Corticotropin-releasing factor-like activity in ACTH producing tumors.

Corticotropin-releasing factor (CRF)-like activity in two different kinds of ACTH-producing tumors (human ectopic ACTH-producing colonic cancer and rat MtT/F4 tumor) was determined by an in vitro method using isolated normal rat pituitary cells. The ACTH content of the post mortem colonic cancer was 5.5 ng/g w.wt. The ACTH content of the medium of MtT/F4 tumor cells was 153+/-32 pg/10(5) cells. The ACTH content of MtT/F4 tumor cell suspensions was elevated with increasing doses of hypothalamic median eminence extract (HME). The response of MtT/F4 tumor cells to HME was suppressed by 1 mug/ml of dexamethasone. Extracts of colonic cancer, MtT/F4 tumor and HME produced elevation of the ACTH content of the medium of isolated rat pituitary cells. The CRF-like activities of two kinds of tumor extracts in multiple dilutions ran parallel to that of HME. The CRF-like activities were 0.037 HME equiv/mg w.wt in MtT/F4 tumor and 0.052 HME equiv/mg w.wt. in colonic cancer. These results demonstrated that CRF-like activity existed in these two kinds of ACTH-producing tumors.

Plasma pituitary hormone responses to the synthetic enkephalin analog (FK 33-824) in normal subjects and patients with pituitary diseases.

D-Ala, Mephe, Met, enkephalin (Sandoz FK 33-824) is a stable long acting analog of methionine-enkephalin. FK 33-824 (0.5 or 1.0 mg), elicited plasma GH and PRL responses in normal subjects. In 23 patients with pituitary dwarfism, the response of plasma GH was markedly impaired, while PRL responded to a variable degree. In patients with acromegaly, there was little or no increase in GH and PRL after FK 33-824. Plasma GH increased to a variable degree after FK 33-824 in patients with hyperprolactinemia, with little change in plasma PRL. FK 33-824 decreased plasma cortisol in normal subjects and patients with pituitary disease. These results show that patients with acromegaly and hyperprolactinemia due to pituitary adenomas and patients with pituitary dwarfism do not respond well to FK 33-824, presumably because of hypothalamic or pituitary derangement.

Human plasma free activin and inhibin levels during the menstrual cycle.

The role of inhibin in gonadal function and reproduction has been confirmed by the measurement of plasma inhibin levels, but there has been no clinical data available on activin because of the lack of a good assay method. We measured plasma free activin levels during the normal menstrual cycle using a newly developed competitive protein binding assay with follistatin as the binding protein. Plasma inhibin levels were measured simultaneously using an alpha-subunit N-terminal fragment RIA with recombinant inhibin as the reference standard. Four normal women, aged 23-29 years, were investigated by obtaining plasma at 3-day intervals. Plasma inhibin levels showed some variation during the follicular phase, but a parallel rise in inhibin and progesterone was observed during the luteal phase. These findings confirmed those of previous studies. In contrast, plasma free activin levels did not show any substantial changes during the menstrual cycle. This study suggests that activin has no endocrine role in modulating the pituitary-gonadal axis during the normal menstrual cycle, while changes of inhibin reflect cyclic gonadal function and indicate an endocrine role for this protein in modulating gonadal activity.

The significance of alpha-subunit as a tumor marker for gonadotropin-producing pituitary adenomas.

We studied gonadotropin hormone alpha-subunit and gonadotropin secretion in four patients with gonadotropin-producing pituitary adenomas. All four patients had elevated plasma alpha-subunit levels, ranging from 2.8-8.5 ng/ml (normal, less than 0.5 ng/ml). alpha-Subunit responses to LHRH were less than those in seven patients with primary gonadal failure. The relative proportions of the gonadotropin and alpha-subunit peaks in one patient were the same before and after LHRH administration, based on gel filtration studies of plasma. The alpha-subunit levels decreased little during testosterone treatment in the two adenoma patients so treated. Immunohistochemical study of the adenomas from two patients demonstrated definite staining with alpha-subunit and gonadotropin antisera. Elevated plasma levels of alpha-subunit and its relative unresponsiveness to LHRH stimulation or testosterone suppression suggest that the alpha-subunit originated in tumor tissue and that its measurement is useful for the diagnosis of a gonadotropin-producing tumor in patients with elevated plasma levels of LH and/or FSH.

Corticotropin-releasing factor test in normal subjects and patients with hypothalamic-pituitary-adrenal disorders.

Corticotropin-releasing factor (CRF) tests were performed in normal subjects and patients with hypothalamic-pituitary-adrenal disorders. In normal subjects, after iv administration of 500 micrograms synthetic ovine CRF, plasma ACTH rose significantly to approximately 3.6 times the basal level at 30-60 min and cortisol reached a peak of 2.3 times the basal level at 60-90 min, whereas aldosterone peaked at 1.6 times the basal level at 60 min. Injection of 100 micrograms CRF in normal subjects also caused a significant increase in plasma ACTH and cortisol levels but only a slight increase in aldosterone. However, the total hormone released and their peak levels were lower than those elicited by the 500-microgram dosage. In patients with Cushing's disease, although the basal and peak levels of plasma ACTH and cortisol induced by administration of CRF were variable, the ratios of increase for the two hormones elicited by CRF were lower than those in normal subjects, especially for cortisol. In patients with Cushing's syndrome due to an adrenal adenoma, basal levels of ACTH were markedly suppressed and plasma ACTH and cortisol did not rise after CRF. In patients with isolated ACTH deficiency or Sheehan's syndrome the basal level of plasma ACTH was less than 5 pg/ml and no change in plasma ACTH occurred after injection of CRF. In patients with Nelson's syndrome or Addison's disease the basal levels of ACTH were extremely elevated but infusion of CRF increased plasma ACTH to even higher levels.

Effect of immobilization stress on testosterone and inhibin in male rats.

Adult male Wistar rats were subjected to acute and chronic immobilization stress. Changes in plasma levels of LH, FSH and testosterone and in the content of testicular inhibin and testosterone were studied. Plasma LH levels decreased significantly in response to both acute and chronic stress. Significant decreases in plasma testosterone content were also observed after chronic stress. In contrast, plasma FSH and testicular bioassayable inhibin content did not change after acute or chronic stress. These findings indicate that in male rats immobilization stress induced a dissociation in LH and FSH responses, and decreased testosterone while inhibin remained unaffected.