[Effect of long-term treatment with octreotide-lar in a TSH-secreting pituitary macroadenoma and secondary hyperthyroidism]. / Effetto del trattamento a lungo termine con octreotide-Lar in un caso di macroadenoma ipofisario TSH-secernente.

A 74 year-old man was admitted to the hospital for heart failure and atrial fibrillation episodes. He had been irregularly treated for hyperthyroidism during the previous 3 years, with poor control. Thyroid function evaluation showed secondary hyperthyroidism, with high free thyroid hormone levels and TSH inappropriately in the high-normal range (4.2 mU/ml), only slightly responsive to TRH-stimulation (6 microU/ml). Alpha-subunits were hyper-responsive to TRH stimulation (+123%). Thyroid autoimmunity tests were negative and ultrasonography evidenced a diffusely enlarged gland. Magnetic resonance (MR) imaging of the pituitary showed a macroadenoma. The patient underwent transphenoidal adenomectomy, and immunohistochemistry confirmed the diagnosis of a TSH-secreting pituitary macroadenoma. A moderate secondary hyperthyroidism was still present and a new MR evidenced residual disease, involving the right cavernous sinus. A (111)In-octreoscan revealed an increased captation in this area. The patient was treated with octreotide-Lar (20 mg/monthly), which normalized FT3, FT4 and TSH levels already after 3 months of therapy. This effect is still maintained at 42 months of treatment. MR imaging showed a reduction in the residual lesion after 18 months (>50% in comparison with postsurgical MR) and a further decrease after 36 months of treatment). This suggests that the antiproliferative effect on the adenomatous cells is progressive and continues over time. This patients did not receive radiotherapy, so this action is entirely due to the medical treatment. No significant side effects developed and the patient's compliance was good. He has not had further arrhythmic episodes.

Leydig cell tumour-induced bilateral gynaecomastia in a young man: endocrine abnormalities.

Among the various causes of gynaecomastia, testicular malignancies are an uncommon, life-threatening condition, which require prompt treatment. The case of a 26-year-old healthy man is described, who reported a 6-month painful bilateral gynaecomastia associated with secondary hypogonadism. Normal circulating 17beta-oestradiol (E2) levels showed an enhanced response to human chorionic gonadotrophin (hCG) testing, which led to a reduced testosterone (T)/E2 ratio. Both clinical and hormonal findings normalized following surgical exeresis of a left testicular mass, which proved to be a Leydig cell tumour (LCT) at histology. This report underlines the importance of ultrasonographic evaluation of the testes, whenever breast enlargement occurs in a healthy man, despite unremarkable findings on testicular examination. In addition, our case demonstrates that normal unstimulated circulating E2 levels do not allow the presence of a stromal testicular tumour to be ruled out and that the response of restored T levels to hCG testing can remain blunted up to 1 year after surgery. Finally, we claim that T/E2 ratio may be a useful tool in evaluating derangement of the endocrine milieu secondary to LCT.

[Severe postmenopausal hyperandrogenism due to an ovarian lipoid cell tumor: a case report]. / Descrizione di un caso clinico di severo iper-androgenismo postmenopausale dovuto a un tumore ovarico a cellule lipidiche.

The case of a 62-year-old woman with severe post-menopausal hirsutism is described. Her clinical history revealed regular menstrual periods until menopause at the age of 50, hysterectomy for fibromatosis at 58 years, non-insulin dependent diabetes mellitus, hypertension, obesity, severe hirsutism, which had developed in the previous 3 years, with a deeping of the voice. Examination showed android obesity, hypertension and severe hirsutism involving the face and the trunk. Endocrine evaluation pointed out regular adrenal function, serum total and free-testosterone in the adult male range, with normal androstenedione, DHEAS and 17OHP levels. Estradiol was slightly increased and LH and FSH were inappropriately low for her post-menopausal age. Computed tomography of the abdomen showed regular adrenal glands, and a radio-labeled cholesterol scan was negative. A further pelvic transvaginal ultrasonography revealed a small cystic formation near the right ovary and a slight increase in the size of the left ovary. The patient underwent bilateral ovariectomy. Histological examination showed a lipoid cell tumor within the left ovary. Immunohistochemical studies were positive for inhibin and cytokeratin. After surgery, serum testosterone fell to normal levels, gonadotropins increased to menopausal levels, confirming that the tumor was able to produce both LH, and FSH-inhibiting factors, and hirsutism greatly improved. Periodic hormonal tests remained normal and CT of the abdomen and pelvic ultrasonography did not show alterations at a 3 years follow-up.

Use of an artificial neural network to predict Graves' disease outcome within 2 years of drug withdrawal.

BACKGROUND: Graves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism, which can relapse in many patients after antithyroid drug treatment withdrawal. Several studies have been performed to predict the clinical course of GD in patients treated with antithyroid drugs, without conclusive results. The aim of this study was to define a set of easily achievable variables able to predict, as early as possible, the clinical outcome of GD after antithyroid therapy. METHODS: We studied 71 patients with GD treated with methimazole for 18 months: 27 of them achieved stable remission for at least 2 years after methimazole therapy withdrawal, whereas 44 patients relapsed. We used for the first time a perceptron-like artificial neural network (ANN) approach to predict remission or relapse after methimazole withdrawal. Twenty-seven variables obtained at diagnosis or during treatment were considered. RESULTS: Among different combinations, we identified an optimal set of seven variables available at the time of diagnosis, whose combination was useful to efficiently predict the outcome of the disease following therapy withdrawal in approximately 80% of cases. This set consists of the following variables: heart rate, presence of thyroid bruits, psycological symptoms requiring psychotropic drugs, serum TGAb and fT4 levels at presentation, thyroid-ultrasonography findings and cigarette smoking. CONCLUSIONS: This study reveals that perceptron-like ANN is potentially a useful approach for GD-management in choosing the most appropriate therapy schedule at the time of diagnosis.

[Genotypic sex and phenotypic sex: clinical, biochemical and molecular aspects in a patient with male hypogonadism and 46XX-45XO karyotype]. / Sesso genotipico e sesso fenotipico: aspetti clinici, biochimici e molecolari in un paziente con ipogonadismo maschile e cariotipo 46XX-45X0.

We report here the case of a patient with primary male ipogonadism, with small testes and deficient virilization of the external genitalia, but with 46XX, 45X0 karyotype. Hormonal determinations showed high LH and FSH and low testosterone levels. Ultrasonography confirmed the presence of small testes within the scrotum. Cytogenetic analysis demonstrated a female karyotype, with 90% 46XX, 10% 45X0 mosaicism. Using DNA probes for genes located on the Y chromosome, the presence of the "Sex-Determining Region" of the Y chromosome (SRY) was evidenced in the genomic DNA of this patient. By Fluorescence in Situ Hybridization (FISH), SRY locus was localized in the p terminal region of an X chromosome. SRY is the primary inducer of testis development; it acts as a transcription factor leading to a sequence of gene activations critical in the process of testicular differentiation and morphogenesis. A condition characterized by testicular development in subjects who lack a normal Y chromosome has been described; most of these patients are carriers of the short arm of the Y chromosome transferred to one of the two X chromosome, suggesting a form of X-Y paternal interchange. In our patient, the development of male gonade in the absence of an Y chromosome was explained by the demonstration of the SRY gene in an X chromosome.

[Pituitary pathology in elderly patients admitted in a division of internal medicine. Description of 3 cases]. / Patologia ipofisaria in anziani ricoverati presso una Divisione di Medicina Interna. Descrizione di tre casi.

Pituitary diseases are often unrecognized in the elderly, although if they can be at the basis of several pathological conditions. We report three clinical cases. Patient n. 1: 87 years old woman, in poor general condition. Thyroid function evaluation showed secondary hypothyroidism. Subsequent pituitary function evaluation demonstrated hypopituitarism with empty sella. The diagnosis was "hypopituitarism with secondary hypothyroidism and adrenocortical insufficiency, in empty sella" starting substitutive treatment with glucocorticoids and L-thyroxine, with improvement in her clinical conditions. Patient n. 2: 74 years old woman, with severe congestive heart failure. Her clinical history revealed hypothyroidism. An endocrine evaluation (in absence of therapy) demonstrated panhypopituitarism with secondary hypothyroidism and adrenocortical insufficiency in presence of empty sella. The patients was started on substitutive treatment and her conditions improved. Patient n. 3: 74 years old man with several atrial fibrillation episodes and hyperthyroidism. Thyroid function evaluation suggested secondary hyperthyroidism confirmed by the presence of a pituitary macroadenoma. The patient underwent surgical adenomectomy by trans-sphenoidal route. The clinical conditions of the patient improved, but a slight secondary hyperthyroidism was still present caused by the persistence of residual pathological tissue in the right cavernous sinus region confirmed by octreoscan suggesting the presence of a lesion endowed with somatostatin receptors. The patient was started on long acting octreotide treatment, which is still in progress. In conclusion, pituitary diseases pass often unrecognized in the elderly. Their prompt recognition and treatment can resolve dangerous situations for the patients.

The impact of obesity on hormonal parameters in hirsute and nonhirsute women.

The influence of obesity on sex hormone-binding globulin (SHBG) and androgen concentrations in hirsute and nonhirsute women has been evaluated. The study was performed in 226 hirsute women (88 obese and 138 non-obese) classified as being affected by polycystic ovarian syndrome (PCOS) or by idiopathic hirsutism (IH) and in 100 nonhirsute control women ([C] 60 lean and 40 obese). SHBG, free testosterone (fT), androstenedione (A), estradiol (E2), dehydroepiandrosterone sulfate (DHEAS), and gonadotropin levels were measured during the first week of the menstrual cycle by radioimmunoassay (RIA). A significant negative correlation between SHBG and body mass index (BMI) was observed in PCOS, IH, and C women. In obese women--whether PCOS, IH, or C-fT levels were significantly higher and, conversely, SHBG levels were lower than in non-obese women. A negative correlation between SHBG and fT was evidenced in each group. Upper-body obesity was associated with lower SHBG and higher fT levels than lower-body obesity. In conclusion, obesity, particularly upper-body obesity, is associated with a reduction in SHBG and an increase in fT in both nonhirsute and hirsute women.

Increased 17 alpha-hydroxyprogesterone response to ACTH in silent adrenal adenoma: cause or effect?

OBJECTIVE: Recent studies suggest a possible connection between silent adrenal nodules and mild forms of 21-hydroxylase deficiency. It remains unclear whether the enzymatic deficiency is generalized or intrinsic to the adrenal mass. To help to clarify this, we have studied 17 alpha-OH-progesterone (17OH-P) response to ACTH stimulation in a group of patients with adrenal 'incidentaloma' in comparison with normal subjects. In patients who underwent surgical treatment, the test was repeated to evaluate possible modifications in 17OH-P behaviour after resection of the adrenal mass. SUBJECTS AND METHODS: Fifteen subjects with incidentally discovered asymptomatic adrenal masses were studied. Basal hormone evaluations were normal, with normal cortisol suppression after low-dose dexamethasone. Iodocholesterol scanning, performed in 12 patients, showed normal bilateral adrenal uptake in 2 subjects and an increased uptake on the side of the lesion in 10 subjects. In every patient, ACTH stimulation was performed to evaluate the secretory response of cortisol, 17OH-P, progesterone and dehydroepiandrosterone sulphate. An identical test was performed in 10 control subjects with normal adrenal glands, matched for age and sex. In six patients with an adrenal lesion > 3.5 cm, the ACTH stimulation test was repeated one month after surgery. RESULTS: The 17OH-P response to ACTH stimulation was significantly higher in subjects with adrenal 'incidentaloma' than in controls (P < 0.01). In particular, 10 subjects out of 15 (66%) evidenced a 17OH-P peak > 18 nmol/l at 60 minutes. No differences were seen in baseline 17OH-P or cortisol levels or in cortisol response to ACTH between the two groups. Dehydroepiandrosterone sulphate concentrations were significantly lower in patients with adrenal 'incidentaloma' than in normals. In six patients who had an increased 17OH-P response to ACTH on initial evaluation, the ACTH test was repeated one month after surgery. In five of these patients, 17OH-P response to ACTH was clearly reduced, suggesting that in these cases the enzymatic defect was restricted to the adenoma. In the other patient, however, stimulated 17OH-P levels remained unchanged. In this case, therefore, all of the adrenal tissue seems to be involved, suggesting a late-onset 21-hydroxylase deficiency. No significant modifications in cortisol response to ACTH were observed. CONCLUSION: It seems therefore that in some cases of incidentaloma the steroidogenic enzymatic defect may be secondary to the adenomatous proliferation, while in others such defects may induce the development of silent adrenal nodules.

Endocrine evaluation in patients treated with interferon-alpha for chronic hepatitis C.

The aim of our study was to evaluate the hormonal profile in a group of 31 subjects who underwent recombinant interferon-alpha therapy for chronic active hepatitis C. Hormonal determinations were performed before treatment began and at the end of the 3rd and 6th months of therapy. Free-T4 concentrations, though remaining in the normal range, showed a significant reduction (p < 0.05) after 3 and 6 months of therapy compared with pretreatment levels. A lesser decrease in free-T3 levels was also seen. TSH basal values did not show any variation, while an increased secretory response to TRH stimulation was observed at the end of the 6th month. Thyroglobulin and calcitonin levels remained normal, while an increase in antithyroglobulin and antithyreoperoxidase antibody levels was observed in 4 patients (12.9%). No modifications in the other pituitary hormones or in adrenal and sex steroid concentrations were noticed. A significant increase in IGF-I concentrations (p < 0.05) was observed during treatment, and an inverse correlation was seen between IGF-I and alanine aminotransferase levels (p < 0.01). This study supports the view that interferon treatment can influence thyroid function. The increase in IGF-I concentration observed during therapy may reflect an improvement in patients with hepatic disease, but a direct stimulatory effect of interferon on IGF-I secretion cannot be excluded.

The use of flutamide in the management of hirsutism.

The aim of our study was to evaluate the clinical efficacy of flutamide (Flu), when used alone, on the course of hirsutism and to assess its effect on hormonal secretion. Thirty-six hirsute women [11 patients were affected by polycystic ovarian syndrome (PCOs), and 25 were classified as having idiopathic hirsutism (IH)] were treated with Flu, 375 mg daily for a 4-month period. We found a marked clinical improvement in the degree of hirsutism in all patients. Testosterone and free testosterone fell significantly in both groups, while SHBG concentrations showed an increase in PCOs. In these patients, a reduction in androstenedione levels was also evident. Basal DHEAS concentrations showed a significant decrease only in PCO women. No significant modifications in gonadotropin response to LHRH nor in adrenal steroid response to ACTH stimulation were observed in 12 of the IH women before therapy and after the first month. Although the main action of flutamide is attributed to its peripheral antiandrogenic properties, the decrease in circulating androgen levels observed during treatment suggests that it can also modulate androgen production and/or metabolism.

Another postnatal-onset obesity syndrome.

We describe an apparently newly recognized postnatal-onset obesity syndrome with short stature, mental deficiency, hypogonadism, micropenis, contractures of the fingers, and cleft lip-palate. Comparison is made with other postnatal-onset obesity syndromes, particularly Vasquez syndrome and Urban syndrome. The cause of our patient's syndrome is unknown at present. We encourage the reporting of other cases to help clarify whether our patient represents a separate entity.

LH-RH analogue treatment in adenocarcinoma of the pancreas: a phase II study. Gruppo Ligure per lo Studio del Pancreas.

In this phase II study, we treated 7 patients, all males, with stage III or IV pancreatic cancer with goserelin (an LH-RH analogue). Goserelin was administered at a dose of 3.6 mg every 4 weeks. The tumour response was assessed by measuring lesions with US- or CT-scan studies, according to WHO criteria. No response was observed. The median survival was 8 months in locally unresectable tumours and 4 months in advanced disease. The accrual was actually stopped at 7 cases because there were no responses in either of our series or in those published during our study. The authors conclude that the treatment with LH-RH analogue alone cannot be recommended for further studies.

Effects of dihydrotestosterone and hydroxyflutamide on androgen receptors in cultured human breast cancer cells (EVSA-T).

The purpose of our study was to evaluate the effects of 5 alpha-dihydrotestosterone (DHT) and hydroxyflutamide (HF), alone or in combination, on androgen receptor (AR) dynamics and on cellular growth in cultured breast cancer cells (EVSA-T). The incubation of cells with DHT increased the concentration of nuclear AR after 24 and 48 h. HF was also able to promote the nuclear accumulation of AR after 24 and 48 h of treatment. When HF-treated cells are incubated with DHT, the nuclear AR concentration is lower than that found in cells treated with DHT alone. We conclude that HF acts by increasing nuclear accumulation of receptor-antiandrogen complexes. Moreover, DHT stimulates cell growth while HF has an inhibitory effect. Thymidine incorporation in cells also increased after DHT treatment and decreased after HF incubation. The HF-induced inhibition of cell growth persisted both after renewal of the medium and after the addition of DHT to cultures. It may be hypothesized that either DHT is converted to inactive metabolites or that HF exerts a persistent inhibitory effect. In the latter case, the antiandrogen action of HF could be exerted by retention of high levels of antiandrogen in cells or by such a depressed protein synthesis that the renewal of growth is slower than the 48 h period studied.

Cytosolic and nuclear androgen receptors in colorectal adenomas.

The aim of this study was to verify the presence of androgen receptors (AR) in human colorectal adenomas and in normal adjacent mucosa, and to determine whether there is any difference in AR tissue content between females and males. Our data show higher levels of nuclear AR in normal mucosa than in adenomas (p less than 0.001). A significant difference was also present in males between normal and pathological tissue both in cytosolic (p less than 0.05) and nuclear receptors (p less than 0.01). In female subjects this difference was also evident, but not significant. Our results seem to support the hypothesis of protective effects of androgens in colonic mucosa.

Androgen receptors in normal and pathological thyroids.

The purpose of this study was to determine the presence of cytosolic and nuclear androgen receptors (AR) in both normal and nodular thyroid tissues from twelve women and six men. Samples of benign thyroid nodules and corresponding surrounding normal tissue were processed by the single saturation point assay, using [3H] R1881 ([3H] Methyltrienolone) at final concentration of 5 nM. The results show the presence of AR (cytosolic and/or nuclear) in all examined tissue samples. The nuclear AR content was higher (p less than 0.01) in normal rather than in nodular thyroid tissues. The same pattern was observed when nuclear AR were analyzed according to the sex. In addition, nuclear AR content was significantly (p less than 0.05) higher in normal thyroid tissue from men than from women. Our data suggest an androgen influence on thyroid tissue. If androgens are supposed to exert an antagonist role on estrogen actions also in thyroid tissue, the presence of higher nuclear AR concentration in the male rather than in the female normal thyroid may justify the lower incidence of thyroid diseases in men. Moreover, the lower AR levels found in male as well as in female nodular and goitrous tissues support the hypothesis that androgens may act with an antagonist mechanism on thyroid growth.

Aggressive factors or altered protective capacity of the gastric mucosa in chronic liver disease.

This study was conducted to assess the behavior of various parameters involved in mucosal protection (mucus and prostaglandins) and of presumed aggressive factors (hydrochloric acid and Helicobacter (Campylobacter) pylori in 20 patients with chronic liver disease, with or without clinical and instrumental signs of portal hypertension. The two groups of patients showed no difference from controls with respect to gastric acid secretion and the presence of antral Helicobacter pylori. The amount of gastric soluble mucus was reduced and the quality altered in cirrhotic patients with portal hypertension. The mucus of subjects with chronic active liver disease with no gross signs of portal hypertension showed significant qualitative differences from that of normal controls. The prostaglandin E2 concentration in the gastric mucosa was lower than normal in both groups of liver disease patients, but prostaglandin F2 alpha did not appear to differ between patients and controls.