Prostaglandin E2 induces up-regulation of murine macrophage beta-endorphin receptors.

Cultured murine bone marrow macrophages specifically bound 125I-labeled beta-endorphin. Binding was displaceable by 100 times molar excess of full-length beta-endorphin but was insensitive to the opioid receptor antagonist, naloxone. Binding was inhibited by beta-endorphin's C-terminal tetrapeptide, lys-lys-gly-glu, but not by the truncated N-terminal 27 amino acid fragment, indicating that binding of beta-endorphin to this receptor is dependent on its C-terminus. Macrophages incubated for 24 h with 10(-8)-10(-5) M prostaglandin E2 showed a dose-dependent increase in beta-endorphin binding, implying receptor up-regulation. This was also observed in response to the phosphodiesterase inhibitor, isobutylmethylxanthine, indicating that regulation of these receptors may be mediated through a cAMP-dependent process. This is the first demonstration that beta-endorphin receptor expression can be positively regulated.

Adrenal androgens and cortisol in major depression.

Nine depressed subjects and nine comparison subjects completed a study of abnormalities in adrenal androgen and cortisol metabolism. Serum levels of cortisol and dehydroepiandrosterone (DHA) at 8:00 a.m. and 4:00 p.m. revealed hypercortisolemia and loss of diurnal DHA variation but not cortisol variation in the depressed group. These findings suggest that in depression, adrenal androgens, in contrast to cortisol, are partially regulated by mechanisms independent of ACTH.

Malignant transformation of a Hürthle cell tumor: case report and survey of the literature.

Hürthle cell carcinoma is a relatively uncommon type of well-differentiated thyroid carcinoma. Its diagnosis has been controversial due to the difficulty in separating Hürthle cell adenoma from Hürthle cell carcinoma, thus the term Hürthle cell tumor is often used to describe both lesions. The present case of anaplastic giant-cell carcinoma in an 81-yr-old woman arose in a Hürthle cell tumor. This case illustrates the propensity of Hürthle cell tumor to undergo "malignant transformation" and argues for a more aggressive approach to such tumors.

Control of adrenal androgen secretion.

The human adrenal gland secretes large amounts of androgens and androgenic precursors as compared with the adrenal glands of other species. In part, this pattern of secretion is regulated by ACTH, analogous to the control of cortisol. However, in many instances, including adrenarche, puberty, aging, and severe illness, secretion of adrenal androgens and cortisol diverge for reasons which are not clear. Factors endogenous to the adrenal gland may have a role in the modulation of adrenal androgen secretion. These include the centripetal blood supply of the adrenal gland, availability of cofactors of steroidogenic enzymes, and intrinsic properties of adrenal cells or enzymes. However, these mechanisms may, in turn, be modified by factors exogenous to the adrenal gland. Possible evidence for a regulatory role for such known substances as growth hormone, IGF-1, gonadotropins, estrogens, angiotensins, prostaglandins, insulin, EGF, and POMC-related peptides is discussed. Furthermore, pituitary or extrapituitary substances, in addition to known hormones, may have a role in the control of adrenal androgen secretion. Several lines of evidence include the inability of ACTH to maintain a normal adrenal androgen/cortisol ratio in adrenally suppressed patients, or experimentally, in hypophysectomized chimpanzees. Evidence for such factors derived from fetal and adult human pituitary gland is discussed.

Adrenarche.

Between 6 and 8 years of age, while cortisol concentrations and production rates remain constant, urinary excretion and circulating concentrations of DHA, DHAS, and other adrenal androgens increase progressively. These hormonal changes, which constitute the adrenarche, are accompanied by the appearance of axillary and pubic hair and a transient acceleration of linear growth and bone maturation. Increased adrenarchal concentrations of adrenal androgens may also contribute to the observed developmental decrease in concentration of SHBG and increase in bioavailable testosterone that occur in preadolescent boys. It is not known if extraadrenal factors, intraadrenal factors, or a combination of both are responsible for the occurrence of adrenarche. However, known hormones, such as ACTH, prolactin, gonadotropins, and estrogens, do not appear to cause the adrenarche. During adolescence, ACTH and cortisol concentrations remain constant, but concentrations of adrenal androgens continue to increase. The existence of a relationship between adrenarche and puberty has been suggested, partly because increased concentrations of adrenal androgens in undertreated congenital adrenal hyperplasia have been associated with cases of true precocious puberty in boys. However, there is evidence against a causal relationship, including the observation that children with treated primary adrenal insufficiency have been found to enter puberty normally. Adrenarche may cause a transient acceleration of growth and serve as a permissive factor in male puberty but does not appear to be necessary for the initiation of puberty.

Dehydroepiandrosterone reduces cancellous bone osteopenia in ovariectomized rats.

The effects of dehydroepiandrosterone (DHA) on cortical bone at the tibial diaphysis and cancellous bone at the tibial metaphysis were determined in intact and ovariectomized rats. Total plasma DHA was reduced at 10 and 16 wk after ovariectomy. Intact and ovariectomized rats were implanted monthly with controlled-release subcutaneous pellets containing 2.5 mg of DHA or placebo. Plasma DHA was elevated in DHA-treated intact rats and was near normal in hormone-treated ovariectomized rats. Ovariectomy resulted in severe cancellous bone osteopenia, which was reduced in DHA-treated animals. Cross-sectional and cortical areas were increased at the diaphysis in ovariectomized rats, and this was not altered by DHA treatment. Bone formation at the endosteal and periosteal surfaces of the tibial diaphysis was decreased 16 wk after ovariectomy, and DHA treatment appeared to antagonize these changes. We interpret these results as evidence that decreased peripheral DHA levels contribute to the skeletal changes in ovariectomized rats.

Induction of type II T4-5'-monodeiodinase activity in brown adipose tissue in fasted mice.

In order to study the effect of starvation on brown adipose tissue (BAT) type II 5'-monodeiodinating activity (5'MDI), type II 5'MDI was measured in vitro in the presence of 20 mM dithiothreitol, 1 mM propylthiouracil, 2 nM thyroxine (T4) and appropriate amounts of 600 X g infranatant of BAT from fed control or 3 day fasted mice, with or without daily T4 replacement (1.2 micrograms/100 g bw) during starvation. I- released from 125I-T4 was measured by ion-exchange column chromatography. Activity of BAT 5'MDI was markedly elevated in the 3 day fasted group (133 +/- 28 fmol I-/h per mg protein vs. 26 +/- 6.4; p less than 0.05). Kinetic studies using BAT infranatant suggested that fasting-induced activity is associated with a similar change in the Vmax, but no demonstrable change in apparent Km of T4 monodeiodination. T4 replacement during fasting, which normalized both serum T4 and T3 in fed and 3 day fasted groups, did not stop the increase of BAT 5'MDI in the fasted group (p less than 0.01). The data suggest that: (1) the fasting-induced increase in BAT 5'MDI is due mainly to the changes in capacity rather than the affinity of the enzyme, and (2) the fasting-induced increase in BAT 5'MDI is not mediated entirely through changes in serum thyroid hormone concentration.

Recurrence of papillary thyroid carcinoma presenting as a focal neurologic deficit.

Papillary-follicular thyroid carcinoma usually remains localized to the thyroid bed and, in cases of metastasis, almost always involves the lung, bone, or liver. The two patients described here presented with papillary carcinoma and neurologic dysfunction. Total body iodine 131 scans disclosed cerebral uptake, and cerebral masses were confirmed by computed tomographic scan. Both patients presented diagnostic and therapeutic dilemmas, and ultimately underwent craniotomy. One patient's cerebral metastasis recurred and was treated by a second craniotomy. The other patient received postoperative external cerebral radiotherapy and a novel intraoperative treatment: implantation of 22 iodine 125 seeds in the tumor bed, estimated to yield 16,000 rad (160 Gy) in one year. To date, cerebral metastases have not recurred in the latter patient, although tumor has reappeared in other sites. There is little reported in the medical literature concerning cerebral metastases of thyroid carcinoma, and the present report reviews this experience and discusses treatment alternatives.

Treatment of gynecomastia with tamoxifen: a double-blind crossover study.

Benign asymptomatic or painful enlargement of the male breast is a common problem, postulated to be due to an increased estrogen/testosterone ration or due to increased estrogenic or decreased androgenic stimulation via estrogen or androgen receptor interactions. Treatment at present consists of analgesic medication or surgery. However, treatment directed against the preponderance of estrogenic stimulation would seem to represent a more specific form of therapy. In the present double-blind crossover study, one-month courses of a placebo or the antiestrogen tamoxifen (10 mg given orally bid) were compared in random order. Seven of ten patients experienced a decrease in the size of their gynecomastia due to tamoxifen (P less than 0.005). Overall, the decrease for gynecomastia for the whole group was significant (P less than 0.01). There was no beneficial effect of placebo (P greater than 0.1). Additionally, all four patients with painful gynecomastia experienced symptomatic relief. There was no toxicity. The reduction of breast size was partial and may indicate the need for a longer course of therapy. A followup examination was performed in eight out of ten patients nine months to one year after discontinuing placebo and tamoxifen. There were no significant changes from the end of the initial study period except for one tamoxifen responder who developed a recurrence of breast tenderness after six months, and one nonresponder who demonstrated an increase in breast size and a new onset of tenderness after ten months. Therefore, antiestrogenic treatment with tamoxifen may represent a safe and effective mode of treatment for selected cases of cosmetically disturbing or painful gynecomastia.

A genetic component to the variation of dehydroepiandrosterone sulfate.

Previous studies have shown wide variation in the normal range of serum concentrations of adrenal androgens, including dehydroepiandrosterone (DHA), and DHA sulfate (DHAS). Much of this variability has been shown to be due to the marked variation of the concentrations of these hormones with age. In a search for other sources of this variation, we examined the distribution of DHAS levels in 178 individuals drawn from 26 families. DHAS was chosen because of its relatively high serum concentration, long half-life, and lack of pulsatile variation. As expected, we observed a large age effect, such that it accounted for 68% of the overall variability. In addition, however, when age was factored out by appropriate polynomial regression, there was a significant genetic component to the residual variation, with a heritability of 65%. Thus there appeared to be a significant genetic determination to DHAS serum levels. The results are in accord with previous studies suggesting a genetic component to the variation in testosterone and sex hormone globulin concentrations, and the known correlation of DHAS and testosterone levels. Thus there appears to be significant genetic control of androgen concentrations in humans.

Carcinoma of the thyroid with a mixed medullary, papillary, follicular, and undifferentiated pattern.

While papillary and follicular thyroid carcinomas are frequently mixed, this is a case of a medullary, papillary, follicular, and undifferentiated carcinoma of the same gland. In addition, all four tumor types were metastatic to regional lymph nodes. The patient described herein did not demonstrate features of the multiple endocrine neoplasia type 2 syndrome. Immunoperoxidase staining for calcitonin and thyroglobulin was positive in the follicular and medullary areas of tumor. Because the embryologic origin of the thyroidal follicular cells is from the endoderm and the origin of the parafollicular cells of the medullary carcinoma is from the ectodermal neural crest, this case seems noteworthy for demonstrating mixed metastatic tumor of composite embryologic origin. Alternatively, this case may represent an extension of what has recently been termed differentiated thyroid carcinoma, intermediate type by Ljungberg and co-workers.

Evidence for adrenocortical adaptation to severe illness.

During serious illness, there are characteristic increases in serum cortisol concentrations and urinary cortisol excretion. In the present studies, we investigated these changes in glucocorticoid metabolism in relation to adrenal androgen metabolism, as measured by RIA of dehydroepiandrosterone (DHA) and DHA sulfate (DHAS). A group of 23 seriously ill men with various disorders, ill for a week or longer, was age-matched to a control group of 25 men, and the following changes were found: 1) basal serum cortisol concentrations were elevated in the ill group (P less than 0.001), 2) basal serum DHA and DHAS concentrations tended to be lower in the ill group (P less than 0.1); 3) basal serum DHA to cortisol and DHAS to cortisol ratios were decreased in the ill group by 80.3% and 77.2%, respectively (P less than 0.001); 4) ACTH-stimulated serum cortisol concentrations increased by the same absolute amount in both groups, whereas the increase in stimulated DHA concentrations in the ill group was 57.2% less (P less than 0.05), indicating a defect in ACTH-stimulated DHA reserve in serious illness; 5) basal daily unconjugated DHA excretion was lower in the ill group (P less than 0.05); (6) basal daily cortisol excretion was higher in the ill group (P less than 0.05); and 7) the basal daily urinary unconjugated DHA to cortisol ratio was 85.4% lower in the ill group (P less than 0.001). Recently, Zipser et al. described the entity of hyperreninemic hypoaldosteronism in the seriously ill. Their findings combined with our own indicate a relative shift in the metabolism of adrenal pregnenolone in serious illness away from mineralocorticoids and adrenal androgens and toward glucocorticoids. The cause of this change is unknown. We speculate that this shift of relative biochemical pathway predominance may be a factor necessary for survival during chronic severe stress.

Analysis of nonprescription capsules purported to contain an adrenal androgen.

The content of nonprescription capsules purported to contain dehydroepiandrosterone was analyzed. Five capsules labeled "dehydroepiandrosterone (DHEA) 500 mg and natural precursors" were analyzed; all were from a single lot and container. Ether extracts were used to test for DHEA, cortisol, testosterone, and androstenedione using radioimmunoassay (RIA). The protein, starch, reducing-sugar, sodium, potassium, calcium, and magnesium contents were also measured. The mean (+/- S.D.) DHEA content per capsule was 14.40 + 5.16 micrograms. A mean androstenedione concentration of 1.22 + 0.21 micrograms was measured. Cortisol and testosterone were not detectable by RIA. Concentrations of the other ingredients (mean +/- S.D. for five capsules) were as follows: protein 35.2 +/- 2.3 mg, starch 39.9 +/- 2.7 mg, reducing sugars 3.2 +/- 0.2 mg, sodium less than 1.5 mM, potassium less than 0.15 mM, magnesium 0.60 mg, and calcium 3.45 mg. The total amount of free DHEA contained in the capsules was only a small fraction of the labeled amount of that steroid and was probably inadequate for producing any measurable effects.

I-131 total-body scan: localization of disseminated gastric adenocarcinoma. Case report and survey of the literature.

This is a case of striking radioiodine and [99mTc]pertechnetate uptake by disseminated nonthyroidal (gastric) adenocarcinoma. A 65-yr-old man was euthyroid and serum thyroglobulin concentration was normal at 11 ng/ml. Bone-marrow biopsy showed that the metastatic tumor cells were negative for thyroglobulin on immunoperoxidase stain and the secretory product was mucicarmine-positive. We estimate that radioiodine uptake in the normal thyroid gland was less than 10% of total tumor uptake. At autopsy, the stomach was the site of the primary tumor, which had the same cellular and histochemical characteristics as the metastatic lesions in bone and liver. It is emphasized that the use of pertechnetate for screening patients with gastric adenocarcinoma may be clinically useful in the early detection of metastatic lesions.

Control of adrenal androgen production.

The major adrenal androgens are dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione (delta 4). Studies by Cutler et al in 1978 demonstrated that these androgens are detectable in blood of all domestic and laboratory animals studied, but that only 4 species show increase in one or more with sexual maturation: rabbit, dog, chimpanzee and man. Studies by Grover and Odell in 1975 show these androgens do not bind to the androgen receptor obtained from rat prostate and thus probably are androgens only by conversion to an active androgen in vivo. Thomas and Oake in 1974 showed human skin converted DHEA to testosterone. The control of adrenal androgen secretion is in part modulated by ACTH. However, other factors or hormones must exist also, for a variety of clinical observations show dissociation in adrenal androgen versus cortisol secretion. Other substances that have been said to be controllers of adrenal androgen secretion include estrogens, prolactin, growth hormone, gonadotropins and lipotropin. None of these appear to be the usual physiological modulator, although under some circumstances each may increase androgen production. Studies from our laboratory using in vivo experiments in the castrate dog and published in 1979 indicated that crude extracts of bovine pituitary contained a substance that either modified ACTH stimulation of adrenal androgen secretion, or stimulated secretion itself - Cortisol Androgen Stimulating Hormone. Parker et al in 1983 showed a 60,000 MW glycoprotein was extractable from human pituitaries, which stimulated DHA secretion by dispersed canine adrenal cells in vitro, but did not stimulate cortisol secretion. This material contained no ACTH by radioimmunoassay. In 1982 Brubaker et al reported a substance was also present in human fetal pituitaries, which stimulated DHA secretion, but did not effect cortisol.

A 60,000 molecular weight human pituitary glycopeptide stimulates adrenal androgen secretion.

An approximately 60,000 mol wt glycopeptide has been isolated from acetone-dried human pituitary glands which stimulates production of the adrenal androgen dehydroepiandrosterone, but not cortisol, in acute suspensions of collagenase-dispersed dog adrenal cells. Adrenal androgen secretion has generally been considered, like cortisol, to be under the control of ACTH. This new pituitary glycopeptide, with a molecular weight greater than that of proopiocortin, ACTH, PRL, or LH, may help explain instances during adrenarche, puberty, aging, and stress in which cortisol and adrenal androgen metabolism diverge.