Vaginal administration of allopregnanolone to postmenopausal women undergoing estrogen replacement therapy: preliminary results.

OBJECTIVE: To assess the tolerability and endometrial effects of vaginal administration of an allopregnanolone gel to postmenopausal women undergoing estrogen therapy. METHODS: Thirteen postmenopausal women included in the study were divided into two groups and submitted to two consecutive cycles of 28 days during which they received 2 mg oral estradiol valerate daily and vaginally administered allopregnanolone gel during the last 10 days of the second cycle (group 1) or during the last 10 days of each cycle (group 2). Systemic adverse effects, vaginal bleeding and endometrial histology were characterized, with group 1 patients being submitted to two endometrial biopsies (days 28 and 56) and group 2 patients to one biopsy (day 56). RESULTS: Five patients did not show any adverse effect. Mastalgia was the most frequently reported adverse effect (four cases), followed by headache and abdominal pain (two cases each). The adverse effects were mild and did not interfere with the adequate use of the medication prescribed. Vaginal bleeding due to deprivation was observed in three of the seven patients submitted to one treatment cycle with allopregnanolone (group 1) and in two of six patients submitted to two treatment cycles (group 2). Endometrial biopsy findings did not suggest any secretory action after exposure to allopregnanolone. CONCLUSIONS: Tolerability of vaginal administration of allopregnanolone gel was good. Studies employing a larger series and longer time of follow-up are necessary to determine the endometrial effects of this drug.

Neocortical hyperexcitability after GABA withdrawal in vitro.

The sharp interruption of the intracortical instillation of exogenous gamma-aminobutyric acid (GABA), generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal last several days or weeks. The present work reports that GABA withdrawal-induced hyperexcitability can be produced in vitro: a sudden withdrawal of GABA (5 mM; 120 min) or benzodiazepine (60 microM flunitrazepam) from the superfusion, induced a gradual increase in the amplitude of the evoked population spike (PS) recorded on neocortical slices. PS enhancement reached 150% above the control value 2.5 h after GABA withdrawal. GABA withdrawal-induced hyperexcitability was facilitated by progesterone. PS enhancement induced by GABA withdrawal was associated with an impairment of GABA transmission occurring before epileptiform discharges were fully established. Paired pulse inhibition and evoked [3H]-GABA release appear decreased; suggesting that cortical hyperexcitability as a result of GABA withdrawal involves pre-synaptic changes. Specific muscimol binding decreased during GABA superfusion but recovered after GABA withdrawal. However, the sensitivity of the post-synaptic response to 3alpha-OH-5alpha-pregnan-20-one or allopregnanolone (alloP) was enhanced after GABA withdrawal, suggesting a functional change in the GABA(A) receptors. The changes described may be the cellular correlates of the withdrawal syndromes appearing after interruption of the administration of GABA(A) receptor agonists.