Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test.

BACKGROUND: Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A). METHODS: Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4-7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all. RESULTS: Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671-0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, P< 0.01). Glucose intolerance was absent in PCOS-A, but present in 30% of PCOS-T (P < 0.001). Most of the PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese. CONCLUSIONS: Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction.

Functional significance of polycystic-size ovaries in healthy adolescents.

CONTEXT: The relevance of adult polycystic ovary criteria to adolescence is unclear. OBJECTIVE: The objective was to determine the functional significance of polycystic-size ovaries (PSO) in healthy adolescents. DESIGN/SETTING/PARTICIPANTS/INTERVENTIONS: Healthy 11- to 18-yr-old postmenarcheal volunteers (n = 22) were recruited and divided into groups with normal size ovaries (VNSO; n = 10) or a polycystic-size ovary (VPSO; n = 12). They were secondarily compared with adolescents with polycystic ovary syndrome (PCOS; n = 8) matched for gynecological age and a PSO. All underwent GnRH agonist (GnRHag), oral glucose tolerance, and ACTH1-24 testing in our General Clinical Research Center. RESULTS: VPSO had a higher peak 17-hydroxyprogesterone (17PROG) response to GnRHag than VNSO (146 +/- 14 ng/dl, mean +/- sem, vs. 85 +/- 11; P = 0.008), as well as larger ovaries (13.3 +/- 0.7 cc vs. 8.5 +/- 0.8 cc). VPSO peak 17PROG was elevated (>137 ng/dl) in 42% (5 of 12). However, VPSO and VNSO androgen levels were similar, with the exception of one VPSO subject who had hyperandrogenemia and thus met criteria for PCOS. VPSO were similar to VNSO in LH, FSH, estradiol, and adrenal androgenic function. Although the VPSO group resembled the PCOS group in their 17PROG response to the GnRHag test, they differed in having significantly smaller ovaries and lower body mass index and in lacking evidence of peripheral androgen excess and of insulin resistance. CONCLUSION: A PSO in asymptomatic adolescents seems typically to be a normal variant. However, about half have a subclinical PCOS type of ovarian dysfunction; it is unknown whether this indicates a genetic carrier state or a risk for anovulation.

Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries.

OBJECTIVE: To determine the relationship of antimüllerian hormone (AMH) levels to polycystic ovaries and ovarian androgenic function. DESIGN: Prospective case-control study. SETTING: General clinical research center. PARTICIPANT(S): Eumenorrheic asymptomatic volunteers without (V-NO; n = 19; reference population) or with (V-PCO; n = 28) a polycystic ovary and hyperandrogenemic anovulatory subjects grouped according to ovarian function into typical PCOS (PCOS-T; n = 37) and atypical PCOS (PCOS-A; n = 18). INTERVENTION(S): Pelvic ultrasonography, short dexamethasone androgen-suppression test (SDAST), and GnRH agonist (GnRHag) test. MAIN OUTCOME MEASURE(S): Baseline AMH levels were related to polycystic ovary status, testosterone response to SDAST, and 17-hydroxyprogesterone response to GnRHag test. RESULT(S): AMH levels correlated with SDAST and GnRHag test outcomes. AMH was elevated (>6.2 ng/mL) in 32% of V-PCO versus 5% V-NO. The 21% of V-PCO who met Rotterdam PCOS criteria all had functional ovarian hyperandrogenism, but AMH levels were similar to nonhyperandrogenic V-PCO. AMH >10.7 ng/mL discriminated V-PCO from PCOS with 96% specificity and 41% sensitivity for PCOS-T, and insignificantly for PCOS-A. CONCLUSION(S): AMH levels are independently related to ovarian androgenic function and polycystic ovaries. Very high AMH levels are specific but insensitive for PCOS. In the absence of hyperandrogenism, moderate AMH elevation in women with normal-variant polycystic ovaries seems to indicate an enlarged oocyte pool.

Asymptomatic volunteers with a polycystic ovary are a functionally distinct but heterogeneous population.

CONTEXT/OBJECTIVE: Our objective was to determine the ovarian function of asymptomatic volunteers with a polycystic ovary (V-PCO). PARTICIPANTS: Non-hirsute eumenorrheic V-PCO (n = 32) and volunteers with ultrasonographically normal ovaries (V-NO) (n = 21) were compared with one another and with polycystic ovary syndrome (PCOS) patients who met National Institute of Health criteria (n = 90). DESIGN/SETTING/INTERVENTIONS: GnRH agonist (GnRHag), ACTH, and oral glucose tolerance tests were prospectively performed in a General Clinical Research Center. RESULTS: The distribution of 17-hydroxyprogesterone (17OHP) responses to GnRHag of V-PCO formed a distinct population intermediate between that of V-NO, the reference population, and PCOS. Nevertheless, the V-PCO population was heterogeneous. There were 53% (seventeen of 32) that were functionally normal, with 17OHP responses and free testosterone levels like V-NO. A total of 25% (eight of 32) had an elevated free testosterone, thus meeting Rotterdam criteria for PCOS; one third of these had 17OHP hyperresponsiveness to GnRHag testing. The remaining 22% (seven of 32) had 17OHP hyperresponsiveness to GnRHag, but normal free testosterone. Of PCOS, 69% had elevated 17OHP hyperresponsiveness to GnRHag. Ovarian volume correlated significantly with 17OHP responses only in PCOS, accounting for just 10% of the variance. CONCLUSIONS: Many asymptomatic volunteers have a PCO. They are a distinct, but heterogeneous, population with respect to ovarian function, ranging from normal (53%) to occult PCOS by Rotterdam criteria (25%). Nearly one quarter (22%) had the typical PCOS type of ovarian dysfunction without hyperandrogenemia, termed a "dysregulated PCO"; they or their offspring may be at risk for PCOS. Ovarian ultrasonographic characteristics must be considered when establishing norms for ovarian function.

Characterization of functionally typical and atypical types of polycystic ovary syndrome.

CONTEXT: The typical polycystic ovary syndrome (PCOS) phenotype includes 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHag) testing. Functionally atypical PCOS lacks this feature. OBJECTIVE: The hypothesis was tested that the typical PCOS ovarian dysfunction results from intrinsically increased sensitivity to LH/human chorionic gonadotropin (hCG) due to a flaw in FSH action. PARTICIPANTS/DESIGN/INTERVENTIONS/MAIN OUTCOME MEASURES: After phenotyping a cohort of 60 women, steroid and inhibin-B responses to gonadotropins were evaluated in representative typical (n = 7) and atypical (n = 5) PCOS and healthy controls (n = 8). Submaximal hCG testing before and after an FSH test dose was performed in random order before and after prolonged ovarian suppression by depot GnRHag. SETTING: The study was performed at a Clinical Research Center. RESULTS: Of our PCOS cohort, 68% were the typical type. Typical PCOS had 17OHP hyperresponsiveness and, unlike controls, significant androgen and estradiol responses to hCG. FSH increased inhibin-B and did not inhibit free testosterone or enhance estradiol responsiveness to hCG, all unlike controls. After ovarian suppression, 17OHP, androstenedione, and inhibin-B responsiveness to gonadotropin testing persisted. Atypical PCOS had significantly higher body mass index but lower ovarian volume and plasma free testosterone than typical PCOS. Steroid responses to hCG were insignificant and similar to controls. FSH suppressed free testosterone but stimulated inhibin-B. The estradiol level after combined hCG-FSH was subnormal. Free testosterone was less GnRHag suppressible than in typical PCOS. CONCLUSIONS: Typical PCOS is characterized by intrinsic ovarian hypersensitivity to hCG to which excessive paracrine FSH signaling via inhibin-B may contribute. Atypical PCOS is due to a unique type of ovarian dysfunction that is relatively gonadotropin hyposensitive.