Usefulness of granulocyte count measurement four hours after injection of granulocyte colony-stimulating factor for detecting recovery from antithyroid drug-induced granulocytopenia.

This prospective study was designed to investigate the usefulness of granulocyte count measurements 4 hours after injection of granulocyte colony-stimulating factor (G-CSF) for detecting recovery from antithyroid drug (ATD)-induced granulocytopenia or agranulocytosis. Granulocyte and white blood cell counts were measured 4 hours and 24 hours after patients with ATD-induced granulocytopenia had been given an injection of 75 micrograms of G-CSF (1.1 to 1.9 micrograms/kg; 1.5 +/- 0.2 micrograms/kg [mean +/- standard deviation]). Thirty-seven patients were studied and divided into three groups based on their initial granulocytopenic granulocyte count: 28 with mild (granulocyte count 0.501 to 1.0 x 10(9)/L), 6 with moderate (granulocyte count 0.101 to 0.5 x 10(9)/L), and 3 with severe (granulocyte count less than 0.1 x 10(9)/L) ATD-induced granulocytopenia. Twenty-five of the 28 patients with mild granulocytopenia and 4 of the 6 patients with moderate granulocytopenia were found to have recovered from the granulocytopenia both 4 hours and 24 hours after injection, and their granulocyte counts remained normal thereafter. However, the other 3 patients with mild granulocytopenia, 2 patients with moderate granulocytopenia, and all 3 patients with severe granulocytopenia had not recovered by either 4 or 24 hours after the G-CSF injection. Despite daily G-CSF injections, the granulocyte continued to decrease in most cases. It took 2 to 11 days for these counts to recover from granulocytopenia. These results indicate that granulocyte count measurement 4 hours after injection of G-CSF is useful for detecting recovery from ATD-induced granulocytopenia or agranulocytosis and for predicting disease severity. Accordingly, its measurement enables physicians to make an appropriate decision about whether a patient with ATD-induced granulocytopenia should be treated in the hospital or in the outpatient clinic.

Thyroglobulin and lactic dehydrogenase isozymes in cystic fluid of thyroid nodules.

Although fine needle aspiration biopsy (FNAB) is most valuable in the diagnosis of thyroid cancer, it is hampered by the fact that no specimen suitable for cytological examination can be collected from all cystic lesions. Often inadequate aspirates, consisting only of fluid or a few foamy cells and lacking the necessary epithelial cells, are all that an aspirationist is able to collect. Therefore an alternative method of determining the benign or malignant characteristics of cyst fluid is of vital importance. In this study we examine thyroglobulin (Tg) concentrations and lactic dehydrogenase (LDH) isozyme patterns of cyst fluid and discuss how these variables help us estimate the probability of malignancy. Fifty-three differentiated cancers (39 papillary and 14 follicular carcinomas) and 72 surgically resected benign thyroid nodules (40 adenomas, 19 colloid goiters, and 13 cysts) were analyzed. Only 28 (53%) of 53 malignant lesions were correctly diagnosed by FNAB. The mean logarithmic value for the Tg concentration (log10 Tg) was significantly lower in malignant cyst fluid than it was in benign nodules (mean +/- SD: 5.8 +/- 1.0 vs. 6.8 +/- 1.0; P < 0.001). The LDH 1 and 2 isozyme percentage was greater in the malignant group than in the benign group (49.1 +/- 12.7% vs. 38.1 +/- 16.9%; P < 0.01). In multiple logistic regression analysis, log10 Tg and the total of LDH 1+2 percentage was significant in estimating the probability of malignant nodules. The results of our study suggest that determining the Tg concentration and the LDH isozyme patterns of cyst fluid could provide new information for the evaluation of cystic thyroid nodules.

[Granulocyte colony-stimulating factor treatment (G-CSF) of antithyroid drug-induced granulocytopenia: granulocyte count measurement after 4 hours of G-CSF injection is useful for the detection of recovery from granulocytopenia].

The primary objective of this study was to ascertain the usefulness of granulocyte count measurement after 4 hours of granulocyte colony-stimulating factor (G-CSF) injections for the detection of recovery from granulocytopenia. Four Graves' patients with antithyroid drug-induced granulocytopenia (granulocyte count between 500 and 1000/mm3) and three Graves' patients with antithyroid drug-induced agranulocytosis (granulocyte count < 500/mm3) each received a daily dose of 75 mu g of G-CSF administered subcutaneously. In all granulocytopenic patients, after 4 hours of G-CSF injection the granulocyte counts increased to 5623, 4050, 8923 and 4647/mm3, and the granulocyte count after 24 hours of G-CSF injection was 3008, 4634, 4854, 4200/mm3. In one of the three agranulocytic patients, the granulocyte count increased from 238/mm3 to 5982/mm3 after 4 hours of G-CSF injection, and the granulocyte count after 24 hours of G-CSF injection was 4800/mm3. Although the granulocyte counts before G-CSF injection of the remaining two agranulocytic patients were 138 and 126/mm3, the granulocyte counts after 4 hours of G-CSF injection were 837 and 59/mm3 and those after 24 hours of G-CSF injection were 817 and 0/mm3. These results indicated that granulocyte count measurement after 4 hours of G-CSF injection was useful for detecting the recovery from granulocytopenia and agranulocytosis.

Extraocular muscles in Graves ophthalmopathy: usefulness of T2 relaxation time measurements.

PURPOSE: To determine if T2 relaxation time measurements with magnetic resonance (MR) imaging in patients with Graves ophthalmopathy (GO) can predict response to therapy. MATERIALS AND METHODS: Studied were 84 patients with GO, 27 with Graves disease without ophthalmopathy (GD), and 12 control subjects without Graves disease. T2 times of extraocular muscles and retrobulbar fat tissue were measured. Twenty-five patients with GO were treated with systemic corticosteroids and retroorbital radiation therapy. RESULTS: T2 relaxation times of muscles in patients with GD were the same as those in controls but were longer in patients with GO (P < .05). T2 times of fat in all patients were the same as those of the controls. The predicted probability of response to treatment increased with increased mean T2 relaxation times of extraocular muscles prior to therapy. Of the 25 patients with combined therapy, only those with particularly prolonged T2 relaxation times showed impressive response. CONCLUSIONS: T2 relaxation time measurements with MR allow noninvasive detection of acute muscle inflammation and predict which patients with GO will likely benefit from antiinflammatory therapy.

[Antithyroid drug-induced agranulocytosis: special reference to normal white blood cell count agranulocytosis].

This retrospective study was aimed at establishing the importance of the leukocyte differentiated count and not only routine white blood cell count in patients treated with antithyroid drug. From 1975 to September 1992, 77 patients with antithyroid drug-induced agranulocytosis were examined. In 12 patients (15.6%), the total white blood cell (WBC) count was greater than 3000/mm3. Eight of them showed a downward trend in their leukocyte counts (3000-4000/mm3). Consequently, granulocyte counts were measured. Two of the 12 patients had "symptomatic" agranulocytosis detected after the occurrence of infection. Because antithyroid drug-induced agranulocytosis was strongly suspected, granulocyte counts were checked. In the remaining two patients, the total WBC count was 5700/mm3 and 5900/mm3, respectively. One was hospitalized to receive thyroid surgery. Although she was asymptomatic, agranulocytosis was unexpectedly detected on a routine preoperative examination. The other was diagnosed as agranulocytosis by routine WBC and granulocyte count monitoring since June 1989. Correct diagnosis was based on the leukocyte differentiated counts. We concluded that the leukocyte differentiated count and not only routine white blood count was critically important for the correct diagnosis of antithyroid drug-induced agranulocytosis in patients with Graves' disease.

[Studies on onset patterns in antithyroid drug-induced agranulocytosis].

We studied the patterns of the onset of antithyroid drug-induced agranulocytosis. From 1975 to 1990, 19,050 patients with Graves' disease receiving treatment with antithyroid drugs were seen at our clinic. For all patients with Graves' disease treated with an antithyroid drug, a routine white blood cell count was done every 2 weeks until euthyroid state was gained, and a count was done once every moth thereafter. Of these, 70 were found to have agranulocytosis. Agranulocytosis was defined as a granulocyte count of 500/mm3 or less. In only 19 of the 70 was agranulocytosis detected after the occurrence of infection (symptomatic: classical agranulocytosis). The remaining 51 patients were asymptomatic when agranulocytosis was detected during routine white blood cell and granulocyte count monitoring. However, 17 of the 51 patients became symptomatic several days after the withdrawal of antithyroid drug treatment (shifted from asymptomatic to symptomatic agranulocytosis). Thirty-four patients had no symptoms of infection throughout the course of the disease (asymptomatic agranulocytosis). In conclusion, 1) We found three patterns in the onset of antithyroid drug-induced agranulocytosis: classical (symptomatic), a shift from asymptomatic to symptomatic, and asymptomatic agranulocytosis, 2) Unexpectedly, classical (symptomatic) agranulocytosis was seen in only 19 of the 70 patients, 3) We were again remained of the importance of routine white blood cell and granulocyte count monitoring.

Serum sialic acid levels in the diagnosis and follow-up of subacute granulomatous thyroiditis.

To evaluate the usefulness of monitoring serum sialic acid (SA) levels for diagnosis and follow-up of subacute granulomatous thyroiditis (SAT), 43 patients were studied at our clinic. In the acute phase of the disease their SA levels averaged 104.9 +/- 19.7 mg/dl (normal 44-69 mg/dl). In the recovery phase SA levels returned to a range of 60.5 +/- 6.9 mg/dl. However, an increase in SA (87.4 +/- 18.2 mg/dl) was detected at the time of recurrence in 14 patients. In 29 non-recurrent patients, serum SA gradually reduced during the course of therapy and normalized in all patients by the time glucocorticoid therapy was discontinued. Thyroglobulin (Tg) and the erythrocyte sedimentation rate (ESR), however, had normalized in only half the cases even at the time of cessation of therapy (Tg 5/11, ESR 4/8). C-reactive protein (CRP) returned to negative in most patients (19/24) only one week after initiation of the therapy. These results suggested that the monitoring of SA levels can be a useful tool in diagnosis and follow-up of SAT.

Granulocyte colony-stimulating factor treatment of antithyroid drug-induced granulocytopenia.

The primary objective of this study was to ascertain the effectiveness of granulocyte colony-stimulating factor in the treatment of antithyroid drug-induced granulocytopenia of varying degree. Sixteen patients with Graves' disease with antithyroid drug-induced granulocytopenia (granulocyte counts < 1.0 x 10(9)/L) each received a daily dose of 75 micrograms of granulocyte colony-stimulating factor administered subcutaneously. Within 24 hours of the first injection, the granulocyte count increased (0.6 to 12.3 x 10(9)/L) in all 10 patients with mild granulocytopenia (granulocyte counts between 0.5 and 1.0 x 10(9)/L) and all three with moderate granulocytopenia (granulocyte counts < 0.5 x 10(9)/L). The three remaining patients with severe granulocytopenia (agranulocytic), whose granulocyte counts were zero, did not recover from granulocytopenia until the 6th, 7th, and 14th days of treatment with granulocyte colony-stimulating factor. Examination of bone marrow taken at the onset of the disease in all three agranulocytic patients showed a prominent decrease in granulocytic series, while identical examination in six of eight patients with mild to moderate granulocytopenia showed close to normal granulocytic series. There was no elevation of serum granulocyte colony-stimulating factor concentration in four patients with mild granulocytopenia and one with moderate granulocytopenia at the onset of their disease, whereas those of the remaining three patients with severe granulocytopenia (agranulocytic) increased at onset of agranulocytosis. This information led us to conclude that: (1) granulocyte colony-stimulating factor is effective in the treatment of antithyroid drug-induced mild to moderate granulocytopenia and (2) in severe agranulocytic cases, granulocyte colony-stimulating factor is not effective. Accordingly, we were again reminded of the importance of early diagnosis and treatment of antithyroid drug-induced agranulocytosis.

Comparison of the incidence of association of periodic paralysis and hyperthyroidism in Japan in 1957 and 1991.

Periodic paralysis has been known to be associated with thyrotoxicosis in Japan. The incidence was 8.6% among male and 0.4% among female thyrotoxic patients according to a survey performed in the three major thyroid clinics in Japan in 1957. To determine the changes in the incidence during the intervening 34 years, the same type of survey was carried out again in 1991 at the same three major thyroid clinics previously involved. The incidence of paralysis in 1991 was 4.3% among male and 0.04% among female thyrotoxic patients, indicating more than a 40% decrease in the incidence. The possible cause of the decrease is related to the changes in food consumption, namely, to the fact that less carbohydrate and more potassium were taken in 1991 than in 1957.

Two cases of hypothyroidism associated with alpha-interferon therapy.

Alpha-interferon was used for anti-cancer or anti-viral therapy in two patients with preexisting autoimmune thyroid disease and in seven patients with chronic viral hepatitis who had no history of thyroid dysfunction. Primary hypothyroidism developed in the two patients who had a history of autoimmune thyroid disease, while no changes in thyroid function were observed in the other seven patients. Modulation of the immune system by alpha-interferon may have been responsible for the development of hypothyroidism in these two patients. Therefore, autoantibodies to the thyroid and the thyroid function should be assessed in patients undergoing alpha-interferon therapy.

Prediction of the outcome of postoperative hypocalcemia in Graves' disease.

Symptomatic hypocalcemia sometimes follows subtotal thyroidectomy for Graves' disease. Irreversible damage to the parathyroids contributes to permanent hypocalcemia and the mechanism for a transient hypocalcemia is thought to be different from that of a permanent one. However, sensitive assays for parathyroid hormones (PTH), which had recently become available, revealed that levels of PTH decrease in patients with transient hypocalcemia. In order to differentiate a prolonged hypocalcemia from a transient one, calcium and inorganic phosphate concentrations in serum as well as in urine, and whole molecule-PTH levels were determined in 18 Graves' disease patients with postoperative hypocalcemia just after the initial symptoms for hypocalcemia appeared. In 13 patients, medication was withdrawn within one month since serum calcium levels had returned to normal (transient hypocalcemia). In five other patients, medication was required for six months or more to maintain normocalcemia (prolonged hypocalcemia). The same parameters were determined after surgery in eight Graves' disease patients without hypocalcemia. Urinary inorganic phosphate concentrations in patients with prolonged hypocalcemia (0.02 +/- 0.01 mmol/mmol Cr) were significantly lower (P less than 0.01) than those in patients with transient hypocalcemia (1.59 +/- 1.59 mmol/mmol Cr) or those in control patients (1.27 +/- 0.70 mmol/mmol Cr). Preoperative concentrations of calcium and inorganic phosphate in serum and urine, and serum alkaline-phosphatase activities were also determined. However, there were no significant differences in these parameters between patients with prolonged and those with transient hypocalcemia. It is concluded that prolonged hypocalcemia is discriminated from the transient type by determining the urinary inorganic phosphate at the time of appearance of the initial symptoms for hypocalcemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum free triiodothyronine to free thyroxine ratio enables early prediction of the outcome of antithyroid drug therapy in patients with Graves' hyperthyroidism.

This study scrutinizes the correlation between serum free triiodothyronine (FT3) to free thyroxine (FT4) ratios and the eventual outcome of antithyroid drug (ATD) therapy in patients with Graves' disease. Forty-four patients with Graves' thyrotoxicosis were treated with methylmercaptoimidazole (methimazole). During the follow-up, 16 patients relapsed in the short period of one to five months after cessation of the drug (relapse group), and 28 patients remained in remission when checked at 12 to 20 months after treatment (remission group). Serum FT3 to FT4 ratios [(pg/ml/ng/dl) x 10] were less than 55 throughout ATD therapy in 27 of the 28 remission patients whereas the ratios of the relapse group exceeded 55 from the early phase of methimazole treatment in 10 of 16 patients. In eight of these 10 patients the increased ratios were detected within three months of therapy (1 month, 3 patients; 2 months, 4 patients; 3 months, 1 patient). The ratios for the remaining two patients rose above 55 at the fifth and sixth months. There was no statistical difference between the remission and relapse groups in the FT3 to FT4 ratios either before nor at the completion of the treatment. However, a clear difference could be measured at a point during the therapy. Those in whom this difference was pronounced later underwent relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum levels and thyroid tissue expression of CA50 and CA 19-9 in patients with thyroid tumor.

A 77-year-old man was admitted to the hospital with a thyroid nodule. The levels of serum tumor-associated carbohydrate antigens (CA 50, CA 19-9) and thyroglobulin (HTG) were markedly increased. We performed total thyroidectomy and right neck lymph node dissection. After treatment, the serum CA 50, CA 19-9 and HTG levels were markedly decreased. Histological examination of the thyroid tumor showed papillary adenocarcinoma and the dissected neck lymph nodes contained metastatic adenocarcinoma. The expression of CA 50 and CA 19-9 (defined by the monoclonal antibodies) was studied by immunoperoxidase staining from the normal and carcinomatous thyroid tissues and the dissected neck lymph node. CA 50 was expressed more strongly by the carcinoma cells than CA 19-9. The positive rates for serum CA 50 and CA 19-9 levels in other patients with papillary adenocarcinoma were not significantly higher compared with patients with benign nodules and normal subjects. But a significant positive correlation was found between the diameter of the carcinoma and the serum levels of CA 50 and CA 19-9. These results suggest that the serum levels of CA 50 and CA 19-9 might not become useful markers for diagnosing carcinoma of the thyroid, but might be useful markers for monitoring the growth or recurrence of papillary adenocarcinoma of the thyroid in patients with high serum levels of CA 50 and CA 19-9.

Pentavalent technetium-99m-DMSA uptake in a patient having multiple myeloma without amyloidosis.

A pentavalent 99mTc-dimercaptosuccinic acid (DMSA) scan was performed on a patient with multiple myeloma without amyloidosis. A high accumulation of the tracer was found in numerous tumors. We believe that the accumulation of DMSA is unrelated to amyloidosis and that the DMSA scan may have potential for the staging of tumors in patients presenting with multiple myeloma.

Antithyroid drug therapy for Graves' hyperthyroidism: is long-term administration of a small maintenance dose necessary?

This retrospective study serves as an inquiry into the common practice of long-term administration of small maintenance doses of either methyl-mercaptoimidazole (MMI) or propylthiouracil (PTU) to Graves' hyperthyroid patients who became euthyroid with primary large doses of the same drugs. One hundred and two patients with Graves' hyperthyroidism treated with antithyroid drug (ATD) were studied. Sixty-one were treated with conventional long term therapy and 41 were treated with short-term therapy. Small maintenance doses of ATDs were not administered to the short-term therapy patients. The duration of long-term therapy was 28.6 +/- 20.2 months (from 12 to 48 months) and that of short-term therapy was 8.4 +/- 1.8 months (from 5 to 11). Post therapy and follow-up observation continued for 19.0 +/- 2.7 months (16-25 months) in both long-term and short-term patients. Of the 61 long-term therapy patients, 20 were relapsed and 41 (67.2%) continue to remain in remission. So too, of the 41 short-term therapy patients, 14 relapsed and 27 (65.9%) still remain in remission. There was no statistical difference between the long-term and short-term therapy group in age, sex, duration of symptoms before diagnosis, antithyroid antibodies, radioactive iodine uptake, free thyroid hormone levels or goiter size before treatment or in TBII levels at cessation of ATD. It is concluded that 'short-term ATD therapy' without a maintenance dose is sufficient and saves several months of the patient's and clinician's time.

Plasma atrial natriuretic peptide in patients with Graves' disease.

In order to clarify the effect of thyroid hormone on the plasma atrial natriuretic peptide (ANP) concentration, 14 patients with Graves' disease and 6 normal control subjects were studied. They were all under constant sodium intake because dietary sodium is known to affect the amount of plasma ANP. Sodium intake remained constant at 171 mEq daily for five consecutive days at which time the ANP concentration was measured. Graves' disease patients were tested both before and after surgery. The preoperative, hyperthyroid ANP level concentration in Graves' disease patients was 6.7 +/- 2.3 fmol/ml compared to a significantly lower level of 4.2 +/- 1.4 fmol/in normal control subjects. Seven days after surgery when Graves' disease patients became euthyroid their ANP markedly decreased to 4.2 +/- 2.9 fmol/ml. In the present study we were able to confirm that under a constant sodium diet, high plasma ANP in patients with Graves' disease was reduced after surgery when they became euthyroid. Results also suggest that high circulating ANP might play an important role in sodium and water metabolism and hemodynamic changes in hyperthyroidism.

Antithyroid drug-induced agranulocytosis. The usefulness of routine white blood cell count monitoring.

This study was aimed at establishing the importance of routine monitoring of white blood cell counts in patients with Graves' disease receiving antithyroid drug treatment. In the 12-year period from 1975 to 1987, 15,398 patients with Graves' disease receiving treatment with antithyroid drugs were seen at our clinic. Of these, 55 (0.4%) were found to have agranulocytosis. Agranulocytosis was defined as a granulocyte count of 0.5 x 10(9)/L or less. In only 12 of the 55 patients was agranulocytosis detected after the occurrence of infection (symptomatic; classic agranulocytosis). The remaining 43 patients were asymptomatic when agranulocytosis was detected during routine white blood cell count monitoring. However, 14 of these 43 patients became symptomatic several days after withdrawal of antithyroid drug treatment despite antimicrobial treatment (asymptomatic to symptomatic). Twenty-nine patients who were treated appropriately had no symptom of infection throughout the course of the disease, despite the absence of or an extremely small number of granulocytes in circulation (asymptomatic). These results suggest that a "routine monitoring" of the white blood cell count could be the most effective way of predicting and detecting agranulocytosis due to antithyroid drug treatment.

Destructive thyrotoxicosis in a patient with anaplastic thyroid cancer.

A 55-year-old man was admitted to our hospital with an anterior neck tumor, hoarseness, and dysphagia that had continued for a few weeks. He was diagnosed as anaplastic thyroid cancer by fine-needle aspiration cytology. He was treated by external radiation and chemotherapy, but left hemothorax developed and he died of respiratory failure on the 76th day in hospital. On admission, the levels of serum free triiodothyronine (FT3), free thyroxine (FT4), and TSH were 12.8 pg/ml, 4.2 ng/dl, and 0 microU/ml, respectively. The simultaneous thyroidal I-131 uptake rate was 1.2% at 24 hours. The levels of free thyroid hormones fell gradually without antithyroid drugs to result in hypothyroidism (FT3 0.8 pg/ml, FT4 0 ng/dl, and TSH 36 microU/ml). The rapid growth of anaplastic thyroid cancer seemed to be responsible for destructive thyrotoxicosis followed by hypothyroidism in this patient.

Follicular thyroid carcinoma with clear cell change showing unusual ultrastructural features.

We report a case of follicular thyroid carcinoma with clear cell change displaying unusual ultrastructural features. Light microscopy revealed a metastatic neoplasm in the 12th thoracic vertebra that was composed of nests consisting mainly of clear cells. The tumor was interpreted as a metastasis of a clear cell type of thyroid carcinoma, based on positive immunohistochemical staining for thyroglobulin. However, unlike the metastatic bone lesions, the primary tumor in the thyroid consisted mainly of neoplastic follicular cells with lightly eosinophilic cytoplasm. A distinct follicular formation was noted throughout the tumor. In a portion of the tumor, a solid or stratified disposition of the cells was also observed. The primary tumor contained only a few clear cells similar to those seen in the metastatic bone lesions. In addition, we noted a transition between the follicular cells and the clear cells. Thus, this neoplasm was diagnosed as a follicular thyroid carcinoma with clear cell change, but not a specific type of thyroid neoplasm. Electron-microscopic examination revealed that the cells corresponding to clear cells under light microscopy had abundant cytoplasm characterized by varying degrees of dilation of rough endoplasmic reticulum (RER), which might reflect increased synthesis, storage of secretory products, or both.

The effect of iopanoic acid on thyrotropin secretion in patients with cirrhosis of the liver.

Ten patients with liver cirrhosis and six normal subjects were studied to evaluate the effect of iopanoic acid (IA) on thyrotropin secretion. A thyrotropin-releasing-hormone (TRH) test was performed before and 5 days after IA administration (single oral dose of 3 g). After IA administration, a significant increase in TSH response to TRH was observed in normal subjects. In cirrhotics, however, it did not significantly increase after IA administration. The serum T3 and T3/TBG ratio were significantly decreased and the serum T4 and T4/TBG ratio were increased after IA administration in normal subjects and cirrhotics. There was no significant difference in the % decrease in serum T3, % increase in serum T4 or other thyroid hormone parameters including TSH in IA induced TSH responders (R) and non-responders (NR). However, r-T3 before and after IA in R was higher than those in NR. The values for hepatic function tests such as serum albumin, prothrombin time, 45 minutes retention rate of bromsulphalein (BSP 45 min) and the cholinesterase (ChE) level in R were not different from those of NR. These results suggested that in cirrhotics, abnormal regulation of the hypothalamo-pituitary system might exist.