bioactivity than the normal ~-subunit. The authors conclude that mutations in the LH ~-subunit gene may cause reproductive dysfunction in some patients. Comment. The authors have assessed for two specific mutations in 54 women with menstrual disorders. Five patients homozygous for mutations in the LH ~-subunit gene were identified. All had menstrual irregularity without hyperandrogenism. Four of the five had elevated LH responses to GnRH stimulation. Thus, these patients appear to have an inactive LH molecule. The relationship of these mutations to LH biological activity, if any, is confused by the bioassay used which measures testosterone production in mouse interstitial cells. The species variation may contribute to the observed results. Nevertheless, this is an interesting paper which suggests that mutations in the LH ~-subunit gene occur and may be associated with ovarian dysfunction. Additional different mutations may be identified in the LH ~-sub unit.
Dunaif A, Xia J, Book C-B, et al: Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. J CHn Invest 1995; 96: 801-810. Insulin resistance occurs frequently in polycystic ovary syndrome (PCOS). The interrelationships between hyperandrogenism and insulin resistance have been extensively studied and are yet to be fully understood. Insulin action is mediated through the insulin receptor which, following ligand binding, initiates a cascade of phosphorylation-dephosphorylation events starting with autophosphorylation of specific tyrosine residues in the intracellular portion of the insulin receptor. In PCOS, the insulin resistance appears to be due to impaired postreceptor signal transduction. During investigation into the mechanism of defective postreceptor insulin action, these investigators identified a novel abnormality of the insulin receptor. Sixteen women with PCOS (10 obese, 6 nonobese) and 9 healthy control women (5 obese, 4 nonobese) participated in the study. Oral glucose tolerance tests showed impaired glucose tolerance in some of the PCOS women, but not in any of the healthy controls. Fibroblast cultures were established from skin biopsies. Muscle biopsies were performed in two subjects and one control. To study insulin signal transduction, insulin receptors were partially purified from the fibroblast cultures and muscle biopsy tissues. Insulin-stimulated autophosphorylation was significantly decreased in fibroblast insulin receptors obtained from pcas women. Among the pcas women, two groups of insulin receptors were apparent; one group had increased basal autophosphorylation and one group had basal autophosphorylation comparable to the control group. Phosphoamino acid analysis revealed that the increased basal phosphorylation could be attributed to in-
creased phosphorylation of serine residues in the insulin receptor. The tyrosine kinase activity of the insulin receptor was assessed by the ability of the insulin receptors to phosphorylate poly GLUT4:TYR1, an artificial substrate. The serine phosphorylated insulin receptors demonstrated impaired tyrosine kinase activity. Partially purified insulin receptors obtained from skeletal muscle showed similar phosphorylation patterns. Thus, increased phosphorylation of serine residues decreases the tyrosine kinase activity of the insulin receptor. In doing so, serine phosphorylation may "terminate" insulin's signal. These investigators hypothesize that increased serine phosphorylation of the insulin receptor may be the mechanism of insulin resistance in some PCOS patients. Comment. These investigators have proposed a novel explanation for the insulin resistance associated with PCOS. Increased serine phosphorylation may impair insulin signal transduction leading to decreased insulin sensitivity. The serine kinase activity appears to be independent of the insulin receptor and remains to be identified.
Zhang L-H, Rodriguez H, Ohno S, et al: Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci 1995; 92: 10619-10623. One enzyme, P450c17, possesses both 17a-hydroxylase and 17,20-lyase activities. This enzyme, coded for by a single gene mapped to chromosome 1Oq24-q25, functions as the steroidogenic gatekeeper which decides how much mineralocorticoid (or progesterone in the ovary), glucocorticoid, or sex steroid is produced. One of the earliest manifestations of puberty is increasing adrenal androgen secretion known as adrenarche. No apparent negative feedback control exists for adrenal androgen secretion. Yet, the physiological mechanism initiating and maintaining adrenarche is unclear. These investigators explored the effects of increased serine phosphorylation on the 17,20-lyase activity of P450c 17. Metabolic labeling of an adrenocortical cell line showed that cAMP treatment induced increased phosphorylation of P450c17 protein which appeared to be catalyzed by a cAMP-dependent protein kinase. Phosphoamino acid analysis showed that most of the phosphorylation occurred at serine residues with a small amount as threonine residues. Alkaline phosphatase treatment of fetal adrenal microsomes (dephosphorylation) was associated with decreased 17,20-lyase activity without changes in the 17a-hydroxylase activity. Thus, these investigators suggest that increased serine phosphorylation of P450c 17 protein leads to increased 17,20-lyase activity and increased C19 steroid production. They hypothesize that serine phosphorylation may