Refractory Cushing's disease caused by multinodular ACTH-cell hyperplasia.

A patient with pituitary-dependent hypercortisolism, unresponsive to resection of nodules in the anterior lobe, is described. Histochemical stains of the nodules showed multiple, focal, cellular expansions of the fibrovascular stroma. Transitions between normal and expanded adenohypophysial acini were present. Immunoperoxidase stains for ACTH and other pituitary hormones revealed that these multiple foci contained an excess of ACTH-positive cells. Less than 10% of the cells in these foci were negative for ACTH and positive for other hormones. Serial sections showed that these foci of predominantly ACTH-producing acini were not connected. Clinical, morphological, and immunohistochemical data indicated that ACTH-cell hyperplasia caused Crushing's disease in this patient. Pathologic study of individual cases should concentrate on determining whether hyperplasia or adenoma exist at the time of surgical exploration of the pituitary gland, since this determination is important to proper treatment. Tentative criteria to recognize ACTH-cell hyperplasia are: 1. Multiple foci of ACTH laden cells. 2. A minor subpopulation of cells of alternate hormone series. 3. Expansion without destruction of acini in the adenohypophysis.

Zinc does not acutely suppress prolactin in normal or hyperprolactinemic women.

In rat pituitary cells in vitro physiological zinc concentrations selectively inhibit basal and stimulated PRL release. This study was done to investigate the serum PRL response to an oral zinc challenge in vivo. Eight hyperprolactinemic [mean serum PRL, 76.0 +/- 43.8 (+/- SD) micrograms/L] and 10 normal (mean serum PRL, 9.6 +/- 2.8 micrograms/L) women were studied. All women had normal thyroid, renal, and hepatic function, and none was taking any medications. Each was studied twice, after both oral zinc (50 mg) and placebo, given in random order. Blood was withdrawn every 15 min from 30 min before to 210 min after zinc or placebo administration; TRH (500 micrograms) was given iv at 180 min. Both hyperprolactinemic and normal women absorbed the zinc well, achieving similar maximal plasma zinc levels [hyperprolactinemic women, 39.5 +/- 6.9 (+/- SD) mumol/L; normal women, 33.3 +/- 7.0; P less than 0.001 vs. placebo]. When 2 women who became symptomatic after zinc administration were excluded, there were no significant differences in basal or TRH-stimulated serum PRL levels after zinc vs. placebo. These findings indicate that zinc is not involved in the acute in vivo regulation of PRL secretion in humans.

Morphine inhibits the pituitary-adrenal response to ovine corticotropin-releasing hormone in normal subjects.

To determine the locus of opiate modulation of ACTH secretion, 11 normal subjects were given ovine corticotropin-releasing hormone (CRH) 30 min after receiving either placebo or morphine sulfate. Plasma ACTH, cortisol, arginine vasopressin (AVP), epinephrine, norepinephrine, and CRH were measured 30 min before and up to 150 min after CRH administration. Morphine blunted the ACTH response for the first 60 min and cortisol response for the first 90 min after CRH administration. Morphine did not lower arginine vasopressin or catecholamine levels. To determine whether morphine's effect on ACTH and cortisol was due to a direct action on the corticotroph cell, dispersed rat pituitary cells were perifused with medium containing 1 microgram/ml morphine sulfate or medium alone. Morphine had no effect on the ACTH response of these cells to 10 nM CRH pulses. Similarly, morphine had no effect on ACTH production by dispersed rat pituitary cells in monolayer culture in response to 90- and 180-min incubations with 5 nM CRH. We conclude that morphine blunts the early response of the pituitary gland to CRH in vivo. Based on the lack of a direct effect of morphine on rat pituitary cells in vitro, we postulate that morphine given in vivo may modulate the pituitary ACTH response to CRH through other suprapituitary factors.

Vertebral body bone mineral content in hyperprolactinemic women.

Hyperprolactinemia with amenorrhea and galactorrhea generally has a benign clinical course without treatment. Prolonged amenorrhea due to early surgical castration or premature menopause is, however, associated with reduced bone mass and increased risk of fractures. Previous studies in hyperprolactinemic women suggested an association with decreased cortical bone density. To determine whether hyperprolactinemia is associated with reduced trabecular bone mineral, we studied 13 hyperprolactinemic women and matched normal women by quantitative computed tomographic scans of the vertebral bodies. No patient had taken bromocriptine and one patient had previously unsuccessful transsphenoidal surgery. Each patient was matched with a normal woman on the basis of race, age +/- 52 weeks, parity, exercise, tobacco use, oral contraceptive (OCP) use, and alcohol use. No subject was currently taking OCPs. Calcium, phosphorus, and protein intakes were estimated from a 3-day diet diary. The mean duration of amenorrhea was 98.9 +/- 79.7 (SD) months. The mean height, weight, serum 25-hydroxyvitamin D (25,OHD), serum 1,25 dihydroxyvitamin D [1,25(OH)2D] and daily intakes of calcium, phosphorus, and protein were not different. The bone mineral content for each patient fell within +/- SD of the mean of the normal subjects. The mean bone mineral content (mg K2HPO4 eq/ml) of the patients was 10% less than in the normal subjects (144.6 +/- 31.4 (SD) vs. 160.1 +/- 26.6, P less than 0.05). The slope of the regression of bone mineral content and age (mg K2HPO4 eq/ml X yr) was similar in patients (-2.4 +/- 1.1) and normal subjects (-2.3 +/- 1.0). We conclude that hyperprolactinemia is associated with reduced bone mineral content, but does not necessarily produce persistent acceleration of the age-related decline in bone density.

Effect of bromocriptine on affect and libido in hyperprolactinemia.

Six women with primary hyperprolactinemia (mean prolactin level, 50 ng/ml) were matched with six normal women on eight factors influencing life style. Observers blind to endocrine status followed the subjects weekly for 10 weeks. Patients took bromocriptine, 2.5 mg twice daily, or placebo in a randomized double-blind sequence with crossover at 5 weeks. The mean Hamilton score for the patients was compatible with mild depression and higher than that for normal subjects during placebo but not during bromocriptine treatment. Libido was similar in both groups during placebo and bromocriptine. The mean number of orgasms reported per day was lower in patients than in normal subjects during both treatment conditions, although one patient reported orgasms during drug treatment only. Hyperprolactinemia in women may be associated with mild depression and a decrease in orgasmic frequency.

The effects of prolactin on rat ovarian function.

Hyperprolactinemia has been associated with several reproductive disorders. To investigate whether hyperprolactinemia directly affects rat ovarian function, we examined the ovarian histopathology and the activities of the four ovarian enzymes 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17-hydroxylase (17-OH), 17,20-desmolase (17,20-D) and aromatase in hyperprolactinemic rats and controls. Hypophysectomized, gonadotropin-treated Fisher rats were made hyperprolactinemic by isografting pituitary glands under the kidney capsule. The control animals received skeletal muscle. The ovaries were resected, pooled according to prolactin levels and microsomal enzyme activities were measured from each pool. Prolactin (PRL) levels were 344 +/- 23 ng/ml in the hyperprolactinemic rats and 18 +/- 5 ng/ml in the controls (p less than 0.001). Estradiol concentrations were 609 +/- 47 pg/ml in the hyperprolactinemic animals and 56 +/- 13 pg/ml in the controls (p less than 0.001). Ovarian and uterine weights were significantly higher in the hyperprolactinemic rats (p less than 0.02). Ovarian histopathology demonstrated benign polycystic transformation in the hyperprolactinemic animals. Hyperprolactinemia had no effect on 3 beta-HSD, but was associated with significant decreases in the 17-OH, 17,20-D and aromatase activities when compared to controls (p less than 0.001). We conclude that prolactin has a direct effect on rat ovarian function which appears to be independent of changes in gonadotropin secretion.

A potential role for prolactin in zinc homeostasis.

Zinc is an important trace metal co-factor for many metallo-enzymes and may have a critical role in the stabilization and function of biomembranes. Zinc-depleted animals increase their fractional absorption of zinc to restore zinc homeostasis. This increase in fractional absorption is not currently known to be hormonally-mediated. Recently, zinc has been shown to suppress the output of prolactin from dispersed pituitary cells in vitro at physiologic concentrations. Clinical states associated with a tendency to zinc deficiency are also associated with a tendency to hyperprolactinemia. These observations are consistent with the hypothesis that prolactin regulates the uptake and distribution of zinc and that zinc suppresses prolactin in closure of a negative feedback regulatory loop.

Amenorrhea-galactorrhea due to occult hypothyroidism.

A 25-year-old woman with galactorrhea, oligomenorrhea, hyperprolactinemia, and CT evidence of pituitary enlargement had transsphenoidal microsurgery with initial resolution of hyperprolactinemia, but persistent oligomenorrhea and galactorrhea. In retrospect, she had biochemical evidence of primary hypothyroidism before operation, despite being clinically euthyroid. Administration of thyroid hormone resulted in resolution of the pituitary enlargement and the symptoms.

Hyperprolactinemia, amenorrhea, and galactorrhea. A retrospective assessment of twenty-five cases.

The syndrome of hyperprolactinemia, galactorrhea, and amenorrhea is frequently caused by a pituitary tumor. Transsphenoidal surgical removal is often advocated for microadenomas, tumors smaller than 10 mm, to prevent the progression of these small adenomas into large tumors. Because no strong evidence indicates that microadenomas naturally progress to macroadenomas, we studied 25 women who had had hyperprolactinemia, amenorrhea, or galactorrhea for a mean duration of 11.3 years. Their mean initial prolactin level was 225 ng/mL (normal, less than 36 ng/mL). Of 22 patients presenting with amenorrhea, 7 resumed menses spontaneously. Galactorrhea resolved completely in 6 of the 19 patients with this disorder. Only 1 patient had progression of a sellar abnormality, and this was slight. Visual fields remained full in all patients, and basal adrenal and thyroid functions remained normal. The mean prolactin level was 155 ng/mL at the reevaluation (p less than 0.01, initial versus reevaluation levels). Hyperprolactinemia apparently has a benign clinical course in most women, and we advocate a conservative approach to management of this disorder.

The effects of prolactin on rat testicular steroidogenic enzyme activities.

To investigate whether hyperprolactinemia directly affects rat testicular steroidogenesis, we examined the effects of prolactin (PRL) on microsomal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) 17-hydroxylase (17-OH), 17,20-desmolase (17,20-D), 17-ketosteroid reductase (17-KSR) and aromatase enzyme activities. Adult hypophysectomized, gonadotropin-treated Fisher rats were rendered hyperprolactinemic by isografting pituitaries under the kidney capsule. The controls received skeletal muscle. All rats were sacrificed 7 days later and serum PRL was measured in each animal. PRL levels were 198 +/- 14 ng/ml in the hyperprolactinemic rats and 4.3 +/- 0.6 ng/ml in the controls (P less than 0.001). The testes were resected, pooled according to PRL levels, and microsomes were prepared from each pool. The activities of the 3 beta-HSD, 17-OH, 17,20-D, 17-KSR and aromatase were measured using as substrates 14C dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, androstenedione and testosterone, respectively. Hyperprolactinemia was associated with significant decreases in 3 beta-HSD, 17-OH, 17,20-D, 17-KSR and aromatase activities when compared to controls (P less than 0.005). We conclude that prolactin may have a direct effect on rat testicular steroidogenesis which appears to be independent of changes in gonadotropin secretion.