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The clinical behavior of growth hormone (GH)-producing pituitary tumors is known to vary greatly; however, the events underlying this variability remain poorly understood. Herein we demonstrate that tumor overexpression of the GH-releasing hormone (GHRH) gene is one prognostically informative event associated with the clinical aggressiveness of somatotroph pituitary tumors. Accumulation of GHRH mRNA transcripts was demonstrated in 91 of a consecutive series of 100 somatotroph tumors by in situ hybridization; these findings were corroborated by Northern analysis and reverse transcriptase polymerase chain reaction, and protein translation was confirmed by Western blotting. By comparison, transcript accumulation was absent or negligibly low in 30 normal pituitary glands. GHRH transcripts were found to preferentially accumulate among clinically aggressive tumors. Specifically, GHRH mRNA signal intensity was 1) linearly correlated with Ki-67 tumor growth fractions (r = 0.71; P < 0.001), 2) linearly correlated with preoperative serum GH levels (r = 0.56; p = 0.01), 3) higher among invasive tumors (P < 0.001), and 4) highest in those tumors in which post-operative remission was not achieved (P < 0.001). Using multivariate logistic regression, a model of postoperative remission likelihood was derived wherein remission was defined by the single criterion of suppressibility of GH levels to less than 2 ng/ml during an oral glucose tolerance test. In this outcome model, GHRH mRNA signal intensity proved to be the most important explanatory variable overall, eclipsing any and all conventional clinicopathological predictors as the single most significant predictor of postoperative remission; increases in GHRH mRNA signal were associated with marked declines in remission likelihood. The generalizability of this outcome model was further validated by the model's significant performance in predicting postoperative remission in a random sample of 30 somatotroph tumors treated at another institution. These data indicate that overexpression of GHRH gene is an event associated with the neoplastic progression and clinical aggressiveness of somatotroph adenomas. More generally, these data merge essential elements of the hypothalamic and pituitary hypotheses of pituitary tumorigenesis, providing for a more unified concept of neoplastic progression in the pituitary.

The case of a 35-year-old man with pituitary macroadenoma who was complaining of reduced sexual activity is presented. Histologic examination showed a chromophobic adenoma corresponding mainly to a null cell adenoma at the ultrastructural level. Focal plurihormonality and plurimorphous differentiation of adenoma cells were demonstrated by immunohistochemical and electron-microscopic studies. It is suggested that adenomatous null cells represent pluripotent progenitor cells capable of transforming to different hormone-producing cell types. The factors accounting for differentiating to various cell populations have yet to be elucidated.

Among 300 surgically removed pituitary adenomas, 17 tumors containing immunoreactive 1-39 adrenocorticotropin (ACTH) and/or 19-39 ACTH, beta-lipotropin, and alpha-endorphin but unassociated with clinical signs of Cushing's disease have been detected. These neoplasms were divided into basophilic adenomas with strong periodic acid-Schiff (PAS) and lead-hematoxylin positivity and chromophobic tumors with moderate or no PAS and lead-hematoxylin positivity. The former were densely granulated tumors with a fine structure strikingly similar to that of functioning corticotropic cell adenomas. The latter were sparsely granulated with varying ultrastructural patterns. The marked morphologic diversity suggests that these adenomas, despite their similar immunocytologic characteristics, represent more than one entity. Clinically, the most common finding was a rapidly progressing visual defect. An unusually high incidence of infarction (5 cases) and recurrence (5 cases) was noted, underlining the importance of correct morphologic diagnosis and careful follow-up.

We have studied a kindred in which two parts of siblings, maternal first cousins, have a form of "minimal" androgen insensitivity that permits morphogenesis of unambiguous male external genitalia, but interferes with normal virilization at puberty. All four had gynecomastia that required reductive surgery. Apart from this common phenotype, they varied considerably in the temporal and regional aspects of their subvirilization and appreciably in their androgenic responsiveness to pharmacological doses of testosterone. The cultured genital skin fibroblasts from one set of siblings have an androgen-receptor activity with the following properties: (1) a normal maximum-binding capacity (Bmax) with 5 alpha-dihydrotestosterone (DHT), or the synthetic androgen, methyltrienolone (MT; R1881) as ligand; (2) a higher than normal apparent equilibrium dissociation constant (Kd) for DHT (0.77 nM) but not for MT; and (3) an elevated dissociation rate (k) of DHT-receptor (0.013 min-1, 37 degrees C), but not MT-receptor, complexes within intact cells. In addition, prolonged incubation with MT, but not DHT, augments the specific androgen-binding activity of the mutant cells as much as that of the controls. Normal cells yield lower values of apparent Kd for DHT (0.1-0.3 nM) after 2- than after 0.5-hr incubation (0.3-1.8 nM), and 1-hr values are intermediate. This occurs despite concurrent catabolic consumption of DHT from the medium and is considered to reflect transformation of initial, low-affinity DHT-receptor complexes to subsequent, higher-affinity states by a process that depends on time and initial ligand concentration. The mutant complexes described here can readily attain the highest state of affinity with MT, but have an impeded, variably expressed ability to do so with DHT. These findings suggest that a structural mutation at the X-linked locus that encodes the androgen-receptor protein is responsible for its androgen-selective dysfunction. Synthetic, nonhepatotoxic androgens, with corrective effects in vitro comparable to those of MT, may be therapeutically useful for these subjects.

Pituitary adenomas, removed surgically from three women with normal or slightly elevated serum growth hormone levels and no evidence of acromegaly, were studied. The tumor cells were shown by electron microscopy to correspond to sparsely granulated somatotrophs but immunocytochemistry showed that they contained no, moderate, or little growth hormone. Two tumors examined in vitro secreted small amounts of growth hormone in the tissue culture medium initially with a spontaneous rise after several days, and responded to growth hormone-releasing hormone stimulation with increased growth hormone release. In situ hybridization demonstrated growth hormone mRNA expression in adenoma cells. Clinically silent somatotroph adenomas represent a hitherto undescribed entity; electron microscopy shows that they consist of somatotrophs, and express growth hormone mRNA but do not secrete growth hormone in amounts needed to raise substantially serum growth hormone levels and cause acromegaly. Further work is required to clarify the mechanisms accounting for the lack of clinical and biochemical evidence of hormone excess associated with these tumors.

The clinical use of hypothalamic releasing hormones for diagnostic purposes has dramatically improved our understanding of the neural control of pituitary function. The potential therapeutic value of these compounds for treatment of infertility and hypogonadism will evolve in the near future. Analogues of LH-RH which antagonize LH-RH have been developed and may have a future role in fertility control. The clinical application of these hypothalamic hormones will evolve in the next few years.

Breast carcinoma tissue is capable of forming estrogens from circulating androgen precursors. In this study, aromatase was examined in homogenates of breast adipose and breast carcinoma tissue, in normal and abnormal parenchymal breast tissue, and in breast carcinoma cells in culture. Homogenates of carcinoma tissue showed a wide range of activity in the conversion of adrostenedione to estrone. The mean conversion in carcinoma tissue was greater than that seen in parenchymal tissue from patients with gynecomastia and mammary dysplasia. Homogenates of breast adipose tissue from patients with benign and malignant disorders showed comparable aromatase activity. Three cell lines isolated from a primary breast carcinoma differed in their aromatase activity demonstrating a heterogeneity of aromatase activity in cells from a single tumor. Studies of aromatase activity in breast carcinoma cells in culture over a period of 8 hr demonstrated progressive estrone formation. Testosterone formation from androstenedione was noted in all studies using both homogenates and cell cultures. Testosterone formation from androstenedione was approximately 10-fold greater than was the formation of estrone from androstenedione in all studies. The metabolism of androstenedione to other androgens examined in homogenates of normal and carcinomatous breast tissue revealed that the major products were androsterone, 5 beta-androsterone, dihydrotestosterone, and epiandrosterone. Both estrogen and androgen formation within the cell may be important in determining the cellular response.

A patient with Cushing's syndrome whose clinical manifestations began at approximately 9 years of age was followed for a period of four years. Initial laboratory studies revealed urinary 170HCS and 17 KS levels which were elevated for her age, with a normal diurnal variation of plasma cortisol and normal suppression of urinary 170HCS by 1.5 mg. of dexamethasone daily. It was not until four years after the onset of the disease that laboratory studies unequivocally supported the diagnosis of Cushing's syndrome resulting in definitive therapy. Clinical features consisted primarily of cessation of growth, obesity, and hirsutism, with no evidence of protein depletion. It is suggested that the clinical and laboratory features of Cushing's syndrome in childhood may present differences from those found in the adult. Failure to recognize these differences may result in delay in therapy with subsequent persisting stigmata of the disorder.