Effects of chromium picolinate supplementation on insulin sensitivity, serum lipids, and body composition in healthy, nonobese, older men and women.

BACKGROUND: Chromium is an essential nutrient required for carbohydrate and lipid metabolism. Chromium supplementation in humans has been reported to improve glucose metabolism and improve serum lipid parameters and to reduce body fat; parameters that worsen with aging. As a result, chromium picolinate has been widely promoted as a health aid for the general population. The purpose of the study was to examine the effects of chromium supplementation on insulin sensitivity, serum lipids, and body composition in nonobese, healthy men and women of advanced age. METHODS: A randomized, double-blind, placebo-controlled study with 19 subjects (9 men and 10 women), aged 63-77, were given either chromium picolinate, 1,000 microg/d, or a placebo for 8 weeks. Serum lipids were measured at baseline and 8 weeks. Insulin sensitivity and body composition were measured with the minimal-model intravenous glucose tolerance test and dual-energy x-ray absorptiometry scan, respectively, at baseline and after 8 weeks of chromium or placebo supplementation. RESULTS: No significant change in serum lipids, insulin sensitivity, or body composition was observed in the chromium group compared with the placebo group. CONCLUSIONS: Chromium picolinate supplementation alone does not appear to improve insulin sensitivity, serum lipids, or change body composition in nonobese, healthy men and women of advanced age.

The insulin-like growth factor system in the GT1-7 GnRH neuronal cell line.

Evidence suggests that insulin-like growth factors (IGFs; IGF-I and IGF-II) are involved in the regulation of reproductive function including the development of the gonadotropin-releasing hormone (GnRH) neuronal system and the modulation of GnRH secretory activities. To further characterize the regulatory role of the IGF system on GnRH neuronal function, we have examined the gene expression of IGF-I, IGF-II, IGF-I receptor (IGF-IR), and IGF-binding proteins (IGFBPs) in a GnRH neuronal cell line (GT1-7 cells). The relative effects of IGFs and insulin on GnRH secretion by these cells was also investigated. RT-PCR analysis demonstrated IGF-I, IGF-II and IGF-IR mRNAs in GT1-7 cells. The mRNAs for IGFBP-2, -3, -4, -5 and -6 but not IGFBP-1 were also detected. Immunoreactive protein bands for IGFBP-2, -4 and -5 but not for other IGFBPs were demonstrated by Western blot with IGFBP-5 appearing to be the most abundant IGFBP secreted by GT1-7 cells. IGFBP-5 production by GT1-7 cells was stimulated by both IGF-I and IGF-II in a dose-dependent manner with approximately equal potency, whereas insulin caused no significant effect. GnRH secretion by GT1-7 cells treated with IGF-I or IGF-II but not insulin showed an increase (80-100%) at 2 h of treatment followed by a decrease (46%) at 6 h that continued up to 24 h. We conclude that the expression of IGFs, IGF-IR and IGFBPs and their interactions in the regulation of GnRH secretion by GT1-7 cells as demonstrated by our study provide a basis for an autocrine regulatory role for the IGF system in GnRH neuronal secretory activities.

Effects of lifestyle and body composition on the ovary.

Reduction of metabolic fuel availability below the critical level by food restriction or increased expenditure is appropriately accompanied by activations of multiple neuroendocrine-metabolic changes resulting in anovulation and amenorrhea, an important device for endogenous hypothalamic contraception. This reproductive strategy in women is required because of the enormous nutritional demand for reproductive success.

Melatonin enhances cortisol levels in aged women: reversible by estrogens.

The administration of melatonin increases cortisol levels in postmenopausal women. Aging and hypoestrogenism are believed to impair the regulation of the hypothalamo-pituitary-adrenal axis and may participate in the determination of this altered response. In this study the implications of hypoestrogenism were tested. Seven postmenopausal women were studied. At 08.00 hr for 2 consecutive days, each woman received randomly and in a double blind fashion a pill of placebo or melatonin (100 mg). Serum melatonin and cortisol levels were evaluated at 20 min intervals, for 48 hr. Measurements were performed in the same subjects both during no estrogen supplementation and at least two cycles of conjugated estrogens administration (0.625 mg/day). During estrogen supplementation, postmenopausal women showed slightly lower cortisol levels at lunch and early night (20.00-01.00 hr). The onset of the nocturnal melatonin rise was not modified, but that of cortisol was delayed of about 60 min (P < 0.02). The administration of melatonin elicited a marked increase in daytime cortisol levels in postmenopausal women (P < 0.02), but this stimulus completely disappeared during estrogen administration. Mean nighttime (20.00-08.00 hr) cortisol levels were not modified by daytime administration of melatonin. The present data reveal that in aged postmenopausal women, reversal of hypoestrogenism, resulting from supplemental estrogens, may improve the regulation of the hypothalamopituitary-adrenal axis.

Female hypogonadotropic hypogonadism. Hypothalamic amenorrhea syndrome.

The neuroendocrine-metabolic repertoire governing the reproductive cyclicity in women can be interrupted by a variety of social, environmental, nutritional, and psychological aberrations. Clinical conditions including exercise-related and psychogenic amenorrhea, and desynchronization of biological rhythms in the development of hypothalamic gonadotropin-releasing hormone dysfunction are discussed. Clinical and laboratory evaluations and modes of management are presented.

Acceleration of luteinizing hormone pulse frequency in functional hypothalamic amenorrhea by dopaminergic blockade.

A constellation of neuroendocrine secretory aberrations, including reduced LH pulse frequency and PRL concentrations, has been documented in women with functional hypothalamic amenorrhea (FHA). As pituitary function was preserved, these aberrations were attributed to an alteration in hypothalamic neuromodulation. To investigate the participation of the dopaminergic system in the genesis of the reduced LH pulse frequency and suppressed PRL levels in FHA, we studied six women with FHA and six cyclic women in the early follicular phase by obtaining blood samples at 15-min intervals for 48 h during sequential 24-h infusions of saline and a dopamine receptor blocker, metoclopramide (MCP). A hypothalamic vs. pituitary site of action was inferred from the pulsatility characteristics. MCP consistently elicited an increase in the LH pulse frequency in the women with FHA [7.3 +/- 1.2 (+/- SE) to 10.5 +/- 1.3 pulses/24 h; P less than 0.005]. In contrast, the eumenorrheic women did not show a significant change in LH pulse frequency in response to MCP (15.2 +/- 1.0 to 14.3 +/- 0.9 pulses/24 h). While the PRL concentrations were significantly lower in the FHA group during the infusion of saline (P less than 0.001) and MCP (P less than 0.005), the relative increases in PRL during MCP were similar in both groups. The acceleration of LH pulse frequency by blockade of dopamine receptors implies that there is increased hypothalamic dopaminergic inhibition of GnRH pulse frequency in women with FHA.

Altered waveform of plasma nocturnal melatonin secretion in premenstrual depression.

The nocturnal secretion of plasma melatonin was determined under dim to dark conditions in eight patients with prospectively confirmed premenstrual syndrome and in eight age- and menstrual cycle phase-matched normal control subjects. Plasma samples for melatonin were collected every 30 minutes from 6 PM to 9 AM during the early follicular, late follicular, midluteal and late luteal phases of the menstrual cycle. Compared with normal controls, patients with premenstrual syndrome had an earlier (phase-advanced) offset of melatonin secretion, which contributed to a shorter secretion duration and a decreased area under the curve. No statistically significant differences were found between women with premenstrual syndrome and normal controls for melatonin onset or peak concentration, or for estradiol or progesterone levels. The data demonstrate that women with premenstrual syndrome have chronobiological abnormalities of melatonin secretion. The fact that these patients respond to treatments that affect circadian physiology, such as sleep deprivation and phototherapy, suggests that circadian abnormalities may contribute to the pathogenesis of premenstrual syndrome.

Pituitary function in isolated gonadotrophin deficiency.

Hypothalamic-pituitary function was assessed in 24 individuals with isolated gonadotrophin deficiency (IGD). Thirteen had normal olfaction (Group I) while 11 (Group II) had anosmia (Kallmann's syndrome). In response to a 10 micrograms intravenous (i.v.) bolus of GnRH, the minimal dose required to evoke a consistent gonadotrophin response in normal subjects, the patients responded with significant LH and FSH increases over baseline (P less than 0.01). In Group II patients, large doses (150 micrograms) of GnRH, which elicit maximal release of gonadotrophin in normal subjects did not increase gonadotrophin release beyond that produced by a 10 micrograms bolus. In response to two 10 micrograms GnRH doses, at times 0 and 120 min, the IGD patients responded with similar LH increases to both boluses (both P less than 0.01 compared to baseline). The maximal PRL responses to arginine infusion and to TRH in the male patients were similar to those of normal males. However, in the IGD females, the PRL response to TRH was less than in normal females. The TSH responses to TRH in IGD males and females were similar to each other and similar to normal. The IGD male GH response to arginine infusion was comparable to that in normal males. We conclude that (1) IGD patients appear to retain minimal endogenous GnRH secretion so that the IGD pituitary responds to a minimal dose of GnRH without priming; (2) IGD is a heterogeneous syndrome in which affected individuals with and without normal olfaction represent parts of the spectrum of the same disease; and (3) except for the PRL response in females, the PRL, TSH and GH responses demonstrate that the IGD pituitaries are largely intact.

Alterations of the adrenocorticotropin-cortisol axis in normal weight bulimic women: evidence for a central mechanism.

We studied pituitary-adrenal function in eight women with normal weight bulimia and seven normal women by measuring plasma ACTH and serum cortisol levels at 20-min intervals for 24 h and the responses to human CRH (hCRH) and to a noon meal. The bulimic women had increased 24-h transverse mean plasma ACTH [1.09 +/- 0.06 (+/- SE) vs. 0.75 +/- 0.14 pmol/L; P less than 0.05] and serum cortisol (235 +/- 21 vs. 152 +/- 9 nmol/L; P less than 0.005) concentrations. While the 24-h ACTH and cortisol pulse frequencies were unaltered, the bulimic women had higher (P less than 0.05) mean peak ACTH (1.46 +/- 0.09 vs. 1.03 +/- 0.15 pmol/L) and cortisol values (331 +/- 33 vs. 239 +/- 17 nmol/L). Despite having higher mean and peak plasma ACTH and serum cortisol values, the bulimic women had a blunted response of both ACTH (P less than 0.001) and cortisol (P less than 0.005) to hCRH, which included a lower mean maximal plasma ACTH response, decreased (P less than 0.05) integrated area under the ACTH response curve (161 +/- 12 vs. 231 +/- 23 pmol/min.L), a lower (P less than 0.05) maximum cortisol response (284 +/- 35 vs. 413 +/- 19 nmol/L), and decreased (P less than 0.05) area under the cortisol curve (11.1 +/- 1.9 vs. 15.9 +/- 1.3 X 10(3) nmol/min.L). The circadian variations of both ACTH and cortisol were maintained in the bulimic women; the nadir and acrophase times were similar to those of the normal women. However, the rise in serum cortisol that occurred within 1 h after the lunch meal in the normal women (104 +/- 35 nmol) did not occur in the bulimic women (P less than 0.05). These data demonstrate that marked changes in hypothalamic-pituitary-adrenal function occur in bulimia in the absence of weight disturbance and suggest central activation of CRH and/or synergistic factors as well as alterations in signals from gut to brain in this syndrome.

Neuroendocrine aberrations in women with functional hypothalamic amenorrhea.

To further elucidate the neuroendocrine regulation of anterior pituitary function in women with functional hypothalamic amenorrhea (FHA), we measured serum LH, FSH, cortisol, GH, PRL, TSH concentrations simultaneously at frequent intervals for 24 h in 10 women with FHA and in 10 normal women in the early follicular phase (NC). Using the same data, we separately analyzed the cortisol-PRL responses to meals in these women. In addition, the pituitary responses to the simultaneous administration of GnRH, CRH, GHRH, and TRH were assessed in 6 FHA and 6 normal women. The 24-h secretory pattern of each hormone except TSH was altered in the women with FHA. Compared to normal women, the women with FHA had a 53% reduction in LH pulse frequency (P less than 0.0001) and an increase in the mean LH interpulse interval (P less than 0.01); LH pulse amplitude was similar. The 24-h integrated LH and FSH concentrations were reduced 30% (P = 0.01) and 19% (P less than 0.05), respectively. The mean cortisol pulse frequency, amplitude, interpulse interval, and duration were similar in the two groups, but integrated 24-h cortisol secretion was 17% higher in the women with FHA (P less than 0.05). This increase was greatest from 0800-1600 h, but also was present from 2400-0800 h. Cortisol levels were similar in the two groups from 1600-2400 h, resulting in an amplified circadian excursion. In contrast, the 24-h serum PRL levels were markedly lower at all times (P less than 0.0001), the sleep-associated nocturnal elevation of PRL was proportionately greater (P less than 0.05), and serum GH levels were increased at night in the women with FHA (P less than 0.05). Although 24-h serum TSH levels were similar at all times, T3 (P less than 0.05) and T4 (P less than 0.01) levels were lower in the FHA women. The responses of serum cortisol to lunch (P less than 0.01) and dinner (P less than 0.05) and those of serum PRL to lunch (P less than 0.05) and dinner (P = 0.08) were blunted in the women with FHA. Pituitary hormone increments in response to the simultaneous iv administration of GnRH, CRH, GHRH, and TRH were similar in the two groups, except for a blunted PRL response to TRH in the women with FHA (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Human fetal hypothalamic GnRH neurosecretion: dopaminergic regulation in vitro.

An in-vitro perifusion system was used to investigate GnRH release from fetal (21-23 weeks gestation) human hypothalami in response to dopamine (DA) and the DA receptor antagonist haloperidol. Administration of 1 mumol/l DA during five perifusions in which 1 mumol/l haloperidol was added to the medium failed to alter basal GnRH release. In contrast DA evoked a rapid and sustained 95.8 +/- 20.3% increase (P less than 0.01) in GnRH release during five matching perifusions with medium containing the alpha-adrenergic antagonist phentolamine. While exposure to 0.01 mumol/l DA failed to alter basal GnRH release during three perifusions, 0.1 mumol/l DA elicited a 145.7 +/- 65.2% increase (P less than 0.05) in GnRH release in three matching perifusions, indicating a dose-dependent effect. These studies demonstrate that DA can stimulate in-vitro release of GnRH from the mid-gestation fetal human hypothalamus by a DA receptor mediated mechanism.

Calcium-regulating hormones across the menstrual cycle.

Midcycle elevations of serum PTH, calcitonin (CT), and 1,25-dihydroxyvitamin D [1,25-(OH)2D] in women have been reported. To examine the effects of cyclic changes in ovarian steroid secretion on calcitropic hormone concentrations, we used a cytoreceptor assay for 1,25-(OH)2D and homologous RIAs for PTH and CT to measure these hormones in daily blood samples obtained from six women throughout the menstrual cycle. Significant changes in serum PTH, CT, 1,25-(OH)2D, calcium, and phosphorus concentrations during the cycle were not found; transverse means (+/- SE) were 101 +/- 3.5 pg/ml for PTH, 30.8 +/- 1.8 pg/ml for CT, and 40.1 +/- 1.7 pg/ml for 1,25-(OH)2D. In addition, CT reserve was assessed by calcium infusion (3 mg/kg, iv, in 10 min) during the early and late follicular and midluteal phases of the cycle. Although serum CT increased significantly (P less than 0.01) after calcium infusion, the mean (+/- SE) increment (23.2 +/- 2.2 pg/ml) did not significantly differ in the three phases of the cycle (early follicular, 23.8 +/- 4.0; late follicular, 23.3 +/- 3.4; midluteal, 22.5 +/- 4.1). Our data do not support previous reports of midcycle elevations in serum PTH, CT, and 1,25-(OH)2D concentrations, and we conclude that serum concentrations of the calcitropic hormones do not significantly vary during the menstrual cycle.

Gonadotropin-releasing hormone neurosecretion in the human hypothalamus: in vitro regulation by dopamine.

An in vitro perifusion system was used to investigate GnRH release from adult human hypothalami in response to dopamine (DA) and the DA receptor antagonist haloperidol (HAL). Administration of a 1-microM pulse of DA consistently elicited a mean +/- SE 218 +/- 59% increase (P less than 0.05; n = 5) in GnRH release, whereas 1 microM HAL had no effect. Administration of 1 microM DA during three perifusions in which 1 microM HAL was added to the medium failed to alter basal GnRH release. In contrast, DA did evoke an acute 98 +/- 39% increase (P less than 0.06) in GnRH release during three matching perifusions with medium containing the alpha-adrenergic antagonist phentolamine. These studies demonstrate that DA can stimulate in vitro release of GnRH from the adult human hypothalamus by a DA receptor-mediated mechanism.

Evidence for a hypothalamic site of action of clomiphene citrate in women.

To examine the site of action of clomiphene citrate (CC), LH and FSH pulsatile amplitude, frequency, and responsiveness to GnRH (10 micrograms, iv) were studied in 11 women during the early follicular phase of the menstrual cycle. Six women received CC (150 mg/day) on cycle days 2, 3, and 4, while 5 women received placebo tablets. Blood samples were drawn at 10-min intervals for 8 h before and after the treatment regimen on cycle days 2 and 5, respectively. All women treated with CC had multiple follicular development, as determined by ultrasound. Peripheral levels of estradiol did not change after CC treatment, while progesterone levels decreased slightly. Mean levels of LH increased from 7.5 +/- 0.9 (+/- SEM) to 10.7 +/- 1.4 mIU/ml (P less than 0.05), and FSH increased from 6.7 +/- 0.9 to 10.1 +/- 0.9 mIU/ml (P less than 0.01). After exposure to CC, the pulse frequency of LH during an 8-h period increased significantly (3.3 +/- 0.7 on day 2 vs. 6.8 +/- 0.8 on day 5; P less than 0.01), while the pulse frequency of FSH increased from 3.8 +/- 0.6 to 5 +/- 1.4, as determined by computer pulse analyses. The pulse amplitude of LH and FSH was not significantly altered. In the placebo-treated group, neither pulse amplitude nor pulse frequency changed significantly between cycle days 2 and 5. Pituitary sensitivity to exogenous GnRH did not change after CC treatment. Since the pulsatile frequency of LH is governed by hypothalamic influences, these findings provide compelling evidence for a hypothalamic site of action for CC, probably by inducing an increase in the frequency of GnRH secretion.

Neuroendocrinology of opioid peptides and their role in the control of gonadotropin and prolactin secretion.

Substantial evidence now exists to indicate that the endogenous hypothalamic opioidergic mechanism(s) represents one of the important controlling systems for release of gonadotropin-releasing hormone. Modulations of frequency and amplitude of the secretory activity of gonadotropin-releasing hormone appears to be mediated through an inhibitory action of endogenous opioids, and the functional coupling of the opioidergic and gonadotropin-releasing hormone systems is an ovarian steroid-dependent event. There is also evidence to implicate suprahypothalamic mechanism(s) that enhance endogenous opioid inhibition of secretion of gonadotropin-releasing hormone. Although exogenous opioid peptides and their synthetic analogs consistently induce the secretion of prolactin, blockade of opioid receptors in humans by naloxone failed to elicit a decrement in the levels of prolactin under a variety of conditions. On the contrary, naloxone induced a remarkable increment in the secretion of prolactin via an increased frequency of pulsatile release which is synchronized with pulses of luteinizing hormone. These observations suggest that a common neuroendocrine mechanism is involved in the opioidergic control of the secretion of both luteinizing hormone and prolactin in women.

Evidence for decreased endogenous dopamine and opioid inhibitory influences on LH secretion in polycystic ovary syndrome.

The inhibitory role of the dopaminergic and opioidergic mechanisms in the control of LH secretion in patients with polycystic ovary syndrome (PCO) was evaluated. The administration of an opiate receptor antagonist, naloxone, of a dopamine receptor antagonist, metoclopramide, or of human synthetic beta h-endorphin, were unable to alter LH secretory activity in patients with PCO. Since identical doses of these antagonists and the opiate agonist have elicited respectively a rise and fall of LH levels in normal cycling women, these findings suggest that an underlying hypothalamic component of defect in endogenous dopamine and opioid control may be responsible for the inappropriate gonadotrophin secretion in this syndrome.

Progesterone and 20 alpha-hydroxyprogesterone stimulate the in vitro release of GnRH by the isolated mediobasal hypothalamus.

An in vitro perifusion system was used to investigate the effect of progesterone (P4) and 20 alpha-hydroxyprogesterone (20 alpha-OHP) on the release of GnRH from isolated hypothalamic tissue of the adult ovariectomized estradiol-17 beta primed rat. Pulse delivery of P4 stimulated GnRH release not only from the isolated mediobasal hypothalamus-anterior hypothalamus-preoptic area (MBH-AHPOA) complex but also from the MBH alone. Release of GnRH from the MBH was also increased by 20 alpha-OHP. These results suggest that the in vivo increase of circulating P4 or 20 alpha-OHP associated with the initiation of the preovulatory LH surge may play a role in regulating the timing or amplitude of this surge by directly stimulating the release of GnRH from the MBH.