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PubMed2006

Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome.

CONTEXT: We determined the relationship of metabolic syndrome (MBS) to polycystic ovary syndrome (PCOS). OBJECTIVE: We tested the hypothesis that parental MBS is related to the PCOS phenotype in their offspring. DESIGN/SETTING: We phenotyped for MBS and PCOS in our General Clinical Research Center. PATIENTS: Girls with PCOS, 12-19 yr old (n = 36, including one pair of siblings), and their parents (35 mothers, 19 fathers) were recruited from the Pediatric Endocrinology Clinic. Healthy girls, 12-19 yr old (n = 21), were recruited as a reference population. INTERVENTIONS: We measured anthropometrics, blood pressure, fasting lipids and androgens, oral glucose tolerance, and ultrasonographically determined polycystic ovary status. MAIN OUTCOME MEASURES: MBS in parents, and PCOS features in mothers, were related to the presence of PCOS features in probands. RESULTS: Fathers had strikingly high prevalence of excess adiposity (94% were obese or overweight) and MBS (79%). Premenopausal mothers more commonly had MBS (36%) than features of PCOS (< or =22%). Polycystic ovaries in proband offspring of premenopausal mothers were associated with maternal polycystic ovaries only in a minority of cases. Proband polycystic ovary status was completely concordant to fathers' MBS status (P = 0.008), but not their own or their mothers' MBS status, in families whose premenopausal mothers lacked polycystic ovaries. Proband prevalence of MBS was 27.8%, 3-fold greater than expected for obesity status. CONCLUSION: Familial factors related to paternal MBS seem to be fundamental to the pathogenesis of PCOS.

Adolescent↗

PubMed2006

Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome patients undergoing gonadotropin therapy for in vitro fertilization.

CONTEXT: Polycystic ovary syndrome (PCOS) is a reproductive disorder of ovarian hyperandrogenism and insulin resistance characterized by abnormal luteinization of small follicles. After exposure to GnRH analog/FSH stimulation for in vitro fertilization (IVF), however, it is unclear whether such PCOS follicles remain abnormally luteinized during the resumption of oocyte maturation in vivo. OBJECTIVE: The aim of this study was to determine whether PCOS follicles exposed to GnRH analog/FSH stimulation for IVF show abnormal luteinization. DESIGN: This study was a prospective cohort. SETTING: The setting was an institutional practice. PATIENTS: Eleven PCOS and 30 normoandrogenic ovulatory women were included. INTERVENTION(S): All subjects received GnRH analog/FSH therapy after basal serum hormone determinations. MAIN OUTCOME MEASURE(S): Follicle fluid aspirated at oocyte retrieval from the first follicle of each ovary was assayed for gonadotropins, steroids, insulin, and glucose. LH receptor mRNA expression was determined in granulosa cells of the same follicle. RESULTS: In PCOS patients with basal hyperandrogenemia and hyperinsulinemia, total oocyte number was increased and follicle diameter was decreased, despite normal maximal serum estradiol levels. Within PCOS follicles, progesterone levels were reduced (P < 0.01), despite comparable bioactive LH and insulin levels and granulosa cell LH receptor mRNA expression; estradiol levels were normal, despite diminished FSH availability (P < 0.004). Elevated androstenedione (P < 0.01), testosterone (P < 0.001), and glucose (P < 0.01) levels also occurred. In PCOS follicles containing mature oocytes, however, elevated androgen levels were accompanied by both normal progesterone concentrations and a normal inverse relationship between glucose depletion and lactate accumulation. CONCLUSION: Hyperandrogenic follicles with mature oocytes from PCOS women receiving GnRH analog/recombinant human FSH therapy for IVF show sufficient glucose utilization for normal luteinization.

Adult↗

PubMed2006

Increased activation of nuclear factor kappaB triggers inflammation and insulin resistance in polycystic ovary syndrome.

CONTEXT: Insulin resistance and chronic low level inflammation are often present in women with polycystic ovary syndrome (PCOS). OBJECTIVE: The purpose of this study was to determine the effects of hyperglycemia on nuclear factor kappaB (NFkappaB) activation and inhibitory kappaB (IkappaB) from mononuclear cells (MNC) in PCOS. DESIGN AND SETTING: This was a prospective controlled study conducted at an academic medical center. PATIENTS: The study population consisted of 16 reproductive-age women with PCOS (eight lean, eight obese) and 16 age- and body composition-matched controls (eight lean, eight obese). MAIN OUTCOME MEASURES: Insulin sensitivity (IS) was derived from a 2-h 75-g oral glucose tolerance test (IS(OGTT)). Intranuclear NFkappaB and IkappaB protein expression were quantitated from MNC obtained from blood drawn fasting and 2 h after glucose ingestion. RESULTS: IS(OGTT) was lower in PCOS compared with controls (3.3 +/- 0.3 vs. 6.4 +/- 0.9, P < 0.004). The percent change in intranuclear NFkappaB was higher in lean and obese PCOS compared with lean controls (42.5 +/- 19.1 and 54.5 +/- 12.5 vs. -14.1 +/- 10.9, P < 0.006). The percent change in intranuclear NFkappaB correlated positively with 2-h post-glucose ingestion levels (r = 0.37; P < 0.04) and plasma testosterone (r = 0.49; P < 0.006) and correlated negatively with IS(OGTT) (r = 0.39; P < 0.04). The percent change in IkappaB was lower in lean and obese PCOS compared with lean controls (-22.3 +/- 3.2 and -17.0 +/- 5.0 vs. 8.4 +/- 11.8, P < 0.02). CONCLUSION: In response to hyperglycemia, intranuclear NFkappaB increases and IkappaB decreases in MNC of women with PCOS independent of obesity. This may represent a cardinal inflammatory signal that contributes to the induction of insulin resistance and hyperandrogenism in PCOS.

Adult↗

PubMed2006

Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: in defense of the Rotterdam criteria.

CONTEXT: Polycystic ovary syndrome (PCOS) is a very common endocrinopathy with a heterogeneous presentation whose etiology is still uncertain. Not surprisingly, therefore, the definition of, and diagnostic criteria for, PCOS remain controversial. OBJECTIVE: The objective of the study was to review and justify the basis for the recently revised definition of PCOS arising from the joint European Society for Human Reproduction & Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) Rotterdam workshop in 2003. INTERVENTION(S): The Rotterdam criteria take account of the broad spectrum of presenting features of PCOS, including women with hyperandrogenism but regular menses and, more controversially, those with menstrual disturbance without overt androgen excess. POSITIONS: The Rotterdam criteria for definition and diagnosis of PCOS, in the opinion of this author, represent a significant advance in recognizing the broad spectrum of presentation of the syndrome and acknowledge that the clinical and biochemical features may vary with time within individuals. The important refinements when compared to the 1990 NIH definition of PCOS are: 1) inclusion of polycystic ovarian morphology; and 2) inclusion of subjects with hirsutism and regular menses. CONCLUSIONS: These new diagnostic criteria for PCOS reflect the significant advances, particularly from studies of familial PCOS, in understanding of the etiology of the syndrome and the basis for its heterogeneity. Under the revised diagnostic criteria, the inclusion of women with hyperandrogenism and regular cycles has met with general agreement. The inclusion of women with oligomenorrhea and polycystic ovaries who do not have clear evidence of androgen excess is, in the opinion of this author, also justified but remains a contentious issue and one that requires further investigation.

Androgens↗

PubMed2006

Increased anti-Müllerian hormone serum concentrations in prepubertal daughters of women with polycystic ovary syndrome.

CONTEXT: Anti-Müllerian hormone (AMH) is produced by the granulosa cells and reflects follicular development. Adult women with polycystic ovary syndrome (PCOS) have increased levels of AMH associated with an excessive number of growing follicles. However, it is not known whether these abnormalities are present before the clinical onset of PCOS. OBJECTIVE: Our objective was to investigate whether prepubertal daughters of women with PCOS have increased AMH levels. DESIGN: Fourteen female infants (2-3 months old) and 25 prepubertal girls (4-7 yr old) born to PCOS mothers were studied. As a control group, we studied 21 female infants and 24 prepubertal girls born to mothers with regular menses and without hyperandrogenism. The group with PCOS mothers and the control group had normal birth weight and were born from spontaneous singleton pregnancies. Circulating concentrations of gonadotropins, testosterone, androstenedione, estradiol, 17-OH-progesterone, SHBG, inhibin B, and AMH were determined by specific assays. RESULTS: Serum concentrations of AMH were significantly higher in the PCOS group compared with the control group during early infancy (20.4 +/- 15.6 vs. 9.16 +/- 8.6 pmol/liter; P = 0.024) and during childhood (14.8 +/- 7.7 vs. 9.61 +/- 4.4 pmol/liter; P = 0.007). Gonadotropin and serum sex steroid concentrations were similar in both groups during the two study periods, except for FSH, which was lower during childhood in girls born to PCOS mothers. CONCLUSIONS: We conclude that serum AMH concentrations are increased in prepubertal daughters of PCOS women, suggesting that these girls appear to show evidence of an altered follicular development during infancy and childhood.

17-alpha-Hydroxyprogesterone↗

PubMed2006

Variants in the 5alpha-reductase type 1 and type 2 genes are associated with polycystic ovary syndrome and the severity of hirsutism in affected women.

CONTEXT: Despite the importance of dihydrotestosterone in androgen action, polymorphisms in the genes for the two isoforms of 5alpha-reductase (SRD5A1 and SRD5A2) have not been evaluated as risk factors for polycystic ovary syndrome (PCOS). OBJECTIVE: The objective of the study was to test the hypothesis that haplotypes in the SRD5A1 and SRD5A2 genes are risk factors for PCOS and the severity of hirsutism in affected women. DESIGN: PCOS and control subjects were genotyped for seven single-nucleotide polymorphisms in SRD5A1 and eight single-nucleotide polymorphisms in SRD5A2. Haplotypes were determined and tested for association with PCOS diagnosis and component phenotypes. SETTING: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the general surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles. PARTICIPANTS: A total of 287 White women with PCOS and 187 controls participated. MAIN MEASUREMENTS: SRD5A1 and SRD5A2 genotype, quantitative hirsutism score, and hormonal and metabolic phenotypes were assessed. RESULTS: Haplotypes within both genes were associated with PCOS risk. The Leu allele of the Val89Leu variant in SRD5A2 was associated with protection against PCOS; this allele is known to modestly reduce 5alpha-reductase activity. Haplotypes in SRD5A1 but not SRD5A2 were also associated with the degree of hirsutism in affected women. CONCLUSIONS: This study presents genetic evidence suggesting an important role of both isoforms of 5alpha-reductase in the pathogenesis of PCOS. That only SRD5A1 haplotypes were associated with hirsutism suggests that only this isoform is important in the hair follicle.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2006

Clinical review: Identifying children at risk for polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) appears to arise as a complex trait with contributions from both heritable and nonheritable factors. Polygenic influences appear to account for about 70% of the variance in pathogenesis. In view of this evidence for congenital contributions to the syndrome, childhood manifestations may be expected. OBJECTIVE: The objective has been to review the evidence that risk factors for PCOS can be recognized in childhood. DESIGN: This study consisted of screening of the PCOS literature for articles pertaining to potential childhood and adolescent antecedents. RESULTS: Congenital virilizing disorders; above average or low birth weight for gestational age; premature adrenarche, particularly exaggerated adrenarche; atypical sexual precocity; or intractable obesity with acanthosis nigricans, metabolic syndrome, and pseudo-Cushing syndrome or pseudo-acromegaly in early childhood have been identified as independent prepubertal risk factors for the development of PCOS. During adolescence, PCOS may masquerade as physiological adolescent anovulation. Asymptomatic adolescents with a polycystic ovary occasionally (8%) have subclinical PCOS but often (42%) have a subclinical PCOS type of ovarian dysfunction, the prognosis for which is unclear. CONCLUSION: Identifying children at risk for PCOS offers the prospect of eventually preventing some of the long-term complications associated with this syndrome once our understanding of the basis of the disorder improves.

Adolescent↗

PubMed1990

Androgen response to endogenous insulin secretion during the frequently sampled intravenous glucose tolerance test in normal and hyperandrogenic women.

Women with ovarian hyperandrogenism frequently have insulin resistance, whose underlying mechanism remains to be determined. In the present study we have investigated the relationship between insulin sensitivity and the acute effect of endogenous insulin secretion on circulating androgen levels. Insulin sensitivity, glucose-mediated insulin release, and glucose/insulin-stimulated androgen responses were determined during a frequently sampled iv glucose tolerance test in a group of 19 women with clinical evidence of polycystic ovary syndrome (PCOS) and 9 age- and weight-matched controls. Insulin (I), glucose, androstenedione, testosterone (T), free T, and dehydroepiandrosterone (DHEA) levels were measured before and during the 3 h following iv administration of glucose (300 mg/kg). Intravenous tolbutamide (300-500 mg) was injected 20 min after the glucose injection. Insulin sensitivity (SI) was calculated by application of the minimal model of glucose kinetics. Fasting androstenedione, T, free T, and I concentrations were significantly higher in the women with PCOS than in controls (P less than 0.02). In PCOS subjects, fasting I was correlated with both T (r = 0.51; P less than 0.05) and DHEA (r = 0.706; P less than 0.01). SI was significantly lower in PCOS subjects [SI, 68.35 +/- 8.34 min-1/(nmol/mL] than in control subjects (SI, 133.36 +/- 21.7 min-1/(nmol/mL)]. A significant decline in DHEA levels was observed in control subjects 3 h after glucose administration (from 28.4 +/- 3.0; final, 16.2 +/- 2.4; P less than 0.02). PCOS women with normal insulin sensitivity [SI, greater than 75.0 min-1/(nmol/mL)] showed a similar fall in DHEA (from 20.3 +/- 2.5 to 12.8 +/- 1.8 nmol/L; P less than 0.02). No significant change occurred in insulin-resistant PCOS subjects [SI, less than 75.0 min-1/(nmol/mL)]. Other androgen levels showed a modest nonsignificant decline during the study in PCOS and control groups. These findings confirm the weight-independent insulin resistance of some hyperandrogenic women. The failure of glucose-stimulated endogenous insulin secretion to significantly depress DHEA levels in insulin-resistant women with PCOS may account in part for their androgen excess.

Adult↗

PubMed1995

Variations of steroid hormone metabolites in serum and urine in polycystic ovary syndrome after nafarelin stimulation: evidence for an altered corticoid excretion.

To evaluate the clinical relevance of testing pituitary-ovarian responses in patients suffering from polycystic ovary syndrome (PCOS) with the GnRH agonist nafarelin, a 1.2-mg dose of nafarelin was given intranasally to 19 women with PCOS and 15 healthy premenopausal women. The subsequent analysis of steroids in both serum and urine during the test was carried out at several time points for up to 24 h. Serum levels of 17 alpha-hydroxyprogesterone were elevated at all time points of the test in PCOS patients vs. controls [at baseline, 3.5 +/- 0.2 vs. 1.8 +/- 0.1 nmol/L (P < 0.001); at 24 h, 9.9 +/- 0.9 vs. 4.9 +/- 0.3 nmol/L (P < 0.001)]. Basal levels of androstenedione were higher in the patient group, but there was no significant change during the test in either group. Serum testosterone levels were also found to differ in PCOS patients compared with the control values at baseline (2.2 +/- 0.2 vs. 1.5 +/- 0.1 nmol/L; P < 0.05) and after nafarelin treatment (at 24 h, 3.2 +/- 0.4 vs. 1.8 +/- 0.2 nmol/L; P < 0.05). Serum estradiol levels rose significantly in both groups during the test; the posttest levels were significantly higher in PCOS than in controls. The PCOS patients displayed a significant increase in androgen and gestagen metabolites as well as in glucocorticoid metabolites excreted in the urine during the 24 h. In the control subjects, except for 17 alpha-hydroxypregnanolone, which rose significantly, none of the urinary steroids investigated showed relevant changes during the nafarelin test. The posttest excretion of allo-tetrahydrocortisol (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) and the increase in 17 alpha-hydroxypregnanolone excretion (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) were distinctly higher in PCOS patients than in the controls; the diagnostic sensitivity of the combination of both parameters was 89% at a 93% specificity. Thus, measurements of 17 alpha-hydroxyprogesterone levels in serum and of urinary allo-tetrahydrocortisol and 17 alpha-hydroxypregnanolone after nafarelin treatment make this stimulation test a valuable diagnostic tool for identifying PCOS patients. The significant changes in the excretion of urinary androgen and gestagen metabolites, unmasked by GnRH agonist stimulation, suggest a functional alteration of the pituitary-ovarian axis. The reason for the increased excretion of glucocorticoid metabolites after nafarelin stimulation remains to be clarified.

Administration, Intranasal↗

PubMed1997

Leptin concentrations in the polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is characterized by menstrual disturbances, chronic anovulation and hyperandrogenism and is associated with insulin resistance and hyperinsulinemia. Leptin, the product of the ob gene, is an adipocyte-secreted molecule that signals the magnitude of energy stores to the brain and has been recently shown to have important effects on the reproductive axis of rodents. To assess the potential contribution of leptin to the pathogenesis of PCOS, we measured leptin levels in 24 obese women with PCOS and 12 weight- and age-matched controls and determined whether alterations in hyperinsulinemia produced by administration of the insulin-sensitizing agent troglitazone had an effect on serum leptin levels. Leptin concentrations at baseline were not different in women with PCOS (38.1 +/- 2.15 ng/mL) and controls (33.12 +/- 2.39 ng/mL). Moreover, leptin concentrations remained unchanged after treatment with troglitazone (38.1 +/- 2.15 vs. 39.21 +/- 2.65 ng/mL). Baseline leptin correlated strongly with body mass index in both controls (r = 0.59; P < 0.05) and women with PCOS (r = 0.70; P = 0.0004). Leptin levels were not associated with baseline insulin, testosterone, non-sex hormone-binding globulin (SHBG)-bound testosterone, dehydroepiandrosterone sulfate, estradiol, or SHBG. Finally, despite significantly reduced insulin, non-SHBG-bound testosterone, and estradiol levels after troglitazone treatment of women with PCOS, their leptin levels remained unchanged. We conclude that circulating leptin levels in patients with PCOS do not differ from those in age- and weight-matched controls. Furthermore, increased circulating insulin due to insulin resistance does not appear to alter circulating leptin levels in women with PCOS.

Adult↗

PubMed2002

Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome.

Insulin resistance is common in adults with polycystic ovary syndrome (PCOS). Although recent data demonstrate that insulin resistance is present in the early stages of PCOS, the prevalence of insulin resistance in adolescents with PCOS has not been determined. Likewise, the prevalence of impaired glucose tolerance (IGT) or type 2 diabetes mellitus (DM) in adolescent cohorts has not been established. In this study we sought to obtain preliminary data regarding the prevalence of IGT and DM in adolescents with PCOS and to assess the ability of screening tests to predict these abnormalities within this population. Twenty-seven adolescents with PCOS underwent oral glucose tolerance tests. Plasma glucose and insulin levels were obtained at baseline, and glucose was measured 2 h after a 75-g glucose challenge. The 2-h plasma glucose level was used to categorize subjects as having IGT or the provisional diagnosis of DM. Eight of our 27 subjects had IGT, and 1 had previously undiagnosed DM. These abnormalities were seen among lean and obese subjects. Fasting plasma glucose levels and simple measures of insulin resistance were suboptimal predictors of IGT and DM within our cohort. As in adults, our results indicate that adolescents with PCOS are at increased risk for IGT and DM and that the 2-h plasma glucose level after an oral glucose challenge appears to be the most reliable screening test for these abnormalities. Our results need to be corroborated by future studies that determine the prevalence of abnormalities in glucose tolerance among large populations of adolescents, both with and without PCOS. However, as DM may be preventable by lifestyle modifications, we would recommend that adolescents with PCOS undergo periodic screening for abnormal glucose tolerance using 2-h postchallenge plasma glucose levels.

Adolescent↗

PubMed2002

A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome.

There is increasing evidence that elevated plasma levels of hemostatic factors [fibrinogen, factor VII, von Willebrand factor, fibrin D-dimer, and tissue plasminogen activator (t-PA) antigen] are independently linked to risk for coronary heart disease (CHD). Women with polycystic ovary syndrome (PCOS) are insulin-resistant and have increased risk for CHD and type 2 diabetes, but there are few data on hemostatic markers in women with PCOS. Seventeen women with PCOS (defined on the basis of elevated testosterone and oligomenorrhea) and 15 healthy women matched as a group for body mass index (BMI) were recruited. Insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique. Factor VIIc was determined by a clotting assay; fibrinogen was determined by nephelometry; and t-PA, D-dimer, and von Willebrand factor antigens were measured by ELISA techniques. Of these hemostatic markers, only t-PA concentration was significantly (P = 0.013) elevated in women with PCOS relative to controls. t-PA correlated with BMI in both PCOS and controls (r = 0.428, P < 0.1; and r = 0.686, P < 0.01) and inversely with the insulin sensitivity index (r = -0.590, P < 0.05; and r = -0.620, P < 0.05, respectively). After further adjustment for BMI and insulin sensitivity, there remained a significant difference in t-PA between cases and controls (P = 0.017). Together, age and insulin sensitivity explained 39% of the variance in t-PA in women with PCOS (P < 0.05). Total testosterone did not correlate significantly with t-PA in either group. We conclude that women with PCOS have significantly increased t-PA concentrations relative to women with normal menstrual rhythm and normal androgens. We suggest that elevated t-PA and dysfibrinolysis may be a factor in the increased cardiovascular morbidity seen in PCOS.

Adult↗

PubMed2004

Abnormal gene expression profiles in human ovaries from polycystic ovary syndrome patients.

Polycystic ovary syndrome (PCOS) represents the most common cause of anovulatory infertility and affects 5-10% of women of reproductive age. The etiology of PCOS is still unknown. The current study is the first to describe consistent differences in gene expression profiles in human ovaries comparing PCOS patients vs. healthy normoovulatory individuals. The microarray analysis of PCOS vs. normal ovaries identifies dysregulated expression of genes encoding components of several biological pathways or systems such as Wnt signaling, extracellular matrix components, and immunological factors. Resulting data may provide novel clues for ovarian dysfunction in PCOS. Intriguingly, the gene expression profiles of ovaries from (long-term) androgen-treated female-to-male transsexuals (TSX) show considerable overlap with PCOS. This observation provides supportive evidence that androgens play a key role in the pathogenesis of PCOS. Presented data may contribute to a better understanding of dysregulated pathways in PCOS, which might ultimately reveal novel leads for therapeutic intervention.

Adult↗

PubMed2004

Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome.

We have investigated the involvement of the MAPK signaling pathway in increased androgen biosynthesis and CYP17 gene expression in women with polycystic ovary syndrome (PCOS). A comparison of MAPK kinase (MEK1/2) and ERK1/2 phosphorylation in propagated normal and PCOS theca cells, revealed that MEK1/2 phosphorylation was decreased more than 70%, and ERK1/2 phosphorylation was reduced 50% in PCOS cells as compared with normal cells. Infection with dominant-negative MEK1 increased CYP17 mRNA and dehydroepiandrosterone (DHEA) abundance, whereas constitutively active MEK1 reduced DHEA production and CYP17 mRNA abundance. Similarly, the MEK inhibitor, PD98059, increased CYP17 mRNA accumulation and CYP17 promoter activity to levels observed in PCOS cells. Remarkably, in theca cells maintained in the complete absence of insulin, ERK1/2 phosphorylation was decreased in PCOS theca cells as compared with normal theca cells, and CYP17 mRNA and DHEA synthesis were increased in PCOS theca cells. These studies demonstrate that in PCOS cells reduced levels of activated MEK1/2 and ERK1/2 are correlated with increased androgen production, irrespective of the insulin concentration. These findings implicate alterations in the MAPK pathway in the pathogenesis of excessive ovarian androgen production in PCOS.

Adenoviridae↗

PubMed1999

Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries.

To test the hypothesis that the hyperandrogenemia associated with polycystic ovary syndrome (PCOS) results from an intrinsic abnormality in ovarian theca cell steroidogenesis, we examined steroid hormone production, steroidogenic enzyme activity, and mRNA expression in normal and PCOS theca cells propagated in long-term culture. Progesterone (P4), 17alpha-hydroxyprogesterone (17OHP4), and testosterone (T) production per cell were markedly increased in PCOS theca cell cultures. Moreover, basal and forskolin-stimulated pregnenolone, P4, and dehydroepiandrosterone metabolism were increased dramatically in PCOS theca cells. PCOS theca cells were capable of substantial metabolism of precursors into T, reflecting expression of an androgenic 17beta-hydroxysteroid dehydrogenase. Forskolin-stimulated cholesterol side chain cleavage enzyme (CYP11A) and 17alpha-hydroxylase/17,20-desmolase (CYP17) expression were augmented in PCOS theca cells compared with normal cells, whereas no differences were found in steroidogenic acute regulatory protein mRNA expression. Collectively, these observations establish that increased CYP11A and CYP17 mRNA expression, as well as increased CYP17, 3beta-hydroxysteroid dehydrogenase, and 17beta-hydroxysteroid dehydrogenase enzyme activity per theca cell, and consequently increased production of P4, 17OHP4, and T, are stable properties of PCOS theca cells. These findings are consistent with the notion that there is an intrinsic alteration in the steroidogenic activity of PCOS thecal cells that encompasses multiple steps in the biosynthetic pathway.

17-Hydroxysteroid Dehydrogenases↗

PubMed2004

Plasma homocysteine levels in polycystic ovary syndrome and congenital adrenal hyperplasia.

The purpose of this study was to determine whether polycystic ovary syndrome (PCOS) and nonclassic 21-hydroxylase deficiency (CAH) are related to hyperhomocysteinemia, and to investigate if there is a correlation between homocysteine levels and insulin sensitivity in women with PCOS and CAH. Fifty patients with PCOS, 50 patients with CAH and 25 control women were included in the study. Blood samplings were performed in the early follicular phase for measuring hormone profile, Vitamin B(12), folate, homocysteine levels and fasting blood glucose. Ovulatory status was assessed with timed serum progesterone measurements. Homeostasis model assessment-insulin resistance (HOMA-IR) was calculated as a measure of insulin resistance. Mean homocysteine levels were found as (8.9 + 1.9 micromol/l and 17.7 + 3.6 micromol/l) in the normal group and PCOS respectively (p<0.001), but there was no statistical significance between nonclassic 21-hydroxylase deficiency (9.0 + 2.2 micromol/l) and control group. Most of the patients in PCOS group (35 of 50) were significantly insulin resistant. However, there was no insulin resistant patient in CAH or control group. When we compare the two subgroups of PCOS women, the patients with insulin resistance had significantly higher homocysteine levels than the ones who were not insulin resistant. There were positive correlations among serum homocysteine, insulin and androgen levels in PCOS patients. There were no correlations among these parameters in CAH and control groups. Increased homocysteine levels may contribute to increased cardiovascular disease risk in patients with PCOS. The reason for hyperhomocysteinemia seems to be related to insulin resistance but not high androgen levels.

Adrenal Hyperplasia, Congenital↗

PubMed1980

Ovarian steroidogenesis in Japanese patients with polycystic ovary syndrome.

Gonadotropin and steroid hormone levels in both peripheral and ovarian venous blood were measured in samples obtained from 20 Japanese patients with polycystic ovary syndrome (PCOs) and 10 normal women in early follicular phase (normal women) by radioimmunoassay. The change in the amount of steroid hormone following intravenous human menopausal gonadotropin (HMG) or dexamethasone administration was investigated. The mean concentration in patients with PCOs was significantly higher than the concentrations found in normal women for LH (p less than 0.001), but not for FSH in peripheral blood. Significantly elevated ovarian venous steroid hormone levels in PCOs were found for 17 alpha-hydroxypregnenolone (p less than 0.05), progesterone (p less than 0.05), 17 alpha-hydroxyprogesterone (p less than 0.01), 4 delta-androstenedione (p less 0.01), testosterone (p less than 0.01), estrone (p less than 0.01) and estradiol (p less than 0.05), but not for dehydroepiandrosterone-sulfate (DHEAS). The ovarian dehydroepiandrosterone (DHEA) level was slightly elevated in PCOs. The concentration of ovarian 4 delta-androstenedione in PCOs reached twelve times as much as that in normal women. After the administration of HMG, all of the ovarian venus steroid hormone levels were elevated slightly and without significance in the short observation time for 10 min. The DHEAS level was suppressed while the ovarian DHEA level remained high in PCOs following dexamethasone administration. These findings seem to indicate there is no adrenal involvement and no adrenal-like component in the ovary of PCOs, and no evidence of 3 beta-hydroxysteroid dehydrogenase and/or aromatase deficiency in this study. The increase in the steroid hormone secretion in PCOs is explained by the increase in ovarian production in polycystic enlarged ovaries.

Adult↗

PubMed1993

Growth of the dominant follicle is similar to normal in patients with gonadotrophin-stimulated polycystic ovary syndrome exhibiting monofollicular development during a decremental dose regimen.

The aim of this study was to investigate the late follicular phase of seven gonadotrophin-treated patients with polycystic ovary syndrome (PCOS) exhibiting monofollicular growth and to compare developmental characteristics with the dominant follicle in seven regularly cycling control women. Daily serum follicle-stimulating hormone (FSH) levels in patients with PCOS decreased more rapidly compared to controls (-0.3 +/- 0.2 IU/day in controls versus -0.7 +/- 0.4 IU/day in PCOS; p < 0.02). No statistically significant differences were seen in daily increase (30% in controls and PCOS) and mean peak levels (825 +/- 94 pmol/l in controls versus 937 +/- 231 pmol/l in PCOS) of oestradiol (E2) serum levels when comparing both groups. Mean daily growth of the dominant follicle (1.7 +/- 0.4 mm in controls versus 1.9 +/- 0.6 mm in PCOS) was not significantly different. It is concluded from the present study that in patients with PCOS treated with gonadotrophin plus adjuvant gonadotrophin-releasing hormone agonist, development of a single follicle can occur using a decreasing dose regimen resulting in decreasing serum FSH levels. In addition, growth and oestrogen production by the dominant follicle in PCOS is not significantly different from follicle growth under normal conditions.

Adult↗