Estrogen and progesterone receptors in gynecomastia.

The etiology of gynecomastia is unknown. There seems to be no increased incidence of malignancies in patients with idiopathic gynecomastia; however, patients with Klinefelter syndrome exhibit an increased incidence of malignancy. The authors reviewed the results of 34 patients with gynecomastia diagnosed in adolescence who, following initial evaluation, had a mastectomy. The estrogen and progesterone receptors were analyzed in these patients. Three of the patients were diagnosed with Klinefelter syndrome. These three patients exhibited elevated amounts of estrogen and progesterone receptors. None of the patients who were not diagnosed with this syndrome demonstrated significant elevation of their estrogen or progesterone receptors. The presence of elevated estrogen and progesterone receptors in patients with Klinefelter syndrome provides a potential mechanism by which these patients may develop breast neoplasms. The absence of elevated estrogen and progesterone receptors in patients with idiopathic gynecomastia may serve to clarify why these patients' disease rarely degenerates into malignancy.

Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker.

PURPOSE: This report summarizes our experiences on the protective effect of angiotensin-converting enzyme (ACE) inhibitors, especially captopril and an angiotensin II type 1 receptor blocker on radiation-induced pulmonary injury. METHOD: In the first series of experiments, adult male Sprague Dawley rats were given a single dose of either 20 or 30 Gy of gamma rays to a 35 cm2 right hemithorax port, whilst shielding the left, contralateral, lung. Perfusion scans and autopsies were performed at intervals up to 12 months post-radiation. Three different ACE inhibitors, penicillamine and pentoxifylline were given as radiation protectors and their activity compared. A model of irradiation for total bone marrow transplant (BMT) was used for the second group of experiments. Male WAC/Rij/MCW rats received total-body irradiation and a regimen of cyclophosphamide (CTX) in preparation for bone marrow transplant. The modifiers were two ACE inhibitors, captopril and enalapril, and L-158,809, an angiotensin II (A II) type 1 receptor blocker. All drugs were administered in the rats' drinking water and all were well-tolerated. RESULTS: In the irradiated rats, pulmonary damage progressed from the presence of blebs and detachment from basement membranes of endothelial cells a few days after injury, to severe arteritis and interstitial collagen deposition at 3 months, and then on to severe pneumonitis and extensive pulmonary fibrosis at 6 months. Marked increase of hydroxyproline was also found in the lungs at 6 months. These morphological changes were associated with significant decrease of ACE and plasminogen activator activity (PLA) and a marked increase of prostaglandins (PG12) and thromboxane (Txa2), substances considered as indicators of endothelial pulmonary damage. ACE inhibitors captopril, CL 24817, enalapril and CGS 13945 prevented the markers of endothelial dysfunction. Captopril and CL 24817, which contain a sulphydryl (-SH) radical in their moiety and the AII type 1 receptor blocker, L-158,809, were the most efficient in protecting the lung parenchyma from the inflammatory response and subsequent fibrosis. Penicillamine, an SH-containing compound with weak ACE inhibitory activity was also a strong antifibrotic agent but showed only modest anti-inflammatory properties. Additionally, in the irradiated rats, captopril also reduced the incidence of squamous cell skin carcinomas and subcutaneous sarcomas consequent to the highest doses of radiation. CONCLUSION: ACE inhibitors and one AII type 1 receptor blocker were effective in protecting lungs from radiation-induced pneumonitis and the development of lung fibrosis in two models of rat radiation injury. In the first series of experiments (unilateral irradiation), those ACE inhibitors containing a sulphydryl radical were more effective than those without it. This observation led to the question of whether this protective effect is related to inhibition of AII synthesis or rather to some of the collateral pharmacologic properties of these drugs, such as anti-oxidation or protease inhibition. The AII receptor blocker, however, was shown to be equally effective, if not better, in its antifibrotic capacity than any ACE inhibitor with or without an SH radical, reaffirming the role of AII in modulation of collagen synthesis.

In vitro hormonal effects of soybean isoflavones.

Isoflavones exhibit a multitude of biological effects that influence cell growth and regulation, and, thus, may have potential value in the prevention and treatment of cancer. Isoflavones are weak estrogens and can function both as estrogen agonists and antagonists depending on the hormonal milieu and the target tissue and species under investigation. Genistein, one of the two primary isoflavones in soybeans, has attracted much attention from the research community, not only because of its potential antiestrogenic effects, but because it inhibits several key enzymes thought to be involved in carcinogenesis. Although still speculative, greater dietary incorporation of soybean products, because of the high concentration of isoflavones, may be a safe and effective means of reducing cancer risk.

Plasma copper and iron changes in sheep after left lung inhalation injury: effect of the thromboxane antagonist BM 13.177 (Solutroban).

A significant decline in plasma concentrations of copper and iron were observed in sheep exposed to preferential smoke inhalation of the left lung. The decline was evident 30 minutes after smoke inhalation, and the levels of both trace metals persisted at quite low levels for up to the 18-hour time interval after injury. From that time a gradual recover for copper but not for iron levels was observed so that by 24 hours the levels of copper were in the same range of those at baseline. Copper and iron levels showed an inverse correlation to airway peak and plateau pressures and left lung vascular resistance index and a direct correlation to left lung blood flow. Administration of BM 13.177 (Solutroban), a thromboxane antagonist, before exposure to smoke inhalation protected the sheep from the decline of copper and iron levels in plasma. In these animals airway peak and plateau pressure, left lung vascular resistance, and blood flow were also unmodified. Lipid peroxidation of the lung tissue by oxygen free radicals were lower than in those animals that did not receive BM 13.177. There was likewise a tendency of a decreased wet-to-dry weight ratios in the animals treated with BM 13.177. BM 13.177 treatment in an inhalation injury model might partly protect lung damage and parallels unchanged plasma copper and iron levels. The plasma copper and iron may therefore be an indicator of acute lung damage.

Angiotensin-1-converting enzyme activity as index of pulmonary damage in thermal injury with or without smoke inhalation.

Serum angiotensin-converting enzyme (ACE) activity, plasma renin activity (PRA), and serum aldosterone levels were measured up to four weeks in a population of adults exposed to thermal injury, with or without concomitant exposure to smoke inhalation. In 10 patients, plasma levels of angiotensin-2 and ACE activity in bronchial lavage were also evaluated. Patients with severe burn injury had a significant decline of serum ACE activity while the concentrations of aldosterone and PRA were markedly elevated. Smoke inhalation seemed to counterbalance the decline of serum ACE activity, and, in the last group of patients, ACE concentrations were higher than those recorded in patients suffering only from cutaneous burn. The ACE activity was evidenced in bronchial lavage of patients exposed to smoke inhalation with the highest values present in the first day after the injury. The same patients had also very elevated levels of plasma angiotensin 2. In conclusion, serum ACE activity decreases in burn patients according to the severity of the cutaneous burn; smoke inhalation influences serum levels of the enzyme with concentration values opposite to the low ones present in cutaneous burn. Finally, the enzyme activity has an independent pattern from that of the other components of the renin angiotensin aldosterone system. The evaluation of ACE activity may be a marker of pulmonary damage in smoke inhalation.

Effect of acute smoke inhalation on angiotensin converting enzyme, plasminogen activator, and angiotensin-II in the dog.

Smoke inhalation injuries in humans are associated with many uncontrolled variables which impact on the lung and make the cause of the pulmonary response difficult to assess. In this report, an established model of smoke inhalation injury in the dog was used to study the early responses of tissue and serum angiotensin-converting enzyme (ACE), tissue plasminogen activator (PLA), and plasma angiotensin II. Animals were exposed to smoke from burning sawdust and kerosene for five minutes. The hemodynamic and pulmonary mechanical responses were typical with a rise in pulmonary artery pressure, pulmonary vascular resistance, and venous admixture (shunt fraction) while dynamic compliance fell. Within five minutes of smoke exposure, lung ACE declined without any change in serum ACE. Lung PLA dropped one hour after injury. Plasma angiotensin II increased within 30 minutes without evidence for systemic hypertension. These early enzymatic changes substantiate the presence of pulmonary endothelial damage known to occur in this form of chemical injury. These changes may condition the lung's physiologic response to the injury and to additional stresses which are multiple when smoke inhalation occurs in conjunction with a cutaneous burn.

Serum copper concentration as an index of clinical lung injury.

The purpose of this ongoing study is to determine whether thoracic radiotherapy for lung cancer produces an early increase in serum copper (Cu) concentration, an increase which might predict clinical outcome. Copper and iron concentrations were measured in serum obtained from nonsmall cell lung cancer patients at 0, 1, 2, 4, and 6 weeks after the start of radiotherapy. Control groups included patients irradiated for breast cancer (low dose of radiation to the lung), for endometrial, cervical or prostatic cancer (no dose to lung), and patients with congestive heart failure, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), and cutaneous burns with or without smoke inhalation (no irradiation). Serum Cu concentration increased at least 10 micrograms/dl from the pretreatment level in approximately 75% of the adenocarcinoma and squamous cell lung cancer patients, but in only 1 of 4 undifferentiated lung cancer cases. In virtually all of these responders, serum Cu increased to a maximum at 2 weeks after the start of therapy, then plateaued or decreased slightly despite continuing irradiation. Within the subset of squamous cell lung cancers, there was a direct correlation between the degree of histologic differentiation and both baseline serum Cu concentration and the probability of an early increase therein. In contrast, only 33% of breast cancer patients and 15% of endometrial, cervical and prostate cancer patients exhibited an increase in serum Cu concentration at 2 weeks after the start of radiotherapy. Serum Cu concentration was within normal limits in virtually all patients with congestive heart failure, pulmonary hypertension, and COPD. Burn patients exhibited a significant reduction in serum Cu, although concomitant smoke inhalation increased serum Cu back to low-normal levels. Serum iron concentration did not change significantly in any category of patients. These data suggest that thoracic radiotherapy for well differentiated non-small cell lung cancer is accompanied by an early increase in serum Cu concentration. This increase is partly but not wholly related to lung dose in particular rather than tissue dose in general, and specifically reflects radiation-induced lung injury rather than pneumopathy in general. In lung cancer patients, the change in serum Cu concentration during the first 2 weeks of radiotherapy exhibits a sufficiently broad range (+60 to -13 micrograms/dl) to permit testing this parameter as a predictor of tumor response and pulmonary complications.

Brain surface exposure to CO2 and NdYag laser application: effect on pulmonary endothelium response in the rat.

Pulmonary endothelial cells and the renin-angiotensin-aldosterone (RAA) system respond to different types of injury (direct or indirect) with variations in their functions. These variations influence the regulatory mechanisms of pulmonary and systemic blood pressure, electrolyte balance and fibrinolysis. Concentration changes of some components of the RAA system and lung plasminogen activator were observed following NdYag laser application to the brain surface in rats. These changes were similar to those observed in cutaneous burn and haemorrhagic hypotension. CO2 laser application did not cause the same changes.

Effect of wood combustion smoke inhalation on angiotensin-1-converting enzyme in the dog.

One lung of each dog was exposed to smoke from burning pine wood, while the other was subjected to acute hypoxia. Angiotensin-1-converting enzyme (ACE) activity in biopsied tissue of the smoke-exposed lung was markedly increased immediately after the injury and even higher 30 minutes later. No change in ACE activity was observed in the hypoxic contralateral lung. Serum ACE activity did not change significantly following anesthesia and before smoke inhalation. Serum aldosterone and cortisol levels increased at this juncture. Smoke inhalation caused intra-alveolar hemorrhages and edema. Pulmonary and systolic, diastolic and mean pressures, pulmonary capillary, wedge pressure, cardiac output and systemic and pulmonary arteriolar resistances remained unchanged throughout the experiment. The changes of ACE activity are presumably a direct effect of smoke inhalation. They are seen as an early response of the lung endothelial cells to many types of injury (chronic hypoxia, bleomycin or monocrotaline administration) and may represent an important step in the development of the organ's response to the injury.

Prolactin, corticotropin, and gonadotropin concentrations following thermal injury in adults.

The concentration of serum prolactin (PRL), plasma corticotropin (ACTH), serum follicle stimulating (FSH), and luteinizing (LH) hormones were measured in 28 adult burned patients (25 males and three females). Morning and night determinations were performed for each hormone. Serum PRL was elevated in males up to the fourth week after the thermal injury. Plasma ACTH increased significantly on the second day postburn and returned gradually to normal on the fifth; serum FSH and LH increased on day 1, then decreased significantly on day 2 and remained low for about 2 weeks. In females, while PRL increased significantly, the gonadotropins were slightly elevated and the ACTH remained within normal limits for the 3 days during which it was possible to study these patients. In all subjects the circadian rhythm of the four measured hormones showed significant variations from the normal pattern.

Estradiol receptor-binding protein in head and neck neoplastic and normal tissue.

Estradiol (E2) receptor-binding protein was measured in 42 neoplasms and normal tissues from the head and neck region. Tissues with high E2 receptor protein content included normal skin and normal mucosa of the nose and the floor of the mouth and of the parotid and submandibular salivary glands. Two of four papillary carcinomas of the thyroid, three of five pleomorphic adenomas of the parotid, four of six squamous cell carcinomas of the oral cavity, one of angiofibroma of the nose, and an eye (sclera) melanoma also had a high content of E2-binding protein. The demonstration of estrogen receptors in these neoplasms may indicate that these tumors also, as many breast lesions, may be hormone-dependent. If this is correct, an appropriate hormonal treatment may influence their biological evolution.

Circadian rhythms of serum aldosterone, cortisol and plasma renin activity in burn injuries.

Circadian rhythm of serum aldosterone and cortisol concentrations and of plasma renin activity (PRA) were measured by radioimmunoassay in 10 adults with thermal injuries. The determinations were begun 6 to 48 hours after the injury and continued for five consecutive days four times a day. In all patients, the normal pattern of the circadian rhythm for all three hormones disappeared and values remained quite high at any time of the day or the night. Four patients developed an hypertensive crisis with quite elevated levels of aldosterone, cortisol and plasma renin activity. The same hormones were also found very elevated in two hypotensive patients with 80 percent or more of injured body surface who were in agonal conditions and succumbed to the injury.

Incidence of post burn hypertensive crisis in patients admitted to two burn centers and a community hospital in the United States.

Fortynine patients of 193 admitted (25%) with second and third degree burns to 3 hospitals in different geographical areas of the United States developed a hypertensive crisis within three to four days after admission. The crisis usually lasted from 5 days to about two weeks. Serum sodium levels decreased significantly in hypertensive patients one or two days before the peak of the hypertensive crisis and, in the Center where it was measured, plasma renin activity increased in an opposite trend to the fall of sodium. BUN and creatinine reached their highest levels in hypertensive patients two days after the peak of the crisis. Autopsies were performed on 23 patients who succumbed to the injury: eleven of them (48%) were hypertensive and had marked hypertrophy of left and right heart ventricles and of the adrenal glands when compared to the normotensive burn subjects. The cells of the zona fasciculata and the zona glomerulosa of the adrenal glands were very compact at histologic examination thus suggesting hyperactivity. This data shows that the incidence of hypertension in burn subjects is twice as high as that of the US population. Further studies of the renin-angiotensin-aldosterone system and the adrenal cortical function are indicated by the changes in plasma renin activity and the glandular weight and morphology seen at autopsy.