R. M. G. Nair

Platelet adhesion and aggregation in diabetes mellitus

Platelets from diabetic patients show both increased platelet adhesiveness and sensitivity to aggregating agents. Plasma levels of the platelet-active von Willebrand Factor and the closely related factor-VIII antigen are significantly elevated, while factor VIII procoagulant activity is not. This may reflect either intravascular coagulation or disproportionate production or degradation. Plasma factors that enhance ADP-induced platelet aggregation are found in 50% of unselected male diabetics. Activity is clearly demonstrated only when plasma is added immediately prior to adding subthreshold doses of ADP to platelet-rich plasma obtained from control subjects. Systematic investigations of the molecular nature of such factors and their interactions with platelets are in progress. In platelets obtained from diabetic subjects, we have previously found increased sensitivity to the aggregating effects of arachidonic acid, and increased synthesis of immunoreactive prostaglandin E-like material. More recent studies have shown that platelets obtained from diabetic subjects are less sensitive to the antiaggregatory effects of imidazole, a thromboxane synthetase inhibitor. These observations suggest that increased synthesis of the labile aggregating substance thromboxane A2 also occurs in platelets obtained from diabetics. Collectively, these platelet and plasma abnormalities may contribute to accelerated vascular disease of diabetes. Prospective studies using antiplatelet agents are presently underway or in the planning stages in diabetics to explore their potential beneficial effects.

Prolactin‐secreting adenoma as part of the multiple endocrine neoplasia—type I (MEN‐I) syndrome

Two patients presented with the galactorrhea‐amenorrhea syndrome. One patient had previously had parathyroid hyperplasia and the other an insulinoma. Preoperative evaluation of each patient revealed hyperprolactinemia and radiological evidence of an abnormal sella turcica. Pituitary adenomas were identified and removed at surgery. Immunostaining techniques confirmed the presence of prolactin‐containing cells in both tumors. We propose that prolactin‐secreting tumors be considered as part of the MEN‐I syndrome, and that patients presenting with the galactorrhea‐amenorrhea syndrome be screened and followed sequentially for evidence of other endocrine neoplasia.

THE EFFECT OF ORAL GLUCOSE ON VON WILLEBRAND FACTOR ACTIVITY IN NORMAL AND DIABETIC SUBJECTS

We have previously noted increased platelet aggregation and high von Willebrand factor activity in patients with chemical diabetes. In this paper we have studied platelet aggregation, plasma glucose, insulin, free fatty acids, growth hormone, and von Willebrand factor activity during the glucose tolerance test in six normal and six chemical diabetic subjects. The results suggest that von Willebrand factor activity is suppressed coincident with the rise of glucose and insulin and provide further evidence of hormonal and metabolic control of levels of von Willebrand factor activity.

Combined Use of Clomiphene and Intranasal Luteinizing Hormone-Releasing Hormone for Induction of Ovulation in Chronically Anovulatory Women * †

Combined therapy with clomiphene and intranasal luteinizing hormone-releasing hormone (LHRH) was used to induce ovulation in eight chronically anovulatory patients under treatment for infertility. Clomiphene, 100 mg daily, was given from the 5th to the 9th day of the cycle. Synthetic LHRH was administered intranasally in different dosages from day 11 to day 14, in an attempt to induce late follicular development and ovulation. Five of the eight patients ovulated, and three conceived. The success achieved with combined clomiphene and intranasal LHRH administration suggests a therapeutic potential in the management of anovulatory infertility.

INTER‐RELATIONSHIP BETWEEN CHANGING PATTERNS OF LHRH AND GONADOTROPHINS IN THE MENSTRUAL CYCLE

Optimum conditions for a sensitive and highly precise radioimmunoassay of LHRH were established. Precipitation and removal of interfering substances and concentration of the resultant LHRH extracts from peripheral plasma were also achieved. Using these methods, daily plasma LHRH levels in females with normal menstrual cycles were measured and correlated with the corresponding LH and FSH levels. The levels of LHRH in the peripheral plasma of postmenopausal females, as well as eugonadal males, were also determined.

PLASMA STEROID CONCENTRATIONS IN PATIENTS WITH HYPOPITUITARISM AND KALLMAN'S SYNDROME: EFFECTS OF TESTOSTERONE REPLACEMENT THERAPY

To determine the adrenal contribution to plasma concentrations of steroids potentially derived from both the adrenal and the testes, plasma levels of pregnenolone (Δ5P), progesterone (P), dehydroepiandrosterone and its sulphate (DHA and DHAS) and androstenedione (Δ4A) were measured in four men with isolated gonadotrophin deficiency and anosmia (Kallmans syndrome). A comparison of these levels with those seen in ten patients with both adrenal and testicular failure (hypopituitarism) and in sixteen normal age‐matched men was made.

Action of gonadotropin-releasing hormone and its superactive analogues on the anterior pituitary: the mechanism of release and synthesis of gonadotropins.

The role of prostaglandins (PG), their active intermediates or the adenylcyclase-cyclic AMP system for gonadotropin release and/or synthesis was evaluated by administering gonadotropin-releasing hormone (Gn-RH) and its superactive analog to normal and aspirin-treated rats. Serum LH levels, anterior pituitary malondialdehyde (MDA) content and cyclic AMP (cAMP) levels were followed. The pituitaries stimulated with Gn-RH or its superactive analog yielded more MDA and cAMP than the controls. Stimulation of the pituitary with the releasing hormones, after aspirin treatment, yielded 40--70% less MDA and lower LH values than the nontreated animals. The cAMP levels were not significantly lowered by the aspirin treatment. These studies suggest that the activation of the PG biosynthesis and the adenyl-cyclase-cyclic AMP system are not sequential but 2 separate physiological events. The active PG intermediates may only be responsible for the release of LH. It is not clear whether the activation of cAMP initiates also the processes preparatory to the synthesis of LH in the endoplasmic reticulum. In vivo studies in rats showed that the analogs (I and II) were 30 times more potent and had a more prolonged action on the pituitary (3 h) than Gn-RH. Ultrastructural studies on the anterior pituitary after hypophyseal stalk portal vessel infusion of Gn-RH and the analog (I and II) provided ample morphological evidence for both Gn-RH and analog induced gonadotropin-release and synthesis. The prolonged action of the superactive analog (I and II) on the gonadotrophs was also indicated by ultrastructural studies.