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Artificial insemination using husband's semen (A.I.H.) was carried out in 74 couples in most of whom the men had low sperm densities and/or a reduced sperm motility. There were 19 pregnancies (24%). The problems encountered and the reasons for failure are discussed.
The study of menstrual pattern and further pregnancy after clomiphene-induced pregnancy showed a comparatively high rate of improved menstrual pattern and of spontaneous conception. 12 of 29 women, who concluded a clomiphene-induced pregnancy more than 2 years ago, showed an improvement of menstrual pattern. Spontaneous conception occurred in 16 of the 29 women, in 2 cases once more. It is remarkable, that 7 of these 16 women conceived spontaneously without any improvement of menstrual pattern following the clomiphene-induced pregnancy. It is therefore difficult, to advise patients and to make a prognosis concerning further fertility. It is not possible to say, that spontaneous conception can be excluded respectively that it will occur. In case of desire for pregnancy another induction of ovulation is indicated, on the contrary contraceptive questions are to be discussed.
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The dose of 15 IU PMSG was found to be optimal for inducing ovulation within 74 hours in 27-day-old immature female rats. There was a significant decrease in the mean number of ova per ovulating animal when the dose was raised beyond this (r = 0.6554, p less than 0.001 for the range from 15 to 100 IU), but the number of ovulating animals did not decrease unless more than 80 IU PMSG were injected. The PMSG-induced ovulation was not affected by treating the animals with 10 or 100 mug clomiphene citrate at 0, 24, 48, 54, 60, 66 hours or at 0, 24, and 48 hours.
Tamoxifen (NSC-180973, ICI-46474), an antiestrogen, was administered to 39 women with stage IV breast cancer at a dose of 20 mg orally every 12 hours. Patients were selected as eligible for endocrine ablative treatment and with disease not so aggressive as to jeopardize further treatment in case the experimental drug failed. Objective remission was obtained in 19 patients (49%) with a mean duration of 11+ months and ten patients are still in remission. No progression was seen in seven patients (18%) lasting 13+ months with only one patient in relapse. Thirteen patients (33%) have failed. Objective remission was obtained in two premenopausal women even though menstrual cycles were not suppressed; bilateral oophorectomy in one of these patients induced a second remission after relapse from tamoxifen. Objective remissions were obtained in two women with proven complete hypophysectomy a direct action of antiestrogens at the tumor level. Positive estrogen receptors were suggestive of being a good predictor of response. Menopausal status and dominant site of metastasis did not affect the response to tamoxifen in this small series. Tamoxifen did not alter prolactin secretion, and side effects from the drug were usually mild and transient in nature. We conclude that tamoxifen is an effective antitumor agent in patients with stage IV breast cancer; further studies are necessary to determine whether it will equal the therapeutic effect of oophorectomy, adrenalectomy, and hypophysectomy.
Repetitively short luteal phases were found in eight infertile women. The short luteal phase was defined as 10 days or less from the presumed time of ovulation (as assessed by basal body temperature recording) to the onset of menses. Clomiphene citrate (Clomid) therapy resulted in pregnancy in two patients and lengthened the luteal phase in the other six. Ultimately, seven of eight patients conceived during Clomid therapy. Clomid therapy can lengthen the luteal phase in patients with luteal temperature elevation of 10 days or less. The occurrence of short luteal phases may be associated with infertility.
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Tamoxifen (NSC-180973; ICI-46474) can provide palliation to patients with advanced breast cancer whose tumors contain estrogen-binding proteins (EBP). The drug is most effective in patients with bone metastasis and minimal prior therapy. In the present study, 72 patients with advanced breast cancer were evaluated for their response to oral tamoxifen therapy administered at a dose of 20 mg twice daily. Twenty-eight of 72 patients (38%) demonstrated objective responses to tamoxifen therapy. For patients with a positive EBP and no prior chemotherapy, eight of 11 (74%) responded. No patient possessing a tumor negative for EBP achieved a remission. Patients with tumors that possessed normal arylsulfatase B and glucose-6-phosphate dehydrogenase enzyme activities responded most favorably to tamoxifen therapy. These results demonstrate that tamoxifen is effective in the treatment of patients with advanced breast cancer, and EBP and specific enzymes might be useful in selecting the patients for hormone manipulation.
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Luteal metabolism was investigated in corpora lutea of early pregnant rats treated with four abortifacient agents. In corpora lutea of rats treated with prostaglandin F2alpha or of rats 1 day postpartum, glucose-6-phosphate dehydrogenase (G6PDH) activity increased 140 to 170% and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) was activated to significantly high levels, whereas malic enzyme activity decreased to 29% of control values. In aminoglutethimide-treated rats, the activities of G6PDH and malic enzyme decreased, while 20alpha-HSD activity was maintained at a very low level. With the increased dose, complete abortion was observed. In corpora lutea of these aborted rats, 20alpha-HSD was activated moderately and G6PDH values were slightly higher than control values, whereas malic enzyme activity fell to lower levels. All rats treated with clomiphene citrate aborted within 63 hours after the last injection. The activities of G6PDH, malic enzyme, and ATP citrate lyase in these corpora lutea decreased to 66, 68, and 72% of control levels, respectively; 20alpha-HSD activity was maintained at a very low level, and activities of 3beta-hydroxysteroid dehydrogenase, 6-phosphogluconate dehydrogenase, and pyruvate kinase were not appreciably altered. These findings indicated that, at the beginning of luteolysis and fetal resorption, the activities of steroidogenic enzymes decreased and 20alpha-HSD was not yet activated. Therefore, we could gauge the early changes of luteolysis by measuring the activities of G6PDH, MALIC ENZYME, AND ATP citrate lyase as well as 20alpha-HSD.
Report on a case of combined pregnancy in a 25 year old patient who was treated with Clomiphen for anovulatory cycles. The left tubal pregnancy was removed at 12 weeks gestation. The intra-uterine pregnancy resulted in a term delivery of a 3 kg. 670 g. normal infant. Combined pregnancies rarely occur without treatment with ovulation inducing agents by superfecundation and superfetation. Ovulation inducing agents increase the theoretical possibility of combined pregnancy. Obstetricians should be alert to the possibility of combined pregnancy following induction of ovulation.
The purpose of this study was to investigate and treat a group of patients referred for "idiopathic" infertility in whom no apparent cause for infertility, apart from inadequate cervical mucus, was found. Hormone investigations revealed that these patients could be divided into two groups: those with low sex steroid profiles despite apparent ovulation, and a second group with normal sex steroid profiles. All patients were treated with ovulation-inducing agents in an attempt to produce "controlled" ovarian hyperstimulation and an improved cervical mucus. Four of six patients conceived. The rationale behind the use of ovulation-inducing agents in this situation is discussed.
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The antiproliferative effect of RU486 and its effect combined with tamoxifen on the growth and cell cycle kinetics parameters on the MCF-7 human carcinoma cells were investigated. When MCF-7 cells in the exponential growth phase were treated with RU486 (10(2) nmol/L), a time-dependent cell growth inhibition was observed which was significant 5 days after the beginning of treatment. This inhibition was accompanied by a time- and dose-dependent decrease in the percentage of S and G2-M phase cells and a concomitant increase in the percentage of cells in the G0/G1 phase of the cell cycle. With tamoxifen (10(5) pmol/L), growth inhibition was obtained after 4 days of treatment of cells, and the blockage of the cell cycle occurred in the G0/G1 phase. In the case of simultaneous treatment of MCF-7 cultures with RU486 (10(2) nmol/L) and tamoxifen (10(5) pmol/L), we observed a synergistic inhibitory effect on the proliferative rate for short treatment (less than or equal to 3 days), whereas RU486 or tamoxifen alone had no effect. For the intermediate treatment (4 days), the combined effect of RU486 and tamoxifen was not significant compared to the effect of tamoxifen alone. For the long treatment (greater than 4 days), there were no differences between the number of cells in the treated cultures under different experimental conditions, but all were inhibited compared to those in control cell cultures. This simultaneous treatment of cells does not induce any change in the distribution of cells in the different cell cycle phases compared to tamoxifen percentages. These results suggest that RU486 is a cell cycle phase-specific growth inhibitory agent, and a combination of antiestrogen/antiprogestin should be considered as a possible improvement in breast cancer endocrine therapy.