day 1-22) and 5 mg medroxyprogesterone acetate (MPA) orally (day 16-22), and, after a washout cycle, during another cycle of treatment with daily 300 micrograms buserelin intranasally (day 1-15) and 5 mg norethisterone acetate (NETA) orally (day 16-22). The serum parameters were investigated on day 1, 15 and 21 during the 4 hours after administration of the drugs. During the treatment, LH release was significantly reduced, whereby additional MPA had no effect whatsoever, while NETA profoundly suppressed LH. During treatment with buserelin and MPA, the average oestradiol levels remained unaltered, but were significantly suppressed by 65% during intake of NETA. Contrary to 17 alpha-hydroxyprogesterone, which did not change, serum testosterone was significantly increased by 30% when buserelin was given with or without MPA, while NETA had no effect. During both regimens, the serum concentrations of SHBG were reduced by 15 to 25%, and those of free testosterone were increased by 30 to 50%. These alterations in hormonal parameters may have contributed to the development of seborrhoeic symptoms and acne of the facial skin which were observed in 6 of the 10 women treated with intranasal buserelin for contraception.

Administration, Intranasal↗
PubMed1991

Oral contraceptives containing 20 or 30 micrograms ethinylestradiol and 150 micrograms desogestrel: pharmacokinetics and pharmacodynamic parameters.

The serum concentrations of ethinylestradiol (EE) and 3-keto-desogestrel (KDG) were compared during treatment with a combination of 20 micrograms EE + 150 micrograms DG (20EE/DG) or of 30 micrograms EE + 150 micrograms DG (30EE/DG). During intake of both preparations, the peak levels and the areas under the curve (AUC) of EE increased significantly by approximately 100% between days 1 and 10. In the steady state, the maximal EE levels were 75 +/- 34 pg/ml (20EE/DG) and 136 +/- 55 pg/ml (30EE/DG), and the AUC were 464 +/- 236 pg.h/ml and 840 +/- 492 pg.h/ml. The KDG levels, which were identical with both preparations, increased between days 1 and 21 by approximately 300% up to values of 4.5 +/- 1.6 ng/ml. There were large interindividual variations in the AUC of EE and KDG and no correlation between the levels of EE and KDG. On day 21 of intake of 30EE/DG, the serum concentrations of sex-hormone- and corticosteroid-binding globulin were higher by 16% and 12%, respectively than with 20EE/DG. Although the morning peak levels of cortisol did not differ, the decrease which occurred thereafter, according to the circadian rhythm, was slower with 30EE/DG. There was no relationship between the serum concentrations of EE and/or KDG and the occurrence of irregular bleedings, which was similar during treatment with both preparations. As most of the women who bled had bleedings both with 20EE/DG and 30EE/DG, an influence of predisposition can be assumed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Pharmacokinetics and pharmacodynamics of oral contraceptive steroids: factors influencing steroid metabolism.

The time-dependent alterations in the serum concentrations of ethinyl estradiol, gestodene, and 3-keto-desogestrel during treatment with 30 micrograms of ethinyl estradiol + 75 micrograms of gestodene or 30 micrograms of ethinyl estradiol + 150 micrograms of desogestrel were investigated during 12 months. The levels of gestodene and 3-keto-desogestrel increased between days 1 and 21 of each cycle, reaching maximal levels during the third and sixth cycles. The serum concentrations of gestodene were fourfold to fivefold higher than those of 3-keto-desogestrel. The ethinyl estradiol levels increased significantly between days 1 and 10 during each cycle and were significantly higher by 70% during intake of ethinyl estradiol/gestodene compared with ethinyl estradiol/desogestrel, although the dose was identical. Intake of gestodene, in addition to 35 micrograms of ethinyl estradiol + 2 mg of cyproterone acetate, caused a rise in ethinyl estradiol levels. During treatment with ethinyl estradiol/gestodene and an additional 150 micrograms of levonorgestrel, there was a continuous increase in gestodene levels, although sex hormone-binding globulin level did not change. During treatment with 30 or 35 micrograms of ethinyl estradiol and 75 micrograms of gestodene, 150 micrograms of desogestrel, or 2 mg of cyproterone acetate, there were large intraindividual and interindividual variations in the steroid levels and ratios of estrogen: progestogen levels. There was no correlation with the occurrence of intermenstrual bleedings. It is concluded that ethinyl estradiol and nortestosterone derivatives may inhibit steroid-metabolizing enzymes in the liver, which results in a rise in the serum levels of contraceptive steroids. The cause of the large intraindividual variations is as yet unknown, but it is probably from changes in steroid metabolism.

Adolescent↗
PubMed1990

Time-dependent alterations in lipid metabolism during treatment with low-dose oral contraceptives.

The effect of sex steroids on lipid metabolism depends on the type and dose of the compounds, the route of administration, and the duration of treatment. Therefore the composition of an oral contraceptive determines the resultant effect on lipids and lipoproteins. During 12 months of treatment, the effects of two oral contraceptives containing 30 micrograms of ethinyl estradiol and 150 micrograms of desogestrel (EE/DG) or 75 micrograms of gestodene (EE/GSD) on 19 serum parameters of lipid metabolism were followed in 11 women each. There was no change in total cholesterol and phospholipids. Total triglyceride levels were significantly elevated only by EE/GSD. After 3 and 6 months of intake of both preparations, a transitory increase in the triglyceride content of very low-density lipoprotein and low-density lipoprotein and a decrease in low-density lipoprotein-phospholipids was observed. After 12 months, very low-density lipoprotein cholesterol, very low-density lipoprotein phospholipids, and apolipoprotein B were significantly elevated, whereas very low-density lipoprotein triglycerides and all components of low-density lipoprotein were unchanged. Most of the components of high-density lipoprotein (HDL) were increased as a result of a rise in HDL3 and apolipoprotein A2, whereas HDL2 and apolipoprotein A1 were not altered. There was no significant difference between the effects of the two preparations, although those of EE/GSD were mostly more pronounced. The increase in high-density lipoprotein, very low-density lipoprotein, and total triglycerides reflects a slight preponderance of the effect of the estrogen component. Because low-density lipoprotein cholesterol and total cholesterol were not changed, treatment with both formulations is in all probability not associated with an elevated risk of atherosclerosis.

Adolescent↗
PubMed1990

Intra- and interindividual variations in contraceptive steroid levels during 12 treatment cycles: no relation to irregular bleedings.

During one year of treatment with oral contraceptives containing 30 micrograms ethinylestradiol and 150 micrograms desogestrel (EE/DG) or 30 micrograms EE and 75 micrograms gestodene (EE/GSD), the serum concentrations of EE, 3-keto-desogestrel (KDG) and GSD were determined on day 1, 10 and 21 of the 1st, 3rd, 6th and 12th cycle. The areas under the time-versus-concentration curves were calculated from the levels before and 0.5, 1, 1.5, 2, 3, 4 and 24 hours after intake of a tablet. There were large intra- and interindividual variations both revealing coefficients of variation (C.V.) between 25% and 80% (EE),, 30% and 50% (KDG) and 30% and 65% (GSD). During each cycle, the EE levels increased significantly between day 1 and 10 by 70% on average reaching a steady-state, while the progestogen concentrations rose by 100% (KDG) and 150% (GSD) up to a steady-state between day 10 and 21. After reaching the steady-state, the C.V. were generally lower. The ratios between the levels of EE and the progestogens showed still higher variations indicating different influences on the estrogen and progestogen component. There was no correlation between the steroid levels and weight, height or age. In spite of the large intraindividual variations, most of the women showed a distinct pattern of the levels of EE and the progestogens throughout the year of treatment indicating a genetic or acquired predisposition. The difference in the average AUC of EE, KDG and GSD between the women was 300% at most. During the first cycle of treatment with EE/DG and EE/GSD, about half of the women recorded intermenstrual bleedings which decreased thereafter. There was no relation between the occurrence of irregular bleedings and the average serum levels of EE and the progestogens of the individual women, neither during the first cycle nor during the whole treatment period of 12 cycles. It is concluded that spottings or breakthrough bleedings during treatment with oral contraceptives are not dependent on a distinct pattern of the serum levels of EE and the progestogen.

Adolescent↗
PubMed1990

Changes in lipid metabolism during 12 months of treatment with two oral contraceptives containing 30 micrograms ethinylestradiol and 75 micrograms gestodene or 150 micrograms desogestrel.

The effect of two oral contraceptives containing 30 micrograms ethinylestradiol + 75 micrograms gestodene (EE/GSD) or 30 micrograms ethinylestradiol + 150 micrograms desogestrel (EE/DG) upon serum lipids and lipoproteins were measured in 11 women each on days 1, 10, and 21 of the first, third, sixth, and twelfth treatment cycle and compared to the levels on days 1, 10, and 21 of the preceding control cycle. There was no change in total cholesterol (CH) and phospholipids (PL), while total triglycerides (TG) were significantly elevated only during treatment with EE/GSD. After 3 and 6 months of intake of both oral contraceptives, a transitory increase in the TG content of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), and a decrease in LDL-PL was observed. After 12 months, VLDL-CH, VLDL-PL, and apolipoprotein B were significantly elevated, while VLDL-TG and all components of LDL were unchanged. Most of the components of high-density lipoprotein (HDL) were increased due to a rise in HDL3 and apolipoprotein A-II, while HDL2 and apolipoprotein A-I were not altered. There was no significant difference between the effects of the two preparations, although those of EE/GSD were mostly more pronounced. The time-dependent change in the effects of the oral contraceptives on various parameters of lipid metabolism demonstrates that the relevance of results of short-time studies may be questionable. There was also a significant alteration in some parameters between day 1 and 10 of the treatment cycles and a tendency to return to the pretreatment levels during the pill-free week, e.g., in total TG and in the PL component of VLDL, LDL and HDL. The increase in HDL, VLDL, and total TG reflects a slight preponderance of the effect of ethinylestradiol on lipid metabolism. The unchanged total CH and LDL-CH and the elevated HDL levels indicate that the risk of the development of atherosclerosis is in all probability not increased during treatment with both preparations.

Adolescent↗
PubMed1990

Pharmacokinetics of oestrogens and progestogens.

There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.

Estrogens↗
PubMed1990

[Ovulation inhibitors: the significance of estrogen dose].

The large prospective studies on adverse effects of oral contraceptives have unanimously revealed an increased risk of thromboembolic diseases, which seem to be associated with the dose of ethinylestradiol (EE). According to the recommendations of several medical committees, the dose of EE has, therefore, been more and more reduced; in some countries there are now ovulation inhibitors containing 20 micrograms EE. Since serious reactions, which have a relatively low incidence, are highly underreported (less than 10%), it is difficult to prove dose-dependent differences in the rates of cardiovascular diseases. There is, however, virtually no doubt that not only the incidence of thromboembolic diseases and stroke, but also that of benign liver tumours and gall bladder diseases is increased in relation to the EE-dose. A series of metabolic serum parameters, e.g. serum binding proteins, coagulation and fibrinolysis factors, angiotensinogen, is changed by EE in a dose-dependent manner which is, however, limited when the effects are receptor-mediated. Higher doses of EE have been shown to facilitate fibrin deposits on vascular subendothelium. The pharmacological effects of EE are to a large extent dependent on the dose, e.g. the irreversible reactions of EE and other ethinylated steroids with hepatic enzymes which are involved in the metabolism of steroids, drugs and toxic compounds. After long-term treatment with combinations containing 50 micrograms EE, in half of the women, abnormal liver function tests with pathological morphological alterations have been found. As combinations with low EE doses and a sufficiently effective progestogen component do not differ from higher dosed oral contraceptives in their contraceptive safety and cycle control, there are no indications for pills containing 50 micrograms EE, except the normophasic sequential preparations for women with sustained irregular bleedings when taking low dose combinations.

Contraceptives, Oral, Hormonal↗
PubMed1989

Interaction with the pharmacokinetics of ethinylestradiol and progestogens contained in oral contraceptives.

The serum concentrations of ethinylestradiol (EE) during the first 4 h and 24 h after intake of an oral contraceptive containing 30 micrograms EE and 75 micrograms gestodene (EE/GSD) were compared to those after intake of a preparation containing the same EE dose and 150 micrograms desogestrel (EE/DG) in each of 11 women on days 1, 10, and 21 of their 1st, 3rd, 6th, and 12th cycles. There were great interindividual variations, but during treatment with EE/GSD the EE levels were higher and the EE peaks occurred by 30 min later than during treatment with EE/DG. The areas under the EE serum concentration-versus-time curves (AUC) between 0 and 4 h were higher by 37% (p less than 0.03) and between 0 and 24 h higher by 70% (p less than 0.002) during treatment with EE/GSD. During each treatment cycle, the EE levels rose between day 1 and 10. The serum levels of corticosteroid-binding globulin (CBG), which is known to be influenced only by the estrogenic component of the combination pill, increased significantly (p less than 0.01) during each treatment cycle. CBG was elevated on day 21 of the 6th and 12th cycle by 150 to 155% and by 120 to 130% with EE/GSD and EE/DG, respectively. The difference between the two drugs was significant (p less than 0.02). During the pill-free intervals of 7 days between the treatment cycles, the CBG levels decreased but were still elevated by 85% with EE/GSD and 50% with EE/DG at the beginning of the following cycle as compared to the control cycle. The serum levels of cortisol were also significantly more elevated (p less than 0.05) during treatment with EE/GSD as compared to EE/DG. Despite the same EE dose during treatment, the higher EE levels with EE/GSD as compared to EE/DG seem to be due to a retardation of the inactivation and elimination of EE caused by the progestogen component. The rise in the EE levels during each cycle seems to be due to a reduction in the oxidative metabolism by EE itself.

Adolescent↗