Prenatal exposure of Long-Evans rats to 17alpha-ethinylestradiol modifies neither latent inhibition nor prepulse inhibition of the startle reflex but elicits minor deficits in exploratory behavior.

Prenatal administration of synthetic estrogens in humans as well as lower mammals was reported to alter behavior in adulthood. The alterations remain to be characterized according to specific pathophysiological hypotheses. In this study, three common behavioral models of schizophrenia were tested, i.e., latent inhibition (LI), prepulse inhibition of the startle response (PPI) and hyperlocomotion under amphetamine. Female Long-Evans rats were injected i.p. with a solution of 17alpha-ethinylestradiol (15 microg kg(-1)) everyday from day 9 to 14 of pregnancy, and behavioral characteristics of their offspring, raised by Wistar foster mothers, were compared to those of rats born from dams injected with the vehicle only, over the same gestation period. LI was tested in a conditioned taste aversion and a conditioned passive avoidance paradigm followed by a parametric study of PPI and an evaluation of locomotion in an open field under saline or amphetamine (1.5 mg kg(-1)). Histological brain measurements were also carried out in a subset of the same rats. Neither LI nor PPI was altered using methods that had proven sensitive in previous pharmacological studies. Treated rats' locomotion was impaired, but amphetamine did not elicit a differential enhancement. A thinner Amon's horn layer was observed in their hippocampus. This indicates that standard models of schizophrenia did not fit to the behavioral abnormalities found by others and confirmed in this study. They were not due to the abnormal maternal care to pups elicited by the treatment.

Medical therapy for chronic gastrointestinal bleeding of obscure origin.

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.

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

Renin-angiotensin mechanisms in oral contraceptive hypertension in conscious rats.

Rats were placed on powdered chow containing either no additives (controls), mestranol (a synthetic estrogen), norethynodrel (a synthetic progestin), or both mestranol and norethynodrel. After 6 mo on these diets, catheters were placed in the carotid artery and jugular vein of each rat. An arterial blood sample was obtained for plasma renin activity (PRA), plasma renin concentration (PRC), and plasma renin substrate concentration (PRS). Mean arterial pressure was measured in each rat. The angiotensin II (ANG II) antagonist, [Sar1-Ile8]ANG II, was infused intravenously for 30 min while blood pressure was recorded. Rats treated with mestranol and/or norethynodrel had PRA and PRC values that were not different from the control rats; however, mestranol-treated rats and rats treated with mestranol plus norethynodrel had PRS values that were substantially (P less than 0.01) higher than the controls. Arterial pressures in rats treated with mestranol and with mestranol plus norethynodrel were significantly (P less than 0.01) elevated when compared with the controls and with the rats treated with norethynodrel alone. Infusion of the ANG II antagonist failed to alter arterial pressure in any of the groups of rats. These results indicated that, in the steroid combination found in the oral contraceptive Enovid, it is the estrogenic component that results in hypertension in this rat model. Also this study found no evidence that ANG II plays a role in maintaining the elevated arterial pressure following long-term treatment with mestranol in rats.

Enovid-induced exacerbation of the propensity for stroke in low protein fish diet-fed stroke-prone/SHR.

Weanling, male and female, stroke-prone, spontaneously hypertensive rats (SP/SHR) were fed either a regular diet, a low protein diet derived from fish tissue + 1% saline drinking water, or the fish diet + 1% saline + daily injections of 0.1 mg Enovid/100 g bw/sc. After 48 days, the Enovid-treated animals developed acute and lethal strokes characterized by massive thrombonecrogenic lesions of the parietal lobe. The blood pressure of the Enovid-treated SP/SHR rose most acutely. The low protein fish diet was markedly catabolic and caused hyperlipidemia, hyperglycemia, elevated ACTH and beta-endorphin levels concomitant with reduced gonadotrophic function. Treatment with Enovid caused severe exacerbation of all of the foregoing changes. It is proposed that a low protein fish diet + 1% saline will accelerate the appearance of strokes in SP/SHR and that Enovid will enhance this effect through its anti-gonadotrophic activity and ability to stimulate increased pituitary-adrenal secretion.

Chronic intestinal ischemia associated with oral contraceptive use.

A 48-yr-old woman with chronic intestinal ischemia and a long history of oral contraceptive use is reported. She presented with a 6-month history of severe diarrhea, abdominal pain, and weight loss. Abdominal arteriography revealed occlusion of the celiac axis at its origin and 90% stenosis of the superior mesenteric artery. This chronic arterial lesion has not been previously noted in association with the use of oral contraceptive agents in otherwise healthy women. The patient's isolated arterial lesions proved amenable to successful surgical bypass. Postoperatively she became completely asymptomatic and has remained so on long-term follow-up.

[Oral contraceptives and liver tumors]. / Az orális fogamzásgátlók és májdaganat.

PIP: The case is described of a 36-year old female patient who developed a benign hepatic cell adenoma after having taken oral contraceptives (OCs) for several years. The tumor, which was situated on the central part of the right lobe, because of disintegration and hemorrhage broke through to the surface and caused a massive subcapsular hemorrhage. After subtotal hepatectomy the patient recovered uneventfully, and has remained symptom-free since that time. As far as is known, this was the 2nd successful subtotal hepatectomy in Hungary. The authors review the literature on the relationship between OCs and liver tumors. They call attention to the rapidly increasing occurrence, in Hungary, of these tumors, and to a tendency to life-threatening hemorrhages, which in the majority of cases require extensive hepatic resection. They describe various possibilities and methods of surgical care.^ieng

[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.

A case of hepatoma in pregnancy associated with earlier oral contraception.

PIP: Since 1973 there have been more than 20 reported cases of malignant and about 200 cases of benign hepatic adenomas associated with oral contraception (OC). This article reports on the case of a 45 year old woman on OC from 1967 to 1971. In 1979 she was admitted to the hospital in the 36th week of her 9th pregnancy for nausea, vomiting, and pain. Cesarean section delivered her of a healthy baby girl, and celiotomy exposed an enlarged liver with several tumors. Resection was not possible and the woman died after 3 days. Necropsy showed numerous tumors and metastases and primary hepatic carcinoma. Even though 8 years had elapsed between OC termination and the onset of cancer, the connection between exposure to OC and liver cancer must be suspected. The time lag might be attributed to delayed development of the neoplasm rather than to its slow growth.^ieng

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.

Oral-contraceptive-associated liver tumours.

PIP: Having read the Feb. 9 paper by Dr. Neuberger and colleagues, we should like to report another case of hepatic adenoma that underwent spontaneous regression upon discontinuance of oral contraceptives. In November 1976, a 55-year old female who had been on norethynodrel with mestranol (Enovid) 5 mg/day for about 10 years without interruption, presented with an acute abdomen. At laparotomy, an enlarged, diffusely bleeding liver was encountered, and biopsy findings were interpreted as hepatic cell adenoma. This was confirmed by Professor William M. Christopherson, University of Louisville School of Medicine, Louisville, Kentucky. A nuclide scan revealed a large mass in the right lobe of the liver. Hepatic angiography disclosed a 6x8 cm avascular mass. The included figures, computerized tomographic scans of the liver done on November 28, 1977 and December 12, 1979, respectively, exhibit reduction in tumor size. The oral contraceptive was discontinued and the patient has remained well.^ieng

Plasma lipid levels and systolic blood pressure in ovariectomized and intact rats treated with contraceptive and other sex steroids.

Ovariectomized rats were treated for three weeks with cottonseed oil, estraiol, progesterone, mestranol-norethynodrel, or testosterone, and intact female rats were treated with cottonseed oil, or testosterone. Plasma total cholesterol, plasma triglycerides, and systolic blood pressure were then measured. Estradiol administration resulted in an increase in plasma cholesterol and triglycerides. Administration of testosterone to intact rats produced a decrease in cholesterol. Rats administered estradiol had significantly higher systolic blood pressure than any other group except the contraceptive treated group. By use of the ovariectomized rat model, the individual effects of sex hormones are delineated and it is demonstrated that estrogen has more effect than progestogen on both plasma lipids and systolic blood pressure.

Does oral contraceptive (Enovid) treatment enhance renal hypertension in rats by inducing sympathetic hyperactivity?

One-kidney renal hypertension was induced in rats that had been given Enovid or corn oil by daily gavage for 5 weeks, and treatment was then continued postoperatively for 10 weeks more. Systolic pressures began to rise almost immediately after hypertension was induced, and from the 4th postoperative week on, the pressure elevation was consistently more pronounced in Enovid-treated than in corn oil-treated rats. When autonomic ganglia were subsequently blocked with mecamylamine, the ensuing blood pressure fall was invariably larger in Enovid-treated than in corn oil-treated rats. In contrast, responses to beta-adrenergic blockade with propranolol were equivocal; heart rates fell while systolic pressures rose slightly to about the same extent in both groups. The larger hypotensive response to ganglion blockade in Enovid-treated rats is in accord with the interpretation that Enovid treatment augments development of renal hypertension by increasing sympathetic vasomotor tone.

[Infecundin and benign liver adenoma]. / Infecundin és "jóindulatú" máj-adenoma.

PIP: The authors describe a case in a 33-year old woman who, after 11 years of taking Infecundin, developed a massive "benign" hepatoma which ruptured and caused a fatal hemorrhage. Death from loss of blood was eventually prevented by tying off the hepatic artery and the gastroduodenal artery. After 82 days the patient died anyway through septic and possibly toxic neural complications. In connection with this tragic case the authors suggest that this is a likely and even a partly substantiated danger of oral contraceptives. They discuss possible surgical treatment of such hepatomas and the hemorrhage which often accompany them.^ieng

Liver tumors and oral contraceptives.

A possible causal relationship between oral contraceptives and liver cell adenomas has been postulated in the recent literature. In this presentation three additional cases are reported to support the existence of such an association. The possible etiologic causes for this newly described condition and specific diagnostic procedures for its accurate diagnosis are presented.