Prolactin Hypersecretion Research Articles

Extensive experience in the management of macroprolactinomas

Macroprolactinomas are pituitary tumours that can be managed with dopamine agonists (DA), surgery and radiotherapy. We aimed to assess the outcomes of these treatment modalities. Retrospective case-note study of patients managed in a single tertiary referral centre. One hundred patients (68 male) diagnosed with macroprolactinoma between 1971 and 2009. We assessed the response to first-line treatment in terms of reduction in serum prolactin, endocrine status, symptomatic improvement and tumour shrinkage. Patients were divided into a group that received only DA therapy and a group that received surgery, radiotherapy or both, with or without a DA. We compared pituitary function at baseline and at last clinic visit between the two groups. In total, there were 1170 patient years of follow-up. Pituitary surgery was performed in 29/100 patients. Fourteen patients received pituitary radiotherapy (8/14 surgery also). At last clinic visit, the nonmedical therapy group had a higher risk of gonadotrophin deficiency (77·4% vs 44·8%, P = 0·0037), TSH deficiency (54·8% vs 25·4%, P = 0·0009) and ACTH deficiency (56·2% vs 17·2%, P = 0·0001). When last reviewed, 23/29 (79·3%) patients who underwent surgery and 10/14 (71·4%) patients who received radiotherapy were taking a DA. Treatment with a DA alone is associated with better outcomes in terms of pituitary function and as such represents the optimal first-line therapy for macroprolactinomas. Surgery and radiotherapy should be reserved for patients who are either intolerant of or resistant to DAs. Following surgery and/or radiotherapy, the majority of patients still require a DA for control of prolactin hypersecretion.

Tumors with simultaneous hypersecretion of somatotropin and prolactin are associated with earlier diagnosis compared with tumors with isolated hysecretion of somatotropin

Tumors with simultaneous hypersecretion of somatotropin and prolactin are associated with earlier diagnosis compared with tumors with isolated hysecretion of somatotropin

English

Hyperprolactenemia refers to the consistent presence of abnormally high levels of prolactin in the blood after ruling out the physiological causes of prolactin hypersecretion. Prolactin is mainly concerned with breast development during pregnancy and induction of lactation. It is secreted in a pulsatile manner, and increases with sleep, stress, pregnancy, chest wall stimulation or trauma. Therefore, hyperprolactenemia could be physiological, pathological or pharmacological. The clinical presentation is varied and may manifest as oligomenorrhoea, amenorrhoea, infertility (as a result of the above), decreased libido and habitual abortion. Premenopausal women may also present with galactorrhoea which requires the presence of both oestrogen and prolactin. Hyperprolactenemia may cause osteopenia and also hyperandrogenism Before giving treatment due consideration must be given to an infertile women regarding her desire for pregnancy. There are three treatment options :- Medical, Surgical and Radiotherapy. All have their pros and cons but medical treatment should be started as soon as possible. It also helps at the time of surgery as it may induce tumor regression enabling resection of a greater part of the tumor leading to better control of prolactin levels.

Macroprolactinemia: new insights in hyperprolactinemia

Hypersecretion of prolactin by lactotroph cells of the anterior pituitary may lead to hyperprolactinemia in physiological, pathological and idiopathic conditions. Most patients with idiopathic hyperprolactinemia may have radiologically undetected microprolactinomas, but some may present other causes of hyperprolactinemia described as macroprolactinemia. This condition corresponds to the predominance of higher molecular mass prolactin forms (big-big prolactin, MW > 150 kDa), that have been postulated to represent prolactin monomer complexed with anti-prolactin immunoglobulins or autoantibodies. The prevalence of macroprolactinemia in hyperprolactinemic populations between 15-46% has been reported. In the pathophysiology of macroprolactinemia it seems that pituitary prolactin has antigenicity, leading to the production of anti-prolactin autoantibodies, and these antibodies reduce prolactin bioactivity and delay prolactin clearance. Antibody-bound prolactin is big enough to be confined to vascular spaces, and therefore macroprolactinemia develops due to the delayed clearance of prolactin rather than increased production. Although the clinical symptoms are less frequent in macroprolactinemic patients, they could not be differentiated from true hyperprolactinemic patients, on the basis of clinical features alone. Although gel filtration chromatography (GFC) is known to be the gold standard for detecting macroprolactin, the polyethylene glycol precipitation (PEG) method has offered a simple, cheap, and highly suitable alternative. In conclusion, macroprolactinemia can be considered a benign condition with low incidence of clinical symptoms and therefore hormonal and imaging investigations as well as medical or surgical treatment and prolonged follow-up are not necessary.

Inactivation of Transcription Factor Pit-1 to Target Tumoral Somatolactotroph Cells

The treatment of growth hormone (GH)- and prolactin (PRL)-secreting tumors resistant to current therapeutic molecules (somatostatin and dopamine analogues) remains challenging. To target these tumors specifically, we chose to inactivate a gene coding for a crucial factor in cell proliferation and hormonal regulation, specifically expressed in pituitary, by using a dominant-negative form of this gene involved in human pituitary deficiencies: transcription factor Pit-1 (POU1F1) mutated on arginine 271 to tryptophan (R271W). After lentiviral transfer, the effect of R271W was studied in vitro on human tumoral somatotroph and lactotroph cells and on the murine mammosomatotroph cell line GH4C1 and in vivo on GH4C1 subcutaneous xenografts in nude mice. R271W induced a decrease in GH and PRL hypersecretion by controlling the transcription of the corresponding hormones. This mutant decreased cell viability by an apoptotic mechanism and in vivo blocked the tumoral growth and GH secretion of xenografts obtained after transplantation of GH4C1 expressing mutant R271W. The strategy of using a dominant-negative form of a main factor controlling cell proliferation and hormonal secretion, and exclusively expressed in pituitary, seems promising for the gene therapy of human pituitary tumors and may be translated to other types of tumors maintaining some differentiation features.

Regulation of prolactin secretion during the estrus in rats: possible role of glucocorticoids

Mifepristone (MIF) administration to cycling rats at proestrus induces hypersecretion of prolactin (PRL) at the following estrus. We aimed to assess whether this effect is due to the antiprogesterone or antiglucocorticoid action of MIF and to help underscore the nature of the circulating hormone(s) regulating PRL secretion at estrus. Female cycling rats in proestrus were treated with vehicle; the progesterone (Pg) and glucocorticoid receptor antagonists, MIF (5 mg/kg) or ORG-33628 (5 mg/kg); the glucocorticoid agonist dexamethasone (DEX; 27 mg/kg)±MIF; or the inhibitor of steroid synthesis aminoglutethimide (AG; 150 mg/kg)±MIF. The animals' blood was sampled the same day at 1800 h and at 1800 h of the following day to assess for circulating PRL and Pg levels. To distinguish antiglucocorticoid from antiprogesterone effects of MIF, we administered a highly specific neutralizing antibody against Pg. None of the antagonists modified serum PRL values at proestrus but increased PRL levels at estrus. DEX decreased the secretion of PRL at proestrus, yet the effect was entirely blocked by MIF. Furthermore, DEX decreased PRL at estrus in a MIF-reversible manner, suggesting that adrenal corticoids during proestrous may regulate PRL secretion at estrus. AG increased PRL secretion at estrus, whereas its association with MIF produced an even higher response. PRL concentration at estrus was not modified by the antiprogesterone antibody, suggesting that the effect of MIF is a consequence of its antiglucocorticoid effect and not due to its antiprogesterone properties. In conclusion, PRL secretion in the afternoon of the estrus is most likely regulated by glucocorticoids through an inhibitory action.

Evaluation of basal hormone levels in hirsute women.

Serum concentrations of 10 hormones in 162 hirsute women were examined. Mean testosterone, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) concentrations in these patients were 0.7 ng/ml, 10.0 ng/ml and 3.3 micrograms/ml, respectively; testosterone was elevated in 60.4% of the patients, DHEA was in 52.2% and DHEA-S was in 53.2%. Significant correlations were revealed among all these androgens. In the women who had normal testosterone levels DHEA was elevated in 50.0% and DHEA-S was in 22.2%. Cortisol levels did not show any significant correlation with the androgens examined in this study. Progesterone had a negative correlation with testosterone. Elevations of basal luteinizing hormone (LH) (greater than 20 mIU/ml) were seen in 21.7% of the patients. Stimulation tests using 25 micrograms luteinizing hormone-releasing hormone (LHRH) revealed enormous increase of LH (greater than 100 mIU/ml) in 18.7% of the women. Serum prolactin (PRL) was elevated in 38.3% of the patients; a bolus injection of metoclopramide (MCP) induced hypersecretion of PRL (greater than 160 ng/ml) in 48.0% of the women. These results indicate that the estimations of basal and LHRH- or MCP-induced hormone concentrations in hirsute women give useful clinical information for the understanding of their pathogenesis. More attention should be paid to basal hormone levels before suppression or stimulation tests of adrenal glands and ovary are performed.

An unusual association of a sellar gangliocytoma with a prolactinoma

The simultaneous occurrence of a hypothalamic and sellar gangliocytoma with a pituitary prolactinoma is very rare. The explanation for such an association is not known. We describe the case of a woman who had a coexisting adjacent pituitary prolactinoma and gangliocytoma within the same sellar mass. The tumor cells of the gangliocytoma demonstrated expression of enkephalin, a product of proopiomelanocortin known to be a prolactin secretagogue. We postulate that in this patient there may be a link between gangliocytoma enkephalin and prolactin hypersecretion.

Clinical presentation and response to therapy in patients with massive prolactin hypersecretion

Prolactin hypersecretion from a pituitary adenoma usually results in a serum prolactin level less than 1,000 ng/ml. During therapy with a dopamine agonist, prolactin levels usually normalize and the tumors shrink substantially. In the past few years, we have seen three men who presented with serum prolactin levels greater than 10,000 ng/ml. All presented with large tumors, visual field deficits, and hypogonadotropic hypogonadism. All other pituitary hormones were normal. In all three patients, significant tumor shrinkage was achieved with improvement or resolution of headaches and visual field deficits. None of our patients has been able to achieve a normal prolactin or testosterone. A literature review identified 32 patients with prolactin levels of more than 10,000 ng/ml. Twenty-six (81%) were males. Most had large tumors, headaches and visual field defects. Even with the addition of surgery and/or radiation therapy to medical therapy, normalization of serum prolactin occurred in only six patients (19%) and only one man achieved a normal testosterone. We conclude that in patients with massive prolactin hypersecretion, therapy with a dopamine agonist will lead to tumor shrinkage and improvement of mass effects, but usually does not normalize prolactin or testosterone. Rather than waiting for maximal prolactin reduction, we would recommend early institution of testosterone replacement therapy.

Drug-induced hyperprolactinemia

Hyperprolactinemia is the most common biochemical abnormality currently encountered in clinical endocrinology. Hyperprolactinemic syndromes are a diverse group of disorders that are common in both men and women. Once the diagnosis of hyperprolactinemia has been established, the patient should be screened for the numerous causes of hormone hypersecretion. Hence, an accurate medical history is extremely important for the clinician to find out the most frequent causes of hypersecretion of prolactin (e.g., drugs). Clinicians should be aware of the possibility of prolactin elevation and associated problems with any drug that has the potential to cause hyperprolactinemia, particularly in patients who have other factors that might stimulate prolactin release.

Acute effects of styrene inhalation on the neuroendocrinological system of rats and the different effects in male and female rats

There have been several epidemiological and experimental studies about styrene from the neuroendocrinological viewpoint. Some reported that styrene exposure affected the neuroendocrinological system and enhanced prolactin (PRL) secretion, but others have denied those effects. It was assumed that styrene exposure caused depletion of dopamine (DA), which is a PRL inhibitor, and that, in consequence, the PRL level increased. However, not only DA but also many other factors control PRL secretion. Therefore, the mechanism of hypersecretion of PRL has not yet been clearly elucidated. In addition, effects of styrene on the female reproductive system have been reported, but the susceptibility needs to be further studied. Therefore, to investigate what causes hypersecretion of PRL and how different the susceptibility is in males and females, we studied acute effects of styrene exposure on the neuroendocrinological system in male and female rats. Immediately after exposure to 150 ppm styrene vapor for 10 days (8 h/day), male and female rats were killed, and blood and brain samples were collected. The styrene concentration in blood, hormones such as PRL, growth hormone (GH) and thyroid-stimulating hormone (TSH) in plasma and neurotransmitters in various brain regions were measured. The styrene concentration in the blood of female rats was higher than that in male rats, and the PRL level was significantly increased in female exposed rats compared with controls. No significant change was observed in male rats. We did not observe any significant changes in DA, 5-hydroxytryptamine (5-HT) or their metabolites. Because neurotransmitters were not affected in either male or female rats, the mechanism enhancing PRL secretion remains unclear. These results suggest that styrene exposure may cause hypersecretion of PRL and that the sensitivity to styrene exposure of the female may be higher than that of the male.

Human pituitary tumor-transforming gene (PTTG1) motif suppresses prolactin expression.

Pituitary tumor-transforming gene (PTTG) originally isolated from GH-secreting pituitary adenoma cells causes in vitro cell transformation, in vivo tumorigenesis, and induces basic fibroblast growth factor. These functions require an intact C-terminal proline-proline-serine-proline motif. PTTG1 is abundantly expressed in human pituitary tumors and plays a role in the early stages of experimental prolactinoma formation. We now determined direct effects of PTTG1 on hormonal phenotypes of functional pituitary tumor cells. Overexpression of PTTG1 C terminus (amino acids 147-202) containing intact proline-proline-serine-proline motifs in rat prolactin (PRL)- and GH-secreting GH3 cells markedly abrogates PRL mRNA expression by more than 90% (P < 0.001) and hormone levels (P < 0.001) and PRL promoter activity (P < 0.01) compared with control vector cells or to a PTTG1 C terminus mutant (P163A, S165Q, P166L, P170L, P172A, and P173L). Wild-type PTTG1 C-terminal transfectants formed smaller (P < 0.05) sc tumors in rats compared with control or mutated PTTG1 C-terminal transfectants. Estrogen (10 nm) treatment for 48 h partially restored PRL expression in stable wild-type PTTG1 C-terminal transfectants. These results indicate that targeting PTTG1-mediated signaling alters the hormonal phenotype in pituitary cells and disrupted PTTG1 action may be a potential subcellular therapeutic tool for repressing PRL hypersecretion.

Effects of 5-day styrene inhalation on serum prolactin and dopamine levels and on hypothalamic and striatal catecholamine concentrations in male rats.

In several studies a hypersecretion of the pituitary hormone prolactin (PRL) in styrene-exposed workers has been described. This should cause reproductive problems like oligomenorrhea, secondary amenorrhea and reduced fertility [Arfini et al. (1987) J Occup Med 29:826-830, Bergamaschi et al. (1996) Neurotoxicology 17:753-760, Mutti and Smargiassi (1998) Toxicol Ind Health 14:311-323]. Secretion of PRL is tonically inhibited by the catecholamine dopamine (DA), which is released from hypothalamic neurons. It has been suggested that the activity of the enzyme dopamine-beta-hydroxylase (DBH) in the serum is a peripheral marker of central dopaminergic function. A slight reduction of such enzymatic activity was observed in styrene-exposed workers, which was associated with hypersecretion of PRL. To further investigate the putative effects of styrene on PRL release, male rats were exposed to styrene vapors (645, 2150 and 6450 mg/m(3)) for 6 h/day on 5 consecutive days. Animals were killed either directly following the last exposure (immediate group) or after a recovery period of 24 h (recovery group). Serum PRL and DA levels were measured by radioimmunoassay. Concentrations of catecholamines and their metabolites in the striatum and mediobasal hypothalamus (MBH) were determined by high performance liquid chromatography with electrochemical detection. Neither in the immediate nor in the recovery group were any statistically significant changes of serum PRL levels observed. Likewise, concentrations of catecholamines and their metabolites in the striatum and MBH remained unaffected. We conclude from these data that styrene, even at very high concentrations, has no adverse effects on the neuroendocrine mechanisms regulating PRL release and DA levels in the brain. With the limitations inherent in any animal model, we suggest that our data indicate that styrene also has no adverse neuroendocrine effects in humans.

Risk factors for glucose intolerance in active acromegaly.

In the present retrospective study we determined the frequency of glucose intolerance in active untreated acromegaly, and searched for risk factors possibly supporting the emergence of the diabetic condition. Among 43 patients, 8 (19%; 95% CI: 8-33%) had diabetes mellitus and 2 (5%; 1-16%) impaired glucose tolerance. No impaired fasting glycemia was demonstrable. The frequency of diabetes was on average 4.5 times higher than in the general Slovak population. Ten factors suspected to support progression to glucose intolerance were studied by comparing the frequency of glucose intolerance between patients with present and absent risk factors. A family history of diabetes and arterial hypertension proved to have a significant promoting effect (P<0.05, chi-square test). A significant association with female gender was demonstrated only after pooling our data with literature data. Concomitant prolactin hypersecretion had a nonsignificant promoting effect. In conclusion, the association of active untreated acromegaly with each of the three categories of glucose intolerance (including impaired fasting glycemia, not yet studied in this connection) was defined as a confidence interval, thus permitting a sound comparison with the findings of future studies. Besides a family history of diabetes, female gender and arterial hypertension were defined as additional, not yet described risk factors.

Hypothalamic-pituitary dysfunction following external cranial irradiation

Background: Deficiency of one or more anterior pituitary hormones may follow treatment with external radiation when the hypothalamic-pituitary axis falls in the fields of radiation. Patients and methods: Twenty eight patients (12 children with a mean age of 6.92±2.78 years and 16 adults with a mean age of 36.56±13.38 years) were included in the study. The radiation dose received ranged from 28 to 50 Gy in children and 45 to 60 in adults. Serum concentration of GH was measured with insulin, basal serum estimation of thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone were estimated before and after irradiation. Results: Eight patients in the pediatric group (66%) and 2 patients in the adult group had GH deficiency. Fifty percent of the pediatric group and 6.25% of the adult group had low serum TSH. Three patients in the pediatric group had ACTH deficiency. Twenty five percent of the pediatric group and 6.25% of the adult group had low serum LH/FSH. Four patients in both groups had elevated PRL. Testosterone level was low in three patients in the pediatric group and one patient in the adult group. There were significant negative correlation between serum peak GH, ACTH, LH/FSH, testosterone and the dose of irradiation. Conclusion: Patients exposed to high-dose radiotherapy (> 35 Gy) to the hypothalamic-pituitary axis, a variety of endocrine abnormalities may occur, including deficiencies of GH, TSH, ACTH and LH/FSH as well as hypersecretion of prolactin.

Newt prolactin and its involvement in reproduction

The amino acid sequence of newt (Cynops pyrrhogaster) prolactin deduced from the nucleotide sequence of its cDNA showed a relatively high homology with sequences of chicken and sea turtle prolactins as well as with those of anuran prolactins. Cynops prolactin receptor transcripts were detected in various tissues and organs, suggesting that prolactin plays multiple roles in urodeles. Urodele prolactin was purified from the pituitaries of C. pyrrhogaster. Antiserum against this prolactin was used for radioimmunoassay of plasma prolactin and immunoneutralization experiments. Endogenous prolactin was shown to induce migration to water, courtship behavior, and cessation of spermatocytogenesis in the Cynops newt. The hormone was found to be involved in the development of cloacal glands such as the lateral and abdominal glands, growth of the tail and Mauthner neurons, secretion of oviducal jelly, and enhanced synthesis of a female attracting pheromone (sodefrin), and responsiveness of the olfactory epithelium to sodefrin. In most of these cases, prolactin was found to act synergistically or antagonistically with sex steroids. We also discovered that hypersecretion of prolactin in the newts subjected to cold temperature was induced by hypothalamic stimulation rather than release from hypothalamic inhibition.Key words: prolactin, newts, reproduction.

Gamma knife radiosurgery as a primary treatment for prolactinomas

Object. The purpose of this study was to estimate the efficacy of gamma knife radiosurgery (GKS) in controlling tumor growth and endocrinopathy associated with prolactinomas. Methods. Between 1993 and 1997, 164 of 469 patients with pituitary adenomas treated by GKS harbored prolactinomas. The dose to the tumor margin ranged from 9 to 35 Gy (mean 31.2 Gy), and the visual pathways were exposed to a dose of less than 10 Gy. The mean tumor diameter was 13.4 mm. The mean follow-up time for 128 cases was 33.2 months (range 6–72 months). Tumor control was observed in all but two patients who underwent surgery 18 and 36 months, respectively, after GKS. Clinical cure was achieved in 67 cases. Clinical improvement was noted with a decrease in the hyperprolactinemia after GKS. Nonetheless, in 31 (29%) of 108 patients who were followed for more than 2 years no improvement in serum prolactin levels was demonstrated, although this could be normalized by bromocriptine administration after treatment. Nine infertile women became pregnant 2 to 13 months after GKS and all gave birth to normal children. There was no visual deterioration related to GKS. Five women experienced premature menopause. In these patients there was subtotal disappearance of the tumor and an empty sella developed. Conclusions. Gamma knife radiosurgery as a primary treatment for prolactinomas can be safe and effective both for controlling tumor growth and for normalization of prolactin hypersecretion. A higher margin dose (≥ 30 Gy) seemed to be associated with a better clinical outcome. Gamma knife radiosurgery may make prolactinomas more sensitive to the bromocriptine.

Newt prolactin and its involvement in reproduction

The amino acid sequence of newt (Cynops pyrrhogaster) prolactin deduced from the nucleotide sequence of its cDNA showed a relatively high homology with sequences of chicken and sea turtle prolactins as well as with those of anuran prolactins. Cynops prolactin receptor transcripts were detected in various tissues and organs, suggesting that prolactin plays multiple roles in urodeles. Urodele prolactin was purified from the pituitaries of C. pyrrhogaster. Antiserum against this prolactin was used for radioimmunoassay of plasma prolactin and immunoneutralization experiments. Endogenous prolactin was shown to induce migration to water, courtship behavior, and cessation of spermatocytogenesis in the Cynops newt. The hormone was found to be involved in the development of cloacal glands such as the lateral and abdominal glands, growth of the tail and Mauthner neurons, secretion of oviducal jelly, and enhanced synthesis of a female attracting pheromone (sodefrin), and responsiveness of the olfactory epithelium to sodefrin. In most of these cases, prolactin was found to act synergistically or antagonistically with sex steroids. We also discovered that hypersecretion of prolactin in the newts subjected to cold temperature was induced by hypothalamic stimulation rather than release from hypothalamic inhibition.

Structure-function correlations of growth hormone or/and prolactin-producing pituitary adenomas: an in vitro study with the reverse hemolytic plaque assay.

The purpose of this study was to detect in vitro growth hormone (GH) and prolactin (PRL) secretion from adenomas clinically associated with GH or PRL hypersecretion. The reverse hemolytic plaque assay (RHPA) was applied in order to reveal possible differences among various morphologic adenoma types, and to examine the inhibitory effects of octreotide on GH release as well. The 20 surgically resected pituitary adenomas studied included 15 from acromegalic patients and 5 from patients with hyperprolactinemia. All adenomas were diagnosed by histology, immunocytochemistry and electron microscopy. Among tumors associated with acromegaly, 5 were densely granulated (DG), 5 were sparsely granulated (SG) somatotroph (SM) adenomas, 2 were mammosomatotroph (MSM) and 3 mixed somatotroph-lactotroph cell (mixed SM-LT) adenomas; tumors causing hyperprolactinemia included 4 lactotroph (LT) adenomas and 1 mixed SM-LT adenoma. GH release assessed by the RHPA corresponded to in vivo hormone secretion and to tissue immunoreactivity. Statistical analysis showed significant differences among all morphologic types of SM adenomas, exclusive of SG-SM adenomas compared to mixed SM-LT adenomas. The mean plaque size in DG-SM and MSM adenomas was significantly greater than that of SG-SM and mixed SM-LT adenomas, indicating higher GH secretion by the former two types during the same incubation time. PRL secretion was documented in 2 mixed SM-LT adenomas. Plaques for PRL, but not for GH were formed in all LT adenomas. In all SM and LT adenomas, cells producing large plaques represented a minority of the plaque-forming cell population, however, they accounted for the largest part of the total plaque area, thus the largest part of hormone secretion. Octreotide effects on GH release were studied in 6 adenomas by the RHPA. Octreotide treatment induced a rapid and significant reduction in GH secretion by SM cells in vitro, with a selective effect on high-secreting cells.

Radiation-induced tumorigenesis of mammary glands in pituitary transplanted rats ovariectomized before onset of estrous cycle

The role of prolactin in the initiation of mammary tumorigenesis by radiation was evaluated in ovarian hormone-free rats. Rats were bilaterally ovariectomized at 23 days of age, and then, at 2.5 months of age, two pituitaries obtained from mature rats of the same strain were transplanted underneath the kidney capsule as a means of increasing the serum prolactin level to provide stimulation of development of mammary glands. After 2 weeks, the ovariectomized rats with ectopic pituitary glands were exposed to whole body irradiation of 2.6 Gy of γ-rays from a 60Co source and then treated with diethylstilbestrol as a tumor promoter. For the control, ovariectomized rats without ectopic pituitary glands were exposed and treated in the same way as the experimental group. A significant increase of serum prolactin level was observed at the time of irradiation by the pituitary transplanted rats, and intense immunohistochemical reaction with a specific anti-prolactin antiserum was detected in the ectopic pituitary glands. Also, mammary glands in the pituitary transplanted rats, ovariectomized before puberty, showed lactiferous ducts without alveolar buds at the time of tumor initiation. The pituitary transplanted rats showed a significantly increased incidence of adenocarcinoma and fibroadenoma compared with the control. Many of the mammary tumors induced in the pituitary transplanted rats given radiation were estrogen receptor (ER) (+) progesterone receptor (PgR) (+) and ER(+)PgR(−) tumors, whereas ER(−)PgR(−) tumors were mainly obtained in the control rats. In the experimental group, many of the fibroadenomas had low concentrations of ER and no PgR, while the adenocarcinomas had moderate concentrations of ER and high PgR. These results suggest that hypersecretion of prolactin from the pituitary transplants developed lactiferous ducts and accelerated the tumorigenesis of mammary glands initiated by radiation in the absence of synergism with ovarian hormones.