Low-dose Ethinyl Estradiol Research Articles

Specific, Time-Dependent Actions of Low-Dose Ethinyl Estradiol Administration on the Episodic Release of Growth Hormone, Follicle-Stimulating Hormone, and Luteinizing Hormone in Prepubertal Girls with Turner's Syndrome *

To investigate the actions of acute and chronic low doses of ethinyl estradiol (EE) on the pulsatile characteristics of GH and gonadotropin release we studied seven girls with Turner's syndrome [mean age, 7.5 +/- 0.75 (+/- SE) yr] on 3 separate study days. At baseline (study I), blood was drawn every 20 min from 2000-0800 h for GH, LH, and FSH determinations. One month after study I the patients were started on 100 ng/kg EE, orally, daily, and an identical study was repeated 1 week (study II) and 5 weeks (study III) from the initiation of low dose EE therapy. A pulse detection algorithm, Cluster, was used to objectively analyze pulsatility profiles. There were consistent and significant increases in all seven patients after 5 weeks of low dose EE therapy in mean GH concentrations (study I, 7.0 +/- 1.1 micrograms/L; study III, 13.4 +/- 1.7; P = 0.008), mean area under the GH pulse (study I, 602 +/- 52 micrograms/L.min; study III, 1350 +/- 261; P = 0.026), and mean GH pulse amplitude (study I, 14.0 +/- 2.2 micrograms/L; study III, 32.8 +/- 6.0; P = 0.018); with no detectable changes in GH pulse frequency (study I, 5.3 +/- 0.6 pulses/12 h; study III, 5.3 +/- 0.4). These findings were not accompanied by any significant changes in plasma somatomedin-C or serum estradiol concentrations or urinary cytological maturation indexes. Conversely, the amount of radioimmunoassayable FSH activity was suppressed after low dose EE therapy, with a decrease in mean FSH concentrations (study I, 23.5 +/- 6.6 IU/L; study III, 5.9 +/- 1.2; P = 0.035) and mean pulse amplitude (study I, 28.6 +/- 8.6 IU/L; study III, 8.2 +/- 1.8; P = 0.038), with no detectable changes in FSH pulse frequency (study I, 7.6 +/- 0.6 pulses/12 h; study III, 7.3 +/- 0.6). Similar qualitative changes in LH pulsatility were observed after low dose estradiol administration. In conclusion, our results demonstrate that low dose EE therapy results in a significant augmentation of pulsatile GH activity, with reciprocal decreases in gonadotropin concentrations in girls with Turner's syndrome. Such observations indicate an exquisite sensitivity of gonadotrope and somatotrope function to low dose estrogen action in this prepubertal hypogonadal model.

A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis parameters : Thromb. Haemostasis; 61/1 (65–69)/1989/

Ethinyl estradiol (EE) is still used to some extent as hormonal replacement therapy (HRT) in the climacteric period. As regards oral contraception, it is well known that the induced increase in cardiovascular disease is related to the estrogen component (invariably EE) in a dose-related fashion. Considerably lower doses of EE are needed in HRT compared to oral contraception. To delineate and compare effects of EE and estradiol valerate (E2V) in doses needed in HRT on haemostasis parameters, 24 postmenopausal women were engaged in a study with an open cross-over design. The doses compared (10 micrograms EE and 2 mg E2V daily) are the lowest which eliminate climacteric symptoms in a majority of women. Unlike E2V, EE caused increased levels of factor VII:Ag, factor VIII:C and beta-thromboglobulin, which may be changes towards hypercoagulability. Both estrogens decreased the AT III activity. Long-term administration (6 + 12 w) of the estrogens induced further changes in haemostatic parameters. 10 micrograms EE increased factor VII:Ag in contrast to 2 mg E2V. Furthermore both estrogens increased factor VIII:C and factor II-VII-X. A decrease in platelet count was induced by both EE and E2V. Oral contraception and adjuvant estrogen therapy in men with prostatic carcinoma are known to imply an increased cardiovascular risk. It is noteworthy that the pattern of changes in haemostatic parameters induced by as little as 10 micrograms of EE is the same as seen after the administration of combined oral contraceptives or the substantially higher doses of EE given as adjuvant therapy to men with prostatic carcinoma.

A Comparison between Effects of Estradiol Valerate and Low Dose Ethinyl Estradiol on Haemostasis Parameters

Ethinyl estradiol (EE) is still used to some extent as hormonal replacement therapy (HRT) in the climacteric period. As regards oral contraception, it is well known that the induced increase in cardiovascular disease is related to the estrogen component (invariably EE) in a dose-related fashion. Considerably lower doses of EE are needed in HRT compared to oral contraception. To delineate and compare effects of EE and estradiol valerate (E2V) in doses needed in HRT on haemostasis parameters, 24 postmenopausal women were engaged in a study with an open cross-over design. The doses compared (10 micrograms EE and 2 mg E2V daily) are the lowest which eliminate climacteric symptoms in a majority of women. Unlike E2V, EE caused increased levels of factor VII:Ag, factor VIII:C and beta-thromboglobulin, which may be changes towards hypercoagulability. Both estrogens decreased the AT III activity. Long-term administration (6 + 12 w) of the estrogens induced further changes in haemostatic parameters. 10 micrograms EE increased factor VII:Ag in contrast to 2 mg E2V. Furthermore both estrogens increased factor VIII:C and factor II-VII-X. A decrease in platelet count was induced by both EE and E2V. Oral contraception and adjuvant estrogen therapy in men with prostatic carcinoma are known to imply an increased cardiovascular risk. It is noteworthy that the pattern of changes in haemostatic parameters induced by as little as 10 micrograms of EE is the same as seen after the administration of combined oral contraceptives or the substantially higher doses of EE given as adjuvant therapy to men with prostatic carcinoma.

Ethinylestradiol administration selectively alters liver sinusoidal membrane lipid fluidity and protein composition.

Administration of high-dose ethinylestradiol to rats decreases bile flow, Na,K-ATPase specific activity, and liver plasma membrane fluidity. By use of highly purified sinusoidal and bile canalicular membrane fractions, the effect of ethinylestradiol administration on the protein and lipid composition and fluidity of plasma membrane fractions was examined. In sinusoidal fractions, ethinylestradiol (EE) administration decreased Na,K-ATPase activity (32%) and increased activities of alkaline phosphatase (254%), Mg2+-ATPase (155%), and a 160-kDa polypeptide (10-fold). Steady-state and dynamic fluorescence polarization was used to study membrane lipid structure. Steady-state polarization of diphenylhexatriene (DPH) was significantly higher in canalicular compared to sinusoidal membrane fractions. Ethinylestradiol (5 mg/kg per day for 5 days) selectively increased sinusoidal polarization values. Similar changes were demonstrated with the probes 2- and 12-anthroyloxystearate. Time-resolved fluorescence polarization measurements indicated that EE administration for 5 days did not change DPH lifetime but increased the order component (r infinity) and decreased the rotation rate (R). However, 1 and 3 days after EE administration and with low doses (10-100 micrograms/kg per day for 5 days) the Na,K-ATPase, bile flow, and order component were altered, but the rotation rate was unchanged. Vesicles prepared from total sinusoidal membrane lipids of EE-treated rats, as well as phospholipid vesicles, demonstrated increased DPH polarization, as did intact plasma membrane fractions. Liver plasma membrane fractions showed no change in free cholesterol or cholesterol/phospholipid molar ratio, while esterified cholesterol content was increased with high-dose but not low-dose ethinylestradiol.(ABSTRACT TRUNCATED AT 250 WORDS)

METHIONYL GROWTH HORMONE (met-GH) IN A DOSAGE OF 4 IU/m2 DAY PROMOTES GROWTH IN TURNER SYNDROME

In a Dutch multi-center study 16 girls with Turner Syndrome were treated with met-GH in a dosage of 4 IU/m2 body surface administered s.c. once a day. In girls older than 13 years low-dose ethinyl-estradiol (EE) therapy (0.1 ug/kg body weight o.d.) was added. Ages ranged from 7.9 to 15.2 years and bone age from 6.0 to 12 “years”. Heights, expressed as standard deviation scores, were between -2.5 and -5.1 (median -3.9). Endogenous GH secretion was assessed by arginine infusion, exercise test, GRF (1-29)-test and plasma SM-C/IGF-I. Mean ( ± S.D.) growth velocities were: During the first 6 months of therapy the mean ( ± S.D.) bone age (Greulich and Pyle) advanced from 9.1 (±1.2) to 9.4 (±1.2)“years” and the predicted adult height from 148.2 (±4.5) to 151.0 (±4.2) cm. The growth response (growth velocity during 9 months of therapy minus baseline) ranged from 0.8 to 7.0 cm/year and was negatively correlated with chronological age (r= -0.48, p<0.05). In the 4 girls older than 13 years, who also received EE, the growth response was 3.3 ± 0.9, compared to 4.0 ± 1.6 in younger girls. Growth response was not correlated with maximum plasma GH levels during provocation tests. Anti-GH antibodies with a binding capacity of > 0.2 U/l were found in 5 out of 10 patients. In one of them a very high value (3.7 U/l) was found.

Growth in Turner's syndrome: long term treatment with low dose ethinyl estradiol.

The growth response to 100 ng/kg BW X day ethinyl estradiol (2-4 micrograms/day) given for 18 months was studied in a group of nine patients with Turner's syndrome, aged 8.6-13.3 yr. All patients were prepubertal and had elevated gonadotropin levels. Growth velocity increased from 3.09 +/- 1.05 (+/-SD) to 7.09 +/- 1.47 cm/yr in the first 6 months, 6.08 +/- 1.78 cm/yr in the second 6 months, and 4.03 +/- 1.65 cm/yr in the third 6 months. Bone age increased a mean of 0.82 +/- 0.34, 0.89 +/- 0.79, and 0.74 +/- 0.59 yr, respectively, in the three 6-month periods. Predicted height prognosis did not change after any period. All patients had pubertal changes, limited in most to slight breast development. Mean diurnal spontaneous GH secretion did not change during treatment. Plasma somatomedin-C levels were low before treatment, and ethinyl estradiol did not significantly increase somatomedin-C values. Our data confirm the ability of a low dose of ethinyl estradiol to increase growth velocity in girls with Turner's syndrome, although the effect diminished with time, and the excess bone age advancement precluded improvement of predicted height.

472 ESTROGEN AT LOW DOSES RAPIDLY AUGMENTS GROWTH HORMONE (GH) RELEASE INDEPENDENTLY OF SOMATOMEDIN-C (SM-C)

We tested whether low doses of ethinyl estradiol (EE) would stimulate GH independently of SM-C inhibition, after we found EE 50 mcg/m2/d × 2d to augment peak GH responses to L-dopa testing (LDT) while lowering SM (Rich et al, Pediatr.Res. 13:329A, 1979). We first examined the effect of one bedtime dose EE(29±2(SEM) mcg/m2) upon GH reserve in 8 prepubertal short-normal children. L-dopa(0.3 gm/m2) stimulated GH to ≥7 ng/ml inconsistently (6/8) before EE. EE resulted in a significant increase in peak GH response (29±5 ng/ml)(p<.05) to LDT. EE (10-30mcg/m2) was then given for 2 days prior to repeat LDT in 15 prepubertal children with the following results. GH responses to LDT were <7 ng/ml in 3/15 prior to EE but were consistently ≥7 ng/ml after EE. Augmentation of the GH response by EE at 27±1 mcg/m2/d was of similar magnitude to that noted with 50 mcg/m2/d EE, but this low-dose EE did not act via lowering SM-C levels (.54±.09 vs .47±.07, n=8). We conclude that a single bedtime dose of EE as low as 29±2 mcg/m2 augments the peak GH response to LDT and enhances the discrimination of L-dopa testing for GH reserve. Our results suggest low-dose estrogen rapidly and directly augments GH release, consistent with its enhancing effect on growth.

Serum lipid and lipoprotein changes induced by new oral contraceptives containing ethinylestradiol plus levonorgestrel or desogestrel

Changes in serum lipid and lipoprotein levels were evaluated in a randomized prospective study conducted in matched healthy young women before and after 6 months'use of three oral contraceptives (OCs): Trigynon (preparation A, n = 13), a triphasic OC containing low doses of ethinylestradiol (EE) and levonorgestrel (LNG); Marvelon (preparation B, n = 14), a monophasic OC containing low doses of EE + Desogestrel (DOG, a new progestogen derived from LNG); and Ovidol (preparation C, n = 11), a sequential OC containing higher doses (50 μg) of EE + DOG. After 6 months of use, total triglyceride levels were non-significantly increased by preparations A (+ 29% from basal values) and B (+ 21%), and very significantly increased by preparation C (+ 90%). Total cholesterol and phospholipids were unchanged by preparations A and B, whereas phospholipids were significantly increased by preparation C. However, HDL-cholesterol, LDL-cholesterol and their epidemiologically important ratios (HDL-chol:total-chol; LDL-chol:HDL-chol) were kept unchanged by all preparations tested. Apolipoprotein A-1 (Apo A-1) was slightly but significantly increased by all three preparations whereas apolipoprotein B (Apo B) was significantly decreased by preparation B. All ratios Apo A-1:Apo B were accordingly (“favorably”) increased, especially during treatment with preparation B. In conclusion, the triphasic OC containing low doses of LNG does not induce obvious, clinically significant, alterations of lipid metabolism, and it is also the case for the low-dose monophasic combination of EE + DOG. The higher-dose sequential preparation of EE + DOG behaves as a more estrogenic compound, increasing total triglyceride concentrations above the normal range.

A comparison of high-dose estrogens versus low-dose ethinylestradiol and norgestrel combination in postcoital interception: a study in 493 women

Ethinylestradiol (EE), at a dosage of 5 mg/day for 5 consecutive days (5 mg EE), has generally been used for interception. A combination of 200 micrograms EE and 2 mg dl-norgestrel (EE + NG) was proposed as an effective alternative. Efficacy and tolerance of these methods were compared in a randomized, double-blind study. A group of 465 women was studied with a follow-up rate of 94.3%. In the 5 mg EE group a pregnancy rate of 0.9% was observed, and in the EE + NG group a rate of 0.4% was found. These rates differ significantly from the expected rates (P less than 0.0005, in both series). Nausea was noted in 59.1% of the 5 mg EE group and in 54.0% of the EE + NG series. Nausea and vomiting occurred in 20.8% and 15.8%, respectively. The efficacy of both methods as alternative morning-after medication was confirmed. The new method is preferable because treatment is limited to only 1 day.

Estrogens promote growth: Experimental and clinical evidence

Although increasing estradiol levels accompany the pubertal growth spurt in girls our understanding of the effects of estrogens on growth has been dominated by the experience with high doses in tall girls. - In male Wistar rats castrated on age day 27 and treated with ethinylestradiol (EE)(250-25-2.5-1-0.25 μg/kg BW d s.c.) until age day 45 the three highest doses showed to be inhibiting body growth, GH, SM and gonado tropins. The lowest dose however enhanced body growth. The effects on bone maturity were inversely related to dose. In girls with multiple pituitary hormone deficiencies (MPHD) treated with low doses of EE (5μg/d p.o.) corresponding observations were made. In 5 patients (CA:x̄=18.0 yrs.; BA:x̄=12.3 yrs) treated for 6-12 mo. with EE(-and constance of other medication-) height velocity increased from x̄=3.4 to 4.5 cm/yr. without unduely advancing BA, but inducing signs of puberty. Preliminary observations suggest positive effects on growth with EE doses suboptimal in respect to the induction of the female sex characteristics.

Plasma hormone levels in women receiving new oral contraceptives containing ethinyl estradiol plus levonorgestrel or desogestrel

The changes in plasma hormone levels were evaluated in matched healthy female volunteers investigated before and after 6 months' use of three new oral contraceptives (OCs): Trigynon R (n = 13), a triphasic OC containing low doses of ethinylestradiol (EE) + levonorgestrel (LNg); Marvelon R (n = 14), a monophasic OC containing low doses of EE + desogestrel (DOG, a new progestogen derived from LNg); and Ovidol R (n = 10), a sequential OC containing higher doses (50 νg) of EE + DOG. Serum levels of FSH, LH, estradiol and progesterone were decreased in all cases to levels incompatible with ovulation. Prolactin concentrations were unchanged. Sex hormone binding globulin (SHBG) and Transcortin (CBG) levels were significantly increased by all three OCs (Ovidol>Marvelon>Trigynon); free testosterone levels decreased significantly while free cortisol concentrations remained unchanged. Collectively, these data indicate that ( a) all three OCs are effective ovulation inhibitors, ( b) Ovidol and Marvelon have greater estrogenic effects than Trigynon, ( c) LNg is more effective than DOG in reducing the EE-induced increase in SHBG levels, and ( d) free testosterone levels are equally well suppressed by all three Ocs.

The effect of low dose oestrogens on short-term growth and concomitant biochemical phenomena in girls with tall stature.

Using a simple non-invasive ulnar length measuring technique a 70 to 80% decrease in ulnar growth velocity was found during one interval of 9 weeks of low dose ethinyloestradiol administration (0.050 mg daily) in girls with tall stature. This decrease in ulnar growth velocity was found to be statistically significant within 6 and even 3 weeks after starting oestrogen loading whereas the change in body growth velocity was only significant after 9 weeks. After interpreting oestrogen administration, ulnar growth velocities increased again but to values tending to be lower than before ethinyloestradiol loading. Serum alkaline phosphatase activities and plasma inorganic phosphorus and calcium levels also decreased significantly during oestrogen therapy within 9 weeks. The results found illustrate that the measuring technique used enables evaluation of the short-term effect of hormonal treatment on growth and thereby related biochemical phenomena.

REPLACEMENT ORAL ETHINYLOESTRADIOL THERAPY FOR GONADAL DYSGENESIS: GROWTH AND ADRENAL ANDROGEN STUDIES

We have studied growth and adrenal dehydroepiandrosterone (DHA) responses to iv synthetic adrenocorticotrophic hormone (ACTH, Cortrosyn) in 6 girls with gonadal dysgenesis before and during treatment with low-dose ethinyloestradiol (EOe2). In all patients there was a statisfactory induction of secondary sexual characteristics including increase in breasts and public hair and onset of withdrawal bleeding within 6 months of therapy. Height velocity increased from 2.8 +/- 0.9 cm/year pre-treatment to 5.3 +/- 1.5 cm/year (P less than 0.02) in the first year. There was deceleration to 1.9 +/- 1.1 cm/year in the second year. There was no disproportionate advancement in bone age and thus, presumably, no loss of ultimate height. We could demonstrate no change in basal or ACTH-stimulated levels of DHA, a specific adrenal androgen, to account for the increased public hair and growth in these patients.

Prostatic carcinoma: Plasma kinetics and intraprostatic metabolism of testosterone in low-dose estrogen-treated patients in vivo

Plasma kinetics, in vivo uptake, and intraprostatic metabolism of 3H testosterone was investigated in 9 patients with advanced carcinoma of the prostate. The metabolic effect of low-dose ethinyl estradiol was studied (estrogen suppressed testosterone, luteinizing hormone, and follicle-stimulating hormone). The production rate of testosterone was lowered, the elimination of androgen from plasma delayed. The uptake of testosterone and metabolites by the prostatic carcinoma was suppressed. Estrogen did not alter significantly the intraprostatic androgen turnover.

A series of cases treated locally by cortisone; a preliminary report to the Medical Council by the panel on the ophthalmological applications of cortisone and ACTH.

<h3>Abstract</h3> <b>Objective</b>: To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of venous thromboembolism. <b>Design</b>: Matched case-control study. <b>Setting</b>: 10 centres in Germany and United Kingdom. <b>Subjects</b>: Cases were 471 women aged 16-44 who had a venous thromboembolism. Controls were 1772 women (at least 3 controls per case) unaffected by venous thromboembolism who were matched with corresponding case for age and for hospital or community setting. <b>Main outcome measures</b>: Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables. <b>Results</b>: Odds ratios (95% confidence intervals) for venous thromboembolism were: for any oral contraceptives versus no use, 4.0 (3.1 to 5.3); for second generation products (low dose ethinyloestradiol, no gestodene or desogestrel) versus no use, 3.2 (2.3 to 4.3); for third generation products (low dose ethinyloestradiol, gestodene or desogestrel) versus no use, 4.8 (3.4 to 6.7); for third generation products versus second generation products, 1.5 (1.1 to 2.1); for products containing gestodene versus second generation products, 1.5 (1.0 to 2.2); and for products containing desogestrel versus second generation products, 1.5 (1.1 to 2.2). Probability of death due to venous thromboembolism for women using third generation products is about 20 per million users per year, for women using second generation products it is about 14 per million users per year, and for non-users it is five per million per year. <b>Conclusions</b>: Risk of venous thromboembolism was slightly increased in users of third generation oral contraceptives compared with users of second generation products. <h3>Key messages</h3> Key messages This case-control study examined risk of venous thromboembolism associated with different types of oral contraceptive Overall, there was a fourfold higher relative risk of thromboembolism associated with current use of any oral contraceptive versus no current use The risk of thromboembolism was 1.5 times higher for third generation contraceptives compared with second generation products Our data indicate the need for clinical prudence but allow doctors and women seeking contraception to exercise informed choice