Atrazine disrupts the hypothalamic control of pituitary-ovarian function.

The chloro-S-triazine herbicides (i.e., atrazine, simazine, cyanazine) constitute the largest group of herbicides sold in the United States. Despite their extensive usage, relatively little is known about the possible human-health effects and mechanism(s) of action of these compounds. Previous studies in our laboratory have shown that the chlorotriazines disrupt the hormonal control of ovarian cycles. Results from these studies led us to hypothesize that these herbicides disrupt endocrine function primarily through their action on the central nervous system. To evaluate this hypothesis, we examined the estrogen-induced surges of luteinizing hormone (LH) and prolactin in ovariectomized Sprague-Dawley (SD) and Long-Evans hooded (LE) rats treated with atrazine (50-300 mg/kg/day, by gavage) for 1, 3, or 21 days. One dose of atrazine (300 mg/kg) suppressed the LH and prolactin surge in ovariectomized LE, but not SD female rats. Atrazine (300 mg/kg) administered to intact LE females on the day of vaginal proestrus was without effect on ovulation but did induce a pseudopregnancy in 7 of 9 females. Three daily doses of atrazine suppressed the estrogen-induced LH and prolactin surges in ovariectomized LE females in a dose-dependent manner, but this same treatment was without effect on serum LH and prolactin in SD females. The estrogen-induced surges of both pituitary hormones were suppressed by atrazine (75-300 mg/kg/day) in a dose-dependent manner in females of both strains evaluated after 21 days of treatment. Three experiments were then performed to determine whether the brain, pituitary, or both organs were the target sites for the chlorotriazines. These included examination of the ability of (1) the pituitary lactotrophs to secrete prolactin, using hypophyosectomized females bearing pituitary autotransplants (ectopic pituitaries); (2) the synthetic gonadotropin-releasing hormone (GnRH) to induce LH secretion in females treated with high concentrations of atrazine for 3 days; and (3) atrazine (administered in vivo or in vitro) to suppress LH and prolactin secretion from pituitaries, using a flow-through perifusion procedure. In conclusion, the results of these studies demonstrate that atrazine alters LH and prolactin serum levels in the LE and SD female rats by altering the hypothalamic control of these hormones. In this regard, the LE female appeared to be more sensitive to the hormone suppressive effects of atrazine, as indicated by the decreases observed on treatment-day 3. These experiments support the hypothesis that the effect of atrazine on LH and prolactin secretion is mediated via a hypothalamic site of action.

Estrous cycle patterns of Sprague-Dawley rats during acute and chronic atrazine administration.

An increased incidence or earlier onset of mammary tumors (MT) has been associated with lifetime feeding of atrazine, an agricultural herbicide, to Sprague-Dawley (SD) female rats. Because MT occur spontaneously in this strain, along with episodes of persistent estrus and acyclic estrogen secretion, it was proposed that atrazine may act to promote this process. SD female rats, 7 to 8 wks old, were administered atrazine while vaginal cytology was monitored. At 200 mg/kg/d by gavage, which clearly exceeded the maximum tolerated dose (MTD), the predominant early response was prolonged vaginal diestrus. Persistent estrous episodes were seen, but less commonly. When atrazine was added to the diet, there was likewise an initial appearance of prolonged diestrus at 400 ppm, but by 13 to 14 wks on test (20 to 21 wks of age), persistent estrus was predominant, rising to >50% of animals by 26 wks on test. Age-matched controls also displayed persistent estrus, but to a lesser degree. At 400 ppm atrazine for 6 mo, animals displayed vaginal estrus for a mean of 62.8% of all days, versus 47.3% in age-matched controls, and 20 to 25% in young animals. The 400 ppm dose also exceeded the MTD. Observed no-effect levels for estrous cycling and body weight change were 50 ppm. Significant effects on estrous cycling occurred only at levels previously associated with enhanced or premature MT formation, and suggest that the tumor response in aging SD female rats can be manipulated by factors controlling the internal estrogen milieu. Because atrazine has no intrinsic estrogenic activity, it is more likely that high-level dosing to a susceptible animal model alters control of ovulation and normal cycling. The requirement of excessive dosing levels, as well as differences in neuroendocrine senescence, makes a risk to human health from this mode of action essentially nonexistent.

Placental villous glucose metabolism and hormone release respond to varying oxygen tensions.

OBJECTIVE: The effects of varying oxygen tensions on tissue metabolic behavior are not well understood, yet many intracellular pathways are influenced by them. In the placenta, optimal in vivo oxygen tension at the villous level is unknown. The purpose of this study was to determine effects of varying oxygen tensions on glucose metabolism and hormone release from perifused placental villous explants. METHODS: Placentas from term normal pregnancies (n = 8) were individually minced into villous fragments, placed into three parallel chambers for each placenta, and continuously perifused for 6 hours with nonrecirculating medium aerated with either 0%, 20%, or 95% oxygen yielding mean oxygen tensions of 76 mmHg, 167 mmHg, and 543 mmHg respectively. Outflow medium was removed at regular intervals and compared to the inflow medium to determine oxygen and glucose consumption as well as lactate, lactate dehydrogenase, hCG, estradiol, and progesterone release. RESULTS: Oxygen consumption was directly proportional to oxygen tension. Glucose consumption was lowest at low oxygen tension, while both lactate and LDH release were lowest at high oxygen tension. Both hCG and progesterone release rates were lowest at high oxygen tensions. Estradiol release demonstrated a trend similar to that of the other hormones although there was no statistically significant difference among the three different levels of oxygen tension. CONCLUSION: Varying oxygen tensions affect placental villous glucose metabolism and hormone release. Under lower oxygen tensions, glucose is metabolized through glycolysis rather than through oxidative phosphorylation and is associated with higher lactate release. Exposure to higher oxygen tensions results in reduced hCG and progesterone release. Higher oxygen tensions may be associated with tissue toxicity.

Effect of atrazine on ovarian function in the rat.

The effect of the chlorotriazine herbicide, atrazine, on ovarian function was studied in Long-Evans hooded (LE-hooded) and Sprague-Dawley (SD) rats. Atrazine was administered by gavage for 21 d to females displaying regular 4-d estrous cycles. In both strains, 75 mg/kg/d disrupted the 4-d ovarian cycle; however, no distinct alteration (i.e., irregular cycles but not persistent estrus or diestrus) was apparent at this dose. At 150 mg/kg/d, atrazine induced repetitive pseudopregnancies in females of both strains. The highest dose tested (300 mg/kg/d) also induced repetitive pseudopregnancies in the SD females, while the ovaries of the LE-hooded female appeared regressed and the smear cytology was indicative of the anestrous condition. Although a NOAEL was not established, the doses employed in this experiment were in excess of those used in chronic feeding studies in which an early onset of mammary gland tumors was noted. These data demonstrate that atrazine can disrupt ovarian function and bring about major changes in the endocrine profile of the female.

Human chorionic gonadotropin: properties and assay methods.

Modern HCG assay methodology provides a level of sensitivity such that "HCG" immunoactivity in normal individuals or other unexplained low-level "HCG" measurements may be problematic. Two-site assays improve specificity for authentic HCG by selectively measuring intact hormone, and such measures correlate well with biological activity. In some cases, 125I has been replaced with nonradioisotopic labels without sacrificing sensitivity. On the negative side, such two-site assays will not reveal the presence of free subunit that may originate from trophoblastic tissue. Because free beta subunit appears in the sera of patients with GTD, monitoring intact HCG alone may pose a risk. Thus, some form of subunit monitoring by total-beta or free-beta assay is desirable. If the beta subunit/HCG ratio reflects the degree of trophoblastic cell differentiation and aggressiveness, a combination of specific whole molecule and free subunit measurements may provide the ideal monitoring for GTD.

hCG, progesterone, alpha-fetoprotein, and estradiol in the identification of ectopic pregnancy.

OBJECTIVE: To enhance the laboratory diagnosis of ectopic pregnancy by determining levels of hCG, progesterone, estradiol (E2), and alpha-fetoprotein (AFP). METHODS: Serum samples and medical records were retrospectively analyzed from 100 gynecologic patients for whom quantitative hCG determination had been ordered. Clinical data and levels of hCG, progesterone, E2, and AFP were examined by univariate and multivariate logistic analyses. RESULTS: Progesterone, hCG, and E2 were highest in viable pregnancies, whereas AFP tended to be higher in ectopic pregnancies. A single progesterone value could differentiate between ectopic and viable pregnancy in more than 80% of patients. The combination of all four biochemical markers predicted ectopic pregnancy with 98.5% specificity and 94.5% accuracy. Clinical diagnosis was less than 75% accurate. CONCLUSION: A combination of biochemical markers including hCG, progesterone, E2, and AFP can be superior to a single progesterone level or clinical evaluation in the diagnosis of ectopic pregnancy.

Delta-9-tetrahydrocannabinol attenuates luteinizing hormone release induced by electrochemical stimulation of the medial preoptic area.

Despite diverse pharmacological actions, drugs commonly used for blocking ovulation in the rat have not been observed to exert differential effects on the LH response to preoptic stimulation, thus suggesting blocking action above the final hypothalamic GnRH pathway. To determine if ovulatory blockade by delta-9-tetrahydrocannabinol (THC) is consistent with that scheme, LH surges evoked by preoptic stimulation were contrasted with those elicited during blockade by atropine (ATR), a classic ovulation-blocking agent with which other drugs have been compared. THC (10 mg/kg) or ATR (350 mg/kg) treatment before the proestrous critical period uniformly blocked LH release and ovulation in sham-stimulated rats. Preoptic stimulation evoked LH surges after both drug treatments (p less than 0.001), peak levels increasing with the intensity of stimulation (p less than 0.05). However, both maximum LH concentration (p less than 0.05) and total integrated LH release (p less than 0.01) were lower in THC-blocked rats. Inspection of the oviducts revealed no difference in the incidence of ovulation or the number of ova discharged. The reduced LH response during THC blockade was not attributable to variation in the extent or locus of histologically determined stimulation sites. These results distinguish THC from ATR and, by extension, other blocking drugs that do not overtly affect the LH response to preoptic stimulation. Thus, ovulatory blockade by THC may involve a different mechanism, which likely includes inhibitory action within the preoptic-to-tuberal GnRH pathway.

Serum human chorionic gonadotropin concentration for predicting multiple gestation in pregnancies conceived with superovulation and intrauterine insemination.

Assisted reproductive technologies are associated with an increased incidence of multiple gestation. Because they provide precise information on the time of ovulation, those technologies afford an opportunity to analyze the association between multiple gestation and maternal serum human chorionic gonadotropin (hCG) concentrations during early pregnancy. We retrospectively evaluated this association in 76 pregnancies (26 multiple) conceived with superovulation and intrauterine insemination. Using multiple linear regression, we discerned that the number of fetuses surviving the first trimester was directly proportional to the log of the hCG concentrations. The mean + 1 SD for the estimated hCG values of singleton pregnancies was selected a priori as the threshold for detecting multiple pregnancies. This threshold value provided a sensitivity of 73%, specificity of 80% and overall accuracy of 78%. Nine of 11 pregnancies with three or more fetuses had hCG concentrations above the threshold values. Although there is a positive correlation between the number of fetuses surviving the first trimester and the hCG concentration early in pregnancy, the predictive value of the hCG concentration is useful only for excluding most triplet and quadruplet pregnancies.

Delayed sexual maturation during prepubertal cannabinoid treatment: importance of the timing of treatment.

Treatment of prepubertal female rats with delta-9-tetrahydrocannabinol (THC) delays first estrus and ovulation. The present study was conducted to determine if treatments initiated at different prepubertal ages would be equally effective in delaying sexual maturation and if changes in prepubertal hormone secretion accompanied the delay. Treatments with THC (10 mg/kg) or vehicle were initiated at 24, 27 or 30 days of age and continued until first estrus was detected by vaginal smears. In one experiment, serum luteinizing hormone (LH) and prolactin (PRL) were measured at 24, 27 or 30 days of age after different durations of treatment. First estrus was delayed (4.8 +/- 1.1 days) when THC treatment started at 27 days of age, but not when treatment started at 24 or 30 days of age. Serum LH was reduced after 1 or 4, but not 7, days of treatment; however, LH suppression was associated with pubertal delay only when it occurred at 27 to 30 days of age. Serum PRL, which increased with age, was suppressed after 1 day of THC treatment at 27 or 30 days of age, but only the former was associated with delayed puberty. Suppression was not evident at 24 days of age after 1 day of THC, or at other ages after treatment for longer than 1 day. These results define a narrow interval, encompassing the ages of 27 to 30 days, during which THC exposure resulted in pubertal delay. Such treatment reduced serum LH and PRL levels, but reductions also occurred with treatments that did not result in maturational delay. The relationship of hormone suppression to the delay thus remains unclear, although the timing of suppression might be a factor.

Human chorionic gonadotropin assays and their uses.

The successful treatment of gestational trophoblastic disease has been partially achieved because of the ability to quantitate serum or urinary concentrations of human chorionic gonadotropin (hCG). Thus, the hCG assay has become essential to the clinical management of trophoblastic disease. This article reviews the various assay methods and discusses their limitations.

Inhibition of suckling-induced milk ejections in the lactating rat by delta 9-tetrahydrocannabinol.

The effect of delta 9-tetrahydrocannabinol (THC) on suckling-induced oxytocin release was investigated by recording intramammary pressure changes in suckled rats treated iv with THC (0.5 mg/kg BW) or vehicle. Latency to the first posttreatment milk ejection and posttreatment milk ejection intervals and pressure wave amplitudes were compared between THC- and vehicle-treated rats. Before treatment, intervals between milk ejections averaged 6.5 +/- 1.3 (+/- SE) and 7.0 +/- 0.7 min for vehicle- and THC-treated groups, respectively. Vehicle injections did not alter the frequency of milk ejections, which continued at an overall mean interval of 7.6 +/- 0.7 min after treatment. In contrast, THC treatment was followed by a transient suspension of milk ejections, with a latency of 59.3 +/- 7.4 min before the first posttreatment milk ejection was recorded (P less than 0.001). Intervals between subsequent ejections averaged 15.3 +/- 2.0 to 16.1 +/- 1.3 min and were lengthened relative to corresponding intervals in vehicle-treated animals (P less than 0.05). The amplitudes of pressure waves were not significantly affected by treatment. Oxytocin (0.5 mU) injections 10 or 30 min after THC treatment evoked abrupt increases in intramammary pressure, indicating continued responsiveness of the mammary gland to oxytocin stimulation. These data suggest that THC interferes with the release of oxytocin in response to suckling. To our knowledge, this provides the first evidence that THC inhibits posterior pituitary function.

Biochemical evidence that human placental lactogen and human chorionic gonadotropin are not stored in cytoplasmic secretion granules.

The intracellular storage sites for the human placental hormones placental lactogen (hPL) and chorionic gonadotropin (hCG) are unknown. To determine whether hPL and hCG are stored in cytoplasmic secretion granules, we have compared the localization of hPL and hCG in placental homogenates following differential and density-gradient centrifugations to those of prolactin (PRL) and luteinizing hormone (LH) in human and rat pituitary homogenates. In the differential centrifugation studies, 93.1 +/- 4.1% (mean +/- SE) of the hPL and 79.4 +/- 6.0% of the hCG were detected in the postmicrosomal supernatant of placental homogenates. In contrast, 95-98% of the hPRL and hLH in the pituitary homogenates were detected in particulate fractions. Following centrifugation on sucrose-density gradients, particulate hPL and hCG were distributed diffusely throughout the gradients, while greater than 90% of the pituitary hormones sedimented as single peaks with densities of 1.22 g/cm3. When human placental and rat pituitary tissues were homogenized together prior to differential and density-gradient centrifugations, similar marked differences were observed between the distribution of the placental and pituitary hormones. These results strongly suggest that the placental hormones hPL and hCG, unlike pituitary PRL and LH, are not stored in large secretory granules. Differences in the intracellular storage sites of the hormones may explain, in part, differences in the regulation of peptide hormone secretion by placental and pituitary tissues.

Tolerance to the luteinizing hormone and prolactin suppressive effects of delta-9-tetrahydrocannabinol develops during chronic prepubertal treatment of female rats.

To determine if prepubertal female rats develop tolerance to the hormone suppressive action of delta-9-tetrahydrocannabinol (THC), we tested the ability of THC (10 mg/kg i.p.) to block luteinizing hormone (LH) and prolactin (PRL) surges acutely at first proestrus in animals that were treated repetitively with THC before puberty. Rats were pretreated with 10 mg THC/kg b.wt. twice daily beginning at 27 days of age and the blocking efficacy of THC treatment at first proestrus was compared to that in animals that were previously untreated or were pretreated only with drug vehicle. Vaginae were opened at 30 days of age to permit identification of first proestrus by vaginal smears, and serial blood samples for LH and PRL radioimmunoassays were collected before and after treatment at proestrus. In previously untreated or vehicle-pretreated animals, THC treatment at 1300 hr on the day of first proestrus inhibited the afternoon surges of LH and PRL, whereas hormone surges occurred in control animals injected with only vehicle at 1300 hr proestrus (P less than .05). In contrast, animals pretreated with THC exhibited marked LH and PRL surges whether treated at 1300 hr proestrus with THC or vehicle. Among animals receiving only vehicle at proestrus, there was no difference in serum LH concentrations or in timing of the LH surge between the group pretreated with THC and the group pretreated with vehicle. These results are consistent with the hypothesis that ovulation eventually occurs in the pubertal rat treated chronically with THC because tolerance develops to its gonadotropin suppressive effects.

Blockade of first ovulation in pubertal rats by delta-9-tetrahydrocannabinol: requirement for advanced treatment due to early initiation of the critical period.

Successful blockade of ovulation in pubertal rats by delta-9-tetrahydrocannabinol (THC) required earlier treatment during proestrus than was required in adults under the same conditions. Only 1 of 8 adult rats ovulated after treatment with THC (10 mg/kg body weight, i.p.) at 1400 h proestrus, whereas 77% of pubertal rats released full sets of ova following similar treatment during proestrus of the first or second vaginal cycle. When treatment of pubertal rats was advanced to 1300 h, only 2 of 10 THC-treated rats exhibited full ovulation, an incidence significantly lower than the 80% ovulation rate observed in vehicle-treated animals (p less than 0.05). To determine whether the requirement for earlier THC treatment in pubertal rats was related specifically to THC or reflected possible age-associated differences in timing of the critical period, the ovulation-blocking efficacy of atropine sulfate (ATR) was tested in pubertal rats for comparison with that of THC. The serum concentrations of luteinizing hormone (LH) during the first proestrus (1200-1900 h) were determined in pubertal rats that remained untreated. The incidence of ovulation in rats treated with ATR (350 mg/kg, s.c.) at 1400 h proestrus was not significantly reduced from that in vehicle-treated rats; however, after ATR treatment at 1300 h, only 2 of 11 animals released full sets of ova whereas all vehicle-treated rats ovulated (p less than 0.025). The mean serum LH concentration in untreated pubertal rats was not significantly increased over baseline at 1300 h proestrus, but was markedly elevated by 1400 h (1009 +/- 375 ng/ml; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of luteinizing hormone release by electrochemical stimulation of the medial preoptic area in delta 9-tetrahydrocannabinol-blocked proestrous rats.

The predominant psychoactive constituent of marijuana, delta 9-tetrahydrocannabinol (THC), blocks the preovulatory luteinizing hormone (LH) surge and ovulation in rats treated with THC (10 mg/kg body weight) during the early afternoon of proestrus. When THC-blocked proestrous rats were subjected to unilateral electrochemical stimulation (100 microA anodal DC for 45 s) in the medial preoptic area (mPOA), serum LH was significantly elevated at 30, 60 and 90 min after stimulation in comparison with LH levels measured in sham-stimulated control animals at those times. The induced LH release was sufficient to elicit ovulatory responses comparable to the spontaneous ovulations observed in control rats treated only with the drug vehicle. These results are consistent with the hypothesis that THC inhibits gonadotropin secretion by action within the central nervous system, but demonstrate that the central inhibitory effect of THC does not prevent the release of LH-releasing hormone (LHRH) when the LHRH neurosecretory units are activated by brain stimulation. Thus, the antiovulatory effect of THC appears to result from an inhibition of LH secretion which does not involve the direct blockade of LHRH release.

Reversal of the delta-9-tetrahydrocannabinol inhibitory effect on prolactin secretion by rostral deafferentation of the medial basal hypothalamus.

The effect of rostral deafferentation of the medial basal hypothalamus (MBH) on delta-9-tetrahydrocannabinol (THC)-induced changes in serum prolactin (PRL) concentrations was investigated in female rats having retrochiasmatic frontal cuts that transected the rostral hypothalamus. Cuts dorsal to the hypothalamus were produced in the same plane in other animals in order to control for possible effects of the surgical procedure or dorsal brain damage. All animals were ovariectomized 28-35 days after stereotaxic surgery to obviate potential confounding effects of differences in ovarian function between groups. Unlesioned rats were ovariectomized to provide a positive control group for THC inhibitory activity. At least 4 weeks after ovariectomy, animals were treated intravenously with THC (0.5 or 1.0 mg/kg body weight) or vehicle at the midpoint of a 110-min experimental period during which blood samples were obtained at 10-min intervals via indwelling atrial cannulae. Serum PRL concentrations were determined by radioimmunoassay and cut locations were confirmed histologically. When administered to ovariectomized animals without brain lesions, THC suppressed serum PRL concentrations from the average treatment level within 30 min (p less than 0.05), and PRL levels remained suppressed for the remainder of the posttreatment sampling period. Treatment with the vehicle alone was without effect. Animals with retrochiasmatic plane cuts that did not transect the rostral hypothalamus similarly displayed PRL suppression in response to THC administration (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Human chorionic gonadotropin alpha-subunit of normal placenta: characterization of synthesis and association with beta-subunit.

The forms of human chorionic gonadotropin (hCG) alpha-subunit synthesized and released by normal placental tissue were examined in explants of first trimester placenta that had been incubated for 30 min with [35S]methionine and then incubated for 6 h in medium containing unlabeled methionine. The media and tissue extracts collected at 0, 0.5, 1, 2, 4, and 6 h after the exposure to [35S]methionine were chromatographed on Sephadex G-100 and the amounts of radioimmunoassayable alpha-subunit and immunoprecipitable 35S-labeled alpha-subunit were determined. In tissue extracts, a single form of alpha-subunit was observed at 0 h that had an apparent molecular weight smaller (Ve/Vo = 1.90) than that of a urinary hCG alpha reference preparation (Ve/Vo = 1.81). With chase times of 0.5, 1, 2, and 4 h, a second peak of alpha-subunit was detected that had a larger apparent molecular weight (Ve/Vo = 1.68), and the ratio of large to small forms increased progressively with incubation time. In contrast to that in the extracts, the 35S-labeled alpha-subunit in the culture medium consisted entirely of the large form. Large and small intracellular forms of free alpha-subunit exhibited less than 2% recombination with beta-subunit, as evidenced by gonadotropin receptor binding activity. These studies suggest that normal placental tissue synthesizes a small precursor form of free hCG alpha-subunit that is converted to a larger form prior to secretion and that the free forms of alpha-subunit do not bind to purified hCG beta-subunit.

Ovulation induction with pulsatile gonadotropin-releasing hormone administration in patients with polycystic ovarian syndrome.

Gonadotropin-releasing hormone (0.025 microgram/kg) was administered intravenously in a pulsatile fashion to four subjects with polycystic ovary syndrome for a total of six cycles. Five of the six cycles culminated in ovulation, although in one course the response occurred too early to be attributed to the therapy alone. No pregnancies resulted. All luteal phases were of normal duration, but progesterone production as manifested by serum progesterone determination was deficient in some. If additional investigation confirms these preliminary findings, this form of therapy may offer a safe and economic alternative for anovulatory patients refractory to clomiphene citrate therapy. The response of the four subjects suggests that pulsatile gonadotropin-releasing hormone administration may override hypothalamic-pituitary dysfunction and result in ovulatory menstrual cycles.

Delayed sexual maturation in the female rat during chronic exposure to delta-9-tetrahydrocannabinol.

delta-9-Tetrahydrocannabinol (THC), the major psychoactive component of marihuana, retarded sexual maturation in the pubertal female rat as indicated by a delayed appearance of estrus and ovulation. Twice daily intraperitoneal injections of 10 mg THC/kg body weight from 27 days of age until the first day of full vaginal cornification delayed the onset of estrus and the occurrence of the first ovulation by an average of 4.3 +/- 0.9 (S.E.M.) days in comparison with pair-fed, vehicle-treated animals (p less than 0.001). Ovulation during the first estrus occurred in 92% of the animals in each treatment group without a difference in the average number of ova ovulated. The delayed sexual maturation in animals treated with THC could not be attributed to reduced body weight gain since body weights in THC- and vehicle-treated groups were equivalent when vehicle-treated animals came into estrus. Delayed ovulation in THC-treated animals did not merely reflect the repeated blockade of ovulation from otherwise competent follicles in that the onset of vaginal cornification was delayed to a comparable extent. Rather, the data suggest retarded development of ovarian follicles, possibly as a result of pituitary suppression. It is noteworthy that, although delayed, both vaginal cornification and ovulation occurred in spite of continued THC treatment, suggesting the development of drug tolerance.

Human chorionic gonadotropin levels in complete and partial hydatidiform moles and in nonmolar abortuses.

The rates of regression of human chorionic gonadotropin (hCG) in patients with complete hydatidiform moles, partial hydatidiform moles, and nonmolar abortions were compared. No difference in rates of regression was found among the three groups, but levels of hCG immediately after uterine evacuation were significantly higher in the group with complete hydatidiform moles. Differences in the time required for hCG levels to become undetectable were attributed to the difference in the degree of initial elevation of hCG.