Myelin basic protein (MBP) and MBP peptides are mitogens for cultured astrocytes.

After CNS demyelination, astrogliosis interferes with axonal regeneration and remyelination. We now provide evidence that myelin basic protein (MBP) can contribute to this observed astrocyte proliferation. We found that astrocytes grown in either serum-containing or serum-free medium proliferate in response to MBP. The mitogenic regions of MBP in both media were MBP(1-44), MBP(88-151) and MBP(152-167). The mitogenic effect of these individual peptides was potentiated by simultaneous treatment with microglia conditioned media (CM). MBP-induced proliferation was inhibited by suramin at concentrations known to block the fibroblast growth factor receptor (FGFR), whereas neither MBP(1-44), MBP(88-151) nor MBP(152-167) were affected. Cholera toxin B, that binds to ganglioside GM(1), inhibited the mitogenicity of MBP(1-44) and had no significant effect on the mitogenicity of MBP, MBP(88-151) or MBP(152-167). Treatment of astrocytes with MBP and MBP(152-167) caused a modest and transitory elevation of intracellular calcium, whereas treatment with MBP(1-44) resulted in a substantial and sustained increase in intracellular calcium. These results suggest that for cultured astrocytes 1) FGFR and extracellular calcium play a major role in MBP mitogenicity; 2) MBP(1-44), MBP(88-151) and MBP(152-167) are the mitogenic regions of MBP; 3) MBP(1-44) and MBP(152-167) interact with ganglioside GM(1) and FGFR, respectively; 4) Component(s) present in microglial CM potentiate the mitogenicity of MBP(1-44), MBP(88-151) and MBP(152-167). These data support the hypothesis that MBP related peptides in conjunction with microglial secreted factors may stimulate astrogliosis after demyelination in vivo.

Insulin-dependent diabetes mellitus and menstrual dysfunction.

Disordered reproductive function has long been recognized as a prevalent problem among women of reproductive age who suffer from insulin-dependent diabetes mellitus (IDDM). Delay in menarchial age is frequently seen if IDDM develops in the peripubertal years and some form of menstrual dysfunction is found in nearly one-third of all women of reproductive age with IDDM. This review summarizes some of the prevailing views regarding the mechanisms through which uncontrolled IDDM is thought to disrupt normal hypothalamic-pituitary-gonadal function. Although animal studies have suggested that poorly controlled IDDM may adversely affect the uterovaginal outflow tract and/or ovarian function, no clinical studies have suggested that abnormal uterine or ovarian function underlies the menstrual dysfunction observed in young diabetic women. Similarly, pituitary function as assessed by basal gonadotrophins and gonadotrophin-releasing hormone (GnRH)-stimulated gonadotrophin release appears to be normal in young women with IDDM. Moreover, although there has been some suggestion that pituitary function may decline with increasing duration of diabetes, this issue has not been thoroughly investigated. It appears that the oligo/amenorrhea noted in IDDM is principally hypothalamic in origin and may represent intermittent (and perhaps reversible) failure of the GnRH pulse generator, similar to the situation observed in women who engage in endurance training or who suffer from anorexia nervosa. Although the exact pathophysiological mechanisms that subserve dysfunction of the GnRH neuronal system are not well understood, attention has focused on increased central opioidergic activity, increased central dopaminergic activity, and central glucose deprivation. In this era of emphasis on tight glycaemic control and its impact in preventing diabetes complications, the consequences of IDDM on reproductive potential appear to be important and must be included in future investigative efforts.

Alterations in luteinizing hormone secretory activity in women with insulin-dependent diabetes mellitus and secondary amenorrhea.

To investigate hypothalamic and/or pituitary abnormalities in women with poorly controlled insulin-dependent diabetes mellitus (IDDM) and secondary amenorrhea, we measured serum LH every 10 min for 24 h and for 2 additional h after the administration of exogenous GnRH in 8 women with IDDM and amenorrhea and compared these to data from 15 eumenorrheic nondiabetic women. LH pulses were characterized by the pulse detection algorithm Cluster, and secretory episodes were evaluated using the multiple parameter deconvolution procedure Deconv. Cluster analysis revealed fewer LH pulses per 24 h (14.3 +/- 1.2 vs. 19.9 +/- 0.6; P < 0.001; mean +/- SEM), a greater peak width (63 +/- 4.9 vs. 44 +/- 2.2 min; P < 0.01), and greater peak area (136 +/- 17 vs. 89 +/- 13 IU/L.min; P < 0.01) in the diabetic women. Analysis with Deconv revealed fewer LH secretory episodes per 24 h in the diabetic women (14.4 +/- 0.9 vs. 20.4 +/- 0.5; P < 0.001) and no statistical difference in LH half-lives. The IDDM women responded to a 10-micrograms GnRH bolus with LH pulses of larger total (51 +/- 15.9 vs. 15 +/- 1.4 IU/L; P < 0.01) and incremental (29 +/- 7.6 vs. 9 +/- 1.2; P < 0.001) amplitude. In summary, we observed that amenorrheic diabetic women have fewer LH pulses/secretory episodes than normal women. However, they respond well to exogenous GnRH, suggesting that compromise of the GnRH pulse generator, rather than pituitary dysfunction, is responsible for their menstrual dysfunction.

Normal reproductive neuroendocrinology in the female.

The reproductive axis in women comprises a number of components that must function in a highly orchestrated manner for reproductive potential to be optimal. The neuroendocrine components of this axis, including the hypothalamus and the pituitary gland, are central to this system. Within the hypothalamus, the specialized neuronal system responsible for synthesizing and secreting gonadotropin-releasing hormone (GnRH) is itself modulated by a number of peptide and biogenic amine neurotransmitters that mediate feedback signals of ovarian origin. The luteinizing hormone and follicle-stimulating hormone secreting anterior pituitary gonadotropes perceive and transduce neural input in the form of GnRH, but are themselves also modulated by the ambient gonadal hormone concentrations. The authors review the physiologic relevance of the pulsatile nature of the GnRH signal, and some proposed mechanisms through which these signals are stimulated and modulated and subsequently perceived and transduced by gonadotropes.