High Pharmacological Doses Research Articles

Synaptic Plasticity in the Hippocampus: Effects of Estrogen from the Gonads or Hippocampus?

Different effects of estrogen on synaptic plasticity have [corrected] been reported. Here, we summarise effects of low, gonad-derived serum estrogen concentrations, of intermediate concentrations, provided by hippocampal cells, and of pharmacological doses of estrogen on synapses and spines and on the expression of synaptic proteins. No effects of low concentrations were found. To study the effects of hippocampus-derived estradiol, we inhibited hippocampal estrogen synthesis by treatment of hippocampal cell cultures with letrozole, an aromatase inhibitor. Alternatively, we used siRNA against Steroidogenic acute regulatory protein (StAR). Spines, synapses, and synaptic proteins were significantly down regulated in response to letrozole and in siRNA-StAR transfected cells. Application of high pharmacological doses of estradiol promoted only synaptophysin expression, a presynaptic protein, but did not increase the number of boutons. Our results point to an essential role of endogenous hippocampal estrogen in hippocampal synaptic plasticity rather than to a direct influence of estrogens derived from peripheral sources, such as the gonads.

Basic Science

Abstract The hormone melatonin has been reported to exhibit antiepileptic properties in clinical trials. However, recent animal studies have demonstrated that melatonin can have opposite effects on brain function, depending on the dose and timing of melatonin administration. In other words, although high pharmacologic doses are able to decrease brain excitability and suppress seizures, smaller doses of melatonin (administered at night when melatonin levels in the brain are highest), similar in amount to what is produced by the brain, can actually increase the excitability of neurons, making them more susceptible to seizure activity. In this study, we used an animal model of epilepsy to study the effects of melatonin on seizure development. We made two important observations: (a) seizures induced by the drug pilocarpine occurred with a shorter latency at night (when brain melatonin levels are highest) than during the day, and (b) when small doses of drug that block melatonin receptors are injected directly into the hippocampus, an area of the brain important for the development and spread of seizures, then seizures during the night were delayed. Furthermore, this effect was reversed by a drug that blocks the activity of GABA, the major inhibitory neurotransmitter in the brain, suggesting that melatonin may decrease GABA-receptor function in the hippocampus. Although we did not study the effects of melatonin directly, our data suggest that endogenous melatonin may enhance brain excitability and contribute to the development of epileptic seizures. This process may be involved with certain forms of nocturnal epilepsy and may raise a caution for persons with epilepsy who take melatonin. Epilepsia 2005;46(4).

Tumor necrosis factor-alpha in the pathogenesis and treatment of cancer.

The critical pathogenic role of tumor necrosis factor (TNF)alpha in inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease is well established. The role played by TNFalpha in both the treatment and pathogenesis of cancer remains less understood. Recent advances help to create a framework for understanding seemingly paradoxical effects of TNFalpha as both an anti-tumour agent and a mediator of tumour growth. High pharmacological doses of TNFalpha combined with chemotherapy can regress otherwise intractable tumours, and efforts continue to optimize delivery to avoid severe toxicities. Mounting evidence demonstrates that pathophysiological concentrations of endogenous TNFalpha act to promote tumour genesis and growth. The cellular and molecular pathways mediating these phenomena are starting to be clarified. Current data support the continued development of both TNFalpha and anti-TNFalpha therapy for clinical treatment of cancers in distinct settings.

Antioxidant vitamins and blood pressure.

Synthesis of free radicals might play a role in the cellular process of atherosclerosis. This process can be stopped by antioxidants such as beta-carotene, vitamin C, or vitamin E, which will inactivate the effects of free radicals. Although antioxidant vitamins have not been proven to prevent cardiovascular diseases through the modulation of lipid peroxidation, it has been suggested that peroxidation might be a pathway to such prevention, mediated through the effects of antioxidants on blood pressure (BP) and arterial stiffness. Several observational epidemiologic studies and some clinical trials have suggested an inverse association between dietary intake of fruits and vegetables, and BP. An inverse link between serum levels of vitamin C and BP has also been determined in observational epidemiologic settings. Some relations between other antioxidant vitamins (retinol and beta-carotene) and BP are reported; they confer the same inverse association. However, results from clinical trials testing the effect of a single, or a combination of antioxidants at high pharmacologic doses have revealed inconsistent BP findings. So far, no evidence confirms that oral antioxidant supplementation is effective in preventing or treating high BP. Additional large studies should be conducted to determine the effect on BP of antioxidant supplementation at nutritional doses.

α-Tocopherol protects against diet induced atherosclerosis in New Zealand white rabbits

In this study, we asked the question "does alpha-tocopherol supplementation prevent an increase in total plasma cholesterol (TPC) concentration and reduce the deposition of cholesterol in arterial plaques of rabbits fed atherogenic diets?" Isocaloric diets containing 0.1% cholesterol to induce atherosclerosis were enriched in one of three fats: saturated fats (SAT), monounsaturated fats (MONO), or n-6 polyunsaturated fats (POLY). Half of each of the three diets were supplemented with 2,500 IU alpha-tocopherol/kg-diet. Unsupplemented diets contained 25 IU alpha-tocopherol/kg-diet. Rabbits supplemented with alpha-tocopherol had plasma alpha-tocopherol concentrations 10-fold higher and an average TPC concentration 31% lower, P = 0.017, than rabbits fed unsupplemented diets. Among the three fat-fed groups, the difference was greatest for the POLY fat fed group (54%, P = 0.041). POLY fat-fed rabbits without alpha-tocopherol supplementation had plasma HDL cholesterol concentrations that were less than half that of rabbits fed other fats, P < or = 0.0001. In general, differences in mean esterified artery cholesterol concentrations among the three fat-fed groups, with and without alpha-tocopherol supplementation, paralleled differences in TPC concentration among the groups. This study suggests that for rabbits fed high pharmacological doses of alpha-tocopherol, atherosclerosis can be diminished in situations where the plasma cholesterol concentrations are also significantly lower.

Effects of vitamin K on calcium and bone metabolism.

The K vitamins, a group of napthoquinones, are required for the carboxylation of a limited number of proteins including the bone matrix protein osteocalcin. Vitamin K1 (phylloquinone) and vitamin K2 (menaquinones), differ regarding food source (green vegetables and fermented products, respectively), bioavailability and intermediate metabolism. Epidemiological studies provide evidence for an association between a low vitamin K intake and an enhanced osteoporotic fracture risk. Doses of vitamin K1 up to 15 times the current recommended dietary allowance have successfully been used to reduce the percentage of undercarboxylated osteocalcin in the circulation. Studies demonstrating clear beneficial effects on bone health, however, are still lacking. In contrast, therapy with very high pharmacological doses of the vitamin K2 menatetrenone has impressively been used to prevent further bone mineral loss and fracture risk in osteoporotic patients.

Chronic administration of pharmacological levels of melatonin does not ameliorate the MPTP-induced degeneration of the nigrostriatal pathway

An extensive literature suggests that melatonin may protect from the degenerative effects of central neurotoxins by acting as a free radical scavenger. The purpose of this study was to determine if melatonin would protect male C57BL6 mice from the toxicity of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to nigral dopamine (DA) neurons. Melatonin was initially dissolved in dimethyl sulfoxide (DMSO), diluted to 16 μg/ml and then provided in the drinking water for 4 weeks. Control mice drank the same final concentration of the DMSO diluent. One week before the termination of the experiment, randomly selected mice from the melatonin-treated and the DMSO-treated groups received two, three or four doses of 2.5 mg/kg MPTP free base administered subcutaneously at 2-h intervals. Additional DMSO-treated and melatonin-treated mice did not receive MPTP. Following tissue collection, melatonin concentration was measured in blood plasma collected from each animal and found to be 20-fold higher in melatonin-treated compared to DMSO-treated mice. Tyrosine hydroxylase (TH) activity and the levels of DA and dihydroxyphenylacetic acid (DOPAC) were not different in striata collected from melatonin-treated versus DMSO-treated mice which did not receive MPTP. Treatment with MPTP significantly reduced striatal TH activity, DA and DOPAC, but there were no significant differences in the reductions in any of these parameters observed in the melatonin-treated versus the DMSO-treated control mice that received the same total dosage of MPTP. These results show that the long-term administration of a high pharmacological dose of melatonin was ineffective in protecting nigral dopaminergic neurons from the neurotoxic effects of MPTP.

Endogenous Glucocorticoids Play a Positive Regulatory Role in the Anti-Keyhole Limpet Hemocyanin In Vivo Antibody Response

Glucocorticoids (GCs) are commonly reported to be immunosuppressive. Studies that support this involve the administration of synthetic GCs such as dexamethasone at high pharmacological doses and using in vitro assay systems that may have limited relevance to the role of GCs during normal in vivo immune responses. Therefore, the following experiments tested the conclusion that GCs are generally immunosuppressive. Adult male Sprague Dawley rats received adrenalectomy (ADX) or sham surgery. ADX rats were given either basal corticosterone (CORT) replacement in their drinking water (25 microg/ml) or no CORT. Rats were immunized with keyhole limpet hemocyanin (KLH), and blood samples were taken. ADX rats with no CORT replacement had reduced anti-KLH IgM and IgG responses compared with sham-operated controls. ADX rats that received basal CORT replacement had partially restored anti-KLH IgM, but still had suppressed anti-KLH IgG. Administration of GC receptor type I (RU28318) and type II (RU40555) receptor antagonists also reduced the anti-KLH IgM and IgG responses. ADX rats that received both basal CORT replacement and low dose injections of CORT on days 5 and 7 after KLH had anti-KLH IgG levels equal to those of sham-operated controls. Finally, the GC elevation 4-7 days after immunization may play a role in stimulating the IgM to IgG2a switch. GC receptor blockade reduced the anti-KLH IgG2a and splenic IFN-gamma, but not the anti-KLH IgG1, response. Given that IFN-gamma is an important regulator of the IgM to IgG2a switch, it is possible that the small rise in GC found 4-7 days after KLH facilitates IgG2a isotype switching.

Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments

Nutrition has a strong influence on the immune system of the elderly. Aging induces dysregulation of the immune system, mainly as a result of changes in cell-mediated immunity. Aging is associated with changes to the equilibrium of peripheral T and B lymphocyte subsets, such as decreases in the ratios of mature to immature, naive to memory, T helper 1 subset (TH1) to TH2, and CD5- to CD5+ cells. As a consequence, cell-mediated immune responses are weaker and neither cell-mediated nor humoral responses are as well adapted to the antigen stimulus. Undernutrition, common in aged populations, also induces lower immune responses, particularly in cell-mediated immunity. Protein-energy malnutrition is associated with decreased lymphocyte proliferation, reduced cytokine release, and lower antibody response to vaccines. Micronutrient deficits, namely of zinc, selenium, and vitamin B-6, all of which are prevalent in aged populations, have the same influence on immune responses. Because aging and malnutrition exert cumulative influences on immune responses, many elderly people have poor cell-mediated immune responses and are therefore at a high risk of infection. Nutritional therapy may improve immune responses of elderly patients with protein-energy malnutrition. Supplementation with high pharmacologic doses of a single nutrient (zinc or vitamin E) may be useful for improving immune responses of self-sufficient elderly people living at home. Therefore, nutritional deficiency must be treated in the elderly to reduce infectious risk and possibly slow the aging process.

Effects of two classes of progestagens, pregnane and 19-nortestosterone derivatives, on cell growth of human breast tumor cells: I. MCF-7 cell lines

The effects of two classes of progestagens, e.g. pregnane [Org 2058, medroxyprogesterone acetate (MPA), R5020, progesterone (PROG)] and 19-nortestosterone derived progestagens [3-ketodesogestrel (KDG), levonorgestrel (LNG), gestodene (GES), norethisterone (NE), Org 30659] on proliferation of three estradiol (E 2)-dependent human breast tumor MCF-7 cell lines of different origin [Van der Burg (B), Litton bionetics (L) and McGrath (M)] were studied. The pregnane derivatives hardly stimulated cell growth at 10 −6 M in MCF-7 B and L cells except for Org 2058 in B cells, whereas in M cells a statistically significant growth induction was observed except for PROG. The 19-nortestosterone derivatives induced cell growth at doses at 10 −7 M or higher in all three cell lines. NE, GES and Org 30659 were more potent stimulators than KDG and LNG at 10 −7 M. E 2 already showed maximal stimulation at 10 −10 M. For all three cell lines, the effects and ranking of the individual progestagens were similar. Antiprogestagens, like RU 38486 and Org 31710 could not block these stimulatory effects while antiestrogens like 4-hydroxytamoxifen and ICI 164,384 could. This suggests that cell growth by the above-mentioned progestagens occurs via an interaction with the estrogen receptor. Indeed, displacement studies with cytosol from MCF-7 M cells revealed that at very high concentrations NE, GES and Org 30659 were able to displace 50% of the radiolabelled E 2, while KDG and LNG could not. Relative binding affinities (RBAs) were 0.010, 0.025 and 0.015% for NE, GES and Org 30659, respectively. The effect of the two classes of progestagens on cell proliferation was also investigated at several dose levels in combination with E 2 (10 −10 M) in the MCF-7 B cell line. This resulted in a statistically significant inhibition of cell growth with R5020, MPA and most of the 19-nortestosterone derivatives at concentrations of 10 −8 M. Org 2058 and NE did not have any influence on E 2-induced growth. The inhibitory effects could not be blocked by antiprogestagens. In summary these studies with 3 subclones of MCF-7 cells show that the pregnane derived progestagens stimulate growth only in one subclone, whereas the 19-nortestosterone derived progestagens do so in all three subclones. The progestagens possess estrogenic activity only at high pharmacological doses, being 10,000 times weaker than estradiol. In combination with estrogens most progestagens gave a reduction of E 2-stimulated growth in the B subclone.

Hydrocortisone regulation of hyaluronan metabolism in human skin organ culture.

We studied the influence of hydrocortisone (HC) on hyaluronan (HA) metabolism in explants of human skin, a model retaining normal three-dimensional architecture of dermal connective tissue and dynamic growth and stratification of epidermal keratinocytes. The synthesis of hyaluronan and proteoglycans (PGs), and DNA, were determined with 3H-glucosamine and 3H-thymidine labelings, respectively. The total content and histological distribution of hyaluronan was studied utilizing a biotinylated aggrecan-link protein complex. A low concentration of HC (10(-9) M) stimulated the incorporation of 3H-glucosamine into hyaluronan in epidermis by 23% and reduced the disappearance rate of hyaluronan by 25% in chase experiments, resulting in a 74% increase in total hyaluronan (per epidermal dry weight) after a 5-day culture in 10(-9) M HC. On the other hand, a high concentration of HC (10(-5) M) reduced both synthesis (-42%) and degradation (-46%) of epidermal hyaluronan during 24 h labeling and chase periods. The cumulative effect of a 5-day treatment was a 24% decrease of total epidermal hyaluronan. The high dose (10(-5) M) also reduced keratinocyte DNA synthesis and epidermal thickness. In dermis, only the high (10(-5) M) concentration of HC was effective, inhibiting the incorporation of 3H-glucosamine into hyaluronan by 28%. No significant influences on total hyaluronan content or the disappearance rate of hyaluronan in dermal tissue was found. All HC concentrations lacked significant effects on newly synthesized PGs in epidermal and dermal tissues, but reduced the labeled PGs diffusing into culture medium. A low physiological concentration of HC thus maintains active synthesis and high concentration of hyaluronan in epidermal tissue, while high pharmacological doses of HC slows hyaluronan turnover and reduces its content in epidermis, an effect correlated with enhanced terminal differentiation, reduced proliferation rate and reduced number of vital keratinocyte layers.

Human, recombinant interleukin-2 induces in vitro histamine release in a dose-dependent manner.

We previously observed that human, recombinant interleukin-2 in a pharmacologic dose (200 u/ml) induced histamine release from monocyte-depleted peripheral blood mononuclear cells in vitro. Therefore, we studied the role of various pharmacologic doses of rIL-2 on in vitro histamine release. Peripheral blood mononuclear cells (5 x 10(6) cells/ml), which also contain basophils, from 13 patients scheduled for elective colorectal cancer surgery and 10 age and sex matched healthy volunteers were stimulated with rIL-2 in concentrations of 0, 50, 100, 200, 450, 900, 1,800 and 3,600 u/ml, respectively, for 1, 24 and 48 hours under standard conditions. Histamine was analysed in supernatants using the glass fiber method. Simultaneously, total cell-bound histamine was analysed in lysate from 5 x 10(6) mononuclear cells from all patients and volunteers, thus allowing determination of percent histamine release. Supernatant histamine concentration from unstimulated cells was 17.2 +/- 1.5 ng/ml in patients compared to 7.9 +/- 1.0 ng/ml in volunteers (#p < 0.05) after 1 hour stimulation, and no further increase was observed after 24 and 48 hours, respectively. Histamine concentration increased significantly in the supernatant from cells stimulated by rIL-2 in a dose-dependent manner both in patients and volunteers. Total cell-bound histamine was 49.3 +/- 4.1 ng/ml in patients compared to 78.5 +/- 7.7 ng/ml in volunteers (p < 0.05). Therefore, both spontaneous and rIL-2-induced histamine release was significantly enhanced in cancer patients compared to volunteers (*p < 0.05). These data suggest that rIL-2 in high pharmacologic doses stimulates in vitro histamine release in a dose-dependent manner in both cancer patients and volunteers. This may in part explain the severe toxicity observed during high-dose rIL-2 therapy.

Lack of effect on the low density lipoprotein receptor in hamsters treated with 17α-ethinyl estradiol

High pharmacological doses of 17α-ethinyl estradiol are known to increase the number of low density lipoproteins (LDL)-receptors in rats and rabbits, leading to a profound decrease in plasma cholesterol levels. Here, using rats as a positive control, we demonstrate that in hamsters ethinyl estradiol does not upregulate liver LDL-receptors, nor change plasma LDL turnover or plasma LDL-cholesterol. The lack of effect in estradiol-treated hamsters suggests that the hormonal control is different from that in rats.

Influence of Subchronic Intake of Melatonin at Various Times of the Day on Fatigue and Hormonal Levels: A Placebo‐Controlled, Double‐Blind Trial

In a double-blind study, melatonin (50 mg) or placebo was administered daily to 25 subjects at 9 am or 7 pm for 1 week. Self-rated fatigue as evaluated by the Stanford Sleepiness Scale (SSS) was significantly increased during the 3 hours following melatonin intake in the morning, whereas, after administration in the evening, no difference between melatonin and placebo could be distinguished. Sleep onset latency slightly decreased in both melatonin groups without reaching statistical significance. No cumulative effects on sleep or behavior were observed. Twelve pituitary and peripheral hormones measured under baseline and partly (in the evening groups) under stimulated conditions before and after the trial did not change. The two most important conclusions are that: 1) the sedative potency of exogenous melatonin depends on the daily time of administration; and 2) the high pharmacological doses used for acute sedation do not seem to have cumulative effects after prolonged application.

The pharmacology of arachidonic acid-induced rat PMN leukocyte infiltration

Arachidonic Acid (AA) injected into a hindpaw of Lewis rats produces high levels of tissue myeloperoxidase (MPO), a biochemical marker for PMN leukocytes. Treatment with a corticosteroid (prednisolone) or dual 5-LO/CO inhibitors of AA metabolism (phenidone, SKF 86002) produced dose-related inhibition of AA-induced elevations in paw tissue MPO levels. In contrast, administration of high pharmacologic doses of selective cyclooxygenase inhibitors (indomethacin, ibuprofen, naproxen), anti-histamine/serotonin agents (cyproheptadine, chlorpheniramine) or an anti-arthritic gold compound (auranofin) produced only slight or moderate effects. Thus, AA-induced hindpaw inflammation is a useful method for determining pharmacologic effects of 5-LO/CO inhibitors on PMN leukocyte infiltration in vivo.

Physiological responses to low dose infusions of atrial peptide in conscious dogs

Mongrel dogs prepared with chronic catheters in their femoral artery and vein and urinary bladder received 60 minute infusions of atrial peptide ranging from 5 to 100 ng/kg/min. Infusion of atrial peptides caused dose dependent increases in plasma atrial peptide concentration with doses of 25 ng/kg/min or less increasing plasma concentrations to levels observed in normal animals during stimulation of endogenous atrial peptide secretion. Atrial peptide infusion at doses of 10 ng/kg/min and above caused significant decreases in mean arterial pressure which were not accompanied by statistically significant changes in heart rate. Atrial peptide infusion at doses of 25 ng/kg/min and above increased urinary sodium excretion and urine flow rate. Atrial peptide infusion was without effect on plasma vasopressin, ACTH and corticosterone concentrations. However, atrial peptide infusion resulted in dose dependent decreases in plasma aldosterone concentration and plasma renin activity, but the decreases were only significant with the high physiologic (25 ng/kg/min) and pharmacologic doses (50 & 100 ng/kg/min). These data show that atrial peptide infusions in conscious dogs have minimal effects when infused in small doses that mimic endogenous atrial peptide release. At higher doses, significant effects on the cardiovascular, renal and endocrine systems can be observed but their physiological significance is unclear.

Effect of small doses of bovine follicular fluid on the tonic secretion of gonadotrophins in the ewe.

Previous work has shown that treatment of ewes with steroid-free bovine follicular fluid (bFF), a rich source of inhibin, partially inhibits the increase in mean plasma concentrations of LH induced by ovariectomy. The present experiment was designed to test the hypothesis that this effect was a reflection of reduced LH pulse amplitude which would only be expressed at high (pharmacological) doses of bFF. To do this, we assessed the dose-response to bFF of the secretion of FSH and LH pulses in intact and acutely ovariectomized ewes. In intact ewes, a low dose of bFF (0.2 ml s.c. every 8 h) had no detectable effect on the secretion of FSH, an intermediate dose (0.6 ml s.c. every 8 h) depressed FSH concentrations for about 24 h and a high dose (1.8 ml s.c. every 8 h) reduced FSH concentrations to undetectable levels. In ewes treated with 1.8 ml bFF, FSH concentrations also remained undetectable after ovariectomy and did not increase until treatment was withdrawn. In ewes treated with 0.6 ml bFF, FSH concentrations were maintained at normal intact levels for about 32 h following ovariectomy but then rose to normal ovariectomized levels. In ewes treated with 0.2 ml bFF, FSH concentrations increased immediately after ovariectomy but more slowly than in control ovariectomized ewes. Profiles of LH pulses were recorded after ovariectomy, during and after the withdrawal of bFF treatment. In ewes treated with the highest dose (1.8 ml s.c. every 8 h), mean LH levels and pulse amplitude were lower than in control ewes and increased significantly following withdrawal of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of three 18F-labeled butyrophenone neuroleptic drugs in the baboon using positron emission tomography.

The butyrophenone neuroleptics spiroperidol, benperidol, and haloperidol were radiolabeled with fluorine-18 and studied in baboon brain using positron emission transaxial tomography (PETT). Pretreatment of the baboon with a high pharmacological dose of (+)-butaclamol reduced the specifically bound component of radioactivity distribution in the striatum to approximately the radioactivity distribution found in the cerebellum. Comparative studies of brain distribution kinetics over a 4-h period indicated that either [18F]spiroperidol or [18F]benperidol may be suitable for specific labeling of neuroleptic receptors. In an 8-h study with [18F]spiroperidol, striatal radioactivity did not decline, suggesting that spiroperidol either has a very slow dissociation rate or that it binds irreversibly to these receptors in vivo. [18F]Haloperidol may not be suitable for in vivo PETT studies, because of a relatively high component of nonspecific distribution and a faster dissociation from the receptor. Analysis of 18F in plasma after injection of [18F]spiroperidol indicated rapid metabolism to polar and acidic metabolites, with only 40% of the total radioactivity being present as unchanged drug after 30 min. Analysis of the metabolic stability of the radioactively labeled compound in rat striatum indicated that greater than 95% of [18F]spiroperidol remains unchanged after 4 h.

The Effect of Graded Doses of Secretin on Serum Trypsin, Serum Pancreatic Amylase, Serum Insulin, Plasma Somatostatin, and Plasma Pancreatic Polypeptide in Man

Six healthy men were studied with intravenous infusions of 0.3, 1.0, and 3.0 CU/kg-h of pure porcine secretin on separate days. The secretin elimination followed a first-order kinetics. Low pharmacological doses of secretin had no significant effects on blood levels of trypsin, pancreatic amylase, insulin, somatostatin, or pancreatic polypeptide (PP), whereas high pharmacological doses significantly elevated the blood levels of trypsin, pancreatic amylase, insulin, and somatostatin but were without effect on PP.

Effect of chronic iodide supplements on thyroid secretion: the role of lysosomes.

The role of thyroid lysosomes in hormonal secretion has been studied in rats fed a low iodine diet and receiving chronic increasing iodide supplements. Thyroid secretion was assessed by plasma TSH, T3, and T4 levels and by the concentration and degree of iodination of thyroglobulin (Tgb). Lysosomal activity was evaluated by the total activity of four lysosomal acid hydrolases and by the integrity and fragility of the lysosomal membrane, which were assessed by the latency of acid phosphatase activity and the susceptibility of the particles to physicochemical manipulations. In glands from animals on a low iodine intake and under chronic TSH hyperstimulation, the integrity of the lysosomes was modified (increased free, but sedimentable, acid phosphatase activity), and the lysosomal membrane cohesion was high (increased resistance to freezingthawing and acid autolysis). In animals receiving increasing physiological iodide supplements, plasma TSH levels were normal, and the size of the intrathyroidal iodine pool autoregulated thyroid secretion; in spite of the increased concentration and iodine content of Tgb, the plasma levels of T3 and T4 remained fairly constant. The total activities of the four lysosomal enzymes tested increased gradually with the iodide supply. The integrity and stability of the lysosomes were not modified. Iodine at high pharmacological doses was not a lysosome stabilizer but induced a labilization of the lysosomal membrane. We suggest that lysosomes may participate in the autoregulation of thyroid secretion by the intrathyroidal iodine pool; the synthesis of new lysosomal hydrolases is induced, which may gradually be involved in the degradation of cellular constituents rather than in the hydrolysis of extracellular Tgb.