Experimental extension of the time interval between oocyte maturation and ovulation: effect on fertilization and first cleavage.

OBJECTIVE: To test the hypothesis that impaired fertility in human patients with high LH concentrations throughout the follicular phase of the menstrual cycle reflects premature maturation of their oocytes. DESIGN: Previous information that resumption of meiosis is induced by lower hCG concentrations than that required for stimulation of follicular rupture was confirmed and used for establishment of a rat animal model in which oocyte maturation and ovulation can be separated experimentally. In further experiments hypophysectomized, pregnant mare serum gonadotropin (PMSG)-primed, immature female rats injected with 1.1 IU of hCG, a dose found to induce maturation in 72.9% +/- 6% of the rats with no effect on ovulation, were administered with a second injection of an ovulatory dose (4 IU) of hCG, 24 hours later. The ovulated eggs were subjected to IVF. RESULTS: Fertilization and first cleavage in oocytes recovered from our experimental animal model were similar to that observed in control PMSG-primed, either hypophysectomized or intact rats, treated by a single injection of 4 IU of hCG. CONCLUSIONS: The extension of the time interval between oocyte maturation and ovulation in the rat does not result in a lower rate of fertilization or a reduced incidence of cleavage. However, an inferior developmental capacity of these embryos cannot be ruled out.

Use of CA-125 response to predict survival parameters of patients with advanced ovarian carcinoma.

The prognostic value of serum CA-125 levels both before chemotherapy and after each cycle of one or two courses was assessed in 48 patients with advanced ovarian adenocarcinoma. All patients received a minimum of six courses of either cyclophosphamide and cisplatinum (CP) or cyclophosphamide, doxorubicin and cisplatinum (CAP). Patients with serum CA-125 values below the normal value of 35 U/ml after two courses had a significantly longer median survival (p < 0.0001) and longer disease-free survival (p = 0.007) than did those patients whose CA-125 levels dropped to normal after the third or a later course of chemotherapy. A response in CA-125 levels after the first two courses of chemotherapy may indicate which patients should continue with the current chemotherapy regimen and which patients should be offered salvage therapy.

Treatment of benign prostatic hypertrophy by a long-acting gonadotropin-releasing hormone analogue: 1-year experience.

Benign prostatic hypertrophy, a common ailment among elderly men, usually is treated by surgery. Since androgens enhance prostatic hypertrophy, their withdrawal seems a logical way to treat this condition. Recently gonadotropin-releasing hormone analogues, known to produce "chemical castration," have been tried in cases of benign prostatic hypertrophy. We report our experience with 20 men treated by a monthly injection of gonadotropin-releasing hormone for prolonged periods. In 17 men treated for 6 months the prostatic volume decreased to an average of 63% of the initial volume; however, this did not correlate with clinical objective improvement. Only 6 men attained normal flow rates. Residual urine volume remained unaltered. Ten patients experienced subjective amelioration, while only 7 (40%) reported objective and subjective improvement. Maximal decrease in prostatic volumes was reached at 9 months of treatment and further treatment did not cause additional shrinkage. At 3 months after discontinuation of treatment prostatic volumes returned to 95 +/- 10.5% of pre-treatment values. A similar decrease in flow rates also was noted. Symptoms remained improved for longer periods. We conclude that this mode of treatment offers little to the majority of men with benign prostatic hypertrophy. Proper patient selection, based perhaps on serum prostate specific antigen, might augment positive results. This therapy should be restricted to patients considered high risk for any surgical and anesthetic intervention, and then it will have to be continued indefinitely.

Receptors for gonadotropin releasing hormone are present in rat oocytes.

Specific receptors for gonadotropin releasing hormone (GnRH) in the rat oocyte have been identified by using two independent methods. Light microscopic autoradiography, utilizing an iodinated biologically active photoaffinity derivative of GnRH, revealed specific binding of the neurohormone to rat oocytes. Furthermore, the presence of GnRH-receptor is also evident from indirect fluorescent immunocytochemistry that shows binding of GnRH-receptor antibodies to rat oocytes which is neither detected with non immune serum nor with antiserum depleted of GnRH-receptor antibodies. These antibodies to the GnRH-receptor, also bind to both cumulus and granulosa cells but not to rat basophilic leukemia cells. The presence of specific GnRH receptors on rat oocytes provides an experimental basis for understanding the molecular events involved in GnRH-induced oocyte maturation.

The suppressive effect of delta-1-tetrahydrocannabinol on the steroidogenic activity of rat granulosa cells in culture.

In previous study the major psychoactive ingredient of marihuana (delta 1-THC) has been shown to inhibit ovarian prostaglandin synthesis when administered to normally cycling rats in the early afternoon of proestrus. These results suggested a direct suppressive effect of the drug on the ovary. The purpose of this study was to evaluate the effect of delta 1-THC on steroidogenesis in granulosa cells (GC) in vitro. Incubation of GC with delta 1-THC (10-50 microM) effectively inhibited LH-stimulatable progestin production. This suppressive effect was not abolished by washing the cells after 24 h of culture in the presence of delta 1-THC, indicating the irreversible nature of the blocking effect of delta 1-THC. By contrast, estradiol production following incubation of GC with testosterone (1 microgram/ml) was not inhibited by similar concentrations of delta 1-THC, thus suggesting that delta 1-THC does not inhibit aromatase activity in GC. In addition, delta 1-THC was shown to inhibit cAMP production as well as 125I-hCG binding capacity to GC. Administration of 8-Br-cAMP did not abolish the delta 1-THC-induced block, suggesting that the drug probably acts distal to the cAMP site of action.

In vitro effects of cannabinoids on follicular function in the rat.

delta 1-Tetrahydrocannabinol (delta 1-TCH), the major psychoactive constituent of marihuana, was found to suppress the preovulatory surge of gonadotropins and thereby to prevent ovulation in rats, rabbits and rhesus monkeys. These studies suggested that the drug acts primarily on the hypothalamus to suppress luteinizing hormone releasing hormone (LHRH) secretion. The aim of the present study was to examine the direct effect of delta 1-THC, the psychoactive constituent of marihuana and cannabidiol (CBD), one of its nonpsychoactive constituents, on preovulatory rat follicles in vitro. Both cannabinoids inhibited follicular steroidogenesis in a dose-dependent manner. Basal accumulation of progesterone (P), testosterone (T) and estradiol-17 beta (E2) was reduced up to 60% by the highest doses examined (100-200 microM). The luteinizing hormone (LH)-stimulated increase in P and T was inhibited by 75-88% by the highest doses of both cannabinoids (50-200 microM), while E2, accumulation was inhibited by only 40%. It appears that the inhibitory action of cannabinoids is exerted beyond LH binding and activation of adenylate cyclase and prior to pregnenolone formation in the gonadal steroidogenic pathway. In addition to this anti-steroidogenic effect, both cannabinoids induced resumption of meiosis in follicle-enclosed oocytes cultured in hormone-free medium; 200 microM delta 1-THC resulted in 80% maturation and CBD in 75%. It seems that the action of cannabinoids on rat follicles in vitro is unrelated to their psychotropic activity.