L. Bartolone

Altered intestinal absorption of L-thyroxine caused by coffee.

OBJECTIVE To report eight case histories, and in vivo and in vitro studies showing coffees potential to impair thyroxine (T4) intestinal absorption. DESIGN Of eight women with inappropriately high or nonsuppressed thyroid-stimulating hormone (TSH) when T4 was swallowed with coffee/espresso, six consented to the evaluation of their T4 intestinal absorption. This in vivo test was also administered to nine volunteers. In three separate tests, two 100 microg T4 tablets were swallowed with coffee, water, or water followed, 60 minutes later, by coffee. Serum T4 was assayed over the 4-hour period of the test. Two patients and two volunteers also agreed on having tested the intestinal absorption of T4 swallowed with solubilized dietary fibers. In the in vitro studies, classical recovery tests on known concentrations of T4 were performed in the presence of saline, coffee, or known T4 sequestrants (dietary fibers, aluminium hydroxide, and sucralfate). MAIN OUTCOME For the in vivo test, average and peak incremental rise of serum T4 (AIRST4 and PIRST4), time of maximal incremental rise of serum T4 (TMIRST4), and area under the curve (AUC) were determined. In patients and volunteers, the four outcome measures were similar in the water and water + coffee tests. In patients and volunteers, compared to water, coffee lowered AIRST4 (by 36% and 29%), PIRST4 (by 30% and 19%), and AUC (by 36% and 27%) and delayed TMIRST4 (by 38 and 43 minutes); bran was a superior interferer. In the in vitro studies, coffee was weaker than known T4 sequestrants. CONCLUSION Coffee should be added to the list of interferers of T4 intestinal absorption, and T4 to the list of compounds whose absorption is affected by coffee.

Shrinkage of a PRL-secreting pituitary macroadenoma resistant to cabergoline

Cabergoline decreases both serum PRL levels and size of prolactinomas, including some tumors resistant to other dopamine-agonists. It is common observation that the shrinkage of the adenoma is preceded by suppression of PRL levels. A minority of patients, who do not show a significant decrease of PRL after a short trial with dopamine-agonists, undergoes neurosurgery or radiotherapy. We report on the case of a 14-year-old girl with a huge prolactinoma who showed, during cabergoline treatment (0.5 mg twice a week), a significant shrinkage of the pituitary mass but no decrease of the very high PRL values. She was referred to us after partial removal of the suprasellar extension of the pituitary tumor. The post-surgical evaluation showed very high PRL levels (9352 μg/l; 20941 μg/l before surgery), which did not decrease during the 2-year treatment with cabergoline (nadir value: 8735 μg/l). However, one month after the beginning of therapy, MRI showed a significant shrinkage of the tumor (tumor volume 5.7 ml, compared with 45.1 ml prior to surgery and 24.4 ml after surgery). Subsequently MRIs demon-strated a progressive reduction of the size with a complete disappearance of the suprasellar and parasellar tissue (tumor volume 1.8, 0.9 and 0.2 ml, at 3, 6 and 12 months, respectively). The MRI performed at the 24th month showed a secondary empty sella, with residual tumor tissue in the right sphenoidal sinus. Increasing cabergoline, up to 3 mg a week, failed to induce any decrease of PRL levels. In conclusion, in such macroprolactinomas the shrinkage of tumor is not strictly correlated with (or it is partially dissociated from) the inhibition of PRL hypersecretion. The choice of other therapeutic options in cabergoline-resistant macroprolacti-nomas needs careful neuroradiological evaluation after a short trial of pharmacological treatment.

Neural response to transcranial magnetic stimulation in adult hypothyroidism and effect of replacement treatment

PURPOSE Despite clinical evidences that hypothyroidism is often associated with cognitive dysfunction, affective disorders and psychosis, the effects of thyroid hormone deficiency on the adult brain have been largely unexplored. We investigated the hypothesis that hypothyroidism might affect cortical excitability and modulates inhibitory and excitatory cortical circuits by using Transcranial Magnetic Stimulation. MATERIALS AND METHODS Cortical excitability was probed in 10 patients with overt hypothyroidism and 10 age-matched healthy controls. We tested motor thresholds and corticospinal excitability, cortical silent period and peripheral silent period, short interval intracortical inhibition, intracortical facilitation. Patients were evaluated at the time of diagnosis, as well as after 3 and 6 months replacement therapy with l-thyroxin. RESULTS At baseline, patients showed decreased cortical excitability, with increased resting and active motor threshold and decreased steepness of the motor evoked potential recruitment curves. These changes were paralleled by longer cortical silent period and decreased short interval intracortical inhibition. After 3 months replacement therapy, all the parameters but short interval intracortical inhibition were restored to normal values. Short interval intracortical inhibition returned to normal values only after 6 months of replacement therapy. CONCLUSIONS Thyroid hormones are needed to modulate cortical excitability and cortical inhibitory circuits in adults.

Abnormalities of GH secretion in a young girl with Floating-Harbor syndrome

We present a 9.1-year-old girl of Calabrian (Italy) ancestry, with clinical features (cranio- facial dysmorphism, short stature with delayed bone age and speech delay) suggesting the diagnosis of Floating-Harbor syndrome (FHS). Physical examination showed: height 113.9 cm (−2.9 SD), with a parent’s target of 156.2 cm (+1.0 SD), weight 20.7 kg, BMI 16.0 (−0.04 SD), and many phenotypic abnormalities: long eyelashes, large bulbous nose with broad nasal bridge, short philtrum, moderately broad mouth, tooth folding and malocclusion, posteriorly rotated ears, low posterior hair line, short neck, clinodactyly of the 5th finger and hyperextensible finger joints. Diffused hyperpigmentation and hypertrichosis with sporadic pubic terminal hairs, but neither clitoromegaly nor other signs of hyperandrogenism and/or precocious puberty, were observed (T1, P1). Carpal bone evaluation showed a delayed bone age (TW2: 5–5/10, −3.6 yr) and the statural age/bone age ratio was 1.1. Other dysmorphic syndromes were excluded on the basis of clinical evidence, also evaluated by a computer-assisted search (P.O.S.S.U.M. version 3.5, 1992). Analysis of chromosome 22 by the FISH method, using specific probes Cos29 and Tuple1, excluded microdeletions in the region 22q11.2, typical of Velo-cardio-facial syndrome. In this case, we report the impairment of serum GH responsiveness (GH baseline values: 0.2–1.9 ng/ml) to the administration of oral 150 μg clonidine [peak 4.7 ng/ml, normal values (nv)>10 ng/ml] and oral 4 mg dexamethasone (8.1 ng/ml, nv>10 ng/ml). Moreover, the evaluation of spontaneous 24-h GH secretion (Carmeda AB, Stockholm, Sweden) showed low mean GH levels (1.75 ng/ml, nv>3.0 ng/ml), with a maximum sleep-related peak of 2.8 ng/ml. Serum IGF-1 values were in the low-normal range (80–176 ng/ml, nv 133–626 ng/ml). While in FHS the cranio-facial features minimize with advancement of age, the impairment of growth velocity is permanent and results in severe dwarfism. In our case, treatment with recombinant GH (0.10 U/kg/day), administered by a needle-free device, induced a dramatic increase of growth velocity, increasing the height from −2.8 to −1.9 SD after 18 months, thus indirectly confirming a role of GH deficiency in the pathogenesis of FHS dwarfism.

Thyroid follicular oncogenesis in iodine-deficient and iodine-sufficient areas: Search for alterations of the ras, met and bFGF oncogenes and of the Rb anti-oncogene

To gain insights into the role of iodine deficiency in favoring thyroid tumorigenesis (particularly of the follicular histotype), 22 Sicilian patients with thyroid tumors were selected for having lived permanently in either one of two areas of different iodine availability. Eleven patients (age 46.1 ±14.6 years, mean±SD; 10 females and 1 male) were from the iodine-deficient (ID) areas of the provinces of Messina and Catania (mean urinary excretion of iodine=48.1 µg/2A hours). Thyroid tumors were follicular or Hürthle cell adenomas (no.=3), follicular carcinomas (FC, no.=4), papillary carcinomas (PC, no.=2) and anaplastic carcinomas (no.=2). Eleven patients (age 47.1±15.2 years; 10 females and 1 male) were from the metropolitan area of Messina, an area of relative iodine-sufficiency (IS) (urinary excretion of iodine=95.2 µg/24 hours). These 11 patients had serum levels of TSH that were significantly lower than the corresponding values of the 11 patients from the ID area (0.76±0.33 vs 1.80±1.22 mU/l, p=0.01) The tumors of the 11 patients from the IS area were: follicular or Hürthle cell adenomas (no.=6), Hürthle cell carcinoma (no.=1), FC (no.=2), PC (no.=2). Molecular biology studies revealed that both the normal as well as the tumor tissue of all 22 patients did not harbor any of the three classical activating mutations (codons 12, 13 and 61) in any of the three ras oncogenes. Similar negative results were obtained as far as loss of heterozygosity of the retinoblastoma (Rb) anti-oncogene is concerned. Immunohistochemistry studies were performed to investigate expression of c-met and basic fibroblast growth factor (bFGF) proto-oncogenes. Only one Hürthle cell carcinoma and the two PC from the IS group, and one FC and the two PC from the ID group stained for the c-met oncogene. Expression of c-met was greater (3+) in the four PC (concerning 70–80% of the tumor cells) than in the other two cancers (1+; <5% of the tumor cells). In the IS group, positivity for bFGF was detected in 3/6 adenomas, 1/2 FC, the Hürthle cell carcinoma and the two PC. In the ID group, positivity for bFGF was observed in 2/3 adenomas, 2/4 FC, the two PC and the two anaplastic carcinomas. The 8 positive cases from the ID group had a greater level of bFGF expression than the 7 positive cases from the IS group (intensity of staining = 2.0+ vs 1.57+). Interestingly, the greatest expression of bFGF was seen in the cases with peri-tumoral lymphocytic infiltration from either group. In the ID group correlations between (i.) pre-intervention serum TSH and intensity of tumoral staining for bFGF, (ii.) serum TSH and per cent of tumoral cells reactive with anti-bFGF and (iii.) between intensity of staining for bFGF and per cent of tumoral cells bFGF +ve were higher than in the IS group. We conclude that activating mutations of ras, loss of DNA from the Rb locus and over-expression of both c-met and bFGF are of no pathogenetic relevance in driving thyroid tumorigenesis of iodine-deficient areas.

Thyroid iodide transporter: Local sequence homologies with thyroid autoantigens

Here we show the existence of local amino acid (aa) sequence homologies between rat thyroid iodide transporter (Na+/l− symporter or NIS), whose gene was recently cloned, and known human thyroid autoantigens [thyroglobulin (Tg), thyroid peroxidase (TPO) and thyrotropin receptor (TSHR)] NIS sequences corresponding to the fourth (aa 264–282) and fifth extracellular loop (aa 386–414) are 15 to 40% identical and 30 to 60% similar to sequences corresponding to known or putative epitopes of Tg, TPO and TSHR. The sixth extracellular loop (aa 465–485) beared homology (44% identity, 52% similarity) only to a region of Tg which flanks one of its immunodominant domains. Sequences of thyroid autoantigens other than NIS shared homology, especially Tg and TPO. We conclude that in all likelihood NIS is an additional thyroid antigen, which shares common epitopes with the other thyroid autoantigens.Addendum: A study in abstract form appeared after submission of our paper finds experimental evidence for the antigenicity of two extracellular segments (aa 262–280 and 468–487) and of a portion of the intracellular C-terminus (aa 560–579).

Extremely high levels of estradiol and testosterone in a case of polycystic ovarian syndrome. Hormone and clinical similarities with the phenotype of the α estrogen receptor null mice

A 19-year-old nulliparous hirsute woman was evaluated for the very high serum levels of testosterone (T) and estradiol (E2) measured in an outside laboratory. Menarche had occurred at 11 years and was followed by regular menses. We confirmed the high levels of T (9–16 ng/ml, nv 0.2–0.8) and E2 (>1000 pg/ml, nv 30–120). LH and FSH were consistently high (73–118 mU/l and 18-29 mU/l, respectively; LH/FSH ratio=4.1-4.7) and responsive to iv GnRH (LH baseline=118 mU/l, 30 min=290; FSH baseline=25 mU/l, 30 min=46). The unstimulated values contrasted with those (LH=12, FSH=8 mU/l) measured in the outside laboratory, suggesting antigenically anomalous gonadotropins. 17-OH-progesterone was normal (0.5 ng/ml). After 1 mg dexamethasone, serum cortisol was normally suppressed (24→0.4 μg/dl), T declined minimally (9→8.6 ng/ml) and E2 remained high (>1000 pg/ml). An exploratory laparotomy was performed, and two enlarged ovaries with multiple cysts as in a typical polycystic ovarian syndrome (PCOS) were seen. Before the wedge resection of the ovaries, hormones were assayed in the ovary veins (right ovary: T=30 ng/ml, Pg=17 ng/ml, E2=>5000 pg/ml; left: T=14 ng/ml, Pg=14 ng/ml, E2=>5000 pg/ml). Histologically, the follicle cysts showed luteinization of the theca interna; there was no evidence for ovary tumor in either ovary. After 21 days of 35 μg ethynyl-E2+2 mg cyproterone acetate (CA), E2=3,000 pg/ml, T=1.4 ng/ml, LH=10.5 mU/l and FSH=4.1 mU/l. After three cycles of the said therapy (but with 50 mg CA in the first 10 days of each cycle), E2 was 1600 pg/ml, T 1.7 ng/ml, LH 7.1 and FSH 4.6 mU/l. Based on similarities with the phenotype of the α estrogen receptor knockout female mice (αERKO), one possible explanation for the puzzling clinical and biochemical picture of our patient is resistance of αER to estrogens. This is the first case of PCOS with extremely high E2 and T. Thus, the differential diagnosis of high levels of E2±T should include PCOS.