The effectiveness of the interview for predicting the presence of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a leading cause of female infertility, occurs in approximately 4% of women of reproductive age. Multifamily studies have established that PCOS has strong inherited traits. Although diagnosis of PCOS in the relatives of affected women can readily be made by clinical and biochemical evaluations, these methods are costly and laborious. The aim of this investigation was to determine whether clinically evident PCOS could be detected by a written questionnaire, which is a significantly less expensive means of detection than direct determination. A questionnaire about the history of possible androgenic symptoms of PCOS was presented to patients and their first-degree female relatives, who were also evaluated by physical and laboratory examinations. The sensitivity, specificity, and positive predictive value (PPV) and negative predictive value (NPV) for the detection of PCOS by interview were calculated. The NPV of the proband interview was significantly lower for sisters than for mothers (82% vs. 100%, respectively; p < 0.05). When the family member completed the written questionnaire directly, the specificity and NPV of self-reporting were equally high (> 90%) for both mothers and sisters. Thus direct interviewing of PCOS patients or their mothers and sisters reliably predicts affected status, but patient interview alone will not predict PCOS in almost 50% of the affected sisters.

Steroidogenic acute regulatory protein (StAR) in the ovaries of healthy women and those with polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome is the most common cause of oligo-ovulation, affecting approximately 4% of women. A primary defect of steroidogenesis resulting in increased ovarian and adrenal androgen production may be responsible for polycystic ovary syndrome, at least in some patients. Because the action of the steroidogenic acute regulatory protein (StAR) initiates the process of steroidogenesis, we proceeded to test the hypothesis that increased production or concentration of StAR may result in the abnormality of steroidogenesis found in polycystic ovary syndrome. STUDY DESIGN: We examined the ovaries from 10 healthy women and 7 women with polycystic ovary syndrome, determining the relative concentration of StAR in total protein extracts by use of Western blotting, and the overall distribution and staining intensity of StAR in prepared tissue sections. RESULTS: Overall the ovaries of healthy women and women with polycystic ovary syndrome demonstrated a similar prevalence and size of follicular cysts, although the ovaries of women with polycystic ovary syndrome had a greater mean number of follicular cysts. In general, the distribution of StAR immunoreactivity within most of the ovarian structures was not different in the ovaries of women with polycystic ovary syndrome compared to those of the healthy ovaries. However, the ovaries from the cases demonstrated a significantly greater number of follicular cysts with staining for StAR immunoreactivity in the thecal cells than did the ovaries from healthy women (100% vs 38%, P <.05). CONCLUSION: These data suggest that the exaggeration in androgen biosynthesis in the ovaries of patients with polycystic ovary syndrome may be occurring at its earliest step (ie, that involving StAR), such that an increased amount of cholesterol is made available for androgen biosynthesis in the polycystic ovary.

Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS.

OBJECTIVE: To determine the rate of clinically evident polycystic ovary syndrome (PCOS) among first-degree female relatives within families with a proband affected by PCOS. DESIGN: Clinical and biochemical evaluation of the mothers and sisters of 93 patients with PCOS. The diagnosis of PCOS was established by: [1] a history of oligomenorrhea, [2] clinical evidence (i.e., hirsutism) or biochemical evidence (i.e., elevated total or free T) of hyperandrogenism, and [3] the exclusion of related disorders. SETTING: Tertiary care university. PATIENT(S): Patients with PCOS and their mothers and sisters. INTERVENTION(S): Interview, physical examination, and hormonal testing on blood samples were performed for all subjects. MAIN OUTCOME MEASURE(S): The presence of hirsutism and hyperandrogenemia was determined in the mothers and sisters of the patients with PCOS. RESULT(S): Of the 78 mothers and 50 sisters evaluated clinically, 19 (24%) and 16 (32%) were affected with PCOS, respectively. A higher rate of PCOS was observed when only premenopausal women not taking hormones (i.e., untreated) were considered (i.e., 35% of mothers and 40% of sisters), consistent with amelioration of symptoms with hormonal therapy or aging. These rates of PCOS are significantly higher than that observed in our general population (approximately 4%) and suggest the involvement of a major genetic component in the disorder. CONCLUSION(S): The rates of PCOS in mothers and sisters of patients with PCOS were 24% and 32%, respectively, although the risk was higher when considering untreated premenopausal women only.

A variant of the glucocorticoid receptor gene is not associated with adrenal androgen excess in women with polycystic ovary syndrome.

OBJECTIVE: To determine whether the frequency of the N363S variant of the glucocorticoid receptor (GRL) was increased in women with PCOS and adrenal androgen (AA) excess. DESIGN: Prospective case-control study. SETTING: University reproductive endocrinology laboratory and outpatient clinic. PATIENT(S): Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 92). INTERVENTION(S): Blood and DNA sampling before hormonal therapy. MAIN OUTCOME MEASURE(S): PCOS patient and healthy control genotypes, with the N363S allele representing a variant of GRL. RESULT(S): Fifty-four PCOS patients with (DHEAS > or = 3000 ng/mL) and 55 without (DHEAS < or = 2,500 ng/mL) AA excess, respectively, were studied. Six of 109 (5.5%) patients studied were found to be heterozygous carriers of the A-->G base pair substitution at cDNA position 1220, resulting in the missense mutation N363S. Of these six, four had excessive AA secretion (i.e., excess DHEAS levels). There was no significant difference in the allele frequency of the GRL variant between PCOS patients with and without AA excess and controls (3.7% [95% confidence interval: 1.0%-5.7%], 1.8% [0.2%-6. 0%], and 3.3% [2.3%-6.0%]). None of the subjects were found to be homozygous for the N363S allele. CONCLUSION(S): The N363S variant of GRL was an uncommon occurrence in our population of healthy women and PCOS patients and did not appear to play a major role in the genetic predisposition to PCOS or to AA excess in PCOS.

Dopamine D3 receptor polymorphism is not associated with the polycystic ovary syndrome.

OBJECTIVE: To determine if a polymorphism of the dopamine D3 receptor gene (2 allele), which has been reported previously to be associated with polycystic ovary syndrome (PCOS) in a population of United States Hispanic women, is associated with the disorder in the southeastern United States. DESIGN: Prospective case-control study. SETTING: University reproductive endocrinology laboratory and outpatient clinic. PATIENT(S): Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 152) and healthy controls (n = 96). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patient and control dopamine D3 receptor genotypes, with the 1 allele representing the wild type and the 2 allele denoting a highly prevalent polymorphism. RESULT(S): No difference was noted in the distribution of the three dopamine D3 receptor genotypes (i.e., 1:1, 1:2, and 2:2) among PCOS patients as compared with controls. Furthermore, in contrast to a previous report, the 2:2 genotype was not more prevalent among PCOS patients than among controls. CONCLUSION(S): Our population of non-Hispanic white women from the southeastern United States did not demonstrate an association between a dopamine D3 receptor polymorphism and PCOS.

Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study.

Estimates of the prevalence of the polycystic ovary syndrome (PCOS) in the general population have ranged from 2-20%. The vast majority of these reports have studied White populations in Europe, used limited definitions of the disorder, and/or used bias populations, such as those seeking medical care. To estimate the prevalence of this disorder in the United States and address these limitations, we prospectively determined the prevalence of PCOS in a reproductive-aged population of 369 consecutive women (174 White and 195 Black; aged 18-45 yr), examined at the time of their preemployment physical. Body measures were obtained, and body hair was quantified by a modified Ferriman-Gallwey (F-G) method. All exams were initially performed by 2 trained nurses, and any subject with an F-G score above 3 was reexamined by a physician, the same for all patients. Of the 369 women, 277 (75.1%) also agreed to complete a questionnaire and have additional blood drawn. Subjects were studied regardless of current estrogen/progestin hormonal use (28.5%). PCOS was defined as 1) oligoovulation, 2) clinical hyperandrogenism (i.e. hirsutism) and/or hyperandrogenemia, and 3) exclusion of other related disorders, such as hyperprolactinemia, thyroid abnormalities, and non-classic adrenal hyperplasia. Hirsutism was defined by a F-G score of 6 or more, and hyperandrogenemia was defined as a total or free testosterone, androstenedione, and/or dehydroepiandrosterone sulfate level above the 95th percentile of control values [i.e. all eumenorrheic women in the study, who had no hirsutism (F-G < or = 5) or acne and were receiving no hormonal therapy; n = 98]. Considering all 369 women studied, White and Black women had similar mean ages (29.4 +/- 7.1 and 31.1 +/- 7.8 yr, respectively), although White women had a lesser body mass than Black women (24.9 +/- 6.1 vs. 29.2 +/- 8.1 kg/m2, respectively; P < 0.001). Of these 7.6%, 4.6%, and 1.9% demonstrated a F-G score of 6 or more, 8 or 10, respectively, and there was no significant racial difference, with hirsutism prevalences of 8.0%, 2.8%, and 1.6% in Whites, and 7.1%, 6.1%, and 2.1% in Blacks, respectively. Of the 277 women consenting to a history and hormonal evaluation, 4.0% had PCOS as defined, 4.7% (6 of 129) of Whites and 3.4% (5 of 148) of Blacks. In conclusion, in our consecutive population of unselected women the prevalence of hirsutism varied from 2-8% depending on the chosen cut-off F-G score, with no significant difference between White and Black women. Using an F-G score of 6 or more as indicative of hirsutism, 3.4% of Blacks and 4.7% of Whites had PCOS as defined. These data suggest that PCOS may be one of most common reproductive endocrinological disorders of women.

The development of the polycystic ovary syndrome: family history as a risk factor.

Three general genetic models for the development of the polycystic ovary syndrome (PCOS) can be proposed, namely: (1) the "single-gene Mendelian" model, which considers the majority of defects present in PCOS to be unique; (2) the "multifactorial" model, which suggests that the defects present in PCOS are not unique, and simply represent the conglomeration of abnormalities already present separately, and to a significant degree, in the general population (e.g. as in cardiovascular disease and non-insulin-dependent diabetes); and (3) the "variable expression-single gene" model, a modified version of the above two. Overall, our data support this third model, suggesting that PCOS is a familial disorder, with a single autosomal dominant gene effect, and a variable phenotype. Family history can then be considered as an important factor determining the risk of developing PCOS. Our preliminary data indicate that a woman's risk of developing PCOS is approximately 40% if her sister is affected. Alternatively, only 19% of mothers were affected, suggesting that the inheritance of PCOS may be preferentially paternal, although expanded clinical studies will be required to confirm these findings. Considering PCOS to be a dominant genetic disorder with a high degree of expressivity, we propose that the risk of developing the disorder is governed by family history and the degree of exposure to the selected environmental and/or other genetic influences.