Thyroid-stimulating Hormone Production Research Articles

Ontogeny of pituitary thyrotrophs and regulation by endogenous thyroid hormone feedback in the chick embryo

Increased thyroid hormone production is essential for hatching of the chick and for the increased metabolism necessary for posthatch endothermic life. However, little is known about the ontogeny and distribution of pituitary thyrotrophs during this period or whether pituitary thyroid-stimulating hormone (TSH) production is regulated by endogenous thyroid hormones during chick embryonic development. This study assessed the abundance and location of pituitary thyrotrophs and the regulation of TSH(beta) peptide and mRNA levels by endogenous thyroid hormones prior to hatching. TSH(beta)-containing cells were first detected on embryonic day (e) 11, and the thyrotroph population increased to maximum levels on e17 and e19 and then decreased prior to hatching (d1). Thyrotroph distribution within the cephalic lobe of the anterior pituitary was determined on e19 by whole-mount immunocytochemistry for TSH(beta) peptide and by whole-mount in situ hybridization for TSH(beta) mRNA. Thyrotroph distribution within the cephalic lobe was heterogeneous among embryos, but most commonly extended from the ventral medial region to the dorsal lateral regions, along the boundary of the cephalic and caudal lobes. Inhibition of endogenous thyroid hormone production with methimazole (MMI) decreased plasma thyroxine (T4) levels and increased pituitary TSH(beta) mRNA levels on e19 and d1. However, control pituitaries contained significantly more TSH(beta) peptide than MMI-treated pituitaries on e17 and e19, suggesting higher TSH secretion into the blood in MMI-treated groups. We conclude that thyrotroph abundance and TSH production increase prior to hatching, that thyrotrophs are localized heterogeneously within the cephalic lobe of the anterior pituitary at that time, and that TSH gene expression and secretion are under negative feedback regulation from thyroid hormones during this critical period of development.

Intestinal TSH production is localized in crypt enterocytes and in villus ‘hotblocks’ and is coupled to IL-7 production: evidence for involvement of TSH during acute enteric virus infection

The immune and neuroendocrine systems have been shown to work conjointly in a number of ways. One aspect of this has to do with a potential role for thyroid stimulating hormone (TSH) in the regulation of the mucosal immune system, although the mechanisms by which this occurs remain vague. To more thoroughly understand how TSH participates in intestinal intraepithelial lymphocyte (IEL) development and immunity, experiments have been conducted to define local sites of intestinal TSH production, and to characterize changes that occur in the synthesis of TSH during acute enteric virus infection. Here, we demonstrate that TSH in the small intestine is specifically localized to regions below villus crypts as seen by immunocytochemical staining, which revealed high-level TSH staining in lower crypts in the absence of IL-7 staining, and TSH and IL-7 co-staining in upper crypt regions. Additionally, prominent TSH staining was evident in TSH ‘hotblocks’ sparsely dispersed throughout the epithelial layer. In rotavirus-infected mice, the TSH staining pattern differed significantly from that of non-infected animals. Notably, at 2 and 3 days post-infection, TSH expression was high in and near apical villi where virus infection was greatest. These findings lend credence to the notion that TSH plays a role both in the development of intestinal T cells, and in the process of local immunity during enteric virus infection.

Role of PROP1 in Pituitary Gland Growth

Mutations in the PROP1 transcription factor gene lead to reduced production of thyrotropin, GH, prolactin, and gonadotropins as well as to pituitary hypoplasia in adult humans and mice. Some PROP1-deficient patients initially exhibit pituitary hyperplasia that resolves to hypoplasia. To understand this feature and to explore the mechanism whereby PROP1 regulates anterior pituitary gland growth, we carried out longitudinal studies in normal and Prop1-deficient dwarf mice from early embryogenesis through adulthood, examining the volume of Rathke's pouch and its derivatives, the position and number of dividing cells, the rate of apoptosis, and cell migration by pulse labeling. The results suggest that anterior pituitary progenitors normally leave the perilumenal region of Rathke's pouch and migrate to form the anterior lobe as they differentiate. Some of the cells that seed the anterior lobe during organogenesis have proliferative potential, supporting the expansion of the anterior lobe after birth. Prop1-deficient fetal pituitaries are dysmorphic because mutant cells are retained in the perilumenal area and fail to differentiate. After birth, mutant pituitaries exhibit enhanced apoptosis and reduced proliferation, apparently because the mutant anterior lobe is not seeded with progenitors. These studies suggest a mechanism for Prop1 action and an explanation for some of the clinical findings in human patients.

On lawnmowers and lay-down misères.

On lawnmowers and lay-down misères.

Physiological Relevance of Thyroid Stimulating Hormone and Thyroid Stimulating Hormone Receptor in Tissues other than the Thyroid

Decades of research have provided strong evidence for a reciprocal relationship between the immune system and hormones of the hypothalamus–pituitary–thyroid (HPT) axis. Thyroid stimulating hormone (TSH), in particular, has been shown to have a variety of immune-regulating cytokine-like activities that can influence the outcome of T cell development in the thymus and intestine, and can affect the magnitude of antibody and cell-mediated responses of peripheral lymphocytes. Production of TSH and the expression of the TSH receptor are widely but selectively distributed across many different types of hematopoietic cells in the bone marrow, as well as among subsets of dendritic cells, monocytes and lymphocytes in the spleen and lymph nodes. In addition to their role in immunity, the involvement of TSH-producing hematopoietic cells in the microregulation of thyroid hormone activity represents a novel and potentially important aspect of the TSH-mediated immune-endocrine circuit.

Endocrine diseases in dogs and cats: similarities and differences with endocrine diseases in humans

Over several millennia, humans have created hundreds of dog and cat breeds by selective breeding, including fixation of mutant genes. The domestic dog is unique in the extent of its variation in height, weight and shape as well as its behavior. It is primarily the relatively long persistence of high levels of growth hormone (GH) release at a young age that accounts for the large body size in giant breeds of dogs. Several of the endocrine diseases of humans are also known to occur as similar entities in dogs and cats. With some variations, this is true for conditions such as diabetes mellitus and the hypofunction syndromes of the thyroid and adrenal cortex. Also, the hyperfunction syndromes of hypercortisolism and hyperparathyroidism in dogs and cats have many similarities with their human counterparts. The exception seems to be Graves' disease. This condition, which is due to production of thyroid-stimulating hormone (TSH)-receptor antibodies, has not been observed in dogs and cats. The very common form of hyperthyroidism in cats is due to toxic adenomas. In the 1980s it was discovered that in dogs exogenous progestins and endogenous progesterone can induce GH excess. This GH excess originates form the mammary gland and may give rise to acromegaly and insulin resistance. GH production by the mammary gland is not unique to the dog. It has become clear that cats and humans also express the GH gene in the mammary gland. There is increasing evidence that this locally produced GH not only plays a role in the morphologic changes of the mammary gland associated with the ovarian cycle and gestation, but that it is also involved in the development of breast cancer. In dogs, induction of mammary GH production by progestin administration allows for treatment of GH deficiency.

Etiology, Diagnosis, and Treatment Recommendations for Central Hypothyroidism Associated with Bexarotene Therapy for Cutaneous T-Cell Lymphoma

Bexarotene is a synthetic retinoid X receptor (RXR)–selective retinoid recently approved for treatment of cutaneous T-cell lymphoma. In clinical trials, bexarotene was found to cause severe central hypothyroidism with high frequency, associated with marked reductions in serum concentrations of thyroid-stimulating hormone (TSH) and thyroxine. Further investigation demonstrated a novel mechanism causing this effect, namely reversible, RXR-mediated, thyroid hormone-independent suppression of TSH gene expression. Treatment of patients with bexarotene-induced hypothyroidism commonly requires high doses of thyroid hormone for replacement therapy, often twice the typical doses used to treat more common etiologies of hypothyroidism. These observations suggest that bexarotene probably has two fundamental effects on thyroid function: to suppress TSH production and to increase thyroid hormone metabolic clearance. Recommendations are provided for diagnosis and treatment of this syndrome.

Flow associated (endothelium dependent) vasodilation and TSH-levels in young normotensive and normoglycemic subjects.

Endothelial dysfunction (ED) is regarded as an early step in the development of atherosclerosis. Recent experimental data showed a crosstalk between endothelial NO-synthase activity and thyrotropin production. Therefore we studied whether basal TSH can predict flow associated vasodilation (FAD) in a cohort of healthy young subjects with normal TSH levels. FAD was evaluated in 60 normotensive and normoglycemic subjects (mean age 34 years; range 18-50). The mean thyrotropin level was 1.43 +/- 0.11 microU/ml (range 0.18-3.52 microU/ml). Comparing subjects in the upper, middle and lower tertile of TSH (2.38 +/- 0.14 microU/ml, 1.23 +/- 0.04 microU/ml and 0.65 +/- 0.06 microU/ml respectively) there was no difference in terms of the classical cardiovascular risk factor profiles (24 h blood pressure, HDL- and LDL-cholesterol, triglycerides, oral glucose load and body fat content). Regarding the vascular parameters, we could neither find an independent association with FAD (7.0 +/- 1.1%, 6.4 +/- 1.0% and 5.8 +/- 1.1% respectively) nor with endothelial independent vasodilation (after application of glycerol trinitrate GTN, 17.3 +/- 1.9%, 18.4 +/- 1.7% bzw. 17.5 +/- 1.6% respectively) between the groups. Furthermore, we could not find a significant association between free thyroid hormones (fT3/fT4) and FAD or GTN-induced vasodilation. TSH has no predictive value towards endothelial dysfunction in subjects with thyrotropin levels within the normal range.

Developmental changes in pituitary-thyroid axis, and formation of gonads in leptocephali and glass eels of Anguilla spp.

SUMMARY: Pituitary, thyroid gland and gonads in leptocephali of Japanese eel Anguilla japonica (19.8–32.6 mm in total length), A. obscura (45.0 mm), and A. bicolor pacifica (49.5 mm) and those in glass eels of the Japanese eel were histologically and immunohistochemically examined in order to observe the developmental changes of these endocrine organs in the Anguillidae. The pituitary, consisting of adenohypophysis and neurohypophysis in Japanese eel leptocephali over 22.5 mm, did not contain thyroid stimulating hormone (TSH) immunoreactive cells. Such cells were, however, detectable in the more developed pituitaries of leptocephali of A. obscura and A. bicolor pacifica and in those of glass eels. Conversely, thyroxine (T4)-immunoreactive thyroid follicles could be detected in all specimens, both leptocephalic and glass eel. Only in glass eels, gonads were found in the body cavity, and these gonads harbored one or two primordial germ cells (PGC) per cross-section. Our results indicate that thyroid hormones (TH) production started prior to TSH production, and that TSH and TH are both secreted during the metamorphosis from leptocephalus to glass eel. Therefore, it is plausible that the TSH–TH axis is involved in the metamorphosis from leptocephalus to glass eel, but not in the early growth from preleptocephalus to leptocephalus.

The thyroid gland: physiology and pathophysiology.

The thyroid gland contains many follicular cells that store the thyroid hormones within the thyroglobulin molecule until they are needed by the body. The thyroid hormones, often referred to as the major metabolic hormones, affect virtually every cell in the body. Synthesis and secretion of the thyroid hormones depend on the presence of iodine and tyrosine as well as maturation of the hypothalamic-pituitary-thyroid system. Interruption of this development, as occurs with premature delivery, results in inadequate production of thyroid-stimulating hormone and thyroxine, leading to a variety of physiologic conditions. Pathologic conditions occur in the presence of insufficient thyroid production or a defect in the thyroid gland. Laboratory tests are important in diagnosing conditions of the thyroid gland. A thorough history in combination with clinical manifestations and radiologic findings are also useful in diagnosing specific thyroid conditions. Nurses play an important role in identifying and managing thyroid disorders and in providing supportive care to infants and their families.

Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring

The function of the thyroid gland is to produce the thyroid hormones T3 and T4, which regulate gene transcription throughout the body (1). In medical practice, the thyroid becomes an issue when its size or shape becomes abnormal or when it produces too much or too little hormone. Thus, we typically think of the thyroid with reference to the clinical states of goiter, or hyper- or hypothyroidism. But what is the physiology of the thyroid when the gland and the entire hypothalamic-pituitary-thyroid axis are intact? As first year medical students ask each year, Why exactly do we have a thyroid, at all?

Central hypothyroidism associated with retinoid X receptor-selective ligands.

The occurrence of symptomatic central hypothyroidism (characterized by low serum thyrotropin and thyroxine concentrations) in a patient with cutaneous T-cell lymphoma during therapy with the retinoid X receptor-selective ligand bexarotene led us to hypothesize that such ligands could reversibly suppress thyrotropin production by a thyroid hormone-independent mechanism and thus cause central hypothyroidism. We evaluated thyroid function in 27 patients with cutaneous T-cell lymphoma who were enrolled in trials of high-dose oral bexarotene at one institution. In addition, we evaluated the in vitro effect of triiodothyronine, 9-cis-retinoic acid, and the retinoid X receptor-selective ligand LGD346 on the activity of the thyrotropin beta-subunit gene promoter. The mean serum thyrotropin concentration declined from 2.2 mU per liter at base line to 0.05 mU per liter during treatment with bexarotene (P<0.001), and the mean serum free thyroxine concentration declined from 1.0 ng per deciliter (12.9 pmol per liter) at base line to 0.45 ng per deciliter (5.8 pmol per liter) (P<0.001) during treatment. The degree of suppression of thyrotropin secretion tended to be greater in patients treated with higher doses of bexarotene (>300 mg per square meter of body-surface area per day) and in those with a history of treatment with interferon alfa. Nineteen patients had symptoms or signs of hypothyroidism, particularly fatigue and cold intolerance. The symptoms improved after the initiation of thyroxine therapy, and all patients became euthyroid after treatment with bexarotene was stopped. In vitro, LGD346 suppressed the activity of the thyrotropin beta-subunit gene promoter in thyrotrophs by as much as 50 percent, an effect similar to that of triiodothyronine and 9-cis-retinoic acid. Hypothyroidism may develop in patients with cutaneous T-cell lymphoma who are treated with high-dose bexarotene, most likely because the retinoid X receptor-selective ligand suppresses thyrotropin secretion.

Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and post-natal development.

The biological activities of thyroid hormones are thought to be mediated by receptors generated by the TRalpha and TRbeta loci. The existence of several receptor isoforms suggests that different functions are mediated by specific isoforms and raises the possibility of functional redundancies. We have inactivated both TRalpha and TRbeta genes by homologous recombination in the mouse and compared the phenotypes of wild-type, and single and double mutant mice. We show by this method that the TRbeta receptors are the most potent regulators of the production of thyroid stimulating hormone (TSH). However, in the absence of TRbeta, the products of the TRalpha gene can fulfill this function as, in the absence of any receptors, TSH and thyroid hormone concentrations reach very high levels. We also show that TRbeta, in contrast to TRalpha, is dispensable for the normal development of bone and intestine. In bone, the disruption of both TRalpha and TRbeta genes does not modify the maturation delay observed in TRalpha -/- mice. In the ileum, the absence of any receptor results in a much more severe impairment than that observed in TRalpha -/- animals. We conclude that each of the two families of proteins mediate specific functions of triiodothyronin (T3), and that redundancy is only partial and concerns a limited number of functions.

Thyroid hormones down-regulate thyrotropin β mRNA level in vivo in the turbot (Psetta maxima)

Thyroid stimulating hormone (TSH) is a vertebrate pituitary heterodimeric hormone that stimulates the thyroid gland to produce the thyroid hormones, T3 and T4. We report here the cloning, by PCR on reverse-transcribed pituitary RNAs, of a 180 bp fragment of the cDNA encoding TSH β subunit in the turbot (Psetta maxima). The deduced amino acid sequence displayed 66 and 75% identity with the corresponding sequence from the European eel (Anguilla anguilla) and the rainbow trout (Oncorchyncus mykiss), respectively. This cDNA was then used as a probe for densitometric analysis of individual pituitary Northern blots. TSH β mRNA levels were quantified in turbot where circulating thyroid hormones were modified by dietary treatments or hormone supplementation. Recombinant rainbow trout growth hormone had no effect on circulating thyroid hormone levels or on pituitary TSH β mRNA level. In turbot fed heat-treated rapeseed meal, plasma T4 levels were lowered and TSH β mRNA increased more than two fold. In contrast, when turbot were fed a standard fish-meal supplemented with T3, circulating T3 levels were elevated and there was a dramatic decrease in TSH β mRNA level. It is concluded that both thyroid hormones are able to down-regulate TSH β mRNA level in vivo in the turbot. These results are discussed in the context of the evolution of the TH feed-back on TSH production.

Drug therapy alternatives in the treatment of thyroid cancer.

Therapy of thyroid cancers is based on the removal of the primary disease by surgery, replacement of the hormonal deficiencies and subsequent therapy of the recurrent and metastatic disease. The metabolic characteristics of many thyroid tumors mean that radionuclide techniques have been used in the identification of sites of tumour and their subsequent therapy. Differentiated thyroid cancers, papillary, follicular and mixed papillary follicular, are treated by surgery--usually a total or subtotal thyroidectomy. Postoperatively, patients have thyroxine as a replacement therapy and to suppress thyroid-stimulating hormone production. Radioiodine therapy is often given to ablate the thyroid remnant. This allows (a) adequate follow-up of patients using thyroglobulin measurements and assessment scans as necessary, and (b) further therapy with radioiodine for metastatic disease. Patients with a short effective half-life of radioiodide may require higher activities or pharmacological methods of prolonging the retention half-times of iodine. The use of chemotherapy in this group of tumors is limited and at best provides palliation. The overall prognosis is good for differentiated thyroid cancer; papillary carcinomas have an 80 to 90% 10-year survival, whereas follicular tumors are associated with a 65 to 75% 10-year survival. Medullary carcinomas may be sporadic or familial, and some of the latter form part of a multiple endocrine neoplasia syndrome (MEN). Primary treatment is surgery, and total thyroidectomy is usually recommended since tumours are often multifocal. The use of radiolabelled metaiodobenzylguanidine (MIBG) and 111In octreotide as potential therapeutic agents has been explored and may be potentially useful in palliative care. Chemotherapy is of limited benefit. The 10-year survival for medullary carcinomas is 60 to 70%. Anaplastic tumours of the thyroid are usually aggressive, with a high mortality. Treatment is palliative by surgical debulking; some patients may benefit from local radiotherapy or occasionally chemotherapy. The use of therapeutic doses of radionuclides is well tolerated, although it may be associated with a variety of mostly transient adverse effects, including gastritis, thyroiditis and sialadenitis. Therapy with high activities of radioiodine require radiation protection precautions. Despite retreatment with radioiodine there appear to be no long term effects on the fertility of patients, and healthy children are born to women receiving this treatment. 131I remains perhaps the most specific cancer therapy available today and has few adverse effects. It is difficult to see any marked improvement being developed for differentiated thyroid cancer, with the possible exception of targeted gene therapy.

Rapid stimulation of type I 5′-deiodinase in rat pituitaries by 3,3′,5-triiodo- l-thyronine

The negative feedback control of thyrotropin production by the anterior pituitary involves local 5′-deiodination of l-thyroxine (L-T 4) to the active thyroid hormone 3,3′,5-triiodo- l-thyronine (T 3) by two 5′-deiodinase isozymes which are distinctly regulated by thyroid hormone. T 3 rapidly increased steady-state mRNA levels and activity of type I iodothyronine-5′-deiodinase (5′DI) in rat anterior pituitary and in reaggregate cultures of anterior pituitaries. Type II 5′-deiodinase activity determined in parallel with 3,3′,5′-triiodo- l-thyronine (rT 3) as substrate was markedly lower than that of 5′DI. 5′DI mRNA levels and activity were higher in anterior pituitaries of female compared to male rats. Neither gender differences nor T 3 stimulation of 5′DI activity were found in the posterior part. These data demonstrate a T 3 dependent expression of 5′DI in euthyroid anterior pituitary and suggest that this isozyme serves a major function within the complex network of thyroid hormone homeostasis.

Suppression of maternal pituitary thyroid-stimulating hormone during pregnancy

Maternal serum thyroid-stimulating hormone (TSH) has been estimated in 38 pregnant women with three new specific nonradioactive monoclonal immunoassays which can measure very low concentrations. Values for the Pharmacia-LKB 'DELFIA' fluoroimmunoassay and for the Amersham 'Amerlite' luminescence immunoassay were statistically identical over the range 0.15-1.5 uIU/ml WHO 2nd IRP 80/558, but thereafter the Amersham values were slightly lower. The Abbott 'IMx' assay system gave slightly higher results commensurate with the quoted higher non-pregnant normal values. The Amersham assay was preferred on practical grounds. There was no relationship of TSH levels to HCG levels, or to the length of pregnancy. Four women had apparently zero TSH levels by the Amersham and Pharmacia-LKB assays, although the Abbott assay could detect very low concentrations. Together with women whose TSH levels were below the normal non-pregnant range for each assay, there were a total of eight women (21%) with TSH levels below 'normal'. This suppression of maternal pituitary TSH levels during pregnancy was considered to be due to the central feedback inhibitory thyrotrophic activity of HCG, as a separate placental thyrotrophic hormone is believed not to exist. The enlargement of the maternal thyroid gland and the increased production of thyroid hormones during normal pregnancy is likewise to be attributed to HCG rather than to an increase in TSH production.

The hypothalamic-pituitary-thyroid axis in psychiatric patients and healthy subjects: Parts 1–4: Part 2. Repeated measurements of thyroxine, free thyroxine, triiodothyronine, free triiodothyronine, and reverse triiodothyronine in patients with major depressive disorder and schizophrenia and healthy subjects

Thyroxine (T 4), free T 4, triiodothyronine (T 3), free T 3 (fT 3), and reverse T 3 (rT 3) were measured in 31 patients with major depressive disorder and 15 severely ill schizophrenic patients on admission, after 4 weeks' treatment with antidepressants and neuroleptics, respectively, and following recovery. On admission T 4 and fT 4 were normal in the depressed patients and elevated in the schizophrenic patients. T 3 was normal in both groups, and rises in rT 3 also occurred in both groups. They were correlated to postdexamethasone cortisol concentrations. After recovery T 4, fT 4, and rT 3 fell to below normal values in both groups, whereas T 3 and fT 3 remained unchanged. There were significant correlations between the T 4, fT 4, and rT 3 values of the patients and controls, whereas the correlations between T 3 and fT 3 were much closer in healthy subjects and schizophrenic patients than in depressed patients: this abnormality of the fT 3 values in depression was correlated to weight loss. The results indicate a complex disturbance consisting of elevated T 4 production in schizophrenia, inhibition of the conversion of T 4 to T 3 in most schizophrenic and some depressed patients, and disturbed protein binding of T 3 in some depressed patients. Most surprisingly, the declines of T 4, fT 4, and fT 3 were significantly correlated to clinical response in depression, but not in schizophrenia. As production of thyroid-stimulating hormone remained unaltered, the decreases in thyroid hormone levels might be due to a rise in intracellular concentrations rather than to increased metabolization or diminished production. In the light of the known interactions between catecholamines and thyroid hormones and a possible role of the latter as neuromodulators in the central nervous system, a direct involvement of these hormones in the mechanism of action of antidepressant drugs seems conceivable.

Goitrogens and thyroid follicular cell neoplasia: Evidence for a threshold process

Thyroid neoplasia can result from many different causes. These include low iodine diets, subtotal thyroidectomy, radioactive iodine, natural goitrogens such as rape seed and cabbage, chemotherapeutic agents such as sulfathiazole, and pesticides such as amitrole. All of these appear to act through either direct or indirect interference with thyroid hormone synthesis. Decreased circulating levels of thyroid hormones in the blood result in increased relase of thyroid-stimulating hormone by the anterior pituitary gland. This, in turn, results in hypertrophy and hyperplasia of the thyroid without a corresponding increase in blood thyroid hormone levels. Hyperplasia of the pituitary is also observed due to increased functional demand for continued production of thyroid-stimulating hormone. After prolonged stimulation of the pituitary/thyroid axis, hyperplasia may progress to neoplasia. Cessation of exposure prior to the induction of neoplasia results in a return to the normal state. It is clear that some degree of thyroid inhibition can be accommodated within the bounds of the normal feedback mechanism without the induction of either hyperplasia or neoplasia. A threshold for thyroid follicular neoplasia is therefore indicated.

Inhibition of carcinoma formation and of vascular invasion in grafts of radiation-initiated thyroid clonogens by unirradiated thyroid cells

Quantitative transplantation techniques have been employed to study radiogenic cancer initiation frequency and cell interactions during promotion/progression in grafted clonogenic rat thyroid epithelial cells. The graft recipients were surgically thyroidectomized and maintained on a diet containing less than 50 ng iodine per g. The results confirm that radiogenic initiation is a common cellular event; one of approximately 32 surviving 5-Gy-irradiated thyroid clonogens gave rise to cancer in grafts initially containing approximately 11 clonogens per transplantation site. The data demonstrate that the efficiency of promotion/progression is inversely related to grafted irradiated cell number. As the number of transplanted surviving irradiated clonogens was increased progressively from approximately 11 to approximately 720 clonogens per graft site, the carcinoma frequency per grafted clonogen progressively decreased to one per approximately 920. Addition of unirradiated thyroid cells to the transplant inocula further suppressed promotion/progression of radiation-initiated thyroid clonogens. Furthermore, the probability of vascular invasion, a reflection of metastatic potential in carcinomas which arose from irradiated grafted thyroid clonogens, was reduced by addition of unirradiated thyroid cells to the transplant inocula. Assays of thyroid stimulating hormone (TSH) titers in the sera of thyroidectomized rats 44 weeks after transplantation of clonogenic thyroid cells indicate that the suppression of neoplastic promotion/progression observed with increased numbers of cells per graft site is due at least in part to feed-back inhibition of TSH production by thyroid hormone of graft origin. Whether local cellular interactions are also involved in this inhibitory process is currently under investigation.