Disordered Adrenocorticotropin Secretion in Women with Major Depression

Context: Major depression is accompanied by activation of the hypothalamic pituitary axis and evidence of abnormalities in circadian and ultradian hormone rhythms. In addition, diminished negative feedback of cortisol on adrenocorticotropin (ACTH) has been found. Objective: To compare ACTH and cortisol hormonal patterns in women with major depression to normal control women. Design: Case control study. Setting: General-Clinical Research Center Patients and Other Participants: Healthy, drug free, premenopausal women with major depression and age and menstrual cycle day matched healthy control women. Main Outcome Measure: ACTH and cortisol data measured every 10 minutes for 24H analyzed with approximate entropy and cross-approximate entropy to determine orderliness of hormone secretion and relationship between ACTH and cortisol in terms of feed forward and feedback synchrony. Results: Depressed women manifested increased approximate entropy, indicating more disorderly secretion, of ACTH and elevated forward cross-approximate entropy of ACTH on cortisol, denoting unopposed ACTH drive. Conclusions: These data support other evidence of hormonal rhythm abnormalities in depression and are compatible with accentuated feedforward drive by ACTHNIMH MH 50030 NIDK DK 06717Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49485/2/YoungandVeldhuis.pd

Actions of NPY, and its Y1 and Y2 receptors on pulsatile growth hormone secretion during the fed and fasted state

The hypothalamic NPY system plays an important role in regulating food intake and energy expenditure. Different biological actions of NPY are assigned to NPY receptor subtypes. Recent studies demonstrated a close relationship between food intake and growth hormone (GH) secretion; however, the mechanism through which endogenous NPY modulates GH release remains unknown. Moreover, conclusive evidence demonstrating a role for NPY and Y-receptors in regulating the endogenous pulsatile release of GH does not exist. We used genetically modified mice (germline Npy, Y1, and Y2 receptor knock-out mice) to assess pulsatile GH secretion under both fed and fasting conditions. Deletion of NPY did not impact fed GH release; however, it reversed the fasting-induced suppression of pulsatile GH secretion. The recovery of GH secretion was associated with a reduction in hypothalamic somatotropin release inhibiting factor (Srif; somatostatin) mRNA expression. Moreover, observations revealed a differential role for Y1 and Y2 receptors, wherein the postsynaptic Y1 receptor suppresses GH secretion in fasting. In contrast, the presynaptic Y2 receptor maintains normal GH output under long-term ad libitum-fed conditions. These data demonstrate an integrated neural circuit that modulates GH release relative to food intake, and provide essential information to address the differential roles of Y1 and Y2 receptors in regulating the release of GH under fed and fasting states

Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men

OBJECTIVE : Patients with mutations of neurokinin B (NKB) and its receptor show hypogonadotrophic hypogonadism, but there is little evidence for the importance of this pathway in reproductive function in normal men, or its functional hierarchy with kisspeptin. DESIGN : An open label study wherein men (n = 6) were administered the NK3R antagonist MLE4901 40 mg orally twice a day for 7 days. Kisspeptin-10 (0.3 μg/kg iv bolus) was given before and on day 7 of NK3R antagonist treatment. PATIENTS : Subjects were healthy men. MEASUREMENTS : Reproductive hormones were measured before and during the NK3R antagonist administration, including frequent sampling on two occasions for analysis of pulsatile LH secretion. RESULTS : LH, FSH and testosterone secretion were decreased during NK3R antagonist administration. LH showed a biphasic response, being reduced after 24 hours of treatment (4.5 ± 0.6 IU/L pretreatment to 1.7 ± 0.2 IU/L, P < .05), with partial recovery thereafter, but it was again decreased on day 7 (2.5 ± 0.6 IU/L, P < .05 vs pretreatment). FSH secretion was also suppressed, with a similar temporal pattern to that of LH. Testosterone secretion was decreased from 24 hours (18.4 ± 1.6 pretreatment vs 5.6 ± 1.5 nmol/L, P < .01) and remained suppressed throughout the treatment period. Analysis of LH pulsatility showed that both basal and pulsatile LH secretion were markedly suppressed but there was no detected change in LH pulse frequency. Kisspeptin-10 stimulated LH secretion, with similar responses before and during NK3R antagonist administration. CONCLUSIONS : These data demonstrate a central role for NKB/NK3R in the physiological regulation of reproductive function in men, and that this is functionally upstream of kisspeptin-mediated GnRH secretion.The Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative STMTI and MRC grant G0701682 to RAA and RPMhttp://wileyonlinelibrary.com/journal/cenam2017Mammal Research Institut

Pathophysiology of Male Hypogonadism Associated with Endogenous Hyperestrogenism — Evidence for Dual Defects in the Gonadal Axis

FEMINIZING tumors of the adrenal cortex are associated with symptoms that presumably reflect the combined effects of estrogen excess and androgen deficiency — gynecomastia, diminished libido, attenuated potency, and testicular and prostatic atrophy.1 2 3 4 5 Although such tumors are extremely rare, they provide a unique opportunity to appraise the nature of endogenous estrogen action on the gonadal axis in men. In principle, the pathophysiologic effects of estrogen hypersecretion could be expressed at the level of either the Leydig cell or the hypothalamic–pituitary axis (or both), with consequent suppression of androgen production. In the present studies, we investigated the endocrine consequences of reversible endogenous estrogen excess in a patient with a surgically resectable feminizing adrenal cortical tumor

Neurokinin B Receptor Antagonism in Women with Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial

Context: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high secretion levels of LH and T. Currently, there is no treatment licensed specifically for PCOS. Objective: The objective of this study was to investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and T concentrations and thereby presenting a novel therapeutic approach to the management of PCOS. Design: This study is a double-blind, double-dummy, placebo-controlled, phase 2 trial. Settings: University hospitals and private clinical research centers were included. Participants: Women with PCOS aged 18–45 years participated. Intervention: Intervention included AZD4901 (a specific neurokinin-3 [NK3] receptor antagonist) at a dose of 20, 40, or 80 mg/day or matching placebo for 28 days. Main Outcome Measure: Change from baseline in the area under the LH serum concentration–time curve over 8 hours (area under the curve) on day 7 relative to placebo was measured. Results: Of a total 67 randomized patients, 65 were evaluable. On day 7, the following baseline-adjusted changes relative to placebo were observed in patients receiving AZD4901 80 mg/day: 1) a reduction of 52.0% (95% confidence interval [CI], 29.6–67.3%) in LH area under the curve; 2) a reduction of 28.7% (95% CI, 13.9–40.9%) in total T concentration; and 3) a reduction of 3.55 LH pulses/8 hours (95% CI, 2.0–5.1) (all nominal P &amp;lt; .05). Conclusions: The NK3 receptor antagonist AZD4901 specifically reduced LH pulse frequency and subsequently serum LH and T concentrations, thus presenting NK3 receptor antagonism as a potential approach to treating the central neuroendocrine pathophysiology of PCOS. </jats:sec

Acute and short-term administration of a sulfonylurea (gliclazide) increases pulsatile insulin secretion in type 2 diabetes

W cukrzycy typu 2 występują zaburzenia rytmu wydzielania insuliny, który w warunkach prawidłowych ma charakter pulsacji o wysokiej częstotliwości. W leczeniu cukrzycy powszechnie stosuje się pochodne sulfonylomocznika, jednak dotychczas nie ustalono ostatecznie ich wpływu na sposób uwalniania hormonu. Celem przedstawionego badania było określenie efektu jednorazowej dawki i 5-tygodniowego podawania pochodnej sulfonylomocznika (gliklazydu) na dynamikę wydzielania insuliny u chorych na cukrzycę typu 2. Badanie było podwójnie ślepą, kontrolowaną placebo, skrzyżowaną próbą prospektywną, do której włączono 10 chorych na cukrzycę typu 2 (wiek 53 &plusmn; 2 lata, BMI 27,5 &plusmn; 1,1 kg/m2, glikemia na czczo 9,8 &plusmn; 0,8 mmol/l, HbA1c 7,5 &plusmn; 0,3%). Otrzymywali oni 40&#8211;80 mg gliklazydu lub placebo 2 razy dziennie przez 5 tygodni, po 6-tygodniowym okresie przerwy w podawaniu leków. Pomiary insulinemii wykonywano w odstępach minutowych przez 75 minut: 1) w warunkach wyjściowych; 2) 3 godziny po podaniu pierwszej dawki leku (80 mg gliklazydu), przy utrzymaniu glikemii na poziomie wyjściowym; 3) po 5 tygodniach podawania leku i 4) po 5 tygodniach podawania leku, przy utrzymaniu glikemii jak w warunkach wyjściowych (wzrost 5-tygodniowy). W celu oceny ilościowej charakteru pulsacji i regularności wydzielania insuliny stężenia insuliny w przedziałach czasowych poddano analizie metodą spektralną, autokorelacji, dekonwolucji oraz entropii przybliżonej (ApEn, approximate entropy). Podane wartości p dotyczą porównania działania gliklazydu i placebo; wyniki przedstawiono jako średnie &plusmn; SE. Glikemia na czczo obniżyła się po leczeniu gliklazydem (poziom wyjściowy vs. 5 tygodni: gliklazyd 10,0 &plusmn; 0,9 vs. 7,8 &plusmn; 0,6 mmol/l; placebo 10,0 &plusmn; 0,8 vs. 11,0 &plusmn; 0,9 mmol/l, p = 0,001). Stężenia wydzielanej insuliny zwiększyły się (wyjściowe vs. jednorazowe podanie: gliklazyd 43,0 &plusmn; 12,0 vs. 61,0 &plusmn;17,0 pmol/l/puls; placebo 36,1 &plusmn; 8,4 vs. 30,3 &plusmn; 7,4 pmol/l/puls, p = 0,047; wzrost 5-tygodniowy: gliklazyd vs. placebo 49,7 &plusmn; 13,3 vs. 37,1 &plusmn; 9,5 pmol/l/puls, p < 0,05) z podobnym wzrostem amplitudy wydzielania. Podstawowe (niepulsacyjne) wydzielanie insuliny również było podwyższone (wyjściowo vs. jednorazowe podanie: gliklazyd 8,5 &plusmn; 2,2 vs. 16,7 &plusmn; 4,3 pmol/l/puls; placebo 5,9 &plusmn; 0,9 vs. 7,2 &plusmn; 0,9 pmol/l/puls, p = 0,03; wzrost 5-tygodniowy: gliklazyd vs. placebo 12,2 &plusmn; 2,5 vs. 9,4 &plusmn; 2,1 pmol/l/puls, p = 0,016). Częstotliwość i regularność pulsów wydzielania insuliny nie zmieniły się istotnie po zastosowaniu terapii. Zaobserwowano jednak poprawę regularności pulsów po jednorazowym podaniu leku przy badaniu poszczególnych chorych, co oznaczano metodą ApEn, oraz zmniejszenie glikemii na czczo w czasie krótkoterminowego, 5-tygodniowego leczenia gliklazydem (r = 0,74, p = 0,014; r = 0,77, p = 0,009, odpowiednio dla szczegółowej i ogólnej ApEn). Podsumowując, należy stwierdzić, że pochodna sulfonylomocznika &#8212; gliklazyd &#8212; zwiększa wydzielanie insuliny, nasilając zarówno pulsacyjną, jak i podstawową sekrecję insuliny bez wpływu na częstotliwość i regularność pulsów. Dane uzyskane w badaniu sugerują, że może istnieć związek między krótkoterminową poprawą glikemii i poprawą regularności procesu wydzielania insuliny in vivo.The high-frequency oscillatory pattern of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatment of this disease, their effect on insulin release patterns is not well established. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin secretory dynamics in type 2 diabetic patients. To this end, 10 patients with type 2 diabetes (age 53 &plusmn; 2 years, BMI 27.5 &plusmn; 1.1 kg/m2, fasting plasma glucose 9.8 &plusmn; 0.8 mmol/l, HbA1c 7.5 &plusmn; 0.3%) were studied in a double-blind placebo-controlled prospective crossover design. Patients received 40&#8211;80 mg gliclazide/placebo twice daily for 5 weeks with a 6-week washout period intervening. Insulin pulsatility was assessed by 1-min interval blood sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h after the first dose (80 mg) of gliclazide (acute) with the plasma glucose concentration clamped at the baseline value, 3) after 5 weeks of treatment (5 weeks), and 4) after 5 weeks of treatment with the plasma glucose concentration clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by deconvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gliclazide versus placebo; results are means &plusmn; SE. Fasting plasma glucose was reduced after gliclazide treatment (baseline vs. 5 weeks: gliclazide, 10.0 &plusmn; 0.9 vs. 7.8 &plusmn; 0.6 mmol/l; placebo, 10.0 &plusmn; 0.8 vs. 11.0 &plusmn; 0.9 mmol/l, P = 0.001). Insulin secretory burst mass was increased (baseline vs. acute: gliclazide, 43.0 &plusmn; 12.0 vs. 61.0 &plusmn; 17.0 pmol × l-1 × pulse-1; placebo, 36.1 &plusmn; 8.4 vs. 30.3 &plusmn; 7.4 pmol × l-1 × pulse-1, P = 0.047; 5 weekselevated: gliclazide vs. placebo, 49.7 &plusmn; 13.3 vs. 37.1 &plusmn; 9.5 pmol × l-1 × pulse-1, P < 0.05) with a similar rise in burst amplitude. Basal (i.e., nonoscillatory) insulin secretion also increased (baseline vs. acute: gliclazide, 8.5 &plusmn; 2.2 vs. 16.7 &plusmn; 4.3 pmol × l-1 x pulse&#8211;1; placebo, 5.9 &plusmn; 0.9 vs. 7.2 &plusmn; &plusmn; 0.9 pmol × l-1 × pulse-1, P = 0.03; 5 weeks-elevated: gliclazide vs. placebo, 12.2 &plusmn; 2.5 vs. 9.4 &plusmn; 2.1 pmol × l-1 × pulse-1, P = 0.016). The frequency and regularity of insulin pulses were not modified significantly by the antidiabetic therapy. There was, however, a correlation between individual values for the acute improvement of regularity, as measured by ApEn, and the decrease in fasting plasma glucose during short-term (5-week) gliclazide treatment (r = 0.74, P = 0.014, and r = 0.77, P = 0.009, for fine and coarse ApEn, respectively). In conclusion, the sulfonylurea agent gliclazide augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion without changing secretory burst frequency or regularity. The data suggest a possible relationship between the improvement in short-term glycemic control and the acute improvement of regularity of the in vivo insulin release process

Pathophysiological features of the pulsatile secretion of biologically active luteinizing hormone in man

The development of an in vitro bioassay of high specificity, sensitivity and precision for the measurement of low circulating concentrations of biologically active glycoprotein hormones has offered exciting new insights into the in vivo secretion and metabolic clearance of luteinizing hormone (LH) in various pathophysiological states. Moreover, the most recent combined application of the rat interstitial cell testosterone (RICT) bioassay and a novel multiple-parameter deonvolution model has allowed investigators to dissect plasma concentration profiles of bioactive LH into defined secretory bursts, which have numerically explicit amplitudes, locations in time, and durations, and are acted upon by detenninable subject- and study-specific endogenous metabolic clearance rates. Here, we have: (i) reviewed the ability of the endogenous GnRH pulse signal to regulate the in vivo secretion of biologically active LH molecules as assessed in the RICT and by deconvolution mechanics; (ii) demonstrated that low-dose exogenous GnRH pulses effectively mimic spontaneous bioactive LH pulsatility; (iii) investigated the role of endogenous androgen and estrogen in modulating bioactive gonadotropin secretion in men and women; and (iv) described significant alterations in endogenous LH bioactivity in puberty and healthy aging.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27746/1/0000138.pd

Interactions between neurokinin B and kisspeptin in mediating estrogen feedback in healthy women

CONTEXT: Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women. OBJECTIVE: To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion. DESIGN: Women were treated with neurokinin-3 receptor (NK3R) antagonist followed by transdermal estradiol to induce LH secretion 48 hours later, with kisspeptin-10 or vehicle infusion during estrogen administration in a 2-way crossover study. SETTING: Clinical research facility. PATIENTS OR OTHER PARTICIPANTS: Healthy females with regular menses. INTERVENTION(S): NK3R antagonist AZD4901 40 mg twice daily orally was taken from cycle day 4–6 for 6 days (n = 10, with 10 no treatment controls). Transdermal estradiol patches (200 μg/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 μg/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle. MAIN OUTCOME MEASURE(S): Plasma gonadotropin and estradiol secretion. RESULTS: After an initial suppression, LH secretion was increased 48 hours after estradiol treatment. Kisspeptin-10 increased LH secretion during the inhibitory phase, and LH remained elevated beyond the discontinuation of kisspeptin-10 infusion. NK3R antagonist decreased LH pulse frequency (0.5 ± 0.2 vs 0.7 ± 0.2 pulses/h, P < .05) and stimulated FSH response to kisspeptin-10 infusion (10.7 ± 11.0 vs 5.0 ± 3.6 IU/L, P < .05) with a nonsignificant rise in LH. The duration of LH response was blunted, with LH being lower at 48 hours (7.5 ± 4.8 vs 15.0 ± 11.4 IU/L, P < .05). CONCLUSIONS: These data demonstrate that NKB signaling regulates GnRH/LH secretion in normal women, and is predominantly proximal to kisspeptin in mediating estrogenic positive and negative feedback on LH secretion