The risk of overt diabetes mellitus among women with gestational diabetes: a population-based study.

AIMS: To determine the incidence of postpartum diabetes mellitus in the years following a diagnosis of gestational diabetes mellitus (GDM) and to determine whether the severity of GDM, represented by the magnitude of the deviation of diagnostic tests from the normal values or requirement for medications, is associated with the development of diabetes. METHODS: A retrospective cohort study was performed among 185 416 pregnant women who had glucose challenge test or 3 h oral glucose tolerance test (OGTT) in a large health maintenance organization in Israel. Subsequent diagnosis of diabetes was ascertained by using an automated patient registry. RESULTS: A total of 11 270 subjects were diagnosed with GDM, comprising 6.07% of the cohort. During a total follow-up period of 1 049 334 person-years there were 1067 (16.9 per 1000 person-years) and 1125 (1.1 per 1000 person-years) diagnoses of postpartum diabetes among GDM and non-GDM women, respectively. The cumulative risk of incident diabetes in GDM patients with up to 10 years of follow-up was 15.7%, compared with 1% among the non-GDM population. Gestational diabetes mellitus was associated with nearly an eightfold higher risk of postpartum diabetes after adjusting for important confounders, such as socioeconomic status and body mass index. Among women with a history of GDM, the number of abnormal OGTT values and use of insulin were associated with a substantially higher risk for developing diabetes. CONCLUSIONS: Three or four abnormal OGTT values and GDM requiring insulin or oral hypoglycaemic medications are important predictors of postpartum diabetes risk in women with a history of GDM.

Raising awareness for the diagnosis and treatment of erectile dysfunction in patients with high risk to develop ED.

Prevalence of erectile dysfunction (ED) increases with age and is associated with chronic comorbidities, such as diabetes and hypertension. Even so, ED is underdiagnosed and undertreated. This study investigated the effect of raising awareness of ED diagnosis and treatment in a community setting by physicians' education. Thirty-nine primary care physicians participated in lectures by a trained sexologist, and 20 of them also received computerized lists of their high-risk patients. We matched a control group of 39 primary care physicians who did not receive the intervention; we thus followed 1959 patients in both intervention groups and 1903 patients in the control group. During the period of 6 months before the intervention and 6 months after the intervention, no significant differences were found between the groups in diagnosis of new ED patients, in phosphodiesterase-5 inhibitor prescriptions or in referrals to urologists. We therefore suggest that sporadic lectures and computerized patient lists do not significantly affect the physician's behavior.

School closure may be effective in reducing transmission of respiratory viruses in the community.

Proposed measures to contain pandemic influenza include school closure, although the effectiveness of this has not been investigated. We examined the effect of a nationwide elementary school strike in Israel in 2000 on the incidence of influenza-like illness. In this historical observational study of 1.7 million members of a preferred provider organization, we analysed diagnoses from primary-care visits during the winter months in 1998-2002. We calculated the weekly ratio of influenza-like diagnoses to non-respiratory diagnoses, and fitted regression models for school-aged children, children's household members, and all other individuals aged >12 years. For each population the steepest drop in the ratio of influenza-like diagnoses to non-respiratory diagnoses occurred in the strike year 2 weeks after the start of the strike. The changes in the weekly ratio of influenza-like diagnoses to non-respiratory diagnoses were statistically significant (P=0.0074) for school children for the strike year compared to other years. A smaller decrease was also seen for the adults with no school-aged children in 1999 (P=0.037). The Chanukah holiday had a negative impact on the ratio for school-aged children in 1998, 1999 and 2001 (P=0.008, 0.006 and 0.045, respectively) and was statistically significant for both adult groups in 1999 and for adults with no school-aged children in 2001. School closure should be considered part of the containment strategy in an influenza pandemic.

Long-term trends in hepatitis A incidence following the inclusion of Hepatitis A vaccine in the routine nationwide immunization program.

For many years hepatitis A was one of the most common vaccine preventable diseases in Israel. In 1999, Israel became the first country to introduce an inactivated hepatitis A vaccine into its national childhood vaccination program. The objectives of the present study were to study trends in disease incidence after the implementation of the new vaccination policy and to assess vaccination coverage among children and adults in Israel. We used the databases of the second largest HMO in Israel (1.7 million members) to identify patients who had evidence of hepatitis A in 1998 and 2007 and to collect information on all subjects who received at least one dose of hepatitis A vaccine during the study period. Hepatitis A vaccination coverage in children <5 years and 5-14 years of age increased from 9% and 15% in 1998 to 89% and 68% in 2007, respectively. During this period the annual incidence of hepatitis A dropped from 142.4 per to 7.6 per 100 000. The most prominent reduction in the age-specific annual incidence rates was calculated in children <5 years from 239.4 per 100 000 in 1998 to 2.2 per 100 000 in 2007 and from 310.3 per 100 000 to 3.0 per 100 000 in children aged 5-14 years. In endemic areas, vaccination of infants and children against hepatitis A can greatly reduce the total burden of the disease.

Diabetes as a risk factor for herpes zoster infection: results of a population-based study in Israel.

BACKGROUND: Studies showed that diabetes mellitus (DM) is often accompanied by impaired cell-mediated immunity, which potentially may increase the risk for infectious diseases, including herpes zoster (HZ). However, data on the relation between DM and HZ are scarce. This case-control study explored the association between DM and HZ. PATIENTS AND METHODS: This study was nested within a cohort of all members of a large health maintenance organization (HMO) in Israel. Cases totaled 22,294 members who were diagnosed with HZ between 2002 and 2006. Controls (n=88,895) were randomly selected from the remaining HMO population using frequency-matched age, sex, and duration of follow-up. Personal data on history of DM, lymphoma, leukemia, or AIDS, were obtained from computerized medical records. RESULTS: Adjusted analyses showed that the risk of HZ was associated with history of leukemia, lymphoma, use of steroids or antineoplastic medications, and AIDS, particularly among patients below 45 years of age. In a multivariate analysis, DM was associated with an increased risk of HZ (OR=1.53; 95% CI: 1.44-1.62). CONCLUSIONS: The data suggest that individuals with DM are at increased risk of HZ. Well-designed cohort studies may help to clarify the nature of this association.

The association between glycemic, lipids and blood pressure control among Israeli diabetic patients.

BACKGROUND: It is recommended that in diabetes mellitus patients all risk factors for cardiovascular disease should be controlled. AIM: To evaluate the rate of reaching all glycemic, lipids and blood pressure target levels among diabetic patients in Israel and to analyze demographic and clinical parameters associated with it. DESIGN: A cross-sectional study. METHODS: The study was conducted in Maccabi Healthcare Services, Israel's second largest health maintenance organization. All patients (n = 41 936), older than 20 years, who were listed on Maccabi Healthcare Service's diabetes mellitus computerized database and had all three study parameters (HbA1c, LDL-C and blood pressure levels during 2005) were eligible for the study. The rate of reaching HbA1c <7.0%, LDL-C <100 mg/dl and blood pressure <130/85 mmHg, as well as its association with various demographic and clinical parameters were analyzed. RESULTS: Only 13% of all study patients achieved all three target levels. The parameters which were significantly associated with goal achievement were compliance to medical treatment for all three parameters (OR 1.56, 95% CI 1.44-1.69, P = 0.0001), male gender (OR 1.42, 95% CI 1.31-1.54, P = 0.0001), comorbidity with ischemic heart disease (OR 1.23, 95% CI 1.13-1.34, P = 0.0001), and >12 visits per year to family physician (OR 1.10, 95% CI 1.02-1.19, P = 0.012). CONCLUSION: Non-compliance with treatment and sub-optimal follow-up by family physicians are associated with increased risk of failure to control major risk factor among diabetic patients.

Mandatory computer field for blood pressure measurement improves screening.

METHODS: We evaluated the effectiveness of a compulsory data field in a computerized medical record (CMR) in improving blood pressure (BP) screening. RESULTS: The proportion of study patients who had their BP measured increased from 40.6% to 58.5% (P < 0.001) after the intervention. After adjusting for age, gender and number of visits, patients were 73% more likely to have their BP recorded after the introduction of the compulsory field.

Gender differences in healthcare utilization and medical indicators among patients with diabetes.

OBJECTIVE: To describe differences in healthcare utilization and health indicators of patients with diabetes, according to gender. STUDY DESIGN: A population-based outcome study conducted on 21,277 diabetic patients between the ages of 45 and 64 years who are members of the second largest health maintenance organization in Israel. METHODS: Data on healthcare utilization (process indicators) and health problems (outcome indicators) were obtained from computerized medical records that are stored routinely by the organization. The study period was the year 2002. RESULTS: Significantly (P < 0.05) lower healthcare utilization was observed in men compared with women for all indicators examined (number of visits to physicians and the performance of urine, lipids and creatinine tests). Nonetheless, men showed better health outcomes (lower low-density lipoprotein cholesterol, triglycerides, HbA1c). CONCLUSIONS: Women who suffer from diabetes use more healthcare services and have a higher morbidity rate compared with men. Future research should seek to identify the factors contributing to this observation, which can potentially make an important contribution to the development of disease management strategies that target diabetic women.

The use of organizational data for the evaluation of mass prevention programs.

BACKGROUND: The effectiveness of health promotion campaigns is hard to measure due to complex outcome and external factors. This study presents a method to evaluate a mass women's health promotion campaign held in a large health maintenance organization (HMO) in Israel. METHODS: This population-based study used administrative and medical databases to examine whether postal invitation to 120,231 HMO-female members increased adherence with certain preventive medicine recommendations (LDL-C, bone density test, and mammography breast cancer screening). A comparison was made using three different reference data: pre- and post-campaign periods (1998-2003), HMO-male members who were not targeted by the campaign, and rates of urine tests, which were also not targeted by the campaign. RESULTS: During the 2 months following the campaign, adherence with mammography (3.8%) and LDL-C (12.5%) reached their maximum rates in 5 years. Adherence with bone density test increased from 2.3% in 2000 to 2.8% in the campaign period. No similar trends were observed for urine or LDL-C tests among men. CONCLUSIONS: The use of multiple reference groups through the analysis of administrative and medical databases supports the association between the campaign and improved adherence with screening tests. A similar methodology may be adopted for the analysis of mass health promotion campaigns in large HMOs.

Increasing asthma awareness among physicians: impact on patient management and satisfaction.

Our objective was to investigate the impact of increased asthma awareness among primary care physicians on the asthma control and satisfaction of their patients. Physicians attended an asthma education session with emphasis on patient-physician partnership followed by 4 month monitored follow-up of patients aged 5-44 years with mild to moderate asthma. Findings were compared with a group of patients whose physician attended the session but did not participate in the follow-up and two other control groups. The study included pediatricians and general practitioners of Maccabi Healthcare Services and their patients. Asthma symptoms were rated by patients and physicians. Data on drug prescription and use were derived from the Maccabi central database. Patient response and satisfaction and physician satisfaction were evaluated by telephone interviews. Mean asthma symptom score improved from 2.0 to 1.1 in the study group of patients (p < 0.001). The use of reliever drugs decreased concomitantly with a rise in controller drugs in all patients. An improvement in asthma status was reported by 64% of the study patients and 39% of non-participating patients (p = 0.007). Fifty-eight percent of the patients rated their competence to deal with asthma as high before the intervention compared to 62% of the participating and 55% of the non-participating patients after the intervention (p = 0.002). Most physicians claimed that simply increasing their awareness on asthma led to beneficial results in their patients. Physician education followed by monitored follow-up enhanced asthma control and patient satisfaction. Nevertheless, physician education alone appears to have a significant isolated impact on asthma control.

Rat ovarian prostaglandin endoperoxide synthase-1 and -2: periovulatory expression of granulosa cell-based interleukin-1-dependent enzymes.

This laboratory has previously shown that interleukin-1 (IL-1), a putative intermediary in the ovulatory process, is capable of up-regulating PG biosynthesis by cultured whole ovarian dispersates from immature rats. In part, this phenomenon was attributable to the stimulation of ovarian phospholipase A2 activity. In this communication we examine the possibility that the PG-promoting property of IL-1 is also due to the up-regulation of PG endoperoxide synthase (PGS), the rate-limiting step in prostanoid biosynthesis. The in vivo expression of ovarian PGS-2 transcripts in the course of a simulated estrous cycle rose abruptly to a peak (35-fold increase over the control value; P < 0.05) 8-12 h after hCG administration (i.e. before or during projected ovulation). PGS-1 transcripts, in turn, were not significantly altered during the periovulatory period. Treatment of cultured whole ovarian dispersates with IL-1beta resulted in dose- and time-dependent up-regulation of PGS-2 transcripts (as well as of immunoreactive PGS-2 protein and PGE2 accumulation), characterized by an ED50 of 2 ng/ml and a maximal (72-fold) increase at 10 ng/ml. Although treatment with IL-1beta also led to an increase in PGS-1 transcripts and immunoreactive PGS-1 protein, the relative magnitude of the effect was markedly reduced compared with that of PGS-2. Cotreatment with an IL-1 receptor antagonist completely reversed the IL-1 effects, thereby suggesting mediation via the IL-1 receptor. The ability of IL-1 to up-regulate PGS-2 transcripts proved relatively specific, in that other cellular regulators (insulin-like growth factor I, activin A, endothelin-1, transforming growth factor-alpha, tumor necrosis factor-alpha, vascular endothelial growth factor, leukemia inhibitor factor, hepatocyte growth factor, or keratinocyte growth factor) were not effective. The optimal IL-1 effect required heterologous contact-dependent coculturing of granulosa and thecal-interstitial cells. Taken together, these observations 1) reaffirm (by molecular probing) the granulosa cell as the primary site of ovarian PGS-1 and PGS-2 expression, 2) document an increase in ovarian PGS-2 transcripts before ovulation, and 3) reveal a marked dependence of ovarian PGS (2 >> 1) transcripts, proteins, and activity on IL-1. The effects of IL-1 proved relatively specific, contingent upon somatic cell-cell cooperation, dose and time dependent, and IL-1 receptor mediated. These results are compatible with the proposition that the PG-promoting property of IL-1 is due, in large measure, to the activation of ovarian PGS transcription and translation. The ability of IL-1 to up-regulate ovarian PGS, an obligatory component of ovulation, is in keeping with the idea that IL-1 may constitute an intermediary in the ovulatory process.

Outcome of second-trimester, emergency cervical cerclage in patients with no history of cervical incompetence.

A retrospective, descriptive study was conducted to evaluate the outcome of second-trimester, emergency cervical cerclage in patients with no history of cervical incompetence. Thirty-two women with singleton pregnancies were studied. All had undergone emergency cervical McDonald cerclage at 17 to 25 weeks' gestation because of cervical dilation and effacement. The procedure was carried out after a rest period of 6 or more hours, during which none of the patients demonstrated uterine activity. The mean procedure-to-delivery interval was 6.9 +/- 5.6 (median 5.5, range 0.2 to 18) weeks. Thirteen pregnancies (41%) terminated before 24 weeks. The mean gestational age at delivery was 28.5 +/- 5.8 weeks for the entire group, and 32.3 +/- 4.4 (range 25 to 38) weeks for the 19 who achieved viability. The mean birthweight of the live infants was 1935 +/- 958 g (median 1670, range 905 to 3710 g). Four infants died during the neonatal period. The total survival rate was 47%, and the survival rate corrected for major anomalies was 48.4%. The perinatal mortality rate was significantly higher among patients with membranes protruding through the-cervix on admission, compared to those without (75% vs 17%; p = .003). We concluded that emergency midtrimester cervical cerclage among patients with no prior evidence of cervical incompetence is associated with an approximately 50% survival rate. Membranes protruding through the dilated cervix are a poor prognostic factor for survival in these cases.

The sleeping aviator--aeromedical disposition of Kleine-Levin syndrome.

We present the case of an aviator with Kleine Levin syndrome (KLS). History, physical examination, and special studies presented confirm the diagnosis of this syndrome. Our patient presented as an atypical case of KLS with respect to the presenting symptoms and to frequency of the episodes (6 years apart). He exhibited only intense somnolence, easy arousability, photophobia, hyperacousis, and a voracious appetite. Following a complete medical work up we recommended that an applicant with such a classical case of KLS be disqualified as a crewmember; however, in cases such as that presented above a limited waiver may be considered. The aeromedical significance of this case is to reinforce the importance of screening candidates and seeking precise diagnosis of a past illness or hospitalization.

The ovarian action of interleukin-1 is receptor mediated: reversal by a naturally occurring interleukin-1 receptor antagonist.

OBJECTIVE: To address indirectly the possibility that the ovarian action(s) of interleukin (IL)-1 are receptor mediated and to re-examine the recently reported proposition that the naturally occurring IL-1 receptor antagonist (IL-1ra) may in fact act in the capacity of mixed IL-1 receptor agonist/antagonist. DESIGN: In vitro treatment of isolated granulosa cell (GC) and whole ovarian dispersates of rat origin. RESULTS: Treatment of GC from immature rats with increasing concentrations of IL-1ra (10 to 5,000 ng/mL) proved without effect on either the basal or FSH (100 ng/mL)-supported accumulation of P. Likewise, cellular viability (as assessed by conversion of 3-[4,5-dimethylthiazol-2-yl]-2-5 diphenyltetrazolium bromide to spectrophotometrically detectable formazan) remained unaltered. However, the concomitant addition of increasing concentrations of IL-1ra (10 to 5,000 ng/mL) yielded dose-dependent reversal of the 10 ng/mL IL-1 beta-mediated inhibition of the FSH-supported accumulation of P. Similarly, the ability of IL-1 beta to exert a dose-dependent (0 to 30 ng/mL) anti-gonadotropic effect was attenuated progressively given the concurrent presence of increasing concentrations (1,000 and 5,000 ng/mL) of IL-1ra. Although treatment of whole ovarian dispersates with 10 ng/mL IL-1 beta resulted in a 5.4-fold increase in the accumulation of prostaglandin (PG)E2, this effect too was all but eliminated after the concomitant addition of 5 micrograms/mL IL-1ra. CONCLUSIONS: These observations support the nontoxic nature of IL-1ra, confirm its lack of agonistic activity, validate its utility as an experimental probe, and suggest that neither the basal nor the FSH-stimulated accumulation of P are subject to regulation by endogenously produced GC-derived IL-1-like activity. Moreover, these observations suggest that the ability of IL-1 beta to inhibit the gonadotropin-supported accumulation of P and to increase PGE2 accumulation is receptor-mediated.

Interleukin-1 beta stimulates nitrite production in the rat ovary: evidence for heterologous cell-cell interaction and for insulin-mediated regulation of the inducible isoform of nitric oxide synthase.

Recent studies suggest that endogenously generated nitric oxide (NO) may mediate the effects of cytokines in a variety of tissues. In an effort to determine whether NO generation mediates any of the intraovarian actions of interleukin-1 beta (IL-1 beta), we have looked for and characterized the accumulation of nitrite by IL-1 beta-treated, cultured whole ovarian dispersates. Application of IL-1 beta significantly enhanced basal nitrite release in a dose-, cell density- and time-dependent manner, the latter characterized by a lag time of about 20 h, suggestive of induction of NO synthase (NOS). Cellular NOS activity was also elevated by IL-1 beta. Sustained nitrite accumulation required continuous application of IL-1 beta. The maximally stimulating dose of IL-1 beta (50 ng/ml) produced a 10-fold increase in nitrite accumulation by 96 h of culture, an effect reduced 23% when cells were cultured in substrate (i.e., arginine)-free media. IL-1 beta-stimulated nitrite accumulation was reduced to control levels by the simultaneous application of an IL-1 beta receptor antagonist, thereby suggesting a specific receptor-mediated effect. Both the control and IL-1 beta-stimulated levels of nitrite accumulation were attenuated in a dose-dependent manner by inhibitors that favor the inducible form of NOS. In contrast, selective inhibitors of the constitutive form of NOS were significantly less potent. No inhibition was noted after application of an inactive stereoisomeric analogue. IL-1 beta-induced nitrite accumulation was shown to require cell-cell interaction between granulosa and theca-interstitial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluorescence polarization of serum lipids in pregnancies complicated by hypertensive disorder.

Hypertensive disorders in pregnancy are associated with an increase in serum lipid fractions. Fluorescence Polarization (FP) of lipids in the serum of 80 hypertensive pregnant patients at full term was compared to measurements in a control group of 71 healthy pregnant volunteers. In addition, the FP values were correlated with measurements of serum lipid fraction in 34 hypertensive and 17 control patients. Both chronic hypertension and pregnancy induced hypertensive (PIH) subjects had significantly reduced serum FP values compared to the control group. This difference was however present only in the severely hypertensive patients, independent of the etiology of this disorder. Highly significant correlations were present between the FP values and serum level of Triglycerides r = -0.85, Very Low Density Lipoprotein r = -0.76, and Low Density Lipoprotein r = 0.53. Serum FP values appear to reflect the change in the lipoprotein pattern present in pregnant patients with hypertensive disorders. This change appears to reflect the severity of the condition rather than the etiology of the hypertension.

Receptor-mediated stimulatory effect of IL-1 beta on hyaluronic acid and proteoglycan biosynthesis by cultured rat ovarian cells: role for heterologous cell-cell interactions.

An increasing body of information supports the possibility that intraovarian interleukin (IL)-1 may play an intermediary role in gonadotropin-triggered ovulation. To further evaluate this hypothesis, we have examined the effect of IL-1 beta on ovarian proteoglycan/glycosaminoglycan economy, an established corollary of the preovulatory cascade. Rat ovarian cells were metabolically labeled with [35S]sulfate and [3H]glucosamine for 48h in the absence or presence of IL-1 beta, with or without an IL-1 receptor antagonist (IL-1ra). At the conclusion of this treatment period, total 35S and 3H incorporation into cell-associated and extracellular proteoglycan/glycosaminoglycan species was determined. Treatment of whole ovarian dispersates with IL-1 beta (10 ng/ml) produced substantial increments in the accumulation of extracellular macromolecular material [11.5-, 2.9- and 2.6-fold for hyaluronic acid (HA), heparan sulfate (HS) and dermatan sulfate (DS) proteoglycans, respectively]. In contrast, only modest increments (< or = 1.7-fold) were noted for IL-1 beta-treated granulosa cells (GC), theca-interstitial cells (TC), or 4:1 co-cultures (GC/TC) thereof. Treatment of whole ovarian dispersates with IL-1 beta also resulted in significant (P < 0.001) increments in the cell-associated accumulation of both HA (6.0-fold increase) and DS proteoglycans (3.4-fold increase). However, the cell-associated accumulation of HS proteoglycan was not significantly affected by IL-1 beta regardless of the cellular preparation under study. The concurrent provision of IL-1ra (5 micrograms/ml) all but neutralized the IL-1 beta effect on HA biosynthesis thereby suggesting mediation by specific ovarian IL-1 receptor(s). Taken together, these observations suggest that treatment of ovarian cells with IL-1 beta results in an overall increase in macromolecular biosynthesis as well as in redistribution favoring extracellular HA and DS (but not HS) proteoglycans. Moreover, since whole ovarian dispersates proved more responsive to IL-1 than isolated cellular components thereof, the present observations suggest an obligatory requirement for heterologous cell-cell interaction without which optimal HA or proteoglycan biosynthesis may not be realized. These observations along with the demonstration of IL-1-mediated amplification of gonadotropin-triggered ovulation provide strong indirect support for the view that IL-1 may be the centerpiece of an intraovarian regulatory loop concerned with the promotion of key periovulatory events.

Endothelin-1 as a luteinization inhibitor: inhibition of rat granulosa cell progesterone accumulation via selective modulation of key steroidogenic steps affecting both progesterone formation and degradation.

Endothelin (ET)-1, is a 21 amino acid vasoactive peptide subject to regulation by cellular oxygen tension. However, an increasing body of information now suggests that ET-1 is a multifunctional peptidergic regulator the actions of which are not limited to the vascular system. Although ET-1 has been shown to inhibit the gonadotropin-supported accumulation of progesterone by cultured granulosa cells, the precise cellular mechanism(s) involved remain unknown. It was therefore the objective of this study to examine in greater detail the effects of ET-1 on progestin economy in cultured granulosa cells from immature rats. Treatment with ET-1 was inhibitory to the FSH-supported accumulation of progesterone in a dose-dependent manner, an action characterized by a median inhibitory dose of 2 x 10(-11) M and a maximal inhibitory effect of 90%. This inhibitory action of ET-1 was reversible following extensive washing and could not be accounted for by a decrease in the viable cell mass. Evaluation of the activities of progesterone-forming enzymes revealed ET-1 to be a potent (P < 0.01) inhibitor of cholesterol side-chain cleavage and 3 beta-hydroxysteroid dehydrogenase (HSD)/isomerase (76.1 +/- 1.2% and 47.3 +/- 8.6% inhibition, respectively). Cellular radiolabeling with [3H]pregnenolone confirmed an ET-1-induced inhibition of the FSH-supported accumulation of radiolabeled progesterone. However, this effect was concomitant with enhancement of the accumulation of more distal metabolites, i.e. 20 alpha-dihydroprogesterone, 5 alpha-pregnane-3 alpha, 20 alpha-diol, and 5 alpha-pregnane-3 alpha-ol-20-one. Analysis of the FSH-supported activities of the progesterone-degrading enzymes revealed ET-1 as a potent (P < 0.05) stimulator of 20 alpha-HSD and 5 alpha-reductase (3.6 +/- 1.0 and 1.7 +/- 0.3-fold, stimulation respectively). In contrast, no significant changes were observed in 3 alpha-HSD activity. Taken together, our findings demonstrate that the ET-1 induced inhibition of gonadotropin-supported progesterone accumulation constitutes a complex phenomenon wherein ET-1 inhibits the activities of steroidogenic enzymes concerned with progesterone formation while enhancing the activities of enzymes concerned with progesterone degradation. We speculate that ET-1, possibly of intraovarian origin, acts as a luteinization-inhibitor to suppress premature luteinization at a time when continued preovulatory expression of ET-1 (in the intact but not ruptured follicle) may be contingent upon relative intrafollicular hypoxia.

Granulosa cell-derived insulin-like growth factor (IGF) binding proteins are inhibitory to IGF-I hormonal action. Evidence derived from the use of a truncated IGF-I analogue.

An increasing body of information now suggests that insulin-like growth factor (IGF) binding proteins (BPs) may serve as antigonadotropins at the level of the ovary. It is the objective of the present communication to evaluate the functional role of endogenous (granulosa cell-derived) IGFBPs by exploiting the unique properties of des(1-3)IGF-I, a naturally occurring IGF-I analogue characterized as a weak ligand of IGFBPs but not of type I IGF receptors. Given IGFBP-replete circumstances, des(1-3)IGF-I proved more potent (10-fold) than its intact counterpart in promoting the follicle stimulating hormone (FSH)-stimulated accumulation of progesterone by cultured rat granulosa cells. In contrast, des(1-3)IGF-I proved virtually equipotent to the unmodified principle under IGFBP-deplete circumstances. Taken together, these findings are in keeping with the notion and that the apparently enhanced potency of des(1-3)IGF-I (under IGFBP-replete conditions) is due to its diminished affinity for endogenously generated IGFBPs and that rat granulosa cell-derived IGFBPs are inhibitory to IGF (and thus inevitably to gonadotropin) hormonal action. Accordingly, the reported ability of gonadotropins to attenuate IGFBP release by granulosa cells may be designed to enhance the bioavailability of endogenously generated IGFs in the best interest of ovarian steroidogenesis.