Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome

BACKGROUND Insulin resistance and increased ovarian cytochrome P450c17α activity are both features of the polycystic ovary syndrome. P450c17α, which is involved in androgen biosynthesis, has both 17α-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17α-hydroxyprogesterone in response to stimulation by gonadotropin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17α activity. METHODS We measured serum steroid concentrations during fasting and the response of serum 17α-hydroxyprogesterone to leuprolide, a gonadotropin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome. RESULTS In the 11 women given metformin, the mean (±SE) area under the serum insulin curve after oral glucose administration decreased from 9303±1603 to 4982±911 μU per milliliter per minute (56±10 to 30±6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17α-hydroxyprogesterone concentration from 135±21 to 66±7 ng per deciliter (4.1±0.6 to 2.0±0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17α-hydroxyprogesterone concentration from 455±54 to 281±52 ng per deciliter (13.7±1.6 to 8.5±1.6 nmol per liter) (P = 0.01). The serum 17α-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5±2.2 to 2.8±0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34±0.07 to 0.19±0.05 ng per deciliter (12±3 to 7±2 pmol per liter) (P = 0.009), and the serum sex hormone–binding globulin concentration increased from 0.8±0.2 to 2.3±0.6 μg per deciliter (29±7 to 80±21 nmol per liter) (P CONCLUSIONS In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17α activity and ameliorates hyperandrogenism

Effects of Metformin on Spontaneous and Clomiphene-Induced Ovulation in the Polycystic Ovary Syndrome

ABSTRACT Background Obese women with the polycystic ovary syndrome are relatively unresponsive to the induction of ovulation by clomiphene. We hypothesized that reducing insulin secretion by administering metformin would increase the ovulatory response to clomiphene. Methods We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome. Women who did not ovulate spontaneously were then given 50 mg of clomiphene daily for five days while continuing to take metformin or placebo. Serum progesterone was measured on days 14, 28, 35, 44, and 53, and ovulation was presumed to have occurred if the concentration exceeded 8 ng per milliliter (26 nmol per liter) on any of these days. Results Twenty-one women in the metformin group and 25 women in the placebo group were given clomiphene because they did not ovulate spontaneously during the first phase of the study. Among the 21 women given metformin plus clomiphene, the mean (±SE) area under the serum insulin curve after oral glucose administration decreased from 6745±2021 to 3479±455 µU per milliliter per minute (40.5±12.1 to 20.9±2.7 nmol per liter per minute, P=0.03), but it did not change significantly in the 25 women given placebo plus clomiphene. Nineteen of the 21 women (90 percent) who received metformin plus clomiphene ovulated (mean peak serum progesterone concentration, 23.8±3.4 ng per milliliter [7.6±10.9 nmol per liter]). Two of the 25 women (8 percent) who received placebo plus clomiphene ovulated (P\u3c0.001). Overall, 31 of the 35 women (89 percent) treated with metformin ovulated spontaneously or in response to clomiphene, as compared with 3 of the 26 women (12 percent) treated with placebo. Conclusions The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin. (N Engl J Med 1998;338:1876-80.

Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits.

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer\u27s disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures

Distinct sites of opiate reward and aversion within the midbrain identified using a herpes simplex virus vector expressing GluR1

Repeated administration of morphine increases expression of GluR1 (an AMPA glutamate receptor subunit) in the ventral tegmental area (VTA) of the midbrain, an important neural substrate for the rewarding actions of morphine. Microinjections of a herpes simplex virus (HSV) vector that causes local overexpression of GluR1 (HSV-GluR1) into the VTA can enhance the ability of morphine to establish conditioned place preferences, suggesting that altered GluR1 expression in this region is directly associated with changes in the rewarding efficacy of morphine. We now report that in rats given HSV-GluR1 directly into the VTA, morphine is most rewarding when maximal transgene expression is in the rostral VTA, whereas morphine is aversive when maximal transgene expression is in the caudal VTA. Dual-labeling immunohistochemistry shows that this difference cannot be explained by a different fraction of dopaminergic neurons infected in the rostral versus caudal VTA. No such anatomical specificity is seen in rats given VTA microinjections of HSV-LacZ, a vector expressing a control protein (beta-galactosidase). These results suggest that distinct substrates within the VTA itself differentially contribute to the rewarding and aversive properties of opiates

Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome

BACKGROUND Women with the polycystic ovary syndrome have insulin resistance and hyperinsulinemia, possibly because of a deficiency of a d-chiro-inositol–containing phosphoglycan that mediates the action of insulin. We hypothesized that the administration of d-chiro-inositol would replenish stores of the mediator and improve insulin sensitivity. METHODS We measured steroids in serum and performed oral glucose-tolerance tests before and after the oral administration of 1200 mg of d-chiro-inositol or placebo once daily for six to eight weeks in 44 obese women with the polycystic ovary syndrome. The serum progesterone concentration was measured weekly to monitor for ovulation. RESULTS In the 22 women given d-chiro-inositol, the mean (±SD) area under the plasma insulin curve after the oral administration of glucose decreased from 13,417±11,572 to 5158±6714 μU per milliliter per minute (81±69 to 31±40 nmol per liter per minute) (P=0.007; P=0.07 for the comparison of this change with the change in the placebo group); glucose tolerance did not change significantly. The serum free testosterone concentration in these 22 women decreased from 1.1±0.8 to 0.5±0.5 ng per deciliter (38±28 to 17±17 pmol per liter) (P=0.006 for the comparison with the change in the placebo group). The women\u27s diastolic and systolic blood pressure decreased by 4 mm Hg (Pchiro-inositol ovulated, as compared with 6 of the 22 women in the placebo group (P\u3c0.001). CONCLUSIONS d-Chiro-inositol increases the action of insulin in patients with the polycystic ovary syndrome, thereby improving ovulatory function and decreasing serum androgen concentrations, blood pressure, and plasma triglyceride concentrations

BAZ1B in Nucleus Accumbens Regulates Reward-Related Behaviors in Response to Distinct Emotional Stimuli

ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins

Ultrasound detection by clupeiform fishes

It has previously been shown that at least one species of fish ~the American shad! in the order clupeiforms ~herrings, shads, and relatives! is able to detect sounds up to 180 kHz. However, it has not been clear whether other members of this order are also able to detect ultrasound. It is now demonstrated, using auditory brainstem response ~ABR!, that at least one additional species, the gulf menhaden ~Brevoortia patronus!, is able to detect ultrasound, while several other species including the bay anchovy ~Anchoa mitchilli!, scaled sardine ~Harengula jaguana!, and Spanish sardine ~Sardinella aurita! only detect sounds to about 4 kHz. ABR is used to confirm ultrasonic hearing in the American shad. The results suggest that ultrasound detection may be limited to one subfamily of clupeiforms, the Alosinae. It is suggested that ultrasound detection involves the utricle of the inner ear and speculate as to why, despite having similar ear structures, only one group may detect ultrasound