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No previous controlled studies of ovarian germ cell tumours have been reported; however the tumour is similar to germ cell testicular cancer in terms of histology, age-specific incidence rates (i.e. highest rates in young adulthood), and secular trends of increasing incidence. The investigation was designed to determine if maternal hormonal factors which have been found to increase the risk of testis cancer in male offspring are also risk factors for the ovarian tumour. The analysis is based on 73 cases diagnosed before age 35 and 138 age-race matched controls. The cases were identified by tumour registries in Los Angeles (1972-84) and Seattle (1974-84) and controls were selected from friends and/or neighbourhood residents. Interviews were conducted on the telephone with mothers of cases and controls. The primary finding was that mother's use of exogenous hormones (including the hormonal pregnancy test, DES or other supportive hormones, and inadvertant use of oral contraceptives after conception) increased risk (Odds ratio, OR = 3.60, 95% CL = 1.2-13.1). Other maternal factors associated with elevated risk were high pre-pregnancy body mass (OR = 2.7, 95% CL = 1.0-7.6), more rapid achievement of regular menstruation after menarche (OR = 1.8, 95% CL = 0.9-3.8), and age at index pregnancy under 20 (OR = 2.8, 95% CL = 1.0-10.7). In conclusion, these results support findings from testis cancer studies regarding a hormonal aetiology for germ cell tumours, and a mechanism by which oestrogen may affect the germ cells is proposed.

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Endometriosis was found in 39% and in utero diethylstilbestrol (DES) exposure in 5% of 397 infertile women who had undergone laparoscopy and/or laparotomy among 750 consecutively evaluated infertile couples. Fifty percent of the DES-exposed infertile women also had endometriosis, similar to the 39% with endometriosis among non-DES-exposed women. Cervical stenosis was found in 25% of all DES-exposed patients and in 83% of those who had undergone cryocautery or conization. However, 40% did not have endometriosis. Thus, while the frequency of endometriosis and cervical stenosis is extremely high in infertile women exposed in utero to DES, a significant association beyond that found in non-DES-exposed patients could not be established. Some of the infertility may be associated with cervical stenosis alone.

PIP: Endometriosis was found in 39% and in utero diethylstilbestrol (DES) exposure in 5% of 397 infertile women who had undergone laparoscopy and/or laparotomy among 750 consecutively evaluated infertile couples. 50% of the DES exposed infertile women also had endometriosis, similar to the 39% with endometriosis among non-DES exposed women. Cervical stenosis was found in 25% of all DES-exposed patients and in 83% of those who had undergone cryocautery or conization. However, 40% did not have endometriosis. Thus, while the frequency of endometriosis and cervical stenosis is extremely high in infertile women exposed to DES in utero, a significant association beyond that found in non-DES exposed women could not be established. Some infertility may be associated with cervical stenosis alone.

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Serum testosterone-estradiol binding globulin and total testosterone were measured in 2 groups of male controls (less than 50 and more than 65 years old) and in 7 groups of prostatic cancer patients treated with various endocrine manipulation procedures, including orchiectomy, and estramustine phosphate and diethylstibestrol therapy. There were 133 individuals studied. Total serum testosterone levels were significantly higher in the younger versus the older control group and testosterone-estradiol binding globulin levels were significantly higher in the older men. Whereas orchiectomy reduced serum testosterone to low concentrations (72 plus or minus 11 ng. per 100 ml.) testosterone-estradiol binding globulin levels were not altered. In contrast, estramustine phosphate and diethylstilbestrol therapy, when administered to intact or castrated patients, resulted in depressed testosterone and markedly elevated testosterone-estradiol binding globulin serum levels, particularly in those patients receiving estramustine phosphate (less than 35 ng. per 100 ml. and more than 6 micrograms per 100 ml., respectively). These studies led to the conclusion that diethylstilbestrol or estramustine phosphate therapy is significantly more effective than orchiectomy in eliciting a concomitant elevation of testosterone-estradiol binding globulin and a depression of total testosterone. Even though free serum testosterone was not measured in the present study the law of mass action would indicate that in those patients with high testosterone-estradiol binding globulin (more than 5 microgram. per 100 ml.) and low total testosterone levels (less than 80 ng. per 100 ml.) the availability of biologically active (unbound steroid) testosterone would be negligible.

PIP: This study attempted to determine whether oral administration of diethylstilbestrol (DES) or estramustine phosphate, a mustard compound derivative with unknown mechanism of action, is as effective in the treatment of prostate cancer as castration. Serum testosterone-estradiol binding globulin and total testosterone were measured in 2 groups of male controls (aged under 50 years or over 65 years) and in 7 groups of prostatic cancer patients treated by endocrine manipulation, including orchiectomy and DES or estramustine phosphate. 133 persons were studied. Total serum testosterone levels were significantly higher in younger vs. older controls and testosterone-estradiol binding globulin levels were significantly higher in the older men. Although orchiectomy reduced serum testosterone to low concentrations, the binding globulin level was not altered by surgery. In contrast, estramustine phosphate and DES therapy, administered to intact or castrated patients, led to depressed testosterone and markedly elevated binding globulin levels in serum; this effect was most pronounced among estramustine phosphate users. Therefore, it is concluded that DES or estramustine phosphate therapy is significantly more effective than orchiectomy in eliciting concomitant elevation of the testosterone-estradiol binding globulin and a depression of total testosterone.

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The prolactin response to hypoglycemia was evaluated in 22 control subjects and 8 patients with hypothalamic-pituitary disease but normal basal serum prolactin levels. Eighteen of the 22 control subjects demonstrated at least a twofold prolactin rise in response to hypoglycemia. In contrast to the control subjects, none of the 8 patients demonstrated a prolactin response to hypoglycemia. This blunted prolactin response to hypoglycemia was the only endocrine abnormality in 3 of these 8 patients. In an attempt to better determine the sensitivity of the prolactin response to hypoglycemia as an index of early pituitary disease, the effect of a short course of estrogen on the prolactin response to hypoglycemia was examined. Estrogen was selected because of its known acute stimulatory effect on pituitary mitosis and chronic effects that lead to pituitary tumor formation in rodents. Accordingly, diethylstilbestrol (DES) 5 mg t.i.d. was administered orally to 6 normal men for 3 days, a period known to stimulate pituitary mitotic activity in rodents. Diethylstilbestrol treatment caused significant elevation of the baseline prolactin (8 +/- 2 versus 18 +/- 3 ng/ml, p less than 0.05); however, the prolactin response to hypoglycemia was blunted (8 +/- 2--30 +/- 10 ng/ml, p less than 0.05, before DES; 18 +/- 3--20 +/- 5 ng/ml after DES, p greater than 0.05). This estrogen-induced blunted prolactin response to hypoglycemia resembled the blunted prolactin response to hypoglycemia found in patients with hypothalamic-pituitary disease.

PIP: This study investigated the prolactin response to hypoglycemia in patients with a variety of diseases of the hypothalamic--pituitary axis but with normal basal serum prolactin levels and in normal subjects who received a short course of estrogen, administration of which is known to stimulate prolactin secretion and pituitary mitotic activity in experimental animals, which suggests that estrogen-induced hyperprolactinemia might mark pituitary hyperplasia. Hence, the prolactin response to hypoglycemia was evaluated in 22 controls and 8 patients. 18 of the 22 controls showed at least a 2-fold prolactin rise in response to hypoglycemia. Compared to controls, 0 of 8 patients demonstrated prolactin response to hypoglycemia. To test whether the sensitivity of this prolactin response to hypoglycemia could be an index of early pituitary disease, the short course of estrogen was administered (diethylstilbestrol, 5 mg, t.i.d.) orally to 6 normal men for 3 days. Diethylstilbestrol treatment resulted in significant elevation of baseline prolactin (p .05); On the other hand, prolactin response to hypoglycemia was blunted (P .05 before estrogen and P .05 after estrogen). The blunted response induced by estrogen administration was similar to that seen in patients with hypothalamic-pituitary disease in response to hypoglycemia.

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Reports in the popular press have suggested that exposure to diethylstilbestrol (DES) is followed by an abnormally high incidence of breast cancer. The reports were based on a reanalysis of data not considered ominous originally; and both data and analyses are summarized here. In addition, new data are presented on mothers of young women enrolled in the National DESAD Project at its Mayo Clinic Center. Among 408 women given DES, there were 8 confirmed instances of breast cancer, in comparison with an expected number of 8.1, based on breast cancer incidence rates among parous women in the local population. A previous case-control study of the possible association of antihypertensive therapy and breast cancer in the local population revealed DES exposure in 10% of the breast cancer group and 12% of the controls. These apparently negative results clearly indicate a need of further studies of the alleged effect of DES.

PIP: Preliminary data from the Mayo Clinic Center of the National DESAD Project (DESAD = DES plus Adenosis) bearing on the occurrence of breast cancer in women given DES (diethylstilbestrol) during pregnancy are reported. Data from 408 DES-exposed women were collected in a follow-up study. 8 cases of breast cancer were confirmed in the group. This compares with an expected rate of 8.1 for parous women in that county. These preliminary data do not show an excess of observed over expected cases of breast cancer among a DES-exposed population. A previous case-control study at the Mayo Clinic designed to determine any association between breast cancer and antihypertensive therapy had found a breast cancer rate of 10% in the DES-exposed portion of the group and 12% in the controls, also denying any DES association with breast cancer causation. It is pointed out that an earlier study at the University of Chicago which did find an association between DES usage and breast cancer had utilized higher doses of DES than the current study at Mayo. There is a clear need for further research into the association between DES usage and breast cancer, taking into account dosage and duration of therapy. Excess risk, if it does exist, seems to concentrate in the under-50 age group.

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The physician population delivering obstetric care in Philadelphia between 1950 and 1970 was contacted to ascertain their use of diethylstilbesterol (DES) during pregnancy. Of the 31.8% of the physicians who responded to the questionnaire, 71.8% used DES during pregnancy and 12.7% desired assistance in review of their records. During the 6 years from the initial survey, 830 young women exposed to DES in utero were periodically screened for cervicovaginal abnormalities and clear cell adenocarcinoma. Of these 830 patients 61.7% were found to have cervicovaginal abnormalities, and 65.9% of the patients showed either adenosis or evidence of the prior existence of vaginal adenosis. Eight patients were treated for clear cell adenocarcinoma. Two cases were detected while asymptomatic. Seven of the patients are living with no evidence of cancer, and two of these have survived over 5 years.

PIP: A project, designed to locate the population at risk to diethylstilbestrol (DES) exposure in utero in the greater Philadelphia area from 1950-1970, was implemented by contacting area physicians who might have used the drug in their practices on pregnant women. 216 (31.8%) physicians responded to the questionaire; 155 (71.8%) responded that they had used DES. During the 6 years from initial survey, 830 young women exposed to DES in utero were periodically screened for cervicovaginal abnormalities and clear cell adenocarcinoma. Gross structural cervicovaginal abnormalities were found in 512 (61.7%) of the individuals evaluated. In 38 patients, vaginal adenosis existing alone was documented. In another 279 patients, metaplasia alone was noted in the vagina, and in another 230 patients, both metaplasia and adenosis coexisting in varying degrees were found. Thus, 547 (65.9%) showed either adenosis or evidence of the prior existence of vaginal adenosis. 8 patients with clear cell adenocarcinoma of the vagina or cervix were seen; each individual was born during the decade of the 1950s. 2 cases were detected while asymptomatic; 7 of the patients are living with no evidence of cancer, and 2 of these have survived over 5 years. These results showed a much lower incidence of significant dysplastic squamous changes (1.1%) than that of earlier reports, emphasizing the subjective element of earlier, more alarming reports.

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Our case-control study of the relation between estrogen use and endometrial cancer involved 451 cases and 888 controls. The overall risk of endometrial carcinoma was sixfold for estrogen users as compared with nonusers; long-term users (greater than five years) had a 15-fold risk. Excess risk was present for both diethylstilberstrol and conjugated estrogens. The risk associated with cyclic use was as great as that for continuous use. Increased risk was associated with estrogen use for all histologic grades of the tumor. The risk of advanced-stage carcinoma was fourfold for estrogen users, but rhe confidence interval was wide, and this question requires further study. Finally, this investigation contradicts the speculation that the association between this cancer and estrogen use can be explained by swifter diagnosis for estrogen users, misclassification of estrogen-related hyperplasia or treatment of early symptoms of the tumor with estrogen.

PIP: Comparing cases of endometrial cancer (EC) (451) to matched hospital controls (888), the estimated risk of EC associated with estrogen (E) use in this large-scale study was 6, with a 95% confidence interval of 3.7-9.7; this figure jumped to 15 for long-term E users ( 5 years). The case-control study found that excess risk was present for both diethylstilbestrol and conjugated Es. Cancer risk was associated about equally with cyclic and continuous dosage regimens, and all histologic grades of tumors were associated with increased risk with E use. For State I tumors, all 3 histological grades ("well-differentiated"-"poorly differentiated") were found with E use. The relative risk of advanced-stage carcinoma was 4 for E users, but the confidence interval was wide, and this question remains unclear. Questions of methodology are addressed which apply to all studies of E use and EC; these include suspicions that women under treatment with E receive swifter diagnoses of carcinoma, the misclassification of E-related hyperplasia, and the treatment of early symptoms of the tumor with E.

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PIP: Various postcoital contraceptive regimens are described. An antiemetic can be given to minimize the nausea and vomiting which are side effects of high-dosage estrogen. If pregnancy occurs despite treatment, the possible risk to the fetus is unknown. This method of contraception is only for emergency use. Regular contraception should be employed if sexual exposure is to be continuing.^ieng

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PIP: The exogenous administration of selected steroids to male Rana hexadactyla Lesson was used to investigate the hypophyseal-testicular axis and to determine their influence on the activity of the hypophyseal cell types and the impact of this activity on spermatogenic activity. The frogs were treated as follows: 1) stilbestrol (S), 1.25 in 1 ml Ringer as a single dose or in 1.25 ml Ringer in .25 ml doses every 48 hours for 15 days 2) testosterone (T), 1 mg/ml every day for 15 days; 3) estradiol (E), 5 mg in 15 ml Ringer administered in 1 ml amounts for 15 days; 4) deoxycorticosterone (DOCA), 7.5 mg in 15 ml Ringers in 1 ml amounts for the test period; and 5) cortisol (F) .5 mg in 1 ml Ringer given as a single dose for 15 days. Single dose administration of S resulted in distortion of the histoarchitecture of the par distalis. The split dose of S was ineffective in the par distalis. T reduced the size of B2 cells. In E-treated animals regression of all cell types of the par distalis was observed and increased production of secretory material was indicated. DOCA-treated frogs displayed atypical cellular morphology and cytoplasmic granulations with extensive fibrosis in the par distalis. A regression of all types of adenohypophyseal cells and cytoplasmic degranulations were observed in F-treated frogs. While all steroids cause some changes in cytomorphological features, tinctorial affinities, and secretory activity, the magnitude of change is dependent on the steroid administered. Spermatogenesis was inactivated throughout.^ieng

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Fatal disseminated intravascular coagulation (DIC) was induced in female rats by administration of progesterone in late pregnacy. This prevented parturition, with intrauterine fetal death 2 to 4 days past term and subsequent retention of dead fetuses. Concomitantly with or closely following the intrauterine death of their litters, a large proportion of pregnant rats died with histologically evident DIC. Administration of cortisone, heparin, or disoumarin did not prevent DIC, and xi-aminocaproic acid, acetylsalicylic acid, or an onion-rich diet tended to increase its incidence. Antibiotic regimens gave variable results, with significant decrease in DIC only with a combination of two wide-spectrum penicillins. Neomycin and polymyxin had little effect on susceptible Sprague-dawley derived rats, but polymxin caused a significant increase in DIC in a resistant strain of hooded rats. Fatal maternal DIC was completely prevented only by use of natural or synthetic estrogens concurrently with progesterone, although this did not alter the sequence of abnormally prolonged pregnacy with intrauterine fetal death and retention of dead fetuses. Potencies of estrogens varied greatly, but all compounds tested prevented DIC at adequate dosage levels. Diethylstilbestrol, the most potent drug tested, was completely protective at 1 mug daily given subcutaneously. beta-Estradiol was the most effective natural estrogen, giving complete protection with a 10-mug daily subcutaneous injection. Estrogens were much more potent by subcutaneous injection than by oral ingestion, and toxic side effects were sometimes noted with higher levels of the latter. For estrogen therapy to be effective, it was necessary to begin its use before the expected onset of DIC, and in no instance was there evidence of reversal of this process after signs of illness were observed.

PIP: Fatal disseminated intravascular coagulation (DIC) was induced in female rats by administration of progesterone in late pregnancy. This prevented parturition, with intrauterine fetal death 2-4 days past term and subsequent retention of dead fetuses. Concomitantly with, or closely following the intrauterine death of their litters, a large proportion of pregnant rats died with histologically evident DIC. Administration of cortisone, heparin, or dicoumarin did nothing to prevent DIC, and epsilon-aminocaproic acid, acetylsalicylic acid,or an onion-rich diet tended to increase its incidence. Antibiotic regimens gave variable results, with significant decrease in DIC only with a combination of 2 wide-spectrum penicillins. Neomycin and polymyxin had little effect on susceptible Sprague-Dawley derived rats, but polymyxin caused a significant increase in DIC in a resistant strain of hooded rats. Fatal maternal DIC was completely prevented only by use of natural or synthetic estrogens concurrently with progesterone, although the sequence of abnormally prolonged pregnancy with intrauterine fetal death and retention of dead fetuses remained. Potencies of estrogens varied greatly, but all compounds tested prevented DIC at adequate dosage levels. Diethylstilbestrol, the most potent drug tested, was completely protective at 1 mcg daily given sc. Bate-estradiol was the most effective natural estrogen, giving complete protention with a 10 mcg daily sc injection. Estrogens were much more potent by sc injection than by oral ingestion, and toxic side effects were sometimes noted with higher levels of the latter. For estrogen therapy to be effective, it was necessary to begin its use before the expected onset of DIC. Reversal of this process once DIC has started is beyond the powers of this therapy.

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In view of the risk of vaginal cancer developing in young female subjects exposed in utero to maternally ingested diethylstilbestrol a pilot study was undertaken of male subjects similarly exposed. A healthy questionnaire was mailed to 306 male subjects whose mothers were known to have taken diethylstilbestrol in the early part of their pregnancies and to 231 age and sex-matched controls identified from the same record source. Although there was no increased history of cancer, heart disease or asthma when the groups were compared there was a higher incidence of reported urinary tract symptoms and genital abnormalities in the group exposed to diethylstilbestrol. The presence of these abnormalities was confirmed by physical examination of 15 respondents. Studies in experimental animals also have shown that in certain species maternally ingested stilbestrol may result in abnormalities of the genitaltensive clinical studies be undertaken to determine the level of risk, if any, to which many thousands of young men are subject.

PIP: A health questionnaire was mailed to 306 male subjects whose mothers were known to have taken diethylstibestrol (DES) in the early part of their pregnancies and to 231 controls without this history. Completed questionnaires were returned by 225 (73%) of those treated with DES and by 111(48%) of the controls. The mothers treated with DES had also received more progestin and other estrogens than controls. In 86.7% of of the cases, mean daily dose of more than 25 mg. The 34 mothers whose responses suggested congenital genital abnormalities in their male offspring were requested to bring their sons in for clinical examination. 15 responded,11 exposed and 4 controls. Ages of sons were 15-25 years. 10 mothers exposed to DES described urethral obstruction in their infants, often requiring an operation. Only 2 of the 11 subjects exposed to DES were found to be urologically completely normal while 3 of the 4 controls were normal. There had been 3 cases of unilateral undescended testis, all of which had been corrected by surgery. Of these, 2 also had had meatal stenosis. No cancer cases were found. Male fertility had not been tested. Longer follow-up and more subjects are needed for conclusions.

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PIP: 55 women were administered a series of postcoital contraceptives, 35 of whom received only a single application and 20 received the preparations for more than 1 cycle (more than 2 but less than 13). 34 women of the 1st group (48 hours after unprotected coitus) and 7 women from the 2nd group were administered diethylstilbestrol (DES) for 5 days for a total of 250 mg. The remaining subjects were given norethisterone Spofa for 3 days at 30 mg/day. Results from this administration in the sense of a general contraceptive were not considered favorable, primarily due to contraindications in regard to physiological side effects, particularly with DES. DES proved to be the most successful in preventing pregnancy.^ieng

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PIP: 37 women, 18-45 years old, were administered diethylstilbestrol (DES), 20 mg 3 times daily over the course of 5 days 24-48 hours after unprotected intercourse during the estimated time of ovulation. Pregnancy was registered in only 1 case. The effects of DES on the levels of follicle stimulating hormone, luteinizing hormone (LH), and progesterone were determined in 7 of these women during the entire course of a cycle. A decrease in the level of LH was the only abberation found in comparison with a normal control group. Ovulation was not suppressed by the application of DES. Progesterone values in the luteal phase were normal for 4 women, while 3 showed a more rapid decrease in this level, which preceded menstruation by 3-5 days. It was observed that after the administration of DES luteolysis did not occur in the ovulatory phase, although the ovulatory mechanism was disrupted.^ieng

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The effect of estrogen on the synthesis of plasma very low density lipoproteins (VLDL) in the cockerel was studied both in vivo and in vitro. Synthesis was studied by immunoprecipitation techniques with antisera prepared against VLDL and a major VLDL protein. VLDL were isolated from the plasma of white Leghorn hens and estrogen-treated white Leghorn cockerels by ultracentrifugal flotation at d 1.006 g/ml. After delipidation, the lipid-free proteins (apoproteins) were fractionated on Sephadex G-150 and DEAE-cellulose. Both the hen and the estrogen-treated cockerel VLDL were shown to contain an identical apoprotein with a mol wt of approximately 12,000; the apoprotein is designated fraction B. Reduction and S-carboxy-methylation of fraction B resulted in a reduction of the molecular weight by approximately one-half, indicating a dimer-monomer relationship. Antiserum prepared to the hen VLDL dimer protein gave precipitin lines of complete identity to both the hen and cockerel dimer, monomer, VLDL, apoVLDL, low density lipoproteins, and plasma; no precipitin line was formed with either hen or cockerel high density lipoproteins. After a single subcutaneous injection of diethylstilbestrol into the cockerel, plasma VLDL protein, cholesterol, and triglyceride increased, reaching a maximum 24--48 h after hormone administration. Liver slices from similarly treated animals were incubated in vitro in culture medium in the presence of [3H]lysine for 2 h. Immunoprecipitable radioactivity in VLDL increased within 2 h of diethylstilbestrol treatment and reached a maximum at 24 h; VLDL radioactivity returned to base-line levels by 72 h. At the peak of induction, newly synthesized VLDL represented 11% of the total soluble protein synthesized. When actinomycin-D (5 mg/kg) was administered simultaneously with estrogen, the induction of VLDL synthesis was totally inhibited. To determine whether the effect of estrogen on VLDL synthesis was mediated at the level of transcription, partially-purified cockerel liver mRNA was prepared from estrogen-treated animals and the mRNA activity for fraction B was quantitated in a wheat germ translation system. Fraction B mRNA was found to increase from a low base-line value to a maximum 16-24 h after estrogen treatment, returning towards baseline values at 30 h. At the peak of induction, fraction B constituted 12% of the total protein synthesized. The kinetics of induction of fraction B mRNA activity in the cell-free translation system is very similar to that observed in liver slice experiments. This finding suggests that estrogen stimulates VLDL synthesis, at least partially, by enhancing the accumulation of the mRNA for one of their major apoproteins.

PIP: In vivo and in vitro studies were undertaken to investigate the mechanism of the induction of the synthesis of very low density lipoproteins (VLDL) by estrogens in the cockerel. VLCL were isolated from plasma of white Leghorn hens and estrogen-treated white Leghorn cockerels. VLCL from both these groups contained an identical apoprotein (Fraction B) with a molecular weight of about 12,000. Reduction and S-carboxy-methylation of this fraction reduced its molecular weight by approximately 50%, thus indicating a dimer-monomer relationship. When antiserum was prepared against the hen VLDL dimer protein, completely identical precipitin lines were found for both the hen and cockerel dimer, monomer, VLDL, apoVLDL, low density proteins, and plasma. However, no precipitin line was formed with hen and cockerel high density lipoptoteins. A single sc injection of diethylstilbestrol (DES) into the cockerel increased levels of plasma VLDL protein, cholesterol, and triglyceride, with maximum values occurring 24-48 hours after injection. Immunoprecipitation of liver slices from similarly treated animals showed an increase of radioactivity of VLDL within 2 hours of injection. Values reached a maximum at 24 hours and returned to baseline levles by 72 hours. Newly synthesized VLDL comprised 11% of the total soluble protein synthesized during the period of peak values. Actinomycin-D (5 mg/kg), when administered simultaneously with the estrogen, completely inhibited the induction of VLDL synthesis. In another experiment, partially purified cockerel liver mRNA was prepared from estrogen-treated animals and the mRNA acitivity for Fraction B was measured in a wheat germ translation system. Values for Fraction B mRNA reached a maximum 16-24 hours after estrogen-treatment and returned to baseline levels by 30 hours. Fraction B represented 12% of the total protein synthesized at the peak of induction. The results suggest that estrogen stimulates the synthesis of VLDL by enhancing the accumulationg of the mRNA of 1 of their major components.

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The stability with time of the spontaneous as well as the oxytocin-triggered functional activity of uterine borns isolated from induced estrus rats and immersed in a medium with lactate as the substrate was not affected by the presence of oxomate (an inhibitor of lactate dehydrogenase) at 10 or 20mM. On the contrary, the oxytocin-driven and the spontaneous motility of preparations obtained from 15 days castrated rats diminished significantly following in addition of the enzyme inhibitor. Furthermore, uterine borns from ovariectomized animals injected with 17-beta estradiol, regain the lack of functional sensivity towards oxamate. In addition, determinations of pyruvate levels in homogenates of uterine tissue, previously suspended in lactate medium (as in the functional experiments), demonstrate to be significantly reduced, following oxamate. Several possible reasons, attempting to explain these findings, are discussed.

PIP: The pharmacological effects of oxamate on the spontaneous or the oxytocin-induced motility of isolated rat uterus in a solution with lactate as the sole external substrate were investigated during estrus, following ovariectomy, and after castration accompanied with estradiol replacement therapy. Uterine preparations were tested for mechanical activity (isometric-developed tension and the frequency of contractions). Initial oxytocin-induced activity of the uterus of rats in induced estrus was significantly greater than spontaneous activity (p.01). Oxamate added to the suspension was ineffective in modifying this activity. In castrate rats, however, the addition of oxamate to the medium significantly reduced oxytocin-driven and spontaneous motility. Those ovariectomized rats receiving replacement therapy were also resistant to oxamate effects. The effects of oxamate upon pyruvate levels of oxytocin-exposed uterine tissue were also determined. In the presence of oxamate, levels of uterine pyruvate in all the hormonal conditions were significantly lower than in controls (p.001).

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PIP: The development of oral contraceptives (OCs) is briefly discussed. From reviewing the literature it was seen that the 1st "OC" was the harmless, nontoxic, safe, and very inexpensive synthetic estrogen diethylstilbestrol, or stilbestrol, which is still the best OC in 1975. This OC is still prescribed because a toxic dose, even up to 300,000 mg yearly, has never been encountered. The regimen consists of 3-5 mg daily for 26 nights with 3-5 nights shipped, plus a potent B-complex vitamin (Livitamin) 2-3 times daily. This OC is unique in that ovulation and menstrual flow can be inhibited for 60-120 days. The patient can miss from 7-14 days before ovulation occurs, after 1 course of this OC. This regimen provides a harmless, nontoxic, and 100% effective OC.^ieng

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In men suffering from prostatic cancer, i.v. administration of 12 g diethylstilboestrol diphosphate within 20 days resulted in a decrease of the LH serum level to about 50% (P less than 0.05), whereas the total testosterone level decreased to less than 5% (P less than 0.001) and the apparently free testosterone level to less than 2% of the initial values (P less than 0.001). Hence, the "systemic antiandrogenic effect" of oestrogen can be explained (1) by indirect inhibition of testicular androgen secretion via diminution of hypophyseal gonadotrophin secretion, (2) by direct inhibition of testicular androgen secretion and (3) by elevation of the capacity of testosterone binding beta-globulin.

PIP: In 7 men with prostatic cancer, diethylstilbestrol diphosphate (DSDP) was injected iv in a total dosage of 12 gm within 20 days. Luteinizing hormone (LH) and total testosterone were determined by radioimmunoassay and the apparently free testosterone by equilibrium dialysis before treatment, after 8 days of treatment, and after 30 days of the DSDP treatment. A decrease of the LH serum level to 50% was found (p less than .05). Total testosterone level decreased to less than 5% (p less than .001) and the apparently free testosterone level to less than 2% of the pretreatment values (p less than .001). The antiandrogenic effect of this drug is attributed to either inhibition of testicular secretion caused by diminution of hypophyseal gonadotropin secretion or by direct inhibition of testicular androgen secretion and by elevation of testosterone binding beta-globulin capacity. Some slight local antiandrogenic effect may result in the prostate by inhibition of the 5alpha-reductase activity.

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PIP: The direct action of 60 and 120 mcg/kg/feed diethylstilbestrol (DES) and 120 or 240 mcg/kg/feed estradiol were studied in rats. DES, but not estradiol, inhibited body growth and appetite, and impaired reproductive capacity. It is concluded that low doses of DES have some effect on reproductive function and that an in dose to 90-100 mcg/kg/feed completely inhibits reproductive capacity. It is recommended that DES should not be used in animal husbandry.^ieng

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PIP: A simple method of organ culture was used to study the effects of various hormones on human mammary cancer in vitro. Samples of mammary cancer tissue were taken at mastectomy from 15 patients and processed at once under sterile conditions. The hormones were dissolved in ethyl alcohol to a concentration of .25 mg/ml. Testosterone, estradiol, stilbestrol, and hydrocortisone succinate, each 10 mcg/ml, were tested. After 4 days incubation in an atmosphere of 95% oxygen and 5% carbon dioxide, specimens were prepared for microscopic study. In 5 instances no viable tissues were found. In the remaining 10 specimens there was no evidence that viability was influenced by any hormone. Good survival of the cancer tissue was obtained in only 2 instances. The method is not considered applicable for the determination of treatment or prognosis.^ieng

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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

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