scholarly journals The Effect of Androgen Blockade on Granulosa Cell Estradiol Production after Follicle-Stimulating Hormone Stimulation in Women with Polycystic Ovary Syndrome

2006 ◽  
Vol 91 (9) ◽  
pp. 3503-3506 ◽  
Author(s):  
Rinku V. Mehta ◽  
Pamela J. Malcom ◽  
R. Jeffrey Chang
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Granulosa Cell ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Dehydroepiandrosterone Sulfate ◽  
Ovary Syndrome ◽  
Before And After ◽  
Normal Women ◽  
17 Hydroxyprogesterone

Abstract Context: Previously, we have shown that women with polycystic ovary syndrome (PCOS) exhibit an exaggerated serum estradiol (E2) response to recombinant human FSH (rhFSH) (150 IU) compared with similarly treated normal women. This enhanced granulosa cell responsiveness is consistent with excessive follicular development after gonadotropin therapy and the corresponding risk of ovarian hyperstimulation syndrome. In vitro studies have shown that granulosa cells treated with androgens display greater FSH-induced E2 production than untreated cells, suggesting a role for androgens in granulosa cell responsiveness. Main Objective: This study was conducted to determine whether blockade of androgen action in PCOS women by administration of the antiandrogen flutamide would alter E2 responses to rhFSH. Design: We conducted a prospective cohort study. Subjects and Setting: We studied 11 women with PCOS at an institutional general clinical research center. Intervention: On study d 1, each subject received 150 IU rhFSH iv. Frequent blood samples were obtained over 24 h. After completion of rhFSH stimulation, each subject was treated with flutamide, 125 mg, twice daily, for 6 wk. Thereafter, the rhFSH stimulation test was repeated. Main Outcome Measures: Baseline and stimulated E2 levels before and after treatment were assayed. Results: Mean baseline and maximally stimulated E2, integrated E2 response, and fold change in E2 were not different before and after treatment. Levels of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, estrone, and SHBG before and after treatment were unchanged. Baseline dehydroepiandrosterone sulfate levels declined significantly after flutamide therapy. Conclusion: These findings indicate that in women with PCOS, the E2 hyperresponsiveness to FSH may not be attributable to increased circulating androgens.

scholarly journals Clinical Evidence for Predominance of Delta-5 Steroid Production in Women with Polycystic Ovary Syndrome

2011 ◽  
Vol 96 (4) ◽  
pp. 1106-1113 ◽  
Author(s):  
Marcus A. Rosencrantz ◽  
Mickey S. Coffler ◽  
Annette Haggan ◽  
Kimberly B. Duke ◽  
Michael C. Donohue ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Academic Medical Center ◽  
Ovary Syndrome ◽  
Clinical Research Center ◽  
Normal Women ◽  
17 Hydroxyprogesterone ◽  
A Prospective Study

Abstract 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.

scholarly journals Circadian Clock Genes REV-ERBs Inhibits Granulosa Cells Apoptosis by Regulating Mitochondrial Biogenesis and Autophagy in Polycystic Ovary Syndrome

2021 ◽  
Vol 9 ◽  
Author(s):  
Lihua Sun ◽  
Hui Tian ◽  
Songguo Xue ◽  
Hongjuan Ye ◽  
Xue Xue ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Circadian Clock ◽  
Granulosa Cells ◽  
Clock Genes ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Ovary Syndrome ◽  
Circadian Clock Genes ◽  
Mitochondrial Biosynthesis

Polycystic ovary syndrome (PCOS) is an endocrinopathy with complex pathophysiology that is a common cause of anovulatory infertility in women. Although the disruption of circadian rhythms is indicated in PCOS, the role of the clock in the etiology of these pathologies has yet to be appreciated. The nuclear receptors REV-ERBα and REV-ERBβ are core modulators of the circadian clock and participate in the regulation of a diverse set of biological functions. However, in PCOS, the expression of REV-ERBs and their effects remain unclear. Here, we demonstrate that the levels of REV-ERBα and REV-ERBβ expression were lower in the granulosa cells of PCOS patients than in control subjects. In vitro, we found that the overexpression of REV-ERBα and REV-ERBβ, and their agonist SR9009, promoted the expression of mitochondrial biosynthesis genes PGC-1α, NRF1, and TFAM and inhibited autophagy in KGN cells. Our results also indicate that REV-ERBα and REV-ERBβ can inhibit apoptosis in granulosa cells and promote proliferation. Importantly, the REV-ERB agonist SR9009 ameliorates abnormal follicular development by promoting mitochondrial biosynthesis and inhibiting autophagy in a mouse PCOS model. This allows us to speculate that SR9009 has potential as a therapeutic agent for the treatment of PCOS.

scholarly journals Response of the Pituitary-Adrenal Axis to Hypoglycemic Stress in Women with the Polycystic Ovary Syndrome

1999 ◽  
Vol 84 (1) ◽  
pp. 76-81 ◽  
Author(s):  
Gianluca Gennarelli ◽  
Jan Holte ◽  
Mats Stridsberg ◽  
Ulrika Lundqvist ◽  
Marco Massobrio ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Blood Glucose Concentration ◽  
Polycystic Ovary ◽  
Molar Ratio ◽  
Rapid Decline ◽  
Ovary Syndrome ◽  
Synacthen Test ◽  
Normal Women ◽  
17 Hydroxyprogesterone ◽  
Maximum Increment

The role of the adrenals in the polycystic ovary syndrome (PCOS) is debated. Both single steroid-converting enzyme abnormalities and increased adrenal activity have received support. The conventional Synacthen test using pharmacological doses of ACTH results in unphysiological levels of ACTH. Therefore, we used insulin-induced hypoglycemia (0.15 IU/kg BW) to asses the responses of ACTH, cortisol, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, and androstenedione in 18 women with PCOS and in 17 normal women of similar age and body mass index. The blood glucose concentration at 30 min was 2 mmol/L or less in all women, i.e. well below the threshold of the hormonal counterregulatory response. The women with PCOS showed a lower ACTH response, expressed as the maximum increment above basal [mean (95% confidence interval): PCOS, 11.1 (6.9–15.3); controls, 19.9 (13.8–26) pmol/L; P < 0.05], but a quantita-tively comparable [PCOS, 207.2 (148.5–266.5); controls, 167.1 (100.6–233.2) nmol/L; P = NS] and more prompt cortisol response than the controls (by χ2 test, P < 0.05), resulting in a higher molar ratio between the maximum increments of cortisol and ACTH [PCOS, 13.9 (8.7–19); controls, 8.8 (5.7–12); P < 0.05]. The women with PCOS did, however, show a more rapid decline in cortisol levels than the controls (P < 0.05 at 120 and 180 min). The responses of the androgens and intermediate adrenal steroids were similar in women with PCOS and controls. The findings suggest an adaptation to increased adrenal reactivity to endogenous ACTH in women with PCOS. Exposure to hypoglycemia as a model of stress was not followed by hypersecretion of adrenal androgens and revealed no signs of steroid enzyme disturbances in women with PCOS.

scholarly journals Relationship Between 17-Hydroxyprogesterone Responses to Human Chorionic Gonadotropin and Markers of Ovarian Follicle Morphology in Women With Polycystic Ovary Syndrome

2015 ◽  
Vol 100 (1) ◽  
pp. 293-300 ◽  
Author(s):  
Kevin H. Maas ◽  
Sandy S. Chuan ◽  
Heidi Cook-Andersen ◽  
H. Irene Su ◽  
A. Duleba ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Polycystic Ovary ◽  
Ovarian Follicle ◽  
Academic Medical Center ◽  
Ovary Syndrome ◽  
Gonadotropin Stimulation ◽  
Normal Women ◽  
17 Hydroxyprogesterone

Abstract Context: Women with polycystic ovary syndrome (PCOS) have increased 17-hydroxyprogesterone (17-OHP) responses to gonadotropin stimulation although individual variability is substantial, as reflected by exaggerated as well as normal responses. The relationship between 17-OHP responses to gonadotropin stimulation and markers of ovarian function has not been assessed. Objective: To determine whether 17-OHP responses are associated with antral follicle count (AFC), anti-Mullerian hormone (AMH), or inhibin B (Inh B) levels in PCOS and normal women. Design: Prospective study. Setting: Research center at an academic medical center. Participants: Women with PCOS (n = 18) and normal controls (n = 18). Interventions: Blood samples were obtained before and 24 hours after administration of 25 μg recombinant-human chorionic gonadotropin. Ovarian imaging was conducted with three-dimensional pelvic ultrasound. Main Outcome Measures: Basal and stimulated levels of 17-OHP, androgens, estrogen, AMH, Inh B, and AFC. Results: In women with PCOS, 17-OHP responses were heterogeneous and inversely correlated with AMH and Inh B levels, but not AFC. In a subgroup of PCOS women with exaggerated 17-OHP responses, AMH levels were equivalent to that of normal women. In PCOS women with normal 17-OHP responses, AMH levels were markedly elevated. Conclusion: Based on heterogeneous 17-OHP responses to human chorionic gonadotropin in women with PCOS, AMH levels are inversely linked to ovarian androgen production while positively correlated with AFC. These findings suggest that in PCOS, AMH production may reflect redistribution of the follicle population or regulation by intraovarian mechanisms.

scholarly journals Loss of anti-Müllerian hormone (AMH) immunoactivity due to a homozygous AMH gene variant rs10417628 in a woman with classical polycystic ovary syndrome (PCOS)

2020 ◽  
Vol 35 (10) ◽  
pp. 2294-2302 ◽  
Author(s):  
Luis R Hoyos ◽  
Jenny A Visser ◽  
Anke McLuskey ◽  
Gregorio D Chazenbalk ◽  
Tristan R Grogan ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Phenotypic Expression ◽  
Antral Follicle ◽  
Dehydroepiandrosterone Sulfate ◽  
Normal Weight ◽  
Sex Hormone Binding Globulin ◽  
Transvaginal Sonography ◽  
Ovary Syndrome

ABSTRACT Anti-Müllerian hormone (AMH) is produced by granulosa cells of pre-antral and small antral ovarian follicles. In polycystic ovary syndrome (PCOS), higher levels of serum AMH are usually encountered due to the ample presence of small antral follicles and a high AMH production per follicular unit which have led to the proposal of AMH as a serum diagnostic marker for PCOS or as a surrogate for polycystic ovarian morphology (PCOM). However, heterozygous coding mutations of the AMH gene with decreased in vitro bioactivity have been described in some women with PCOS. Such mutation carriers have a trend toward reduced serum AMH levels compared to noncarriers, although both types of women with PCOS have similar circulating gonadotropin and testosterone (T) levels. This report describes a normal-weight woman with PCOS by NIH criteria with severely reduced AMH levels (index woman with PCOS). Our objective was to examine the molecular basis for her reduced serum AMH levels and to compare her endocrine characteristics to similar-weight women with PCOS and detectable AMH levels. Twenty normoandrogenic ovulatory (control) and 13 age- and BMI-matched women with PCOS (19–35 years; 19–25 kg/m2) underwent transvaginal sonography and serum hormone measures including gonadotropins, sex hormone-binding globulin, total and free T, androstenedione, dehydroepiandrosterone sulfate, estrone, estradiol and AMH. The latter was measured by ELISA (Pico-AMH: Ansh Labs, Webster, TX, USA). Women with PCOS and detectable AMH had higher serum AMH (10.82 (6.74–13.40) ng/ml, median (interquartile range)), total and free T (total T: 55.5 (49.5–62.5) ng/dl; free T: 5.65 (4.75–6.6) pg/ml) levels and greater total antral follicle count (AFC) (46 (39–59) follicles) than controls (AMH: 4.03 (2.47–6.11) ng/ml; total T: 30 (24.5–34.5) ng/dl; free T: 2.2 (1.8–2.45) pg/ml; AFC 16 (14.5–21.5) follicles, P < 0.05, all values), along with a trend toward LH hypersecretion (P = 0.06). The index woman with PCOS had severely reduced serum AMH levels (∼0.1 ng/ml), although she also had a typical NIH-defined PCOS phenotype resembling that of the other women with PCOS and elevated AMH levels. All women with PCOS, including the index woman with PCOS, exhibited LH hypersecretion, hyperandrogenism, reduced serum estrogen/androgen ratios and PCOM. A homozygous Ala515Val variant (rs10417628) in the mature region of AMH was identified in the index woman with PCOS. Recombinant hAMH-515Val displayed normal processing and bioactivity, yet had severely reduced immunoactivity when measured by the commercial pico-AMH ELISA assay by Ansh Labs. In conclusion, homozygous AMH variant rs10417628 may severely impair serum AMH immunoactivity without affecting its bioactivity or PCOS phenotypic expression. Variants in AMH can interfere with serum AMH immunoactivity without affecting the phenotype in PCOS. This observation can be accompanied by discordance between AMH immunoactivity and bioactivity.

scholarly journals Increased Androgen Response to Follicle-Stimulating Hormone Administration in Women with Polycystic Ovary Syndrome

2008 ◽  
Vol 93 (5) ◽  
pp. 1827-1833 ◽  
Author(s):  
Deborah S. Wachs ◽  
Mickey S. Coffler ◽  
Pamela J. Malcom ◽  
Shunichi Shimasaki ◽  
R. Jeffrey Chang
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Outcome Measures ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Academic Medical Center ◽  
Theca Cell ◽  
Ovary Syndrome ◽  
Enhanced Production ◽  
Normal Women ◽  
17 Hydroxyprogesterone

Abstract Context: In women with polycystic ovary syndrome (PCOS), excess ovarian androgen production is driven by increased LH secretion. Studies conducted in animals suggest that the granulosa cell may influence LH-stimulated theca cell androgen production. Objective: The objective of this study was to determine whether FSH enhances androgen production in women with PCOS compared with that of normal women. Design: A prospective study was conducted to compare androgen production in response to FSH in two groups of women. Setting: The study was conducted in a General Clinical Research Center in a tertiary academic medical center. Patients: Women with PCOS, 18–35 yr (n = 20), and normal ovulatory controls, 18–35 yr (n = 10), were recruited for study. Interventions: Serial blood samples were obtained over a 24-h period after an iv injection of recombinant human FSH (150 IU). Main Outcome Measures: The main outcome measures were serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), dehydroepiandrosterone (DHEA), testosterone (T), and inhibin B (Inh B) responses after FSH administration. Results: Basal serum 17-OHP, A, and T levels were markedly increased in women with PCOS compared with that observed in normal women. Basal DHEA and Inh B levels were similar to those of normal controls. After FSH injection, PCOS women demonstrated enhanced production of 17-OHP, A, DHEA, and Inh B, whereas in normal women no increases were observed. T levels declined slightly in both groups. Conclusions: These findings provide evidence that, in PCOS women, theca cell androgen production is enhanced by FSH administration and suggest a granulosa-theca cell paracrine mechanism.

scholarly journals Comparison of Follicle-Stimulating-Hormone-Stimulated Dimeric Inhibin and Estradiol Responses as Indicators of Granulosa Cell Function in Polycystic Ovary Syndrome and Normal Women

2006 ◽  
Vol 91 (8) ◽  
pp. 2920-2925 ◽  
Author(s):  
Deborah S. Wachs ◽  
Mickey S. Coffler ◽  
Pamela J. Malcom ◽  
R. Jeffrey Chang
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Granulosa Cell ◽  
Functional Capacity ◽  
Cell Function ◽  
Polycystic Ovary ◽  
Academic Medical Center ◽  
Inhibin B ◽  
Ovary Syndrome ◽  
Inhibin A ◽  
Normal Women

Abstract Context: Follicular phase secretion of inhibin B, like that of estradiol (E2), correlates with the quantity and quality of developing follicles. However, it has not been established whether inhibin B responses to gonadotropin stimulation parallel those of E2 as a reflection of granulosa cell functional capacity. Objective: Our objective was to determine whether inhibin B responses to FSH stimulation are similar to those of E2 in women with polycystic ovary syndrome (PCOS) and normal women. Design and Setting: We conducted a prospective study to compare ovarian responses in two groups of women at a general clinical research center in a tertiary academic medical center. Patients: Women with PCOS, 18–35 yr (n = 19), and normal ovulatory controls, 18–35 yr (n = 7), were recruited for study. Interventions: Serum samples were measured over a 24-h period after an iv injection of recombinant human FSH, 150 IU. Main Outcome Measures: Serum E2, inhibin A, and inhibin B responses after FSH administration were assessed. Results: In PCOS women, the 24-h production of inhibin B and E2 after FSH was significantly greater than that of normal controls. Within the PCOS group, the fold change in inhibin B was significantly greater than that of E2. Inhibin A responses between groups were similar and of markedly lower magnitude. Conclusions: FSH-stimulated inhibin B responses may be employed to assess the functional capacity of granulosa cells in PCOS and normal women.

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