Long-term 17alpha-ethinyl estradiol treatment decreases cyclin E and cdk2 expression, reduces cdk2 kinase activity and inhibits S phase entry in regenerating rat liver.

BACKGROUND/AIMS: The synthetic estrogen 17alpha-ethinyl estradiol (EE), a potent tumor promoter in rat liver, stimulates growth during short-term treatment but inhibits hepatocyte proliferation upon prolonged treatment. To identify the molecular targets of the mitoinhibitory effect of EE, the expression of proteins regulating G(1)- and S-progression were analyzed during the first cell cycle in EE-treated female Wistar rats. METHODS: Long-term (60 days) EE treatment. Immunohistochemical staining for proliferation cell nuclear antigen (PCNA) to detect cells in S phase and quantification of mitosis. Western blot to monitor protein expression. Cdk2 kinase assay to examine histone H1 phosphorylation. RESULTS: EE reduced the number of cells in S phase and mitosis by about 70%. Cyclin D1 and D3 were unaffected, while cdk4 was moderately decreased. Cyclin E and cdk2 were markedly decreased with concomitant marked reduction of cdk2 kinase activity. EE also decreased cyclin A and increased G1 levels of p53 and p21. CONCLUSIONS: EE causes a cell cycle block before S-phase. The reduction of the cdk2 kinase activity, essential for G1/S-transition, might be involved in the cell cycle block. Also, EE treatment results in p53 activation and upregulation of the cdk inhibitor p21 that might contribute to the G1 arrest.

[Correlative changes of histomorphometry and biomechanical property of lumbar vertebrae body in ovariectomized rats].

This paper presents the correlative changes of cancellous bone histomorphometry, biomechanical property and bone mineral contents of lumbar vertebrae in ovariectomized rats. Forty eight 10.5-month-old female SD rats were randomized to six groups: 1) Basal: at 10.5 mon. of age; 2) sham-1: sham-operated at 13 mon. of age; 3) OVX-1: ovariectomized at 13 mon. of age; 4) sham-2: sham-operated at 16 mon. of age; 5) OVX-2: ovariectomized at 16 mon. of age; and 6) OVX-2 + EE: ovariectomized and treated with 17 alpha-ethynylestradiol (100 micrograms.kg-1.d-1) starting at 13 mon. of age for 12 weeks. Double in vivo fluorochrome labeling was administered to all rats. At the end-point of study, the undecalcified longitudinal fourth lumbar vertebra (LV4) sections were cut and stained with Goldner's Trichrome for bone histomorphometric analyses. The mechanical properties of the compact fifth lumbar vertebra body (LV5) were measured with compression test, the LV5 bodies then were dried constantly with high temperature and digested with acid for testing of bone mineral content. A trend in trabecular bone volume (BV/TV), trabecular thickness (Tb.Th) of LV4, bone break load, break stress, elastic moduli and bone calcium content of LV5 to increase with the increase of age was revealed in the intact rats, but the highest value was at 13 mon. of age. A positive correlation was seen between histomophormetry and bone bio-mechanical properties in the intact rats. Compared with the data from the sham-operated rats, the BV/TV and Tb. Th significantly decreased and bone turnover rate significantly increased in OVX rats at 10 weeks, and the above parameters further decreased 22 weeks post OVX. Correspondingly, the bone break load, break stress, elastic moduli and bone calcium content significantly decreased with the increase of time post OVX was compared with those of sham-operated rats. A positive correlation between histomophormetry and bone biomechanical properties was also observed in OVX rats (r = 0.399, P = 0.018). Bone histomorphometry is good for predicting early physiological and pathological changes and bone biomechanical properties are good parameters for predicting corresponding function of bone such as fracture. Both of them are useful and needful in the animal studies on osteoporosis and related pharmacodynamic observations on new drugs.

Efeitos da Tibolona na evoluçäo dos miomas uterinos em mulheres na pós-menopausa / Tibolone effects on myoma progression in postmenopause women

OBJETIVO: Avaliar o efeito da tibolona (Livial) na evoluçäo de miomas em mulheres na pós-menopausa. TIPO DO ESTUDO: Estudo prospectivo, aberto, multicêntrico e näo comparativo. PACIENTES E MÉTODO: Foram estudadas 12 pacientes menopausadas, portadoras de miomas uterinos dos tipos intramurais ou subserosos, com diâmetro médio de 3 cm, submetidas à terapêutica de reposiçäo hormonal com tibolona na dose de 2,5 mg, durante 48 semanas. Realizou-se ultra-sonografia transvaginal antes, e após 24 e 48 semanas do tratamento. RESULTADOS: Houve reduçäo significativa (p<0,05) no número total de miomas, declinando de 16 para 11 após 48 semanas. Näo ocorreu alteraçäo significativa no diâmetro médio dos nódulos miomatosos, assim como na espessura endometrial, que se traduziu clinicamente por ausência de sangramento durante o tratamento. CONCLUSÕES: a tibolona parece näo interferir com o crescimento do mioma uterino e dve ser considerada como boa opçäo para terapia de reposiçäo hormonal em pacientes na pós-menopausa portadoras dessa neoplasia benigna

Does hormonal therapy have any benefit for bleeding angiodysplasia?

Sixty-four patients took part in a cohort study measuring the efficacy of daily hormonal therapy in diminishing intestinal bleeding from small bowel angiodysplasia. Thirty patients received 5-10 mg norethynodrel either with mestranol, 0.075-0.15 mg (24 patients) or with conjugated estrogens, 0.625 mg (six patients). The cohort group consisted of 34 patients who either refused hormonal therapy (six patients) or were diagnosed early in our experience, before the resurgence of hormonal therapy (28 patients). Mean follow-up was 15.6 months (range 2-31 months) for the treated group and 13.4 months (range 1-23 months) for the untreated group. In addition, the change in monthly transfusion requirement with therapy was analyzed ("within group" analysis). Fifty percent (15 of 30) of the treated group required no further transfusion during therapy, while 44% (15 of 34) of the untreated group required no further therapy (not significant). During therapy, the mean monthly transfusion requirement of packed red blood cells in the treated group was not significantly different from that found before therapy (1.5 vs. 2.2 units, NS) or from that of the control group (1.5 vs. 1.6 units, NS). The findings do not support the use of hormonal therapy for bleeding from small intestinal angiodysplasia.

Oral contraception: a review.

PIP: This review of the development of oral contraceptives (OCs) begins with a summary of research between 1920 and 1950 that led to the first highly effective, orally active progestogen for human use. Enovid by Searle, the first marketed OC, began being distributed in 1960; it was combination of 9.85 mg of norethynodrel and .150 mg of mestranol. Research on combination norethynodrel-containing products revealed that the dosage was too high. Discussion focuses on preparations containing norethisterone, norethisterone acetate, medroxyprogesterone diacetate, norgestrel, other Norgestrel products available outside the US, progestogen, as well as the sequentials and the multiphasics. The active phase of clinical development was during 1950s and 1960s. The Food and Drug Administration (FDA) had an active role in regulating OCs; OCs with more than .05 mg of estrogen were removed from the market; FDA permitted ethinyl estradiol as a substitute for mestranol. Pregnancy rates appear lower in clinical trials than among the general population. 3% during the first year is considered more characteristics of the failure rate among the general population. It appears that intermenstrual bleeding (IMB) has decreased as doses have been decreased, but strict comparison between studies and over time is not possible. There is valid documentation of the rate of IMB with low-dose OCs, or of differences between new OC users and prior OC users, or of the impact of the strength of OC components.^ieng

Hormonal therapy of endometriosis.

Hormonal therapy has long been the mainstay of the medical management of endometriosis. However, there is considerable confusion regarding the appropriate application of hormones in the treatment of endometriosis. This article critically reviews the current status of the steroidal therapy of endometriosis.

Ocular vicarious menstruation.

Vicarious menstruation represents cyclical bleeding in extragenital organs during a normal menstrual cycle. We present an unusual case of ocular vicarious menstruation (bloody tears) in a 17-year-old girl. The indications and treatment of this rare disorder are discussed.

Estrogen-progesterone therapy for recurrent gastrointestinal bleeding secondary to gastrointestinal angiodysplasia.

Recurrent gastrointestinal bleeding ceased after the institution of estrogen-progesterone therapy in a patient with gastrointestinal angiodysplasia without chronic renal failure. The patient did have aortic stenosis and mitral insufficiency murmurs. A therapeutic trial of conjugated estrogen should be considered in patients with recurrent gastrointestinal bleeding secondary to gastrointestinal angiodysplasia after the use of therapeutic endoscopy and/or surgery.

PIP: A case report is presented of a 78-year-old patient with recurrent gastrointestinal bleeding who required frequent hospitalizations and several blood transfusions, both of which ceased after the institution of estrogen-progesterone therapy. The patient was hospitalized in April 1985 with weakness and shortness of breath. Her hemoglobin was 9.8. Indices were suggestive of a microcytic hypochromic anemia. Bone marrow revealed absent iron stores. The patient denied a prior history of melena, hematochezia, or hematemesis. There was no history of peptic ulcer disease. The patient was taking no medications, and she denied alcohol abuse and a family history of bleeding. The physical examination revealed a pale and weak appearing women in no acute distress. An aortic stenosis and mitral insufficiency murmur was her only positive physical finding. Hemoccult positive stool was detected on rectal examination. The patient was transfused with 2 units of packed cells and underwent an evaluation. Subsequently, the patient required 4 more hospitalizations requiring blood transfusions. In October 1985, the patient underwent an exploratory laparotomy and an intraoperative endoscopy of the entire gastrointestinal tract. There was evidence of bleeding in the cecum near the ileocecal valve. The patient underwent an ascending colectomy. The histopathology of the specimen revealed angiodysplasia of the cecum. Postoperatively, during a 5-month period, the patient required 16 units of blood. In March 1985, Enovid E was started, and the patient has not required further hospitalizations or a blood transfusion since. The only side effects of the estrogen-progesterone combination which this patient experienced were vaginal bleeding and mild systolic hypertension. In patients with gastrointestinal angiodysplasia who have cryptogenic gastrointestinal bleeding, despite the use of therapeutic endoscopy and surgery, possibly a trial of estrogen-progesterone therapy should be considered.

[Results of treatment of atypical endometrial hyperplasia]. / Rezultaty lecheniia atipicheskoi giperplazii éndometriia.

PIP: To evaluate the risk of transformation of atypical endometrial hyperplasia (AEH) into endometrial cancer, a group of 190 women who underwent treatment for AEH was followed up. The group included 53 women of child-bearing age, 81 in the premenopausal period, and 56 in the postmenopausal period. The most frequent clinical manifestation of AEH was metrorrhagia. The patients with mild or moderate AEH received conservative treatment, while the patients with severe AEH complicated by other gynecological diseases (uterine myoma or adenomyosis) received surgical treatment. Conservative hormonal treatment included cyclic administration of infecundin, bisecurin, hydroxyprogesterone caproate. The average duration of hormone therapy was 12 months. The 1st follow-up examination was conducted 3 months after the onset of the treatment. Of 53 patients of child-bearing age, 18 had recurrence of AEH (1 within 6 months after the initiation of the treatment, 5 within 6 months, 10 within 1-3 years, 1 within 5 years, and 1 within 9 years). Endometrial cancer was diagnosed in 2 patients (7 and 10 years after treatment of AEH). Of 81 patients in the premenopausal period, 29 developed recurrence of AEH within 3 months to 3 years of the treatment; endometrial cancer was detected in 2. Of 56 patients in the postmenopausal period, 16 developed recurrence within 3-6 months of the treatment; endometrial cancer was diagnosed in 3 patients. These findings indicate that majority of the patients with AEH can be cured by hormonal therapy, but the high risk of cancer development (3.7%) requires longterm follow-up.^ieng

Estrogen-progesterone therapy for bleeding gastrointestinal telangiectasias in chronic renal failure. An uncontrolled trial.

Gastrointestinal telangiectasias cause hemorrhage in patients with chronic renal failure. Therapies using vasoconstrictors, endoscopic application of heat, and surgery have had limited efficacy. Because several reports have suggested that estrogen or estrogen-progesterone therapy may control mucosal bleeding from telangiectasias in patients with hereditary hemorrhagic telangiectasia, we treated seven patients with chronic renal failure and bleeding gastrointestinal telangiectasias with systemic estrogen or estrogen-progesterone in an uncontrolled trial. Bleeding ceased in all patients. Blood transfusion requirements decreased from a mean of 1.2 U/month before treatment to 0.21 U/month after treatment. No significant side effects were noted. Results of this trial indicate the need for controlled investigations of this type of hormonal therapy.

[A new method for managing epistaxis in Osler's disease (author's transl)]. / Neue therapeutische Möglichkeiten bei M. Osler.

We describe a new method for successful management of epistaxis in patients with hereditary hemorrhagic telangiectasias. By so doing, even pulmonary arteriovenous fistulas and gastrointestinal hemorrhages can be successfully managed. During a four year period, 14 patients were treated with an oral contraceptive preparation which combined a reduced dosage of estrogen and progesterone. With this therapy, 11 patients stopped bleeding while 3 responded with significant improvement. We believe that this effect on bleeding by the hormone therapy is a sign of an abnormal increase of specific hormone requirements in patients with Osler's disease.

Treatment of endometriosis: a study of medical management.

Fifty patients with endometriosis were treated with hormones: 27 with danazol and 23 with Enavid (mestranol 75 micrograms and norethynodrel 5 mg). Side effects were more common and potentially more serious in the group treated with Enavid. Fewer women completed treatment with Enavid and their physical signs showed little improvement. Danazol was better tolerated and the results of treatment, as judged by improvement of symptoms or signs and in future fertility rates, were superior to those recorded in the Enavid treated group. Patients with large endometriotic cysts or severe fibrosis did not benefit from medical treatment. Danazol treatment appeared helpful for women who had mild or moderate endometriotic disease. It may be used alone or as a complimentary treatment after conservative surgical operations.

PIP: The results of treatment with the hormones danazol and Enovid were compared in 50 patients with endometriosis. The patients had presented with infertility, or with symptoms or signs of endometriosis. The diagnosis was confirmed either at laparotomy or laparoscopy. In the group treated with danazol, only 6 of the 27 patients needed a dose that exceeded 400 mg daily. Side effects were a significant problem. The side effects were both more common and potentially more serious in the group treated with Enovid. 7 of the 23 patients treated with Enovid failed to complete treatment because of side effects suggesting vascular or clotting dangers. Danazol was better tolerated and the treatment results, as judged by improvement of symptoms or signs and in future fertility rates, were superior to those recorded in the Enovid treated group. The patients with large endometriotic cysts or severe fibrosis failed to benefit from medical treatment. The danazol treatment appeared helpful for those women who had mild or moderate endometriotic disease. It maybe used either alone or as a complementary treatment following conservative surgical operations.

Elevated free testosterone in an obese, hirsute premenarchial girl: effects of norethynodrel and mestranol.

An 11-year-old premenarchial girl who demonstrated the clinical and biochemical abnormalities of the Stein-Leventhal syndrome is reported. Although the concentration of total circulating testosterone was within normal limits, levels of free testosterone and testosterone-estradiol-binding globulin (12.9 to 22.7 pg/ml and 7.9 to 11 X 10(-9) moles/liter, respectively) were markedly different from those of prepubertal girls (1.1 +/- 0.9 pg/ml and 102 +/- 27 X 10%-9) moles/liter, mean +/- 1 SD) and normal women (4.3 +/- 1.2 pg/ml and 82 +/- 30 X 10(-9) moles/liter). Luteinizing hormone but not follicle-stimulating hormone concentrations were increased. In the absence of abnormal adrenal steroid excretion or response to dexamethasone suppression and with a clear biochemical response to oral contraceptives (decreased levels of luteinizing hormone and free testosterone and increased concentrations of testosterone-estradiol-binding globulin), this patient closely resembles older individuals with the Stein-Leventhal syndrome. Therefore, the measurement of testosterone-estradiol-binding globulin and free testosterone may be useful in the laboratory evaluation of any adolescent girl in whom no other cause for hirsutism can be identified.

Estrogen-progestogen therapy for gastrointestinal bleeding in hereditary hemorrhagic telangiectasia.

Described is a patient with severe iron deficiency anemia and chronic gastrointestinal bleeding caused by hereditary hemorrhagic telangiectasia who was successfully treated with a combination of estrogen and progestogen.