Increased Adrenal Androgens in Overweight Peripubertal Girls.

CONTEXT: Peripubertal hyperandrogenemia-a precursor to polycystic ovary syndrome-is prominent in girls with obesity. OBJECTIVE: We examined sources of overnight testosterone (T) and progesterone (P4) and potential sources of obesity-associated hyperandrogenemia during puberty. DESIGN: Cross-sectional. SETTING: Research unit. PARTICIPANTS/INTERVENTIONS: Fifty girls ages 7 to 18 years-both normal weight (NW) and overweight (OW)-underwent dexamethasone (DEX) suppression (1 mg orally; 10 pm) and cosyntropin stimulation testing (0.25 mg intravenously; 8 am the following day), with blood sampled before and 30 and 60 minutes after cosyntropin. Thirty-nine subjects receiving DEX had frequent blood sampling overnight (every 10 minutes from 10 pm to 7 am) and were compared with 70 historical controls who did not receive DEX. OUTCOMES: Random coefficient regression modeling assessed changes in hormone concentrations after DEX and cosyntropin. RESULTS: NW early pubertal controls exhibited early morning increases in free T and P4 levels; NW and OW late pubertal controls exhibited early morning increases in P4. Such changes were not observed in subjects receiving DEX. Post-DEX morning free T levels were fourfold higher in OW vs NW late pubertal girls. Postcosyntropin changes in free T and androstenedione were both 2.3-fold higher in OW vs NW late pubertal girls. CONCLUSIONS: These data suggest that (1) overnight increases in free T and P4 concentrations in NW early pubertal girls and P4 concentrations in late pubertal girls are of adrenal origin and (2) OW late pubertal girls demonstrate elevated nonadrenal free T levels after DEX and exaggerated adrenal androgen (free T and androstenedione) responses to cosyntropin.

The effect of estradiol on granulosa cell responses to FSH in women with polycystic ovary syndrome.

BACKGROUND: The influence of estradiol (E2) on granulosa cell (GC) function has not been tested clinically in women with polycystic ovary syndrome (PCOS). The objective of this study is to determine if E2 influences GC responses to FSH in women with PCOS. METHODS: This is a two phase, single cohort study conducted over a 2-year period at a single academic center. Nine women with PCOS according to NIH criteria. In Phase 1, FSH stimulation of GC responses as measured by E2 and Inhibin B (Inh B) were assessed before and at 5 and 6 weeks after GnRH agonist administration. In Phase 2, the same protocol was employed with the addition of an aromatase inhibitor (letrozole, LET) administered daily beginning at week 4 for 2 weeks. RESULTS: In Phase 1, recovery of FSH, E2 and Inh B from ovarian suppression occurred at 5 and 6 weeks after GnRH agonist injection and preceded resumption of LH and androgen secretion. In Phase 2, hormone recovery after GnRH agonist was characterized by elevated FSH and suppressed E2 levels whereas recovery of LH and androgen levels were unchanged. In Phase 1, FSH stimulated E2 and Inh B responses were unaltered during recovery from ovarian suppression. In Phase 2, E2 and Inh B fold changes after FSH were significantly reduced at weeks 5 (p < 0.04) and 6 (p < 0.01), respectively. CONCLUSION: In anovulatory women with PCOS, chronic, unopposed E2 secretion may contribute, at least in part, to enhanced ovarian responsiveness to FSH. TRIAL REGISTRATION: NCT02389088.

17-Hydroxyprogesterone responses to human chorionic gonadotropin are not associated with serum anti-Mullerian hormone levels among adolescent girls with polycystic ovary syndrome.

BACKGROUND: In adult women with polycystic ovary syndrome (PCOS) 17-OHP responses to human chorionic gonadotropin (hCG) stimulation are highly variable and inversely correlated with serum anti-Mullerian hormone (AMH) levels. The objective of this study was to determine whether adolescents with PCOS exhibit similar variable 17-OHP responsiveness to hCG and whether these responses are correlated to AMH levels. METHODS: In a prospective study, adolescent PCOS (n=14) and normal controls (n=10) received 25 µg of hCG, intravenously. Blood samples were obtained before and 24 h afterwards for measurement of 17-OHP and basal AMH. RESULTS: Variable 17-OHP responses to hCG were observed among PCOS girls similar to that observed in adults. There was no correlation between AMH and 17-OHP responses to hCG. CONCLUSIONS: Among adult and adolescent individuals with PCOS variable 17-OHP production appears to be characteristic of the disorder. In adolescent PCOS, 17-OHP responsiveness to hCG is not correlated to AMH.

Decreased inhibin B responses following recombinant human chorionic gonadotropin administration in normal women and women with polycystic ovary syndrome.

OBJECTIVE: To determine whether granulosa cells contribute to excess androgen production, by assessing inhibin B (Inh B) responses to hCG in women with polycystic ovary syndrome (PCOS) and in normal women. DESIGN: Prospective study. SETTING: Academic medical center. PATIENT(S): Twenty women with PCOS and 16 normal women. INTERVENTION(S): Blood samples obtained before and 24 hours after injection of 25 µg recombinant hCG (r-hCG). MAIN OUTCOME MEASURE(S): Basal and stimulated Inh B, E2, androstenedione (A), and T responses after r-hCG administration. RESULT(S): In normal and PCOS women, r-hCG induced a significant reduction of Inh B levels. Lowered Inh B responses were not related to body mass index, PCOS status, or age by multivariate regression. Recombinant hCG significantly increased serum A and E2 in both normal and PCOS women. CONCLUSION(S): In normal and PCOS women, Inh B production was decreased following r-hCG administration. These findings strongly suggest that in PCOS women androgen excess is not enhanced by LH-stimulated Inh B production. CLINICAL TRIAL REGISTRATION NUMBER: NCT00747617.

Ovarian imaging by magnetic resonance in adolescent girls with polycystic ovary syndrome and age-matched controls.

PURPOSE: To compare ovarian morphology in adolescent girls with and without polycystic ovary syndrome (PCOS) using magnetic resonance imaging (MRI). MATERIALS AND METHODS: In 21 adolescent girls (age 12-18 years) without and 19 adolescents with PCOS (diagnosis based on excessive hair growth and irregular menstrual cycles) ovarian volume, antral follicle count (AFC) per ovary, and follicle size were evaluated. MRI was performed at 1.5 T or 3 T and axial or angled-axial single-shot echo-train spin echo images of 6 mm slice thickness were acquired. In a subset of subjects, 2-mm images were also obtained. PCOS and non-PCOS groups were compared using mixed affects regression. RESULTS: Mean AFC per ovary and ovarian volume were substantially greater in PCOS subjects compared to non-PCOS subjects. Mean follicle size was similar between groups. Follicles exceeding 10 mm were seen in 2/19 PCOS subjects versus 9/21 non-PCOS subjects. Consistently higher follicle counts were detected in images obtained at 2 mm compared to 6-mm slice thickness. CONCLUSION: In adolescence, MRI of the ovary reveals distinct differences between girls with and without PCOS. MRI may help evaluate young patients in whom transvaginal ultrasound is contraindicated.

Clinical evidence for predominance of delta-5 steroid production in women with polycystic ovary syndrome.

CONTEXT: In women with polycystic ovary syndrome (PCOS), the basis for ovarian androgen overproduction involves an overall increase of steroidogenesis, notably in the delta-4 pathway. However, in vitro studies have suggested that excessive androgen production occurs predominantly through the delta-5 pathway. OBJECTIVE: This study was performed to assess androgen dose-responses after human chorionic gonadotropin (hCG) stimulation in PCOS and normal women. DESIGN: We conducted a prospective study to compare androgen production after iv hCG in PCOS and normal women. SETTING: The study was conducted in a General Clinical Research Center in an academic medical center. PARTICIPANTS: Women with PCOS (age, 18-37 yr; n = 10) and normal ovulatory controls (age, 18-37 yr; n = 11) were recruited. INTERVENTIONS: For dose-response studies, blood samples were obtained before and at 0.5, 24, and 48 h after iv recombinant hCG (1, 10, 25, 100, and 250 µg). A subset of subjects underwent frequent blood sampling over 24 h after iv injection of 25 µg of recombinant hCG. MAIN OUTCOME MEASURE(S): We measured basal and stimulated serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T), dehydroepiandrosterone, estradiol, and progesterone responses after hCG administration. RESULTS: In PCOS women, maximal A and T production was observed at the lowest doses of hCG, whereas responses were minimal in normal women. Incremental responses of 17-OHP, estradiol, and progesterone were greater in PCOS compared to normal women. CONCLUSION: In PCOS women, maximal A and T responses to hCG relative to those of 17-OHP are consistent with ovarian androgen overproduction via the delta-5 pathway.

Pyometra after Le Fort colpocleisis resolved with interventional radiology drainage.

BACKGROUND: Le Fort colpocleisis is a surgical treatment option for advanced pelvic organ prolapse in women who are willing to give up future vaginal sexual function. Pelvic abscess, or pyometra, after Le Fort colpocleisis has been reported and is thought to be related to inadequate lateral drainage channels. To date, these cases of postoperative pyometra have been managed using hysterectomy. CASE: : We report a case of pyometra after a Le Fort colpocleisis conservatively managed with interventional radiologically guided abscess drainage and dilation of the lateral drainage tracts. CONCLUSION: Interventional radiology drainage and manual dilation of the lateral drainage tracts can be used as an alternative to hysterectomy in managing Pyometra after a Le Fort colpocleisis.

Androgen regulates follicle-stimulating hormone beta gene expression in an activin-dependent manner in immortalized gonadotropes.

Little is known about the molecular mechanisms of androgen regulation of the FSHbeta gene; however, studies suggest that it consists of a complex feedback loop that involves multiple mechanisms acting at both the level of the hypothalamus and the pituitary. In the present study, we address androgen regulation of the FSHbeta gene in immortalized gonadotrope cells and investigate the roles of activin and GnRH in androgen action. Using transient transfection assays in the FSHbeta-expressing mouse gonadotrope cell line, LbetaT2, we demonstrate that androgens stimulate expression of an ovine FSHbeta reporter gene in a dose-dependent manner. Mutation of either of two conserved androgen response elements at -245/-231 and -153/-139 within the proximal region of the ovine FSHbeta gene promoter abolishes this stimulation, and androgen receptor binds directly to the -244 ARE in vitro. Androgen induction of the FSHbeta reporter gene is also dependent upon the activin autocrine loop present in the LbetaT2 cells, as well as an activin-response element at -138/-124 of the FSHbeta gene. However, activin regulation of other genes remains unaffected by androgens. In addition, androgens stimulate expression of a mouse GnRH receptor reporter gene, and thus may indirectly augment the response of the FSHbeta gene to GnRH. Taken together, these data demonstrate that, in mouse gonadotropes, androgens act directly on the ovine FSHbeta gene to stimulate expression by a mechanism that is dependent upon activin, as well as acting indirectly, potentially through a second mechanism that may be dependent upon induction of GnRH receptor.