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Objectives: To determine the effect of two low-dose monophasic oral contraceptives containing either 2 mg chlormadinone acetate or 150 microg desogestrel on blood clotting and fibrinolysis., Methods: In vivo markers of intravascular coagulatory and fibrinolytic activity were measured in 45 volunteers randomly assigned to a 6-month treatment with one of the two study preparations., Results: During oral contraceptive use, the procoagulatory activity increased (increased prothrombin fragment 1+2), the anticoagulatory capacity changed (increased protein C activity, decreased activated protein C sensitivity, decreased protein S activity and decreased antithrombin III activity) and the fibrinolytic system was activated (increased concentrations of plasmin-antiplasmin complexes and D-dimer as well as total fibrin degradation products). There were no relevant differences between the two medication groups., Conclusion: Our results demonstrate that both oral contraceptive preparations have comparable effects on the hemostatic system. There was a shift towards a new equilibrium of hemostatic activities, both coagulatory and fibrinolytic, at a higher turnover rate. Changes did not exceed the range of normal variation and were comparable to the published effects of other low-dose oral contraceptives. There was no evidence ofa differential risk of deep vein thrombosis between the two preparations.

Although the association between postmenopausal hormone use and breast cancer has not been clarified, there is nothing indefinite about the survival advantage conferred by hormone replacement therapy. Cardiovascular and fracture-related deaths so outnumber breast cancer deaths that even women with family histories of the latter are likely to benefit from low-potency estrogen replacement.

The aim of the study was to evaluate the effects of two therapeutic combinations of ethinylestradiol (EE) and levonorgestrel (LE), which are used in triphasic contraceptives, on the activities of drug-metabolizing enzymes in rat liver and kidney. Sexually mature female Wistar rats were given 0.03 mg EE and 0.05 mg LE, or 0.03 mg EE and 0.125 mg LE for 6 or 18 sexual cycles, i.e. for 30 or 90 days. EE/LE inhibited not only the metabolic capacity of P450, a protein which directly undergoes suicide inhibition, but also the level of rat liver cytochrome b5 (dependent on the heme pool) as well as the activities of NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase in the liver and kidney. The majority of these effects were independent of the gestagen dose and of the duration of treatment, suggesting that estrogen is a predominant inhibiting factor in the EE/LE combination. The study has revealed differences in the enzyme activities between the liver and kidney, which may result from the fact that these organs display different sets of P450 isoforms and, therefore, their monooxygenase systems show distinct capacities to metabolize exogenous steroids.

We tested the hypothesis that the shift in the cutaneous vasodilator response to hyperthermia seen with elevated female reproductive hormones is a prostaglandin-dependent resetting of thermoregulation to higher internal temperatures, similar to that seen in the febrile response to bacterial infection. Using water-perfused suits to control body temperature, we conducted heat stress experiments in resting women under conditions of low and high progesterone and estrogen and repeated these experiments after an acute dose of ibuprofen (800 mg). In six women the hormones were exogenous (oral contraceptives); three women had regular menstrual cycles and were tested in the early follicular and midluteal phases. Resting oral temperature (Tor) was significantly elevated with high hormone status (P < 0.05); this was not affected by ibuprofen treatment (P > 0.2). The Tor threshold for cutaneous vasodilation was significantly increased by high hormone status (+0.27 +/- 0.07 degrees C, P < 0. 02); the shift was not affected by ibuprofen treatment (with ibuprofen: +0.29 +/- 0.08 degrees C, P > 0.2 vs. control experiments). The Tor threshold for sweating was similarly increased by high hormone status (+0.22 +/- 0.05 degrees C, P < 0.05); this shift was not influenced by ibuprofen (with ibuprofen: +0.35 +/- 0. 05, P > 0.1 vs. control experiments). Thus the shift in thermoregulatory control of skin blood flow and sweating mediated by female reproductive steroids is not sensitive to ibuprofen; it therefore appears that this shift is independent of prostaglandins.

Manufacturers have steadily been decreasing the amounts of estrogen and progestin in oral contraceptives (OCs) in an effort to enhance safety and tolerability while preserving contraceptive efficacy. A new formulation containing 20 microg ethinyl estradiol (EE) and 100 microg levonorgestrel (LNG)--representing the lowest available contraceptive dose of each hormone--has undergone extensive clinical testing in the United States and Germany. A total of 1590 women in 61 centers received 20 microg EE and 100 microg LNG for 6 cycles. Overall, 4 pregnancies possibly related to treatment failure were reported, reflecting an overall Pearl Index (number of pregnancies per 100 woman-years of treatment) of 0.65 and a failure rate of 0.34%. Cycle control was typical of low-dose OC use. Spotting and breakthrough bleeding occurred most commonly during the earlier cycles in each study. Adverse events were typical of those seen with OC use and led to study discontinuation in 6.6% of the women. Intermenstrual bleeding was the cause for early study withdrawal in 2.6% of women. The study results suggest that the combination of 20 microg EE and 100 microg LNG offers the benefits of low hormone content with good contraceptive efficacy, cycle control, and tolerability.

The high estrogen doses in the original oral contraceptive (OC) formulations were associated with an increased risk of cardiovascular events. Since then the steroid doses in OC have been reduced steadily, so that current low-estrogen-dose (< or = 35 micrograms) combination OC are associated with a lower risk of arterial and venous events than occurs with higher-estrogen-dose formulations. Based on the currently available epidemiologic evidence, the following conclusions can be made regarding the cardiovascular disease risks associated with use of low-dose OC by healthy, nonsmoking women: there is no increased risk of myocardial infarction (MI) or hemorrhagic or ischemic stroke; and there is a three- to fourfold increased risk of venous thrombosis and embolism (VTE). This risk is about half that associated with pregnancy. Smoking is the most important independent risk factor for MI, and is synergistic with OC use. Women smokers should be advised strongly to stop smoking, but those aged < 35 years may use any OC containing < or = 35 micrograms of estrogen. Women smokers aged > or = 35 years should be advised to use a nonestrogen or nonhormonal contraceptive method.

Purpose: Our purpose was to assess the effect of pretreatment with oral contraceptives (OCs) on the formation of functional ovarian cysts during pituitary suppression with gonadotropin-releasing hormone (GnRH) agonists, subsequent follicular development, and pregnancy rates., Methods: A retrospective case-controlled study of 31 in vitro fertilization (IVF) patients, all of whom in a previous cycle had commenced the long protocol of GnRH-agonist (Buserelin) in the early follicular phase and were pretreated in a subsequent cycle with 2 weeks of an OC containing 30 micrograms of ethinyl estradiol and 150 micrograms of desogestrel prior to GnRH-agonist administration, was undertaken. Follow-up visits were arranged after a minimum of 11 days of GnRH-agonist administration and weekly thereafter until pituitary suppression was achieved., Results: Cysts were detected in 16 (51.6%) of the 31 patients not pretreated with OCs, and in 0 (0%) of the 31 patients pretreated with OCs (odds ratio = 67.1; 95% confidence interval = 5.6-350.7). Patients pretreated with OCs achieved pituitary suppression more rapidly (median difference = 4 days; 95% confidence interval = 2-7) and had comparable gonadotropin requirements and pregnancy rates., Conclusions: Pretreatment with OCs prior to pituitary suppression in the early follicular phase decreases ovarian cyst formation, without an apparent effect on subsequent follicular recruitment or pregnancy rates.

ABSTRACT Four groups of 3 male and 3 female sexually mature Beagle dogs were treated daily po with either ethinyl estradiol (EE) or estradiol (E2). A fifth group of 4 males and 4 females acted as a control group. Three groups of dogs were treated with EE: One group was treated at dose levels of 2.0, 1.5, and 1.0 mg/kg for 6 mo; the other 2 groups received either 0.5 mg/kg or 1.0 mg/kg for 1 yr. The fourth group was treated with 5.0 mg/kg E2 for 1 yr. Results obtained for the clinical, hematological, and biochemical parameters and the histopathologic findings of most organs and tissues in EE- and E2-treated dogs were essentially comparable to those documented in the literature for dogs treated with synthetic or natural estrogens. Chronic treatment with EE or E2 induced similar effects, with the exception of mesothelial proliferation of the genital serosa, which was observed in EE-treated dogs only. Additional new estrogen-related findings were observed in the kidneys and thyroid glands of EE- and E2-treated dogs. Increased interstitial fibrous tissue occurred at the corticomedullary junction and in the outer cortex of the kidney. It appeared to originate primarily from the perivascular fibrous tissue of branches of the renal arteries and veins. Extension of this lesion into the renal parenchyma resulted in secondary atrophic changes of tubules and glomeruli. The treatment relationship and specific characteristics of this renal alteration differentiated it from other chronic renal interstitial and vascular diseases. Squamous metaplasia of urogenital tract epithelia, including renal cortical tubule epithelium, occurred as expected in both EE- and E2-treated dogs. Unexpectedly, squamous metaplasia of thyroid follicular epithelium also occurred. It was present in scattered follicles of both EE- and E2-treated dogs. The renal and thyroid changes did not alter clinicopathological function tests for either of these organs. These 2 new findings extend the list of estrogen-related effects in the dog.

Objective: To compare the effect of starting oral contraceptives on the first day of menses with the effect of starting on the day of menses' cessation (but no later than the 5th day following its onset), on the incidence of early breakthrough bleeding., Method: Oral contraceptives containing 30 micrograms ethinylestradiol and 75 micrograms gestodene were prescribed to 200 consecutive healthy women in whom oral contraceptives were found to be the most suitable method of contraception. In the first 100 women, treatment was started on the 1st day after the onset of menses (Day 1 group), and in the remainder, treatment was started on the day of menses' cessation, but no later than the 5th day following its onset (Flexible group)., Results: The Flexible group had better compliance and a reduced incidence of breakthrough bleeding. No differences were observed between the two groups for age, parity and gravity, or contraceptive failure., Conclusions: Oral contraceptives may be initiated on the day of menses' cessation, but no later than the 5th day following its onset. This regimen might increase patient compliance and lower the incidence of breakthrough bleeding, probably without adversely affecting contraceptive efficacy.

The strong hepatic estrogenic actions of ethinylestradiol (EE) are very likely to be the cause of the cardiovascular morbidity related to the use of combined oral contraceptives (COCs). This survey presents results of EE replacement in COCs with natural 17beta-estradiol (E2) in the following stages: reduction of EE to daily doses of 0.01 mg and concomitant replacement with E2 (as valerate, EV), complete replacement of EE with E2 using a novel multiphasic combination containing EV and the progestin dienogest (DNG), and the use of natural E2 to develop estrogen sulfamates (J 995) showing sufficient dissociation of uterine from liver estrogenicity. Recent data from preclinical and clinical studies show that these approaches seem to be promising.

Fiber formulations are used in human nutrition owing to their beneficial properties for health. It is probable that ingestion of fiber coincides with the oral administration of drugs, and a modification of its oral absorption, and therefore of its pharmacokinetics, can appear. In the present study, the compartmental and noncompartmental pharmacokinetic parameters of ethinylestradiol (EE) in rabbits after oral administration were determined. It was also studied whether the presence of two different fiber formulations [A, wheat bran (76.5%), fruit fiber (12%) and guar gum (2%) and B, Plantago ovata seeds (65%) and P. ovata seed cuticles (2.2%)] in the gastrointestinal tract modified the pharmacokinetics of EE when administered at the same time. Three groups of rabbits were used: control, fiber A and fiber B. The animals in all three groups received 1 mg/kg b. wt. EE. The estrogen was administered alone in the control group and in the presence of 4 g of fiber A and fiber B, respectively, in the other two groups. After compartmental (two-compartment open model) and noncompartmental analyses of plasma concentrations, statistical analysis revealed that the presence of fiber (both A and B) decreased between 29% and 35% the extent of EE absorbed (represented by the pharmacokinetic parameters area under the curve and the maximum plasma concentration) without affecting the rate of the absorption process (represented by the time to reach maximum concentration and the absorption rate constant).

Objective: The aim of this study was to evaluate the effectiveness and safety of combined hormonal therapy in patients with recurring occult gastrointestinal bleeding of obscure origin., Methods: This was a prospective longitudinal observational study. The setting was an outpatient private practice affiliated with a large university-based hospital. A total of 43 patients, comprising 14 men and 29 women with a mean age of 74 yr (range 48-86 yr), were included. They had a history of recurrent gastrointestinal bleeding of unknown origin for a period of > 1 yr and had required multiple hospitalizations and transfusions. Patients were initially treated with one Enovid 5-mg tablet containing 5 mg norethynodrel and 75 microg of mestranol. Enovid became commercially unavailable and treatment was changed to Ortho-Novum 1/50, containing 1 mg norethindrone and 0.05 milligrams of mestranol, given one tablet b.i.d. Patients were treated and followed for a mean time of 535 days (range 25-1551 days). All patients acted as their own controls and were followed for compliant behavior with periodic hematocrit, serial stool hemoccults, medication counts, and clinical histories regarding transfusion requirements or hospitalization for bleeding or anemia., Results: Of 43 patients who initially entered the study, 38 were treated with combination hormonal therapy. The remaining five patients were treated with estrogen alone. In 25 patients, initial enteroscopy revealed AVMs in the stomach or proximal small bowel and these were cauterized. In the remaining 18 patients no source of bleeding was found. None of the 38 patients who were treated with combination hormonal therapy rebled as long as they continued their prescribed dosage. All five of the patients treated with estrogen alone had rebleeding episodes. There was no statistical difference with respect to AVM cauterization in the rebleeding rate between those patients who underwent cauterization of their AVMs and those who did not. Side effects of combination hormonal therapy occurred in 11 patients and all were considered to be mild. Seven of these 11 patients (64%) elected to continue treatment., Conclusion: In this long-term observational study, combination hormonal therapy was shown to stop rebleeding in patients with occult gastrointestinal bleeding of obscure origin.

Objective: To evaluate the clinical efficacy and cardiovascular complications of orchidectomy or polyoestradiol phosphate (PEP) in the treatment of advanced prostatic cancer., Patients and Methods: In a prospective, randomized study 444 patients (mean age 73 years, range 45-91) with T3-4 M0 or T1-4 M1 prostatic cancer were treated either by orchidectomy (group 1, n = 217) or parenteral PEP (group 2, n = 227; 240 mg/month). The patients were examined at 3 and 6 months after start of the therapy and thereafter every 6 months; they were also assessed whenever they had symptoms indicating progression. Possible cardiovascular complications included myocardial infarction, cerebrovascular accident, pulmonary embolism and deep vein thrombosis., Results: After a follow-up of 2 years there was no statistically significant difference between the groups in progression-free time; 65 of 217 (30%) patients in group 1 showed evidence of progression, including seven (3%) who died from prostate cancer. In group 2, 64 of 227 (28%) patients showed progression and eight (3.5%) died from prostatic cancer. There were 10 (5%) cardiovascular complications in patients in group 1, including five (2%) cardiovascular deaths; in group 2 there were 24 (11%) and 14 (6%), respectively. During the first year of treatment there were three (1.4%) cardiovascular complications in group 1 and 14 (6%) in group 2 (P < 0.05), and during the second year, seven (4%) and 10 (6%), respectively., Conclusion: Parenteral PEP (240 mg/month) seems to be as efficient as orchidectomy in inhibiting disease in patients with advanced prostatic cancer (T3-4 M0 and T1-4 M1). There were more cardiovascular complications in patients treated with PEP than after orchidectomy; the difference was statistically significant during the first year of treatment.

The influence of gender on serum concentrations of growth hormone (GH) and 12 other endocrine analytes was investigated in sera drawn from 291 healthy medical students in the ambulatory state in the morning, after fasting overnight. GH was measured with a sensitive noncompetitive fluoroimmunoassay. The median GH value was 80-fold higher in women 21-26 years old than in age-matched men (14.4 vs 0.18 mIU/L), compared with a female/male ratio of 2.2 for 17beta-estradiol and a male/female ratio of 14 for testosterone. Furthermore, the values for sex hormone-binding globulin, follicle-stimulating hormone, luteinizing hormone, prolactin, and insulin-like growth factor 1 (IGF-1) were higher, whereas the values for free thyroxine, triiodothyronine, thyroid-stimulating hormone, and parathyroid hormone were lower in the women. The median GH value was 68-fold higher in women 27-43 years old than in age-matched men (10.9 vs 0.16 mIU/L). Women taking contraceptives with ethinyl estradiol and desogestrel or levonorgestrel had higher GH values, and the desogestrel group had lower IGF-1 values than women not taking contraceptives. The median GH values in these groups were 125- and 117-fold higher, respectively, than in men 21-26 years old. The results suggest that routine morning activity produces a marked GH response in >90% of young women but in very few age-matched men. The effect on GH was even more pronounced in women taking oral contraceptives, suggesting that the intake of ethinyl estradiol contributes to higher GH concentrations in these women.

The influence which female sexual steroids, especially estrogen, have on the development of cancer has not only been shown epidemiologically, but also by experimental findings. Hormones, in spite of a known marginal increase in the risk of thrombosis and endometrial cancer, play an important role in the preventive cancer medication (oral contraceptives: ovarian and endometrial cancer; chemoprevention: high-risk breast cancer patients). Basically, hormone replacement therapy should be administered to all patients suffering from gynecological malignomas. In the case of patients suffering from breast cancer, the advantages of hormone replacement therapy (e.g., less risk of cardiovascular complications) need to be weighed against the disadvantages.

Unlabelled: The present prospective study is aimed to estimate the effect of a low-dose combined oestrogen drug Cyclo-Menorette on climacteric syndrome in women with early menopause., Material and Methods: The criteria for inclusion in the study were ac follows: 9-12 months of menopause, increased FSH levels, moderately expressed climacteric syndrome confirmed by the menopausal index of Kupperman and Hamilton-Anxiety-Scale /HAMA/. According to acceptance of hormone replacement therapy /HRT/ the women were divided into 2 groups--control T /n = 31/ and Cunder treatment T /n = 35/. The degree of climacteric syndrome expression after Kupperman and HAMA was estimated in all patients at the beginning as well as on the 3-d, 6-th 12-d months. The presence and dynamics of side effects were followed in the patients treated with HRT., Results: Spontaneous improvement of complaints was found out in the control group with an increase of intragroup differences during the follow-up period. Most expressed improvement in the group under treatment was established during the first 3-6 months, the beneficial effect being preserved until the end of the study., Conclusion: The use of 1 mg oestradiol valerat in combination with 2 mg oestriol results in a significant decrease of climacteric syndrome manifestation with slightly expressed and transient side effects.

Levels of inhibin A and B as well as other hormones in serum samples obtained during the pill-free interval in women taking combined oral contraceptives (OC) were measured to asses the extent of ovarian activity during that period. Type of pill and day of pill-free interval were recorded during routine gynecologic check-ups, if patients were in the pill-free period and had taken their pills regularly in the previous cycle. In addition to inhibin A and B, serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone were also quantified. Inhibin B levels rise significantly in parallel with rising levels of FSH, LH, and E2. Progesterone levels were completely suppressed and inhibin A levels rose slightly but insignificantly. Inhibins are sensitive biochemical markers of ovarian activity in pill-free intervals.

The incidence of gynecologic malignancies shows considerable regional differences which suggest a decisive role of environmental and endocrine factors in tumor genesis. The risk of developing breast cancer increases with increasing age, a positive family history, prolonged exposure to estrogens (early menarche, late menopause), nulliparity, alcohol consumption, and obesity. A relationship between a long exposure to estrogens and an increased risk of cancer may also be assumed in the case of endometrial cancer. Whether estrogens or their metabolites promote the initiation of cancer remains to be clarified. Endocrine monotherapy with only an estrogen, obesity, nulliparity/infertility as well as a late natural menopause are well-known risk factors of developing endometrial cancer. Whereas estrogens induce a hyperplasia of the endometrial mucosa, gestagens exert a protective effect on the endometrium. Old age, a family history of breast, endometrial and ovarian cancer as well as persistent or treated infertility are the established risk factors of ovarian cancer. Each pregnancy, the intake of oral contraceptives, a hysterectomy or tubal ligation are associated with a decreased risk of developing ovarian cancer; hormonal replacement therapy has no influence on the risk of ovarian cancer.

For some time the anti-ovulatory activity of certain estrogen/progestagen preparations was the main approach in fertility control. Up to date a drastic dosage reduction of both steroid hormones has been accomplished ameliorating the side effects on the one hand, and being active compounds as contraceptives, in the other. Currently, there are a wide variety of oral contraceptives available with a variety of estrogen doses combined with different progestagens. The estrogen content is a high as 80 micrograms and as low as 20 micrograms, moreover, such formulations are prescribed beginning the 1st or the 5th day of the menstrual cycle. By studying plasma and endometrial samples simultaneously obtained from chronic oral contraceptive users taking either 30 micrograms or 50 in such pills; a 17-beta-estradiol pattern was attained as that seen during follicular maturation in the ovulatory cycle only women under the lower dose of synthetic estrogen. However, in the endometrium such a cyclicity did not take place; in parallel circulating progesterone in both groups never reach levels greater than 5.0 ng/ml. Results offer to find a local critical period during the ovulatory menstrual cycle to achieve with much lower hormonal dosages a different approach in future methods of contraception.

Background: The aim of this 5-year retrospective study is to define the efficacy of oestro-progestinic interception., Methods: An oestro-progestinic mixture (0.05 mg ethinyl estradiol and 0.250 mg dlnorgestrel) was prescribed to 6003 women attending the gynaecological outpatients clinic of AIED (Associazione Italiana per l'Educazione Demografica) in Genoa, Italy, without evidence of any previous contra-indications. The prescription was of two pills at once and two pills 12 hours after. Before examination, the doctor asked for personal and medical history (age, date of onset of menses, unprotected intercourse date and anticonceptional failure); patients were also asked to report the data of the following menses to the clinic. The largest age range was between 20 and 24 years, probably because of their inadequate knowledge of contraceptives. The reasons for post-coital contraception were: sexual intercourse without contraceptive, failure of coitus interruptus and of the condom., Results: Post-coital interception efficacy (monthly oestro-progestinic contraception was 99.5%) according to retrospective statistical analysis, was according to Pearl index 92.9% vs 50% without any contraceptive., Conclusions: Finally, the efficacy of this method, together with its easy management and low frequency of severe contra-indications, allows us to indicate the "morning after pill" as one of the most useful outpatient strategies to avoid unwanted pregnancies.

It was hypothesized that estrogen-induced cardioprotection is mediated by up-regulation and down-regulation of expression of nitric oxide (NO) and P-selectin, respectively. Published data on circulating levels of the vasodilator NO, atherogenic glycoprotein P-selectin, and lipoprotein-a [Lp(a)] in users of triphasic contraceptive steroids are lacking. A total of 30 healthy women (nonusers, controls) and 82 women using oral triphasic contraceptive steroids (ethinyl estradiol and levonorgestrel: Triovlar, Schering AG) for 18 to 24 cycles participated in this study. Fasting blood samples were obtained from users and nonusers for the determination of P-selectin and Lp(a) by enzyme immunoassay and NO by a colorimetric method. The serum Lp(a) levels in OC users were significantly higher than those of nonusers. On the other hand, the serum NO levels in OC users were significantly elevated when compared to nonusers. Plasma P-selectin was significantly lowered in OC users p < 0.005. These results demonstrate the beneficial effects of ethinyl estradiol in the triphasic contraceptive regimen. Ethinyl estradiol may afford a degree of anti-atherogenic-cardioprotective effect by up-regulation of the expression of the vasodilator NO and down-regulation of the expression of the atherogenic P-selectin. This may outweigh the cardiovascular risk of the increased atherogenic Lp(a). This study may explain the very low rate of mortality from venous thromboembolism in OC users, which compares favorably with the risks that many people accept in daily life.

Treatment with pharmacological doses of estrogen is the most potent way to stimulate hepatic LDL receptor expression in vivo. The mechanism for this effect is unclear, in part because of difficulties in inducing this stimulation in vitro. A fundamental question, whether estrogen receptors (ERs) mediate this stimulation, has not been addressed. The aim of the current study was to determine the involvement of ERs in the estrogen-induced stimulation of LDL receptors. Treatment of rats with high doses of ethynylestradiol for 7 days increased the hepatic LDL receptor protein and mRNA levels four- and threefold, respectively. LDL receptor stimulation in estrogen-treated rats was not due to their reduced food intake because hepatic LDL receptor expression did not increase in rats fasted for 72 hours. Treatment with antiestrogen (tamoxifen or clomiphene) abolished the LDL receptor stimulatory effect of ethynylestradiol at both the protein and mRNA levels. Antiestrogen alone had no effect on hepatic LDL receptor expression and did not influence the strong resistance to dietary cholesterol normally present in rats. It is concluded that ERs are critically involved in the induction of hepatic LDL receptor expression by ethynylestradiol. The known role of growth hormone for the expression of hepatic ERs may therefore play a role in the modulation of the effects of estrogen on cholesterol metabolism and hepatic LDL receptors in the rat.

Hypoestrogenemia-derived urogenital symptoms after menopause manifest after some years of hormonal deficit and appear commonly in elderly, untreated women. In the urogenital tract low postmenopausal estrogen levels lead to vaginal irritation and dryness and to dyspareunia, often accompanied by other symptoms like uriesthesis, incontinence or recurrent infections. Every systemic estrogen treatment is accepted as efficient for the correction of urogenital symptoms, often even at doses lower than those necessary for the correction of vasomotor symptoms. Diverse local treatments have been proposed: estriol, promestriene and low-dose estrone or estradiol. Promestriene applied locally stimulates differentiation and maturation of vaginal mucosa and compensates local hypoestrogenic effects without marked hormonal effects outside the vagina. Vaginal application of estrone, on the other hand, has rather been proposed for systemic hormone substitution and elevated levels of estrone and estradiol observed in the plasma render this method in-appropriate in cases where strictly local effects are desired. Recently, very low doses of estradiol in a range of 7.5 micrograms/day have been proposed for the treatment of urogenital atrophy by means of a prolonged release regimen. Among the described preparations, those with strictly local (devoid of systemic) effects should be restricted to patients with contraindications for systemic substitution therapy. Local estrogen therapies are recommended for the treatment of complaints due to vulvar and vaginal atrophy. They have also been proposed by certain authors for the acceleration of the cervico-vaginal and vulvar cicatrisation after surgical interventions or postpartum. The presence of miction disorders in elderly postmenopausal women is also a point in favour of local treatment.

Background: Treatment of prostatic disease with GnRH agonists or by orchidectomy affects bone mass negatively. Estrogen treatment has beneficial effects on bone mass in women and might hypothetically have a bone preserving capacity also in patients with prostatic cancer., Methods: We followed serum markers for bone and collagen metabolism and sex steroids for 18 months in patients with prostatic cancer treated by orchidectomy (N = 13) or by single-drug parenteral polyestradiol phosphate (240 mg intramuscularly every second week for the first two months, and then every fourth week; N = 17)., Results: Total and free testosterone reached castration levels within 1.5 months of estrogen treatment. Four patients developing progressive disease and/or signs of metastasis were excluded from the analysis. In the remaining patients, serum osteocalcin, procollagen IIIP (PIIINP), procollagen (PICP), and the crosslinked carboxyterminal telopeptide of type I collagen (ICTP) increased significantly over time following orchidectomy (N = 11). Serum osteocalcin and PICP decreased significantly over time during estrogen treatment (N = 15). Treatment values of all four markers were significantly lower in estrogen-treated than in orchidectomized patients., Conclusions: The changes in serum bone and collagen markers indicate an increased bone turnover in orchidectomized subjects. The opposite pattern was found in the estrogen-treated patients, indicating a reduced turnover. Estrogens may also have a bone mass-preserving capacity in elderly males with prostatic cancer.

Cessation of ovarian activity is accompanied by a more or less marked and more or less accelerated reduction in bone mass; the degree and speed of the process--which occurs in all women--depends on individual (genetic factors influencing peak bone mass, duration of child-bearing period), iatrogenic (treatment with corticosteroids or thyroid hormones) or accidental factors (post-traumatic immobilization). Whatever the factor that triggers off the process, the end result is the destruction of bone tissue. This process may be documented by hematochemical (Nordin's test) and instrumental parameters (MOC and similar techniques). Oestroprogestin (and to a lesser extent calcitonin) hormone replacement therapy has been demonstrated to be highly efficacious in countering this involutive process. The authors report data obtained following the evaluation of 35 women in menopause undergoing. Nordin's test and measurement of the plasma level of estradiol using RIA, before and after twelve months after the start of osteoprotective treatment. Of the 35 patients 9 received only progestin, 22 an oestroprogestin combination (of these 18 patients received estrogen transdermally and 4 orally), and 4 calcitonin administered parenterally. A statistically significant positive correlation with Nordin's test was only found in the group receiving oestrogen therapy. In conclusion, it may be affirmed that in the absence of contraindications oestrogens represent the elective form of treatment for menopausal osteoporosis. Acceptable results have been reported in the literature also using calcitonin, but this treatment could not be evaluated in this study owing to the reduced number of the sample treated.

Several antibiotics have been implicated in oral contraception failure when they are administered at the same time as the oral contraceptive (OC) pill. In the present paper, a study about amoxicillin-ethinylestradiol (EE2) pharmacokinetic potential interaction was studied. Two rabbit groups were utilized, the first group received amoxicillin (10 mg/kg) and EE2 (30, 50 and 100 micrograms/kg, respectively), both by intravenous (i.v.) route. The second group received amoxicillin (oral route, 10 mg/kg/day) and EE2 (i.v. route, 100 mu/kg) on day 1, 4 and 8 of antibiotic treatment, respectively. After compartmental (two-compartment open model) and non-compartmental analysis of plasma concentrations, the statistical study (ANOVA p < or = 0.05) revealed that the presence of amoxicillin did not modify the EE2 distribution and elimination pharmacokinetic parameters (by comparison with those obtained in a previous study where EE2 was administered alone). There also were no significant differences with the time of amoxicillin oral treatment.

Background: The risk of thromboembolic events related to the ethinyl estradiol (EE) dose in oral contraceptive (OC) pills has led to a further dose reduction., Methods: An OC pill with 150 micrograms desogestrel combined with only 20 micrograms EE was compared with a pill containing the same dose of desogestrel but 30 micrograms of EE in a Scandinavian multicentre study with follow-up visits after 3, 6 and 12 months., Results: In almost 5,000 cycles with each pill the numbers of pregnancies due to method failure with the lower and higher EE dose pills were 0 and 2, respectively. Irregular bleedings were slightly more common with the lower EE dose, but tended to decrease over the year of study. Other side effects were uncommon. Regarding metabolic effects, both pills tended to raise the plasma HDL level and the lower EE dose pill also reduced LDL. Free testosterone was reduced by two-thirds with both pills, showing beneficial effects on acne., Conclusions: It is concluded that both these pills are reliable and safe, but that many women would accept a slightly greater risk of irregular bleeding with the 20 micrograms EE dose pill in exchange for a reduction in potential risk related to the estrogenic component of OC pills.

The purpose of this study was to compare the effects of droloxifene (DRO), tamoxifen (TAM), and 17 alpha-ethynyl estradiol (EE) on bone mineral density, bone histomorphometry, total serum cholesterol, and uterine histology in the ovariectomized (ovx) rat model. Sprague-Dawley female rats at five months of age were sham-operated and treated orally with vehicle (n = 8), or ovx (n = 56) and treated (p.o.) with either vehicle, DRO at 0.1 or 1.0 mg/kg daily, TAM at 0.1 or 1 mg/kg daily, or EE at 3 or 30 micrograms/kg daily for 4 weeks. The uterine wet weight and uterine histologic parameters (cross-sectional tissue area, stromal thickness, and luminal epithelial thickness) were determined. Femoral and lumbar vertebral bone mineral density was determined ex vivo using dual energy x-ray absorptiometry. Static and dynamic cancellous bone histomorphometry was performed on double-labeled, undecalcified longitudinal sections from proximal tibial metaphyses. Furthermore, the changes in total serum cholesterol and body weight gain were also determined. Compared to sham controls, ovx for four weeks significantly decreased uterine weight (-72%), uterine cross-sectional tissue area (-74%), stromal thickness (-52%), and luminal epithelial thickness (-53%). ovx rats treated with EE at 30 micrograms/kg/day maintained these parameters at the levels of sham controls. Uterine weight and uterine cross-sectional tissue area in 3 micrograms/kg/day of EE treated ovx rats were higher than that of vehicle-treated ovx rats. In ovx rats treated with TAM at both 0.1 and 1 mg/kg/day, these parameters were significantly less than sham controls but significantly higher than ovx controls. DRO at 0.1 mg/kg/day had no effects on all above parameters. Uterine weight and cross-sectional tissue area in 1 mg/kg/day of DRO treated ovx rats was slightly but significantly higher than that in ovx controls. However, DRO at 1 mg/kg/day had no effects on uterine stromal thickness and luminal epithelial thickness compared to ovx controls. The ovx-induced decrease in femoral and lumbar vertebral bone mineral density was prevented by treatment with EE at 30 micrograms/kg/day, TAM at both 0.1 and 1 mg/kg/day, or DRO at 1 mg/kg/day. Similarly, the decrease in bone mass and the increase in bone resorption and bone turnover in proximal tibial metaphyses were prevented by treatment with EE at 30 micrograms/kg/day or TAM at both 0.1 and 1 mg/kg/day, or DRO at 1 mg/kg/day. Total serum cholesterol decreased significantly in ovx rats treated with either EE, DRO, or TAM at all dose levels compared to vehicle treated ovx controls (-32% to -56%). The ovx-induced body weight gain was completely prevented by EE at 30 micrograms/kg/day, and partially prevented by DRO at 1 mg/kg/day. TAM at both 0.1 and 1 mg doses caused a significant decrease in body weight compared to both sham and ovx controls. Our results indicated that DRO prevented ovx-induced bone loss and lowered total serum cholesterol with an ED50 less than 1 mg/kg/day. The bone protective and cholesterol lowering effects of DRO were comparable to those observed with TAM and EE. However, DRO differed from TAM and EE in its lack of significant estrogenic effects on uterine tissue at doses which were bone protective. These data suggest that DRO may be a significant alternative to EE and TAM for prevention and treatment of postmenopausal osteoporosis.

Objective: To compare the effect of continuous norethindrone acetate (NA)-ethinyl estradiol (EE2) combinations with matching unopposed EE2 or placebo., Design: A 2-year, double-blind, placebo-controlled, parallel-group clinical trial., Setting: Outpatients at 65 centers., Patients: Asymptomatic or mildly symptomatic women aged 40 years or older who had undergone the onset of spontaneous menopause within the last 5 years and who had an intact uterus., Interventions: Patients were equally randomized to placebo or 1 of 8 treatment groups: 0.2 mg of NA and 1 microg of EE2; 0.5 mg of NA and 2.5 microg of EE2; 1 mg of NA and 5 microg of EE2; 1 mg of NA and 10 microg of EE2; 1 microg of EE2; 2.5 microg of EE2; 5 microg of EE2; or 10 microg of EE2., Primary Outcome Measures: Bone mineral density (BMD) measured by quantitative computed tomography, serum lipids, and endometrial effects as assessed by rate of hyperplasia and proliferative status., Results: Twelve hundred sixty-five patients entered the study. Bone mineral density increased significantly from baseline (P<.001) in the 1 mg NA-5 microg EE2 and the 1 mg NA-10 microg EE2 treatment groups at each annual assessment. Among the unopposed EE2 groups, only the 10-microg group had increased BMD above baseline, but also was accompanied by an unacceptably high rate of endometrial hyperplasia. The NA-EE2 treatment groups had a significant linear dose-response trend for increasing BMD. Increased endometrial proliferation and hyperplasia occurred with increasing unopposed estrogen doses. The combination of NA and EE2 effectively protected the endometrium against hyperplasia. The percentage of change in the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol was positive for all treatment groups. The increase in triglyceride levels associated with EE2 was attenuated with NA-EE2 treatment., Conclusions: Daily treatment with NA-EE2 was well tolerated and protected the endometrium from EE2-induced proliferation and hyperplasia. The NA-EE2 treatments produced a dose-related significant increase in BMD that was not present with unopposed EE2 treatment. The overall effect of NA-EE2 treatments on lipid measures was favorable.

The aim of this study was to assess whether during regular OC use ovarian activity might lead to ovulation, as assessed by ultrasound (US) evaluation of follicular growth and blood levels of 17-beta-estradiol and progesterone. A total of 51 healthy women with normal menstrual cycles (28 +/- 3 days) and no gynecological symptoms were recruited. A total of 22 patients were given a triphasic OC pill containing 35 mg ethinyl estradiol (EE) and 50 mg desogestrel (DSG) in the first seven tablets; 30 mg EE and 100 mg DSG in tablets 8 to 14, and 30 mg EE and 150 mg DSG in tablets 15 to 21; 29 patients received one of two OC pills, both containing 20 mg EE plus 150 mg DSG (15 patients) or 75 mg of gestodene (14 patients). A total of 86 cycles were monitored: 51 during the 3rd-4th cycle and 35 during the 6th-8th cycle of OC treatment. Follicular-like structures were observed in nine patients. The frequency of follicular-like structures was similar during the 3rd-4th cycle (9%) and during the 6th-8th cycle (11%). There was no relationship between follicular growth and blood levels of E2 and progesterone, which always appeared suppressed. In conclusion, the results of this study suggest that during OC use (even with low dose of ethinyl estradiol), a little ovarian activity may be present without ovulation.

An open comparison at a single center was performed in volunteers (n = 58) randomly allocated to two treatment groups, one receiving tablets containing 20 micrograms ethinylestradiol (EE) + 75 micrograms gestodene, and the other 30 micrograms EE + 75 micrograms gestodene. The study consisted of three treatment-free pre-cycles, followed by thirteen 28-day treatment cycles. Analysis of results revealed that there were no statistically significant differences between the two groups with regard to the plasma levels of HDL-cholesterol and its subfractions, LDL-cholesterol and apolipoproteins. There was, however, a trend toward a more favorable effect on HDL-cholesterol in the 20 micrograms EE group, where levels increased by 3% compared with the 30 micrograms EE group, where levels decreased by 9%. There was a statistically significant difference between the adjusted mean values of total triglycerides in the two groups in favor of the 20 micrograms EE group (+21%), compared with the 30 micrograms EE group (+64%) (p = 0.029). Two serious adverse events were reported (lymphadenopathy and vertigo), but neither were considered to be causally related to either study medication. The formulation containing 75 micrograms gestodene and 20 micrograms EE was shown to be a reliable and well tolerated oral contraceptive, with a favorable lipid profile.

Estrogens exert a protective effect against atherosclerosis. It is well known that hormone replacement therapy (HRT) can effectively decrease LDL-cholesterol and increase HDL-cholesterol and Apo-Al serum levels. Some recent studies have suggested that estrogens alone or in association with progestins may exert an antioxidant effect on lipids. Besides sex steroids, also vitamins exert an antioxidant effect on LDL and may preserve the endogenous antioxidants of LDL. The aim of our study was to evaluate whether HRT can improve alpha-tocopherol and beta-carotene serum levels in post-menopausal women. Fifteen postmenopausal women with climacteric symptoms were treated with 50 micrograms/24 h estradiol transdermally applied twice a week for 21 days. A daily dose of 10 mg oral medroxyprogesterone acetate was added for 12 days in each treatment cycle. This therapy lasted 6 months. A significant reduction was found in total cholesterol and LDL-cholesterol after treatment. Besides, our study has shown that alpha-toc/LDL and beta-car/LDL ratios significatively increased after treatment, while alpha-tocopherol and beta-carotene serum levels did not change significantly after therapy. These preliminary findings suggest that HRT can preserve the content of alpha-tocopherol and beta-carotene in LDL particles and keep the LDL in a reduced antioxidant state.

It was the aim of the study to compare the pharmacokinetic properties of the two new estrogens, ZK 136295 and ZK 115194, with those of ethinylestradiol (EE2) after single intravenous (60 micrograms) and oral (120 and 240 micrograms) administration in 54 postmenopausal women. In particular, our objective was to examine whether one or both compounds were characterized by an improved oral bioavailability with less inter-subject variability than EE2. Drug serum concentrations were determined using specific radioimmunoassays for EE2 and ZK 136295, and a GC/MS/MS-method for ZK 115194. Following i.v. administration of the new estrogens and of EE2, the drugs were rapidly distributed in the body. The mean terminal half-lives were calculated to be 12.3 +/- 12.4, 28.7 +/- 9.6, and 26.1 +/- 11.1 h for ZK 136295, ZK 115194, and EE2 respectively. After oral administration of 120 micrograms, the absolute bioavailability was calculated to be about 40% for ZK 136295 as well as for EE2 with a high inter-individual variation (variation coefficient: 44 and 67%). By doubling the dose, the systemic availability increased dose-dependently for both drugs to about 70% with the same high inter-individual variation. Following single oral administration of 240 micrograms ZK 115194, the absolute bioavailability amounted to 33 +/- 19%. The present study clearly revealed that although the two new estrogens differed considerably in their pharmacokinetic behavior, they demonstrated a reduced and highly variable systemic availability similar to that of EE2.

Objectives: To assess the effect of oral contraception started on the first day of menses and the fifth day following its onset, on women's compliance and the incidence of early breakthrough bleeding., Methods: Oral contraceptives (OCs) containing 30 micrograms ethinylestradiol and 75 micrograms gestodene were prescribed to 100 consecutive, healthy women for whom OCs were found to be the most suitable method of contraception. In the first 50 women, OCs were started on the first day of menses (day 1 group), while in the remaining 50 women, OCs were started on the fifth day after the onset of menses (day 5 group)., Results: The day 5 group had better compliance and a reduced incidence of breakthrough bleeding. No differences were observed between the two groups regarding age, parity and gravity., Conclusion: Starting an OC regimen should include initiation on the fifth day following the onset of menses. This regimen might increase patient compliance and lower the incidence of breakthrough bleeding.

In a 6-month, randomized, double-blind study the effects of two combined oral contraceptives containing 150 micrograms desogestrel and either 20 or 30 micrograms ethinylestradiol on hemostatic parameters were investigated in 1633 healthy women. Compared with baseline, the 30 micrograms ethinylestradiol formulation increased prothrombin fragment 1 + 2 (+72.2%), D-dimer (+42.4%) and protein C activity (+6.1%), whereas antithrombin-III activity (-6.3%) and protein S activity (-19.7%) were decreased. The use of the 20 micrograms ethinylestradiol formulation was associated with the same pattern of changes, but with lower magnitude (F1+2 + 61.1%, D-dimer +36.0%, antithrombin III -5.3%, protein C +4.6% and protein S-16.0%). The changes from baseline were significantly smaller in the 20 micrograms ethinylestradiol group for D-dimer, antithrombin III and protein S than in the 30 micrograms ethinylestradiol group (p = 0.019, p = 0.038 and p = 0.001, respectively). One woman with a combined deficiency of proteins C and S developed deep venous thrombosis while using the 20 micrograms ethinylestradiol formulation. Use of both formulations was associated with a shift of the coagulation-fibrinolysis balance to an enhanced fibrin-generating and fibrin-degradating activity. The less-pronounced effect on hemostasis with the 20 micrograms ethinylestradiol preparation is reassuring with regard to thromboembolic risk in general. However, women with coagulation inhibitor deficiency should be advised not to use oral contraceptives.

When given orally, estrogens, as well as androgens, lower serum lipoprotein (a)[Lp(a)]levels. To determine whether these effects occur also after parenteral administration of steroids, Lp(a) levels were determined in two groups of elderly males suffering from prostatic carcinoma, who were randomized to treatment with parenteral estrogen (n = 8) or orchidectomy (n = 6). One group of healthy male volunteers (n = 9) was studied after parenteral administration of testosterone. Estrogen was given as im polyestradiol phosphate, 240 mg twice monthly, and testosterone was given as im injections, 250 mg/week. In the orchidectomized subjects, Lp(a) levels increased by 20% by month 3 after treatment (P < 0.05). In spite of drastic changes in serum hormone levels, no change in Lp(a) levels was observed in the estrogen-treated subjects. Concomitantly, low-density lipoprotein cholesterol levels were lowered by 15% and high-density lipoprotein cholesterol levels increased by 20%. Testosterone administration lowered Lp(a) levels by 20% (P < 0.05). No significant changes in serum lipid levels were observed in the testosterone-treated subjects or in the orchidectomy group. Thus, during parenteral administration of estrogens or androgens, diverging effects on Lp(a) and serum lipoproteins were observed. In particular, the mode of administration of estrogen influenced the response in Lp(a) levels. This suggests that the regulatory role of sex hormones on serum Lp(a) levels may depend on their capability to influence hepatic metabolic pathways of Lp(a).

The pharmacokinetics and endocrine effects of polyestradiol phosphate (PEP; Estradurin) were studied by determination of the concentrations of estradiol (E2), unconjugated (E1) and total estrone (tE1; > or = 85% estrone sulfate), and testosterone in serum from 11 prostatic cancer patients after administration of a single intramuscular injection (320 mg). After injection of PEP, serum concentrations of E2, E1, and tE1 increased during 2-3 weeks. Thereafter serum E2 declined monophasically with a mean half-life of 70 days. The elimination of E1 and tE1 seemed to be governed by the formation of E2. The testosterone concentration decreased inversely to the raising E2 level and reached castration levels within 3 weeks and remained at this level for about 2 weeks, whereafter it increased inversely to the decreasing E2 concentrations.

In an open prospective study we evaluated the glycaemic control and lipoprotein metabolism in 22 women with uncomplicated insulin dependent diabetes mellitus during one year of oral contraception with ethinyl oestradiol and gestodene. Twenty women of comparable diabetic status using non hormonal contraception served as controls. No changes in glycaemic control were observed in any of the groups. In the oral contraceptive group decreased serum levels of low-density lipoprotein cholesterol and increased levels of triglycerides and lipoprotein A were noted whereas total cholesterol and high-density lipoprotein cholesterol levels were unchanged. In the control group a decrease of low-density lipoprotein cholesterol was observed. No effect of tobacco smoking on glycometabolic control or lipoprotein metabolism could be demonstrated during hormonal intake. In conclusion, we found no evidence of impaired glycometabolic control or adverse changes in serum levels of lipoproteins known to be associated to atherosclerosis in diabetic women during one year of oral contraception with ethinyl oestradiol and gestodene.

The effects of grapefruit juice on the bioavailability of 17 alpha-ethinylestradiol (EE2) after a single oral administration of 50 micrograms EE2 have been investigated. The pharmacokinetics of EE2 were studied in an open, randomized, cross-over study in which 13 healthy volunteers were administered the drug with herbal tea or grapefruit juice (naringin, 887 mg/ml). In contrast to herbal tea, grapefruit juice increased the peak plasma concentration (Cmax) significantly to 137% (mean; range 64% to 214%, p = 0.0088) and increased the area under plasma concentration-time curve from 0 to 8 hours (AUC0-8) to 128% (mean; range 81% to 180%, p = 0.0186). This study shows that grapefruit juice increases the bioavailable amount of EE2. A possible explanation may be that grapefruit juice inhibits the metabolic degradation of EE2. Whether the increased bioavailability of EE2 following grapefruit juice administration is of clinical importance should be investigated in long-term studies.

In an open, randomized study in an outpatient clinic of a large teaching hospital, thirty-one female volunteers with regular cycles and established ovulation by ultrasonography were given one of two triphasic oral contraceptives containing ethinylestradiol combined with levonorgestrel or desogestrel during six cycles of treatment. The main outcome measures were transvaginal ultrasonography and serum E2 and P measurements in pill cycles 1, 3 and 6. No ovarian activity was found in 10 subjects. Among the remaining 21 women who showed ovarian activity, most follicle-like structures developed in the pill-free week and decreased in size or disappeared in the first pill week. One women taking triphasic desogestrel had evidence of a luteinized unruptured follicle and one women taking triphasic levonorgestrel had a possible ovulation. The latter women also showed symptoms of lower abdominal pain. A statistically significant difference in ovarian activity between the two oral contraceptives could not be established. The two triphasic oral contraceptives suppressed ovarian activity to the same degree. A trend was seen towards increasing ovarian activity with duration of use in both treatment groups.