Neurosteroid withdrawal model of perimenstrual catamenial epilepsy.

PURPOSE: Perimenstrual catamenial epilepsy, the increase in seizure frequency that some women with epilepsy experience near the time of menstruation, may in part be related to withdrawal of the progesterone metabolite allopregnanolone, an endogenous anticonvulsant neurosteroid that is a potent positive allosteric gamma-aminobutyric acidA (GABA(A)) receptor modulator. The objective of this study was to develop an animal model of perimenstrual catamenial epilepsy for use in evaluating drug-treatment strategies. METHODS: A state of prolonged high serum progesterone (pseudopregnancy) was induced in 26-day-old female rats by sequential injection of pregnant mares' serum gonadotropin and human chorionic gonadotropin. Neurosteroid withdrawal was induced by treatment with finasteride (100 mg/kg, i.p.), a 5alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone. Plasma progesterone and allopregnanolone levels were measured by gas chromatography/electron capture negative chemical ionization mass spectrometry. Seizure susceptibility was evaluated with the convulsant pentylenetetrazol (PTZ). RESULTS: Plasma allopregnanolone levels were markedly increased during pseudopregnancy (peak level, 55.1 vs. control diestrous level, 9.3 ng/mL) and were reduced by 86% 24 h after finasteride treatment (6.4 ng/mL). Progesterone levels were unaffected by finasteride. After finasteride-induced withdrawal, rats showed increased susceptibility to PTZ seizures. There was a significant increase in the number of animals exhibiting clonic seizures when challenged with subcutaneous PTZ (60 mg/kg) compared with control pseudopregnant animals not undergoing withdrawal and nonpseudopregnant diestrous females. The CD50 (50% convulsant dose) was 46 mg/kg, compared with 73 mg/kg in nonwithdrawn pseudopregnant animals and 60 mg/kg in diestrous controls. The threshold doses for induction of various seizure signs, measured by constant intravenous infusion of PTZ, were reduced by 30-35% in neurosteroid-withdrawing animals compared with control diestrous females. No change in threshold was observed in pseudopregnant rats treated from days 7 to 11 with finasteride, demonstrating that high levels of progesterone alone do not alter seizure reactivity. CONCLUSIONS: Neurosteroid withdrawal in pseudopregnant rats results in enhanced seizure susceptibility, providing an animal model of perimenstrual catamenial epilepsy that can be used for the evaluation of new therapeutic approaches.

Increased risk for cancer of the breast due to previous medication.

Fifteen patients presenting one or more risk factors for cancer of the breast, who also received medication with prolactin-stimulating effects, were selected. The medication was by hormone derivatives or by non-hormone drugs used for processes other than oncologic . In all cases the medication was for long periods, three or more years, with the exception of one case, where the correlation with the unfavourable evolution of the cancer process was more evident. In patients presenting the classic risk factors for cancer of the breast, it is recommended to avoid the prescription of drugs having a prolactin-stimulating effect. The association of both circumstances (risk factors and prolactin-stimulating medication) is considered as an increased risk for cancer of the breast.

PIP: 15 patients presenting 1 or more risk factors for breast cancer who were also receiving medication with prolactin-stimulating effects were selected for study. The medication was hormone derivatives or nonhormonal drugs used for other than oncologic processes. In all cases, the medication was taken over a long period, 3 or more years, with the exception of 1 patient where the correlation with the unfavorable evolution of cancer was evident. In patients presenting the classic risk factors for breast cancer, it is recommended that drugs with a prolactin-stimulating effect be avoided. The association of both circumstances (risk factors and prolactin-stimulating medication) is considered an increased risk for breast cancer. (author's modified)

[Clinical analysis and evaluation of various hematologic and metabolic constants with the use of monthly microdoses of parenteral contraceptives]. / Análisis clínico y valoración de algunas constantes hematologicas y metabólicas con el uso de un anticonceptivo parenteral mensual en microdósis.

PIP: 75 women of proven fertility were treated as a contraceptive measure with an injection of 75 mg. of duhydroxyprogesterone acetophenide, and of 5 mg. of estradiol enanthate. Doses were half of what regularly used, and were injected between the 7th and the 9th day of the cycle. Total number of cycles studied was 859. Most important side effects of the treatment was headache in 28.3% of patients, spotting in 15.5%, and emotional instability in 10.5%. Metabolic and hematologic data were unchanged, and vaginal cytology was negative. There were no pregnancies. It must be remembered that, in every contraceptive treatment, lower doses are always preferable when equally effective. (Summary in ENG).^ieng

Letter: Synthetic sex hormones.

PIP: A study of 108 mothers with children affected by limb reduction defects showing that 14% of the mothers had a history of exposure to exogenous sex hormones as contrasted to 4% of control mothers with normal children has suggested that progestins taken orally may have a sex-specific effect on the developing fetus. A 30-year-old mother possessing a minor digital anomaly gave birth to a male with reduction deformity of the upper 2/3 of the left femur. The mother had been given estrogens (1 mg daily) for 10 days after each menstrual period in the 2 months prior to conception. Bleeding commenced 29 days later at which time dihydroprogesterone was given for 10 days. It has been speculated that there is a causal relationship between the hormone and the anomaly and that the progestins were directly related to the appearance of the limb defeat. It seems illogical to suppress spontaneous abortion by the use of potentially harmful agentss during pregnancy.^ieng