Circulating Prolidase Activity in Patients with Myocardial Infarction.

BACKGROUND: Collagen is a major determinant of atherosclerotic plaque stability. Thus, identification of differences in enzymes that regulate collagen integrity could be useful for predicting susceptibility to atherothrombosis or for diagnosing plaque rupture. In this study, we sought to determine whether prolidase, the rate-limiting enzyme of collagen turnover, differs in human subjects with acute myocardial infarction (MI) versus those with stable coronary artery disease (CAD). METHODS: We measured serum prolidase activity in 15 patients with stable CAD and 49 patients with acute MI, of which a subset had clearly defined thrombotic MI (n = 22) or non-thrombotic MI (n = 12). Prolidase activity was compared across study time points (at cardiac catheterization, T0; 6 h after presentation, T6; and at a quiescent follow-up, Tf/u) in acute MI and stable CAD subjects. We performed subgroup analyses to evaluate prolidase activity in subjects presenting with acute thrombotic versus non-thrombotic MI. RESULTS: Although prolidase activity was lower at T0 and T6 versus the quiescent phase in acute MI and stable CAD subjects (p < 0.0001), it was not significantly different between acute MI and stable CAD subjects at any time point (T0, T6, and Tf/u) or between thrombotic and non-thrombotic MI groups. Preliminary data from stratified analyses of a small number of diabetic subjects (n = 8) suggested lower prolidase activity in diabetic acute MI subjects compared with non-diabetic acute MI subjects (p = 0.02). CONCLUSION: Circulating prolidase is not significantly different between patients with acute MI and stable CAD or between patients with thrombotic and non-thrombotic MI. Further studies are required to determine if diabetes significantly affects prolidase activity and how this might relate to the risk of MI.

Relationship between serum müllerian-inhibiting substance and other reproductive hormones in untreated women with polycystic ovary syndrome and normal women.

OBJECTIVE: To examine the relationship of serum müllerian-inhibiting substance (MIS), E(2), free-T, LH, and FSH in untreated women with polycystic ovary syndrome (PCOS) and in women with normal menstrual cycles. DESIGN: A prospective study. SETTING: University Departments of Obstetrics and Gynecology and Surgery. PATIENT(S): Twenty-seven women with PCOS and 20 women with normal menstrual cycles. INTERVENTION(S): Serum was collected from women with PCOS and from normal women during the early follicular phase of the menstrual cycle, stored frozen until assayed. MAIN OUTCOME MEASURE(S): Serum levels of MIS, E(2), free-T, TSH, LH, and FSH were measured. RESULT(S): Serum müllerian-inhibiting substance levels in PCOS patients were significantly higher compared with normal women (+/- SE; 5.3 +/- 0.7 and 1.4 +/- 0.2 ng/mL, respectively). An inverse correlation (r = -0.5965) was found between serum levels of MIS and E(2) in PCOS women, but not in normal women. Women with PCOS had higher serum LH levels than those of normal women (15.2 +/- 1.2 and 5.0 +/- 0.7 mIU/mL). CONCLUSION: In this study, women with PCOS have significantly higher serum MIS levels than normal women. The inverse relationship between müllerian-inhibiting substance and E(2) levels suggests that MIS may modulate ovarian E(2) synthesis and have a role in the disordered folliculogenesis characteristic of PCOS.

Müllerian-inhibiting substance inhibits cytochrome P450 aromatase activity in human granulosa lutein cell culture.

OBJECTIVE: To investigate the effects of Müllerian-inhibiting substance (MIS) on cytochrome P450 aromatase (CYP19) gene expression in cultured human granulosa lutein cells (GLC). DESIGN: In vitro primary cell culture study. SETTING: Academic research laboratory and hospital-based fertility center. PATIENT(S): Eight normo-ovulatory patients undergoing IVF procedures due to male factor or tubal infertility. INTERVENTION(S): Serum and follicular fluid (FF) collected and stored at -80 degrees C until assayed. Granulosa lutein cells were harvested from follicular aspirates obtained during oocyte retrieval and cultured for 7 days with media in the presence or absence of MIS (10 ng/mL) or FSH 0.2 IU/mL. MAIN OUTCOME MEASURE(S): Serum and FF levels of E2 and MIS, and E2 production by GLC in culture. Levels of CYP19 mRNA in cultured GLC were determined by quantitative polymerase chain reaction (PCR) and CYP19 protein by Western blot. Statistical comparison used ANOVA and post hoc Tukey tests. RESULT(S): Follicle-stimulating hormone significantly increased E2 production in cultured GLC compared with control. The increase in E2 production is associated with higher levels of CYP19 mRNA and protein in GLC. The presence of MIS significantly inhibited FSH-induced E2 production, with concomitant reduction in CYP19mRNA and protein levels. CONCLUSION(S): Müllerian-inhibiting substance inhibits FSH augmentation of CYP19 enzyme activity and CYP19 gene expression in GLC. These findings may help to explain the association of high MIS levels and low FF E2 levels reported in women with polycystic ovary syndrome (PCOS).

Serum Müllerian-inhibiting substance levels in adolescent girls with normal menstrual cycles or with polycystic ovary syndrome.

OBJECTIVE: To compare serum müllerian-inhibiting substance (MIS) concentrations in adolescent girls with polycystic ovary syndrome (PCOS) or normal menstrual cycles. DESIGN: Prospective study. SETTING: University department of obstetrics and gynecology. PATIENT(S): Thirty-one girls (12-18 years old) with PCOS and 17 girls (12-19 years old) with normal menstrual cycles. INTERVENTION(S): Serum was collected from girls with PCOS or normal cycles during the early follicular phase of the menstrual cycle, stored frozen until assayed. MAIN OUTCOME MEASURE(S): Serum levels of MIS, E2, free-T, androstenedione, LH, and FSH. RESULT(S): Serum MIS levels in girls with PCOS were significantly higher compared with normal girls (4.1 +/- 2.2 [SD] and 2.4 +/- 1.0 ng/mL, respectively). The subjects were stratified for body mass index (BMI) (< and >25 kg/m2). Serum MIS levels in PCOS girls (4.2 +/- 3.0 ng/mL [BMI <25 kg/m2] and 4.0 +/- 1.6 [BMI >25 kg/m2]) were significantly higher compared with normal girls (2.2 +/- 0.8 and 2.6 +/- 0.7 ng/mL, respectively). CONCLUSION(S): Adolescent girls with PCOS have significantly higher serum MIS levels compared with normally cycling girls. Serum MIS levels in PCOS were not influenced by BMI. Increased MIS production may represent an early manifestation of the disease.

The relationship between müllerian inhibiting substance and androgens in boys with hypospadias.

PURPOSE: The etiology of hypospadias is probably multifactorial and disruption of androgen production may have a role. Müllerian inhibiting substance (MIS), a hormone produced by Sertoli cells, has been shown to suppress androgen biosynthesis in Leydig cells by inhibiting cytochrome P450c17 hydroxylase/lyase (CYP17) gene expression. We investigated the relationship between serum MIS and androgens in boys with isolated hypospadias compared with normal boys. MATERIALS AND METHODS: Serum levels of MIS, testosterone and androstenedione were measured in 29 boys with distal hypospadias (midshaft or less) and 21 normal boys undergoing circumcision. The subjects were stratified according to age 12 months or younger (group 1) and 13 to 24 months old (group 2). Statistical evaluation was performed by Student's t test. RESULTS: Mean age plus or minus standard error of mean of normal boys and their respective age matched groups with hypospadias were not significantly different. Within each respective age group serum müllerian inhibiting substance levels in boys with hypospadias were significantly higher compared with those of normal boys (129.6 +/- 1.8 and 96.1 +/- 1.8, p <0.03 for group 1 and 143.2 +/- 2.0 and 77.2 +/- 2.3, p <0.005 for group 2). Serum MIS levels were not statistically different when normal boys or boys with hypospadias were compared across age groups. In group 1 serum testosterone levels in boys with hypospadias were not significantly different from those of normal boys (0.36 +/- 0.20 and 0.56 +/- 0.32 pg./ml., respectively). In group 2 normal boys serum testosterone levels were higher than these in boys with hypospadias (2.36 +/- 0.47 and 0.35 +/- 0.23 pg./ml., p <0.01). Serum androstenedione levels in group 1 boys with hypospadias were significantly lower compared with those of normal boys of similar age (0.29 +/- 0.1 and 0.64 +/- 0.16 ng./ml., respectively, p <0.003). Androstenedione levels among older boys were not different (0.49 +/- 0.25 and 0.32 +/- 0.11 ng./ml., respectively. CONCLUSIONS: The association between elevated serum MIS levels and lower testosterone concentrations in boys with hypospadias suggests that MIS may have some role in the development of hypospadias, possibly mediated by MIS inhibition of CYP17 gene expression.