We studied and compared the pharmacokinetics and bioefficacy of two doses of sublingual testosterone cyclodextrin (SLT; 2.5 and 5.0 mg, administered three times per day) with testosterone enanthate (TE; 200 mg) given once every 20 days by im injections over a 60-day study period in 63 hypogonadal men. After SLT administration, serum testosterone (T) levels peaked at 20 min and then fell, reaching baseline levels by 360 min. The calculated half-lives were 60.3 +/- 7.5 and 68.8 +/- 5.0 min after a single dose of 2.5 and 5.0 mg SLT, respectively. The mean area under curve (AUC) of serum T was computed over 20-day periods for the 3 treatment groups. The mean net AUC of serum T after TE administration was about 4- and 2-fold higher than that in the 2.5 and 5 mg groups over the last 20 days. Serum estradiol and dihydrotestosterone followed the same pattern as serum T. Serum estradiol to T ratios decreased after T replacement in all 3 groups, whereas serum dihydrotestosterone to T ratios were not significantly changed by T treatment. Suppression of serum LH and FSH levels was more marked in the patients treated with TE than in those given SLT. Similarly, serum sex hormone-binding globulin levels showed significant decreases with androgen replacement only in the TE and SLT 5.0 mg range groups. There were no significant adverse effects based on comprehensive physical examinations, urea, electrolytes, and renal or liver function tests. Hematocrit levels increased in the TE-treated group, but remained slightly lower than baseline levels in the SLT groups. Serum high density lipoprotein cholesterol showed a small, but significant, decrease with time of treatment in all groups. Despite the differences in the AUC of serum T levels achieved by different androgen replacement therapies, all patients showed significant improvements in sexual motivation and performance, with no significant difference between the treatment groups. We conclude that SLT may be a useful addition to the currently available injectable and transdermal delivery systems for treatment of hypogonadal men. Because of the ease of administration, rapid reversibility of effects, and lower AUC of serum T levels achieved compared to those of TE injections, SLT may be especially suitable for treatment of boys with delayed puberty and older men with androgen deficiency.

To test the hypothesis that glucose transport is rate limiting for skeletal muscle glucose metabolism, intracellular free glucose was measured in in situ abdominal wall muscle and liver that were rapidly freeze-clamped and removed from normal and streptozocin-induced diabetic (STZ-D) Sprague-Dawley rats exposed to different concentrations of serum insulin and glucose achieved by 90-min glucose clamps. Three groups of anesthetized normal (n = 17) and three groups of STZ-D (n = 19) animals were studied. In each group, infusions were adjusted to expose rats to basal, euglycemic-hyperinsulinemic, and hyperglycemic-hyperinsulinemic conditions. Final steady-state serum glucose and insulin concentrations (mean +/- SE) achieved in the six groups ranged from 112 +/- 2 to 467 +/- 26 mg/dl and from 5.8 +/- 1.9 to 3644 +/- 116 microU/ml, respectively. Intracellular free-glucose content of all tissue was calculated from total tissue glucose content minus the contribution of glucose in extracellular water estimated with [14C]inulin. Intracellular free glucose was not detected in muscle of any of the experimental groups. However, intracellular free glucose was detected in liver from all normal and STZ-D rats, and the calculated intracellular concentrations of free glucose correlated with serum glucose concentrations (r = .68, P less than .001). We conclude that intracellular free glucose does not accumulate, regardless of glucose or insulin concentration, in normal skeletal muscle and muscle made insulin resistant (by STZ-D), suggesting that glucose transport remains rate limiting.

A 59-yr-old woman with a disseminated carcinoid tumor was evaluated for acromegaly. She had previously undergone a hypophysectomy for acromegaly and an enlarged pituitary, with a reduction in her serum GH levels from 100 to 4 micrograms/L. Recurrence of acromegalic symptoms 2 yr later was accompanied by elevated serum GH (16 micrograms/L) and insulin-like growth factor I (IGF-I; 528 micrograms/L) and plasma GHRH levels (12 micrograms/L; normal, less than 30 ng/L). Computed tomographic scan did not reveal pituitary enlargement. Metastatic carcinoid tissue in bone removed at biopsy contained GHRH (100 pg/mg tissue). High performance liquid chromatography of plasma GHRH revealed predominantly GHRH-(3-40)-OH, a biologically inactive GHRH metabolite, along with mature GHRH forms, while carcinoid tissue contained both GHRH-(1-40)-OH and GHRH-(1-44)-NH2. Treatment with pergolide initially resulted in reduction in serum GH and IGF-I levels and amelioration of symptoms of acromegaly. However, after 14 months of pergolide therapy, serum GH levels increased despite administration of up to 1000 micrograms pergolide/day. Plasma GHRH levels remained elevated throughout the treatment period. Subsequent treatment with SMS 201-995, a long-acting somatostatin analog, for over 1 yr resulted in sustained reductions of ectopic GHRH secretion, GH hypersecretion, and IGF-I levels. Plasma GHRH levels correlated with simultaneously measured serum GH levels in response to acute SMS 201-995 administration. SMS 201-995 was an effective medical treatment for acromegaly caused by ectopic GHRH production in this patient.