Müllerian Inhibiting Substance Levels Research Articles

Mullerian inhibiting substance, sex hormone binding globulin and sex hormone levels in stimulant-naïve, first-diagnosed prepubertal boys with attention-deficit/hyperactivity disorder: comparison with matched healthy controls as well as before and after oros-methylpenidate treatment

Objectives: Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder with strong male predominance. Since Müllerian Inhibiting Substance (MIS) produces sex-linked bias in animal studies, we aimed to investigate the role of MIS, Sex Hormone Binding Globulin (SHBG) and sex hormone levels in boys with ADHD.Methods: We compared prepubertal, psychostimulant-naïve boys with ADHD with age-matched healthy control boys (HCs). Patients were re-evaluated after 30 days of methylphenidate treatment assessing ADHD severity, and serum MIS, testosterone, estradiol, and albumin concentrations.Results: Compared to 30 HCs, with ADHD (n = 49, age = 6.9 ± 0.2 years) had lower SHBG (p = .014), and higher free testosterone (p = 0.006) and bioavailable testosterone (p = .002) percentages. Methylphenidate improved ADHD measures (all p < .0001) and abnormal baseline hormonal levels, increasing SHBG levels (p = .024), and lowering free (p = .001) and bioavailable testosterone (p = .016) percentages so that only free testosterone percentages remained higher versus HCs post-treatment (p = .02).Conclusions: Compared to age- and sex-matched HCs, prepubertal, stimulant-naïve boys with ADHD had significantly lower SHBG and higher free and bioavailable testosterone percentages, suggesting a possible contribution of sex hormones to ADHD. Osmotic-release oral system methylphenidate treatment for 30 days significantly improved ADHD symptoms and abnormal sex hormone levels, normalizing SHBG and bioavailable testosterone percentages that were similar to HCs while free testosterone remained elevated versus HCs.Key pointsCompare to healthy matched controls prepubertal stimulant-naïve boys with ADHD had significantly lower SHBG and higher free and bioavailable testosterone percentages, suggesting a possible effect on sex hormones to ADHD.After 30-day methylphenidate treatment, ADHD symptoms significantly improved, and SHBG and bioavailable testosterone percentages normalized which were similar to HCs, while free testosterone remained elevated versus HCs.We found a negative relationship between MIS levels and hyperactivity scores in ADHD boys. This finding suggests that MIS may contribute to hyperactivity symptoms, either directly by affecting behavior or indirectly by affecting sex hormone levels.

Serum Müllerian inhibiting substance levels are lower in premenopausal women with breast precancer and cancer

BackgroundIn preclinical studies, müllerian inhibiting substance (MIS) has a protective affect against breast cancer. Our objective was to determine whether serum MIS concentrations were associated with cancerous or precancerous lesions. Blood from 30 premenopausal women was collected and serum extracted prior to their undergoing breast biopsy to assess a suspicious lesion found on imaging or physical examination. Based on biopsy results, the serum specimens were grouped as cancer (invasive or ductal carcinoma in situ), precancer (atypical hyperplasia or lobular carcinoma in situ), or benign.FindingsSerum from women with cancer and precancer (p = .0009) had lower MIS levels than serum from women with benign disease.ConclusionOur findings provide preliminary evidence for MIS being associated with current breast cancer risk, which should be validated in a larger population.

Changes in plasma müllerian-inhibiting substance and brain-derived neurotrophic factor after chemotherapy in premenopausal women

Eight premenopausal women with cancer had blood drawn for analysis of brain-derived neurotrophic factor (BDNF) and müllerian-inhibiting substance (MIS) before and 3 months after receiving chemotherapy. Unlike MIS, BDNF levels were not reduced after chemotherapy.

Prospective Case-Control Study of Serum Mullerian Inhibiting Substance and Breast Cancer Risk

BackgroundMüllerian inhibiting substance (MIS) is a member of the transforming growth factor β family of growth and differentiation factors that inhibits elongation and branching of mammary ducts and has been shown to inhibit mammary tumor growth in vitro and in animal models. The objective of this study was to determine whether serum MIS levels are associated with breast cancer risk.MethodsWe conducted a prospective case–control study of 309 participants who were registered in the Columbia, Missouri Serum Bank. Each of 105 in situ or invasive breast cancer case patients with prediagnostic serum collected before menopause was matched to two control subjects by age, date, menstrual cycle day, and time of day of blood collection. MIS was measured in serum by using an enzyme-linked immunosorbent assay, and estradiol and testosterone concentrations were quantified by using specific radioimmunoassays. Data were analyzed using conditional logistic regression. All tests of statistical significance were two-sided.ResultsThe relative odds ratio of breast cancer for women in increasing MIS quartiles were 1, 2.8 (95% confidence interval [CI] = 1.0 to 7.4), 5.9 (95% CI = 2.4 to 14.6), and 9.8 (95% CI = 3.3 to 28.9, Ptrend < .001). The association of MIS with breast cancer was weaker in women who were not taking oral contraceptives at the time of blood collection, but adjustment for estradiol and testosterone levels did not materially alter results for these women. The association of MIS with breast cancer did not vary by age at blood collection but was stronger among women who were diagnosed with breast cancer at an older age than among those who were diagnosed at a younger age.ConclusionMIS may be a novel biomarker of increased breast cancer risk. Additional research including confirmatory epidemiological studies and mechanistic studies is needed.

Not all women diagnosed with PCOS share the same cardiovascular risk profiles

Although definitive and confirmatory data are lacking, women with polycystic ovary syndrome (PCOS) are considered to be at increased risk for cardiovascular and metabolic disease. In recent years, the diagnosis of PCOS has broadened considerably to result in several phenotypes. Here we review the evidence for cardiovascular and metabolic risks in PCOS in the classic disorder and the various phenotypes. We conclude that not all women with PCOS should be considered as being similar in terms of cardiovascular risk profiles.

Assay reproducibility and within-person variation of Müllerian inhibiting substance

To assess reproducibility of a commercial müllerian inhibiting substance (MIS) assay and evaluate within-person variation in serum MIS levels. Assay reproducibility was evaluated by measuring MIS in multiple serum aliquots from the same blood collection. Within-person variation was assessed by measuring MIS in serum collected twice from the same individuals. Cancer Prevention Biomarker and Genotyping Facility, fox Chase Cancer Center, Philadelphia, Pennsylvania. Assay reproducibility was evaluated using serum from five volunteers with regular menstrual cycles. Within-person variation was evaluated in serum from 20 premenopausal women who donated blood twice at least 1 year apart. For both studies, samples were randomly ordered in batches and laboratory personnel were blinded to which aliquots were from the same subject. The MIS was measured by ELISA. Within- and between-batch coefficients of variation (CVs) of the assay were 7.9% and 12.3%, respectively. After deleting one subject with extreme values, these CVs decreased to 7.6% and 7.7%, respectively. Within- and between-subject variance in MIS measurements were 2.19 and 0.31, respectively, and the intraclass correlation coefficient was 0.88 (95% confidence interval .77-.98). The MIS serum concentration is relatively stable over 1 year in premenopausal women and can be measured with good reproducibility using a commercial kit.

Variations in serum müllerian inhibiting substance between white, black, and Hispanic women

To compare serum müllerian inhibiting substance (MIS) levels between white, black, and Hispanic women to determine whether ovarian aging occurs at a different time course for women of different racial groups. Longitudinal study of serum MIS levels in women of different race and ethnicity over two different time points. Women's Interagency HIV Study, a multicenter prospective cohort study. Serum samples obtained from 809 participants (122 white, 462 black, and 225 Hispanic women). Comparison of serum MIS between women of different race and ethnicity at two time points (median age 37.5 years and 43.3 years). Variation in MIS by race and ethnicity over time, controlling for age, body mass index, HIV status, and smoking. Compared with white women, average MIS values were lower among black (25.2% lower) and Hispanic (24.6% lower) women, adjusting for age, body mass index, smoking, and HIV status. There is an independent effect of race and ethnicity on the age-related decline in MIS over time.

Müllerian inhibiting substance gene expression is higher in single follicles from women with PCOS

OBJECTIVE: Müllerian inhibiting substance (MIS) is produced and secreted by granulosa cells (GC). The presence of higher concentrations of MIS in the sera and follicular fluid (FF) of women with polycystic ovary syndrome (PCOS) is well documented. The cause of the elevated MIS levels is unclear. Some studies have attributed the higher serum MIS concentration in PCOS women to the presence of the greater number of follicles that are typically present in PCOS women. We have previously reported higher levels of FF MIS in single follicles of PCOS women compared with non-PCOS women.

Protection against cisplatin-induced ovarian damage by the antioxidant sodium 2-mercaptoethanesulfonate (mesna) in female rats

The hypothesis was that the administration of the antioxidant mesna (sodium 2-mercaptoethanesulfonate) during chemotherapy would protect ovaries against follicular damage. Sprague-Dawley rats were treated with saline solution, mesna-plus-cisplatin, or cisplatin. Immunohistochemistry was used to evaluate the Müllerian inhibiting substance (MIS) positive follicles. Serum and ovarian MIS were measured with enzyme-linked immunosorbent assay and Western blot analysis, respectively. Apoptosis in ovaries was studied by terminal deoxynucleotidyl transfer biotin-d UTP nick end labeling (TUNEL) assay. Immunofluorescence staining for MIS was higher in preantral follicles in the mesna-plus-cisplatin group. The ovarian and serum MIS levels were higher in the mesna-plus-cisplatin than in the cisplatin alone group. There were no differences statistically in the TUNEL and the ovarian cyst analyses. Mesna, which was used at the time of cisplatin administration, protected ovaries against damage. The data that are presented challenge the existing clinical paradigm that gonadotropin-releasing hormone agonists represent the only medical method for the protection of ovaries during chemotherapy. Alternative medical means to protect ovaries during chemotherapy may be achievable.

Follicular fluid of single follicles from women with PCOS contains higher levels of müllerian inhibiting substance

Müllerian inhibiting substance (MIS) is produced and secreted by granulosa cells. The presence of higher concentrations of MIS in the sera and follicular fluid (FF) of women with polycystic ovary syndrome (PCOS) is well documented. The cause of the elevated MIS levels is unclear. However, some studies have attributed the higher MIS concentration detected in serum of women with PCOS to be due to the greater number of follicles that are typically present in women with this disorder. The objective of this study is to measure MIS levels in the sera and FF of single follicles from patients with PCOS, tubal factor (TF) or male factor (MF) infertility undergoing in vitro fertilization (IVF) to determine if MIS production differs between groups.

Comparison of serum and plasma measurements of Müllerian inhibiting substance

The authors sought to determine whether measurement of plasma Müllerian inhibiting substance (MIS) is a suitable substitute for measurement of serum MIS. Eighteen samples of serum and plasma were examined that were drawn simultaneously. Levels of MIS were measured with an ELISA kit, and plasma levels were studied in parallel to serum samples. A 98.5% correlation was found between serum and plasma MIS values.

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

To investigate the effects of Müllerian-inhibiting substance (MIS) on cytochrome P450 aromatase (CYP19) gene expression in cultured human granulosa lutein cells (GLC). In vitro primary cell culture study. Academic research laboratory and hospital-based fertility center. Eight normo-ovulatory patients undergoing IVF procedures due to male factor or tubal infertility. 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. 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. 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. 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).

Biologic markers of ovarian reserve and reproductive aging: application in a cohort study of HIV infection in women

To compare Müllerian inhibiting substance (MIS) levels in serum obtained during the early follicular phase to those obtained randomly during the menstrual cycle. To determine whether HIV infection influences early follicular MIS levels, an early marker of ovarian aging. A cross-sectional study. Women's Interagency HIV Study, a multicenter prospective study. Serum samples obtained from 263 (187 HIV infected and 76 uninfected) participants of the Women's Interagency HIV Study who reported menstrual bleeding during the preceding 6 months and who were not taking exogenous hormones. Early follicular (cycle days 2-5) MIS samples were compared with serum samples that had been obtained without regard to menstrual cycle phase. Comparison samples were obtained within 6 weeks before or within 3 to 6 months after the early follicular samples. Early follicular FSH, E(2), inhibin B, and MIS levels were also compared between the HIV infected and uninfected women. Correlation between early follicular MIS and prior and subsequent samples. Comparison of serum markers of ovarian reserve between HIV positive and negative women. The MIS values from early follicular and other random cycle phases were highly correlated with each other (r > 0.93). In multivariate analysis, increased age and FSH level and lower inhibin B levels were associated with lower MIS level; MIS values did not vary by HIV serostatus. Without regard to cycle phase, MIS was similar during early follicular phase and highly correlated with early follicular FSH and inhibin B in women with and without HIV. Measurement of serum MIS offers a simplified method of determining ovarian reserve using specimens obtained without menstrual phase timing. Furthermore, using biologic measures of reproductive aging, we found no evidence that HIV infection influences ovarian aging.

Serum and ovarian Müllerian inhibiting substance, and their decline in reproductive aging

The objectives of this study were to identify whether there is a decline in Müllerian inhibiting substance (MIS) in the female rat during chronological aging, and to define the physiological basis of aging-related changes in MIS. The results demonstrate that there is an exponential decline in both serum and ovarian levels of MIS with increasing female age, and that the histologic origin for the reduction in serum levels of MIS is a decline in the number of small ovarian follicles expressing MIS.

Serum müllerian-inhibiting substance in Down's syndrome pregnancies

To examine whether maternal serum levels of müllerian-inhibiting substance (MIS) differ in Down's syndrome and unaffected pregnancies. Case-control study was conducted using stored serum from an antenatal screening programme. Sera from 25 Down's syndrome pregnancies were retrieved from -20 degrees C storage together with 125 unaffected controls individually matched for maternal age, weeks of gestation and duration of storage. Results were expressed in multiples of the gestation-specific median value (MoM) in controls. The median value in Down's syndrome pregnancies was 0.83 MoM (P = 0.77, two-tail Wilcoxon rank sum test). Among unaffected pregnancies, there was a statistically significant correlation between MIS and pregnancy-associated plasma protein-A (P < 0.05). MIS levels were elevated in pregnancies where assisted reproduction techniques had been used. There is no evidence for a substantial reduction in maternal serum MIS levels in Down's syndrome pregnancies. This study provides useful information regarding serum MIS levels in pregnancy.

Müllerian inhibiting substance as a novel biomarker of cisplatin-induced ovarian damage

Müllerian inhibiting substance (MIS) has been investigated as a possible serum biomarker in human aging to estimate the number of female germ cells remaining. Cisplatin is an effective chemotherapeutic agent that is associated with ovarian injury. In this study, we tested the hypothesis that decreasing serum MIS can serve as a biomarker of ovarian damage after cisplatin. Adult female rats were treated with saline, 4.5, or 6.0 mg/kg cisplatin. The serum MIS levels were lower in both cisplatin groups, in a dose-related fashion. The ovarian lysates of both cisplatin groups had less MIS than control. Immunofluorescence analysis showed that the percentage of MIS-positive follicles was lower in the 6.0 mg/kg group. TUNEL assays showed that there was a dose related increase in the number of apoptotic follicles in the cisplatin groups. In summary, a decrease in serum MIS could serve as a biomarker to discriminate the degree of ovarian damage after cisplatin. These data are the first to establish in the rat that ovarian injury due to a chemotherapeutic agent could be monitored with the non-invasive serum biomarker MIS.

Elevated serum müllerian-inhibiting substance may be a marker for ovarian hyperstimulation syndrome in normal women undergoing in vitro fertilization

We identified patients who experienced ovarian hyperstimulation syndrome (OHSS) (n = 16) and compared their baseline pretreatment levels of müllerian-inhibiting substance (MIS) to age- and weight-matched patients with normal responses to gonadotropins (n = 14). Baseline serum MIS in patients with OHSS were sixfold higher than those seen in normal controls (3.62 +/- 0.87 vs. 0.63 +/- 0.09 ng/mL; P=.0036), indicating that MIS could potentially serve as a useful marker for identifying patients at risk for OHSS.

Müllerian-inhibiting substance reflects ovarian findings in women with polycystic ovary syndrome better than does inhibin B

To investigate Müllerian-inhibiting substance (MIS) levels in women with polycystic ovary syndrome (PCOS), as well as relationships to ovarian morphology, levels of inhibin B, and other reproductive hormones. Prospective clinical study. Academic endocrinology centers in Palermo, Italy and New York. Forty-six women with PCOS, recruited on the basis of the classic criteria of chronic anovulation and hyperandrogenism, and 25 age-matched ovulatory controls. Fasting blood was obtained in all subjects in the early follicular phase (days 5-6) after spontaneous or induced menses (in PCOS), and transvaginal ultrasounds were performed. Assessment of values for luteinizing hormone (LH), testosterone (T), androstenedione (A), estradiol (E2), inhibin B, MIS, fasting insulin, and the calculated quantitative sensitivity check index (QUICKI), as well as assessments of ovarian volume and blood flow. Women with PCOS had higher LH, T, and A; higher insulin and lower QUICKI; and higher ovarian volume and lower pulsatility index. Inhibin B concentrations were statistically significantly higher in PCOS patients (70 +/- 8.0 vs. 40 +/- 3.4 pg/mL), as was MIS (6.7 +/- 0.9 vs. 4.6 +/- 0.5 ng/mL). Inhibin B had a statistically significant direct correlation with levels of MIS (r = 0.351). However, MIS, but not inhibin B, had a statistically significant positive correlation with ovarian size (r = 0.350); the reproductive hormones LH, T, A, and E2; and insulin (r = 0.249), independent of body mass index. Women with PCOS with the highest levels of MIS had higher ovarian volumes and values of LH, T, A, and insulin. Measurements of MIS reflect ovarian findings in PCOS better than levels of inhibin B and are more frequently elevated. However, MIS lacks sensitivity for use as a diagnostic tool in PCOS.

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

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. 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. 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. 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.

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

To compare serum müllerian-inhibiting substance (MIS) concentrations in adolescent girls with polycystic ovary syndrome (PCOS) or normal menstrual cycles. Prospective study. University department of obstetrics and gynecology. Thirty-one girls (12-18 years old) with PCOS and 17 girls (12-19 years old) with normal menstrual cycles. Serum was collected from girls with PCOS or normal cycles during the early follicular phase of the menstrual cycle, stored frozen until assayed. Serum levels of MIS, E2, free-T, androstenedione, LH, and FSH. 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). 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.