Presence of systemic autoimmune disorders in patients with autoimmune thyroid diseases.

OBJECTIVE: To evaluate the prevalence of antinuclear antibodies (ANA) in patients with autoimmune thyroid diseases (ATD) and the presence of systemic autoimmune disorders among ANA positive patients with ATD. METHODS: 168 consecutive patients with ATD with positive antithyroid antibodies and 75 healthy subjects were tested for the presence of ANA. ANA positive patients were further evaluated by complete history, physical examination, blood and urine tests, and immunological studies. Patients with subjective xerophthalmia and xerostomia were examined by objective tests. RESULTS: 58/168 (35%) patients with ATD were ANA positive compared with 7/75 (9%) healthy controls (p = 0.001). Of 58 ANA positive patients, 6 (10%) had anti-Ro antibodies, 1 had anti-Ro and anti-La antibodies, 7 (12%) had anti-dsDNA antibodies, and 7 (12%) had medium levels of IgG and/or IgM anticardiolipin antibodies (aCL). No healthy subjects had positive anti-dsDNA, antibodies against the extractable nuclear antigens, or aCL. 5/58 (9%) patients fulfilled the criteria for Sjögren's syndrome (SS). Two patients had features related to systemic lupus erythematosus. No healthy subjects had clinical or laboratory characteristics of systemic autoimmune disorders. CONCLUSION: ANA are detected in 1/3 of patients with ATD. Anti-dsDNA, anti-Ro, and aCL can also be found in ANA positive patients with ATD. SS occurs in about 1/10 of ANA positive patients with ATD.

Estrogen receptor alpha gene analysis in osteoporosis and familial osteoporosis.

Estrogens are important determinants of bone mineral density (BMD) mediating their effects via estrogen receptor alpha (ERalpha) and beta (ERbeta). The strong genetic predisposition to osteoporosis, and the fact that alterations in the aminoterminal region of ERalpha have been linked to bone disturbances, prompted us to identify genetic alterations in exon 1 and exon 2 of ERalpha in osteoporotic individuals. Sixty-two unrelated normal subjects (age 46.1+/-9.5 years) and 72 unrelated osteoporotic subjects (age 52.3+/-7.9 years) were studied. Their menopausal status was pre- and perimenopausal. We also included 30 related osteoporotic individuals (mother-daughter or sister-sister relationship) (age 46.2+/-12.8 years) belonging to 14 families who where also pre- and perimenopausal. DNA was extracted from peripheral blood, exons 1 and 2 were amplified by polymerase chain reaction (PCR) and were further submitted to denaturing gradient gel electrophoresis (DGGE), single stranded conformational polymorphism (SSCP), restriction fragment length polymorphism (RFLP) and sequence analysis. Bone turnover markers were also determined. Two polymorphisms were identified in exon 1 (codons 10 and 87) in both normal and osteoporotic women. Statistical analysis revealed no difference (P>0.05) in the ERalpha genotype frequencies within osteoporotic families as compared with the same genotypes in the unrelated normal or osteoporotic subjects. Codon 10, codon 87 polymorphisms were not related to BMD or bone turnover markers. No other mutations were found in exons 1 and 2 in all subjects studied. Genetic alterations in exons 1 and 2 of ERalpha are not associated to osteoporosis and familial osteoporosis. Moreover, the codon 10 and codon 87 polymorphisms do not seem to be correlated with BMD and bone turnover markers.

The contribution of vitamin D receptor gene polymorphisms in osteoporosis and familial osteoporosis.

It is well established that genetic factors play a major role in the pathogenesis of osteoporosis. Previous reports have suggested that vitamin D receptor (VDR) gene polymorphisms, particularly the BB, tt and AA genotypes, are associated with low bone mineral density (BMD). If these VDR genotypes are indeed an important determinant of BMD, then a population of related osteoporotic individuals (mother-daughter or sister-sister relationship) should have a high prevalence of the BB, tt or AA VDR genotypes. To test this hypothesis we determined the VDR genotypes in 26 osteoporotic persons (age 44.3 +/- 12.7 years, mean +/- SD) belonging to 12 families. Furthermore, for comparison with existing studies, we applied the VDR genotype analysis in a population of 53 unrelated healthy subjects (age 45.2 +/- 9.8 years, mean +/- SD) and 59 unrelated osteoporotic subjects (age 52.1 +/- 9.0 years, mean +/- SD). The menopausal status of the healthy and osteoporotic populations was pre-, peri- and mostly early postmenopausal. The proportions of the three genotypes, BB, tt and AA, within the 12 osteoporotic families were 15%, 12% and 27%, respectively, whereas the proportions of the other three homozygous genotypes (bb, TT, aa) were 50%, 50% and 23%. The distribution of the BB, tt and AA genotypes in the normal population was 21%, 21% and 36%, respectively (vs bb, TT, aa: 36%, 38%, 21%), whereas in the osteoporotic population it was 24%, 20% and 34% (vs bb, TT, aa: 27%, 34%, 14%). Our data indicate that there is not a statistically significant (p>0.05) difference in the VDR genotype frequencies within osteoporotic families as compared with the same genotypes in the population of unrelated normal or osteoporotic subjects. VDR genotype analysis showed no significant relation between VDR polymorphisms and BMD or Z-score values at the lumbar spine. This study demonstrates the lack of a heritability pattern between the BB, tt and AA genotypes and low BMD.

Cold thyroid nodule as the sole manifestation of Rosai-Dorfman disease with mild lymphadenopathy, coexisting with chronic autoimmune thyroiditis.

A case of thyroid Rosai-Dorfman disease (RDD) without apparent lymphadenopathy in a 49-year-old woman with underlying euthyroid chronic autoimmune thyroiditis, as indicated by high thyroid autoantibodies titers, is presented. The initial presentation was that of a cold, hypoechogenic nodule of left thyroid lobe which increased in size during the two years of follow up, together with new ultrasonographic findings of the right lobe. No biochemical abnormalities were found apart from mild hypercalcemia. A near total thyroidectomy was performed. Histologically, the left lobe nodule as well as the right lobe lesions consisted of typical RDD cellular population, with the pathognomonic phenomenon of emperipolesis. Infiltration to the periphery of the gland was observed and three adjacent lymph nodes were also involved. The uninvolved thyroid parenchyma showed changes compatible with chronic autoimmune thyroiditis. No other localizations or systemic manifestations of RDD were revealed. Normocalcemia was restored promptly and the patient remains free of clinically overt disease one year post-operatively.

Incidentalomas of the adrenal gland: diagnostic and therapeutic implications.

Incidentally discovered adrenal masses are common since the advent and application of sensitive noninvasive imaging methods. The significance of these so-called "incidentalomas" and the question of further evaluation or treatment remains elusive. This report describes a retrospective study of 86 patients with incidentaloma. Adrenalectomy was performed on 26 patients during initial admission. Histologically, two cortisol-producing adenomas, an adenoma with subclinical cortisol production, and two pheochromocytomas (all of the preceding detected during the preoperative hormonal evaluation), three cystic lesions, one myelolipoma, and one hematoma were found. One primary and two metastatic adrenal carcinomas were also found in this series. Sixty patients with a nonfunctioning incidentaloma smaller than 6 cm were observed in an average of 43 months with serial CT scans performed at 3, 9, and 18 months after the initial diagnosis. Enlargement of the mass was detected in two patients; both proved to be nonfunctioning adenomas. Based on these observations, it is concluded that the initial laboratory evaluation is mandatory in cases of incidentalomas, including parameters of adrenocortical and medullar function. Hormonally active incidentalomas and those suspected for malignancy should be treated surgically. Masses greater than 6 cm should also be removed. Smaller incidentalomas without endocrine activity or signs of malignancy should be followed by CT scan at 3, 9, and 18 months after the initial diagnosis.

Sex hormone levels in the serum of patients with pancreatic adenocarcinoma.

The objective of this study was to evaluate the levels of several pituitary and gonadal hormones in pancreatic adenocarcinoma. We examined circulating levels of LH, FSH, Testosterone, Oestradiol, Progesterone and delta 4-Androstenedione in 36 patients with pancreatic adenocarcinoma, 12 patients with chronic pancreatitis and 87 age matched controls. According to our findings males with pancreatic cancer were found to have higher levels of FSH (p < 0.01). LH and oestradiol (p < 0.001) and lower levels of progesterone (p < 0.01) and testosterone (p < 0.05) than the controls. Female patients with pancreatic cancer were found to have higher levels of oestradiol (p < 0.001) and lower levels of LH, FSH and progesterone (p < 0.001), compared with group of healthy volunteers. Our data provide evidence of a generalised dysfunction of the hypothalamic-hypophysial-gonadal axis in pancreatic cancer patients.

Effect of growth hormone cotreatment with human chorionic gonadotropin in testicular steroidogenesis and seminal insulin-like growth factor-1 in oligozoospermia.

OBJECTIVE: To study the GH synergy with hCG in testicular steroidogenesis and seminal insulin-like growth factor-1 (IGF-1) in oligozoospermia. SETTING: University endocrine unit. PATIENTS: Eight oligospermic, non-GH-deficient men. INTERVENTIONS: Three different protocols spaced 3 months apart were applied in each man: plain hCG protocol: 1,500 IU IM three times every other day; GH + hCG protocol: with the addition of 4 IU SC GH daily 8 days before and throughout the hCG phase; placebo + hCG: substitution of GH by NaCL 0.9%. Blood sampling was performed before and on the 8th day (for 2nd- and 3rd-day protocols) and 24 hours after each hCG administration. Semen was collected three times during each protocol. MAIN OUTCOME MEASURES: Plasma for P, 17-OHP, androstenedione, DHEA, DHEAS, T, and E2 and plasma and seminal IGF-1 three times during each study. RESULTS: Serum IGF-1 levels increased more than threefold after GH administration. Seminal IGF-1 activity was unaffected by GH treatment or hCG administration, showing random fluctuations within each subject without correlation to the respective plasma levels. The incremental response of each steroid under hCG did not differ between the three protocols, apart from increased P levels under GH. CONCLUSIONS: Short-term GH cotreatment with hCG did not affect seminal IGF-1 concentration and had a weak synergist effect on steroidogenesis.

Effect of testosterone administration, pre- and postnatally, on the immune system of rats.

This study was undertaken to investigate and compare in vitro and in vivo immune parameters between female and male rats. We analysed the T-cell proliferative responses to syngeneic and allogeneic cellular antigens (syngeneic and allogeneic mixed lymphocyte reaction), as well as the IgG levels in the sera of our study groups. It has also been studied the influence of gonadectomy and the effect of testosterone administration pre- and postnatally on the above parameters. Our findings showed that hormonal manipulations, can alter the differences observed in immune response between female and male rats. In addition, it is demonstrated that pre- and postnatal sexual steroid manipulations could provoke long lasting immunological effects.

Seminal fibronectin-like antigen and transferrin concentrations in infertile and fertile men.

Fibronectin like antigen (Fn) and transferrin (Trs) levels were measured in the seminal plasma of 40 fertile and 102 infertile men. The concentrations of both proteins were significantly (P < 0.001) higher in the fertile controls compared to the infertile groups. The levels of Fn and Trs (mean value +/- SEM) in the fertile men were 857.9 +/- 9.8 micrograms ml-1 and 164.0 +/- 6.5 micrograms ml-1, respectively; in the azoospermic men (n = 17) 552.7 +/- 24.65 micrograms ml-1 and 20.7 +/- 2.19 micrograms ml-1, respectively; in the group of severe oligozoospermia (n = 35) 568.34 +/- 25.7 micrograms ml-1 and 31.1 +/- 4.18 micrograms ml-1, respectively; in the moderate oligozoospermic group (n = 8) 572.50 +/- 47.9 micrograms ml-1 and 43.4 +/- 15.4 micrograms ml-1 respectively, and in the asthenozoospermic group (n = 26) 512.76 +/- 40.4 micrograms ml-1 and 47.0 +/- 7.9 micrograms ml-1, respectively. Of special interest was the finding from a group of 16 normospermic men (partners of couples with unexplained infertility) who showed significantly lower levels of Fn like antigen, 632.5 +/- 26.9 micrograms ml-1 (P < 0.001) and Trs 41.8 +/- 6.94 micrograms ml-1 (P < 0.0001) compared to normals. No correlation was found between Fn levels with either Trs or FSH levels or sperm count. In conclusion, our results indicate that male infertility is associated with changes in seminal plasma Fn like antigen concentrations and that it can be possibly used as an index of sperm fertilizing capacity.

The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches.

OBJECTIVE: The osteoporosis seen in thalassaemia major is of multifactorial origin. The aim of the study was to evaluate the contribution of hypogonadism to the development of this osteoporosis and to assess the efficacy of new sex hormone replacement therapy regimens. DESIGN AND PATIENTS: Sixty-seven patients were studied: 12 were hypogonadal, 32 had been on previous hormone replacement therapy (conjugated oestrogens plus medroxyprogesterone for females, depot testosterone esters for males); 10 had received continuous courses of treatment and 22 3-monthly on/off courses, and 22 were eugonadal without previous replacement therapy. Twenty-seven of the above patients were evaluated prospectively at 16 and 32 months during different therapeutic approaches (12 without treatment, 7 on continuous replacement and 8 on/off schemes followed by continuous therapy during the second observation period). The continuous schemes comprised either transdermal oestradiol (100 micrograms) plus medroxyprogesterone for females or hCG to produce serum testosterone concentrations within normal range, for males. MEASUREMENTS: Bone mineral density (BMD) and bone mineral content (BMC) of lumbar spine and distal end of radius were measured by dual-energy X-ray absorptiometry. RESULTS: Spinal BMD was found to be more than 30% lower than that of controls matched for sex and age with no difference between sexes. Radial BMD was less impaired and showed significantly (P < 0.01) higher levels in males (decrease of 5.8% +/- 2.3, mean +/- SD) than in females (-14.5 +/- 3.4%, mean +/- SD). In the retrospective evaluation it was found that the hypogonadal group had the lowest (P < 0.0001) BMD levels (0.62 +/- 0.01, mean +/- SE) and the highest were observed on the continuous replacement group (0.83 +/- 0.04), whereas the values of the other groups were similar. In a multiple regression analysis model it was found that only sex steroid levels were related to the BMD measurements (for oestradiol t = 2.6, P = 0.01 and for testosterone t = 6.5, P = 0.0001), whereas parameters related to haemolytic anaemia and desferrioxamine treatment were not. In the prospective study the continuous replacement group increased BMD and BMC values more than the on/off treatment courses (P = 0.01). CONCLUSIONS: Hypogonadism seems to play an important role in the development of osteopenia-osteoporosis in thalassaemia major; continuous hormone replacement therapy with transdermal oestrogen for females or hCG for responding males best improves the bone density parameters.

Increased 17-OH-progesterone levels following hCG stimulation in men with idiopathic oligozoospermia and raised FSH levels.

Leydig cell function was investigated in 71 men with idiopathic oligospermia and compared to 14 fertile controls by assessing the steroidogenic response to GnRH and the repetitive administration of hCG (1500 IU x3). The oligospermic men were divided into two groups according to their basal serum FSH values (FSH < 8, n = 35; FSH > 8, n = 36), this level being defined by the mean + 3 SD of the levels in normal men (3.71 + 4.08 mIU/ml). Oversecretion of LH was supported by the findings of: (a) higher basal LH levels (p < 0.0001) in both oligospermic groups, although still within the normal range; (b) higher Dmax LH and area LH (p < 0.0001) levels in the FSH > 8 group; (c) a strong position correlation (p < 0.001) of the above parameters with the respective levels of FSH. No difference in basal testosterone levels was observed between the three groups, whereas basal levels of 17-OHP were significantly higher (p < 0.05) in the group with FSH > 8. The testosterone/LH ratio was significantly (p < 0.0001) lower in the FSH > 8 group, and was correlated inversely to the basal blood levels of FSH (p < 0.0001) and to the area LH (p < 0.04). After the hCG test, there was no difference in the testosterone and oestradiol response between the groups, whereas the secretion of 17-OHP and the ratio of 17-OHP/testosterone was significantly higher (p < 0.0001) in the group with FSH > 8 compared with the other two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal hyperresponsiveness to ACTH stimulation in women with polycystic ovary syndrome: an adrenarchal type of response.

Adrenal responsiveness to ACTH stimulation (1 mg, i.m.) was assessed by measuring cortisol (Cort) and 17-hydroxyprogesterone (17OHP) at 0, 30, 60, and 90 minutes and progesterone (P), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), delta 4-androstenedione (delta 4A), and testosterone (T) at 0, 60, and 90 minutes post-ACTH in 30 women with polycystic ovary syndrome (PCO). The results were compared with those from 12 normally menstruating women. Three distinct patterns of responses of the adrenal steroids were observed in PCO patients, while cortisol response was similar to that of normal controls: (a) normal responders (n = 9, 30% of PCO patients), in whom a delta max response similar to that of normals was observed, although basal delta 4A and T levels were found to be elevated; (b) 21-OH dysfunction group (n = 6, 16.6%), in whom delta max 17OHP levels and delta max 17OHP to delta max Cort ratio were significantly higher than those of normals and the other PCO groups, indicating a dysfunction at the 21-hydroxylase level; (c) adrenarchal type of response group (n = 16, 53%), in whom statistically significant (P less than .0001) hyperresponsiveness of DHEA and, in 11 of them, of delta 4A, with high delta max delta 4A to delta max DHEA to delta max Cort ratios were found, indicative of a selective overproduction of the steroids during steroidogenesis. Moreover, the significantly higher delta max delta 4A to delta max 17OHP ratio found in group c is a further indication of increased 17,20-lyase efficiency, as is encountered during adrenarche.(ABSTRACT TRUNCATED AT 250 WORDS)

Paradoxical growth hormone response following thyroid-stimulating hormone administration in the polycystic ovary syndrome.

Growth hormone (GH) and prolactin (PRL) responses after TRH administration were studied in 31 women presenting with the clinical, biochemical and ultrasonographic characteristics of the polycystic ovarian (PCO) syndrome; their results were compared with those of 20 normally menstruating women investigated during the early follicular phase of the cycle. Based on the GH responses two PCO subgroups were observed: (a) nonresponders (n = 16) who showed delta max GH responses (0.7 +/- 0.27 ng/ml, x +/- SE) similar to those of the normals (0.97 +/- 0.20 ng/ml), and (b) responders (n = 15), 48.4% of the PCO patients who showed a paradoxical increase in GH levels (delta max GH, 18.0 +/- 1.96 ng/ml) following thyrotropin-releasing hormone (TRH) administration significantly higher than those observed either in nonresponder PCO patients or in normals. Furthermore, basal GH levels were found to be significantly higher in the responder PCO subgroup (5.65 +/- 0.75 ng/ml) compared to either nonresponders (1.58 +/- 0.21 ng/ml) or normals (1.8 +/- 0.18 ng/ml). However, no correlation was found between basal GH levels and delta max GH responses observed. Additionally, basal PRL and delta max PRL levels following TRH administration did not differ either between the two PCO subgroups or those observed in normal controls. delta 4A, T and E2 levels were similar between the two PCO subgroups. No correlation was found between the delta max GH responses to delta max PRL or the post-luteinizing hormone-releasing hormone stimulation test delta max luteinizing hormone:follicle-stimulating hormone ratio observed or to steroid levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity of prolactin responses to oestradiol benzoate in women with prolactinomas.

Serum prolactin concentrations were measured for 72 h after intramuscular injection of 1 mg of oestradiol benzoate in six normoprolactinaemic women and nineteen with a prolactinoma (eleven with an obviously enlarged pituitary fossa and eight with a normal pituitary fossa). The group with an obvious tumour showed a rise in mean serum prolactin at 48 h to 122% of basal concentrations (p less than 0.05), and at 72 h to 137% of basal concentrations (p less than 0.01). Individual responses were variable, but in four patients serum prolactin rose to 165% or more of basal concentrations. In the group with a prolactinoma and a normal pituitary fossa serum prolactin at 72 h was 121% of basal concentrations (p less than 0.05). Normoprolactinaemic women showed no significant change in serum prolactin at any time. This study demonstrated a heterogeneity of serum prolactin responses to acute oestradiol administration in women with prolactinomas. Some patients with large tumours had a hypersensitive response to oestradiol. This heterogeneity of response could account for the present unpredictability of expansion of prolactinomas during pregnancy.

Results of three-times-per-week long-term administration of a luteinizing hormone-releasing hormone (LHRH) analog, D-Ser-(TBU)6-LHRH-(EA)10 in primary amenorrhea.

The effectiveness of a luteinizing hormone (LH)-releasing hormone (LHRH) analog, D-Ser-(TBU)6-LHRH-(EA)10 (Hoe 766), applied intranasally in a 3 days-per-week regimen, was assessed in four patients with hypogonadotropic or normogonadotropic primary amenorrhea by measuring LH, follicle-stimulating hormone (FSH), and estradiol (E2) levels before and 4 hours after its application and by observing the clinical effects of these hormones on the genital tract. The LH response increased progressively over the first 21 days (nine applications) in three of the four patients; it was subsequently reduced but never abolished throughout the study, which was terminated with the 25th application on the 59th day. Basal values of E2 increased until the 12th to 14th day (fifth or sixth application) and then showed a definite decline despite the continuing increase in LH response. FSH release attained a maximum by the second to fourth application and its magnitude of response remained remarkably stable thereafter. The clinical response did not correspond to the serum levels of E2. It is postulated that the development of LH unresponsiveness is due to desensitization of the receptors by the analog. The poor response of the genital tissues to the normal levels of E2 and the subsequent decrease in E2 levels, which occurred despite increasing LH responsiveness, are attributed to an inhibitory action of the analog on E2 biosynthesis in the ovary and on E2 receptors in the genital organs.

Prolactin and placental hormone levels during pregnancy in prolactinomas.

Prolactin (PRL) and the placental hormones, estradiol (E2), estriol (E3), progesterone (PG), chorionic gonadotropin (HCG), and placental lactogen (HPL) were serially measured throughout pregnancy and early postpartum in three patients with prolactinomas in whom pregnancy was achieved by one of the three modalities of treatment: bromocriptine administration (patient I), irradiation of the pituitary (patient II), and human gonadotropin administration after excision of the adenoma (patient III). It was found that PRL in patient I reached the high pretreatment levels in the 2nd month of pregnancy and increased to further abnormal concentrations in the last 2 months, but fell at the onset of labor 1 week after an episode of severe headache. The PRL changes in this patient were attributed successively to tumor expansion and apoplexy. In patient II PRL decreased after irradiation, but was not normalized. During pregnancy it remained moderately increased presenting minor fluctuations. The third patient with postoperative GH and TSH pituitary insufficiency had low pretreatment PRL levels which remained practically unchanged throughout pregnancy. The two last patients gave birth to identical twins. The placental hormones were found normal in all three patients but E2 and PG were relatively increased during the last weeks of pregnancy in the twin pregnancies. Amniotic fluid and umbilical cord PRL and E2 concentrations were normal. The patients presented agalactia and suckling did not induce a PRL increase. We conclude that a) serial PRL measurements during pregnancy reflect the changes occurring in the prolactinomas and are essential in monitoring the patients bearing these tumors; b) maternal hyperprolactinemia or failure of PRL to increase during pregnancy do not influence either the secretion of placental hormones or PRL concentration in amniotic fluid and the newborn; and c) hyperprolactinemia during pregnancy is of maternal pituitary origin.