The hypothalamo‐pituitary‐adrenal axis across the normal menstrual cycle and in polycystic ovary syndrome

Stewart, Paul M.; Perm, R.; Holder, Roger; Parton, Andrew; Ratcliffe, John G.; London, David

doi:10.1111/j.1365-2265.1993.tb00519.x

Cited by 37 publications

(16 citation statements)

References 31 publications

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“…Stewart et al (19) suggested that enhanced clearance of cortisol caused by increased 5␣-reductase activity could lead to a counterregulatory activation of the HPA axis and thus to enhanced adrenal androgen generation. However, they failed to demonstrate an increase in ACTH secretion or pulsatility in a follow-up study (25).…”

Section: Discussionmentioning

confidence: 94%

Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5α-Reductase Activity in Women with Polycystic Ovary Syndrome

Faßnacht

Schlenz

Schneider

et al. 2003

The Journal of Clinical Endocrinology & Metabolism

140

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Hyperandrogenism, a main clinical feature of polycystic ovary syndrome (PCOS), is thought to result from enhanced ovarian and adrenal androgen generation. To investigate the contribution of peripheral steroidogenesis, we used an oral challenge with dehydroepiandrosterone (DHEA) and analyzed its downstream conversion toward androgens in eight women with PCOS (age, 20-32 yr; body mass index, 20-41 kg/m(2)) and eight healthy women matched for age and body mass index. They underwent frequent serum sampling and urine collection for 8 h on three occasions: at baseline, and after 4 d of dexamethasone (Dex; 4 x 0.5 mg/d), followed by ingestion of 100 mg DHEA or placebo. Dex induced similar significant suppression of circulating steroids in both groups. The oral DHEA challenge led to similar significant increases in the area under the concentration-time curve (0-8 h after Dex) of serum DHEA, DHEA sulfate, androstenedione, and testosterone. However, after oral DHEA, PCOS women had significantly higher increases in serum 5 alpha-dihydrotestosterone (P < 0.01), its main metabolite androstanediol glucuronide (P < 0.05), and the 5 alpha-reduced urinary androgen metabolite androsterone (P < 0.05). PCOS women also had significantly higher baseline excretion of 5 alpha-reduced glucocorticoid (P < 0.01) and mineralocorticoid metabolites (P < 0.05). Taken together, these data indicate enhanced peripheral 5 alpha-reductase activity in PCOS. Thus, not only ovary and adrenal, but also liver and peripheral target tissues, significantly contribute to steroid alterations in PCOS.

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Section: Discussionmentioning

confidence: 94%

Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5α-Reductase Activity in Women with Polycystic Ovary Syndrome

Faßnacht

Schlenz

Schneider

et al. 2003

The Journal of Clinical Endocrinology & Metabolism

140

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“…The total 24-h F [55], free F [56], the sensitivity or responsivity of F to ACTH stimulation [48], or the F or ACTH levels across the menstrual cycle [57] are relatively normal in PCOS while the 24-h urine free F concentration appear to be increased [58]. This discrepancy between serum measures of F and the urinary excretion of F suggests that the metabolism of this steroid may be accelerated in PCOS.…”

Section: C) Abnormalities In the Metabolism Of Cortisol In Pcosmentioning

confidence: 99%

The adrenal and polycystic ovary syndrome

Yildiz

Azziz

2007

Rev Endocr Metab Disord

115

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Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders characterized by androgen excess, oligo-ovulation and polycystic ovaries. Although ovaries are the main source of increased androgens in the syndrome, between 20 and 30% of patients with PCOS have adrenal androgen (AA) excess, detectable primarily by elevated dehydroepiandrosterone sulfate (DHEAS) levels. Patients with PCOS demonstrate a generalized hypersecretion of adrenocortical products, basally and in response to ACTH stimulation. The mechanisms of these abnormalities are unclear although AA excess in PCOS is likely a complex trait, modulated by both intrinsic and acquired factors. To date, no specific genetic defects have been identified. The production of AAs in response to ACTH appears to be closely related to altered factors regulating glucose-mediated glucose disposal, increased peripheral metabolism of cortisol, and to a less extent to the effects of extra-adrenal androgens, insulin resistance, hyperinsulinemia or obesity. Finally, DHEAS levels and the response of AAs to ACTH are relatively constant over time and are closely correlated between PCOS patients and their siblings suggesting that this abnormality is an inherited trait in PCOS.

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“…Nonetheless, if the HPA axis were subtly, but chronically, overactive, it could result in subclinical hypertrophy and/or hyperplasia of the zonae reticularis/fasciculata, with a consequent overresponse to ACTH stimulation. In support of this hypothesis, Stewart et al reported that the ACTH pulse frequency was lower in seven women with PCOS than in nine controls (3.6 Ϯ 0.4 vs. 5.9 Ϯ 0.6 pulses/12 h; P Ͻ 0.05), with no change in mean pulse amplitude or level, suggesting some blunting of the HPA axis (8). Nonetheless, changes in the HPA axis may actually reflect primary alterations in adrenocortical biosynthesis, e.g.…”

Section: Fig 4 the Mean (ϯSd) Amentioning

confidence: 92%

“…a gland that intrinsically overresponds to ACTH may result in the compensatory reduction or blunting of the hypothalamic-pituitary response. Hence, although very subtle and minimal defects in hypothalamic-pituitary function may be present in PCOS patients with DHS excess (8,20), it is unlikely that we have missed a significant defect.…”

Section: Fig 4 the Mean (ϯSd) Amentioning

confidence: 99%

Adrenal Androgen Excess in the Polycystic Ovary Syndrome: Sensitivity and Responsivity of the Hypothalamic-Pituitary-Adrenal Axis1

Azziz¹,

Black²,

Hines³

et al. 1998

The Journal of Clinical Endocrinology &Amp; Metabolism

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Over 50% of patients with the polycystic ovary syndrome (PCOS) demonstrate excess levels of adrenal androgens (AAs), particularly dehydroepiandrosterone sulfate (DHS). Nonetheless, the mechanism for the AA excess remains unclear. It has been noted that in PCOS the pituitary and ovarian responses to their respective trophic factors (i.e. GnRH and LH, respectively) are exaggerated. Similarly, we have postulated that excess AAs in PCOS arises from dysfunction of the hypothalamic-pituitary-adrenal axis, due to 1) exaggerated pituitary secretion of ACTH in response to hypothalamic CRH, 2) excess sensitivity/responsivity of AAs to ACTH stimulation, or 3) both. To test this hypothesis we studied 12 PCOS patients with AA excess (HI-DHS; DHS, Ͼ8.1 mol/L or 3000 ng/mL), 12 PCOS patients without AA excess (LO-DHS; DHS, Ͻ7.5 mol/L or 2750 ng/mL), and 11 controls (normal subjects). Each subject underwent an acute 90-min ovine CRH stimulation test (1 g/kg) and an 8-h incremental iv stimulation with ACTH-(1-24) at doses ranging from 20 -2880 ng/1.5 m 2 ⅐h) with a final bolus of 0.25 mg. All patient groups had similar mean body mass indexes and ages, and both tests were performed in the morning during the follicular phase (days 3-10) of the same menstrual cycle, separated by 48 -96 h. During the acute ovine CRH stimulation test, no significant differences in the net maximal response (i.e. change from baseline to peak level) for ACTH, dehydroepiandrosterone (DHA), androstenedione (A 4 ), or cortisol (F) or for the DHA/ACTH, A 4 /ACTH, or F/ACTH ratios was observed. Nonetheless, the net response of DHA/F and the areas under the curve (AUCs) for DHA and DHA/F indicated a greater response for HI-DHS vs. LO-DHS or normal subjects. The AUC for A 4 and A 4 /F and the ⌬A 4 /⌬F ratio (⌬ ϭ net maximum change) indicated that HI-DHS and LO-DHS had similar responses, which were greater than that of the normal subjects, although the difference between LO-DHS patients and normal subjects reached significance only for the AUC of the A 4 response. No difference in the sensitivity (i.e. threshold or minimal stimulatory dose) to ACTH was noted between the groups for any of the steroids measured. Nonetheless, the average dose of ACTH-(1-24) required for a threshold response was higher for DHA than for F and A 4 in all groups. No difference in mean responsivity (slope of response to incremental ACTH stimulation) was observed for DHA and F between study groups, whereas the responsivity of A 4 was higher in HI-DHS patients than in normal or LO-DHS women. The net maximal and the overall (i.e. AUC) responses of DHA were greater for HI-DHS than for normal or LO-DHS women. The response of A 4 and the ⌬A 4 /⌬F ratio were greater for HI-DHS patients than for LO-DHS patients or normal subjects. Alternatively, HI-DHS and LO-DHS patients had similar overall responses (i.e. AUC) for A 4 or A 4 /F, although both were greater than those of normal subjects. The relative differences in response to incremental ACTH stimulation between steroids was consisten...

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The hypothalamo‐pituitary‐adrenal axis across the normal menstrual cycle and in polycystic ovary syndrome

Cited by 37 publications

References 31 publications

Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5α-Reductase Activity in Women with Polycystic Ovary Syndrome

Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5α-Reductase Activity in Women with Polycystic Ovary Syndrome

The adrenal and polycystic ovary syndrome

Adrenal Androgen Excess in the Polycystic Ovary Syndrome: Sensitivity and Responsivity of the Hypothalamic-Pituitary-Adrenal Axis1

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