Exaggeration of experimental hypertension in rats by contraceptive steroids (Enovid).

The possibly additive pressor effects of contraceptive steroids were studied by treating hypertensive rats chronically with Enovid. Renal hypertensive rats were unaffected by drug treatment during the first 5 weeks, but, from the 6th to the 8th week, Enovid-treated rats had much higher systolic pressures than those given corn oil alone. However, these differences dwindled and became insignificant from the 9th to the 16th week despite continued treatment. Subsequently, other rats were pretreated with Enovid or corn oil for 5 weeks before hypertension was induced by implanting deoxycorticosterone acetate (Doca). In contrast to the equivocal results obtained previously, Doca hypertension was consistently more pronounced in rats treated with Enovid than in those given corn oil. This pressure difference was later verified by direct measurement of phasic aortic pressures from indwelling catheters and by the postmortem finding that Enovid-treated rats had larger hearts than corn oil-treated ones. The exact mechanism by which Enovid enhances Doca hypertension is still undetermined, but sympathetic hyperactivity was considered an unlikely explanation, since responses to posterior hypothalamic stimulation, norepinephrine, or ganglion blockade with pentolinium were unaltered.

Proceedings: Quantitation of a new serum alpha-macroglobulin in malignant disease, steroid treatment, pregnancy and normal subjects.

PIP: Alpha-macroglobulin was quantitated in patients with malignant disease, steroid treatment, pregnancy, and in normal subjects using the rocket technique of Laurell. Women treated with combined estrogen/progestogen and with mestranol and men treated with stilbesterol showed rises in alpha-macroglobulins. Those treated with norethynodrel did not, indicating that the estrogen is the responsible agent. The level increased during pregnancy and decreased sharply in the first 2 days postpartum. 30% of normal women and 10% of normal men had detectable quantities of the protein (up to 4 mg/100 ml) in their serum. 92% of patients with malignant disease had detectable levels of protein--6 mg/100 ml or higher.^ieng

Reduction of carcinogen-induced breast cancer in rats by an anti-fertility drug.

PIP: The DMBA (dimethylbenz[a]anthracene)-induced mammary cancer systems seemed to be an ideal model for the study of the influence of oral contraceptives (OCs) on endocrine-related cancers. Groups of 20 female Sprague-Dawley rats, age 40-45 days, weight approximately 150 g, were given 3.0 or 0.3 mg of crystalline Enovid suspended in 1 ml of sesame oil per dose for 45 days. The controls consisted of a group of 20 rats given a single dose of 15 mg of DMBA, of 2 groups of 10 rats administered daily doses of 3.0 and 0.3, respectively, of Enovid for 45 days, and of 1 group of 20 rats on sesame oil. In addition to these 6 groups, 3 additional sets of 5 rats each were fed 3.0 or 0.3 mg Enovid per rat, or 0.3 mg Enovid plus the subsequent single dose of 15 mg DMBA. The animals were weighed weekly and thoroughly examined for the appearance of mammary tumors or other grossly apparent lesions. The dosage of Enovid was selected on the basis of preliminary experiments. With doses of 0.005 mg per 150 g rat the estrus cycle was usually but not always arrested 5 days after the treatment began. At doses of 0.05 and 0.5 mg the cycle was interrupted 3-5 days and at 1 day later. In the final studies with doses of 0.3 and 3.0 mg, the microscopic examination of the smears indicated that the estrus cycle was effectively halted in all rats throughout the Enovid, or Enovid plus carcinogen feeding period but returned to normal shortly after the cessation of Enovid administration. DMBA failed to restore the estrus cycle suggesting that Enovid exerts a pronounced effect on the endocrine system. A single dose of 15 mg DMBA yielded an increasing incidence of mammary tumors which reached 100% after about 6 months. The multiplicity also rose and reached an average of 5.8 masses per rat at the end of the planned experiment period of 9 months. Histopathologic examination of the tumors indicated that there were several types, and even the same tumor nodule exhibited areas of varying morphologic aspect. Administration of the lower level of Enovid tended to inhibit slightly the incidence of mammary cancer. Of the 20 sesame oil control animals, only 1, killed after 237 days, had a large fibroadenoma.^ieng

The effects of progesterone and progestins on endometrial proliferation.

A total of 99 premenopausal and 27 postmenopausal women were evaluated to determine the quantity of glandular proliferation resulting from progestin inhibition of estrogen-primed subjects and of subjects without hormonal stimulation. Endometrial glandular proliferation rates were determined by using mitosis counts, proliferating-cell nuclear antigen (PCNA), and nuclear cyclin (MIB1) immunocytological staining. The endometria of normally cycling premenopausal women, of women who received a synthetic progestin, and of untreated postmenopausal women were studied. In untreated normally cycling premenopausal women, the proliferation of the glandular epithelium was increased during the follicular phase and decreased during the luteal phase. Premenopausal women receiving a synthetic progestin and untreated postmenopausal women who were not estrogen-primed showed minimal epithelial proliferation. Endometrial glandular proliferation is inhibited by endogenous progesterone in premenopausal women. Endometrial proliferation is markedly reduced in premenopausal women receiving a synthetic progestin and in untreated postmenopausal women.

PIP: Use of micronized progesterone or a synthetic progestin has been shown to counter the proliferative effect of estrogen on the endometrium in pre- and postmenopausal women. The present study measured endometrial glandular proliferation rates in 99 pre- and 27 postmenopausal US women. Determinations were based on mitosis counts and both proliferating cell nuclear antigen and nuclear cyclin immunocytologic staining of endometrial tissue. In the untreated, normally cycling premenopausal subjects, glandular epithelial proliferation increased during the follicular phase and decreased during the luteal phase. Premenopausal women who received a synthetic progestin and untreated postmenopausal women who were not estrogen-primed showed minimal epithelial proliferation. The mean mitosis rate of proliferative phase glands was 12.3 compared with 1.6 and 0.01 after administration of the oral contraceptives norethindrone or norethynodrel, respectively. Among premenopausal women, the intensity of the stromal pseudodecidualization and inhibition of glandular development was greatest in those receiving monthly medroxyprogesterone acetate injections. The combination of progestin potency, dosage, and duration determined the mitoses, stroma, and glands that were present in the three groups of subjects. The methods used in this study may be of use in determining optimal dosages of exogenous progestins in women who are receiving hormone replacement therapy and the potential exists for predicting adverse endometrial responses to progestational therapy.

Long-term experience with Enovid among clinic patients: results after 2 and one-half to 6 years of individual patient use.

PIP: 64 women clients of Planned Parenthood of Evansville (Indiana) used Enovid (5 mg norethynodrel and .075 mg mestranol, combined) for 2 1/2 to 6 years. A "25-Month Club" card and free pills were given to encourage continuation in the study, and 33 women (52%) remained until study termination. The group ranged in age from 18-40 years, mean 27 years, and in parity 0 to 12, mean 4. No pregnancies, cancer of reproductive organs or thromboembolism occurred. Side effects, recorded by interview according to a standard form, included: cervicitis 48%, vaginal discharge 42%; dysmenorrhea 61% pretreatment, 42% improved, 11% new symptoms; breast complaints 33%; 2-15 lb weight gain 19%. 12% reported no side effects, although the author commented that the 25-Month Club policy might have discouraged reporting of side effects.^ieng

[Primary liver cancer following prolonged use of contraceptive drugs]. / Primaer májrák fogamzásgátló szer tartós alkalmazása után

PIP: The authors have observed cancer of the liver without cirrhosis, in a woman aged 32. The disease manifested itself immediately after childbirth and provoked death 3 months after the delivery. Before her pregnancy, the patient had been taking Infecundin for 7 years. The pregnancy went to term without any difficulty. The symptoms appeared after the delivery: abdominal pain, more and more frequent spasms in the right side, increasing progressively in intensity. The body temperature rose to 38 degrees Celsius. The patient lost some weight and became weaker and weaker every day. A malignant tumor of the liver was discovered. A laparotomy was performed: both lobes of the liver were of considerable size with swollen, grey-white growths the size of cherries. The patient died 3 months after the appearance of the 1st symptoms. A study of the literature published on this subject suggests the possibility of a connection between the malignant tumors in the liver and the prolonged use of oral contraceptives combined with the hormonal changes occuring during pregnancy.^ieng

Norethynodrel.

PIP: This monograph on norethynodrel (NOR) includes chemical and physical data (synonyms and trade names), structural and molecular formulae and molecular weight of NOR, chemical and physical properties of the pure substance (e.g., melting point, optical rotation, and solubility), and the production, use, occurrence, and analysis of the drug. NOR is produced by reducing estradiol 3-methyl ether with lithium in liquid ammonia followed by ethynolation which produces the 3-methyl ether of NOR; treatment with acetic acid realized NOR. NOR is not known to occur naturally. It is used primarily as a progestin in oral contraceptives combined with estrogens. It is also used to treat dysfunctional uterine bleeding and endometriosis. The agent sees greater commerical use in Europe than in the U.S. Analytical methods for determining the bulk chemical are presented tabularly. Biological data relevant to the evaluation of carcinogenic risk in humans are presented in brief. NOR has been tested in rats, mice, and monkeys, alone and combined with estrogens, via various delivery routes. Alone, NOR increased incidences of pituitary tumors in mice of both sexes and of mammary tumors in castrated male mice of 1 strain. Male rats showed increases in liver cell, pituitary, and mammary tumors. NOR combined with mestranol increased incidences of pituitary, mammary, vaginal, and cervical tumors in female mice and of various other tumors in male mice. NOR was reported to be embryolethal in some species and to have teratogenic effects in mice. Human data are not available on NOR alone. Therefore, it is concluded that there is limited evidence for the carcinogenicity of NOR alone and in combination with mestranol in experimental animals. In humans, NOR is implicated in the effects of oral contraceptives which have been causally related:benign liver adenomas increase and benign breast disease decrease.^ieng

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 contraceptive use in patients with thromboembolism following surgery, trauma, or infection.

PIP: 113 hospitalized women aged 15-44 who developed venous thrombosis or pulmonary embolism after surgery, trauma, infection or immobilization were compared to 184 controls matched by race, age, marital status, date of discharge, and degree of predisposition to thromboembolism. The groups were similar in religion, education, family income and number of children, but the married cases weighed an average of 143 lb, compared to 128 for married controls. 21 cases (35%), and 16 controls (16%), had taken oral contraceptives in the month prior to hospitalization. When computed by matched pairs, the relative risk for pill users was 6.5. When computed by groups, the relative risk was 2.7. These results agreed with a previous British study of high-risk cases. The authors concur with the suggestion that the pill be discontinued 1 month prior to surgery.^ieng

Chromosomally competent ovarian failure at adolescence.

Three female adolescents are presented with delayed or incomplete secondary sexual development due to primary ovarian failure. All three patients had normal blood leukocyte and ovarian tissue karyotypes. The importance of performing a diagnostic laparoscopy with ovarian biopsy in the setting of chromosome competent ovarian failure (CCOF) is emphasized.

PIP: The cases are described of 3 female adolescents evaluated at the Cincinnati Adolescent Clinic for delayed or incomplete secondary sexual development due to primary ovarian failure. All 3 patients had normal blood leukocyte and ovarian tissue karyotypes. The clinical, laboratory, and pathological findings are discussed with emphasis on distinguishing chromosome incompetent ovarian failure (CIOF-Turner's syndrome) from chromosome competent ovarian failure (CCOF). The patients included a 15 1/2 year old black female who sought evaluation of obesity and lethargy, a 17 1/2 year old white female with secondary amenorrhea in whom oral provera failed to induce menstrual flow, and a 17 1/2 year old black female with scanty, infrequent menses who achieved a normal amount and duration of menstrual flow with Norinyl 1 + 80. Hypoestrogenization should be suspected in cases of incomplete breast development for age, thin vaginal mucosa with a prepubertal pattern of the vaginal cytology, scant cervical mucus without ferning, and lack of withdrawal bleeding after progesterone administration. If any decrease in ovarian steroid production is clinically suspected in an adolescent with primary or secondary amenorrhea associated with delayed or incomplete puberty, serum gonadotropin levels should be measured. A single elevated follicle stimulating hormone (FSH) level in the menopausal range is diagnostic of primary ovarian failure in an adolescent. If the FSH is low or normal, hypothalamic or pituitary disease would be suspected. A blood leukocyte karyotype is the next diagnostic procedure for patients with primary ovarian failure to distinguish between CCOF and CIOF. If the blood karyotype is XO or a variant without a Y cell line, no further cytogenic workup or visualization of the gonads is needed, but girls with blood karyotype of XX or a mosaic pattern with 1 cell line with a Y chromosome should undergo laparoscopy and gonadal biopsy. A unilateral testis should be removed to avoid malignant changes in later years. Patients with CCOF may have other endocrine dysfunction, particularly autoimmune disease. Other possible diagnoses include resistant ovary syndrome, pure gonadal dysgenesis, premature menopause, or infectious, chemical, or other causes of ovarian failure. The incidence of CIOF is greater than that of CCOF among patients with primary ovarian failure. Optimal treatment requires medical and psychosocial intervention.