L. Morselli

Thyroid function differently affects serum cystatin C and creatinine concentrations.

Cystatin C (Cys C) is a cysteine protease inhibitor produced at a constant rate by nucleated cells, filtered through the glomerular membrane and reabsorbed by kidney tubular cells. Aim of this cross-sectional and longitudinal study was to assess serum Cys C and creatinine (Crea) concentrations in thyroid dysfunction. One hundred and eighty-one patients, 26 with untreated non-toxic nodular goiter, 58 with hyperthyroidism, 31 on L-T4 suppressive therapy for non-toxic nodular goiter, 35 with short-term hypothyroidism after L-T4 withdrawal to perform whole body scan for thyroid cancer, 11 with long-term hypothyroidism due to chronic autoimmune thyroiditis and 20 patients with mild hypothyroidism were enrolled in the study. Fifty-seven age- and sex-matched normal subjects served as controls. Serum Cys C, Crea, free T4 (FT4), FT3 and TSH were assessed. Thirty hyperthyroid patients and 35 short-term hypothyroid patients were followed prospectively until euthyroidism was reached by methimazole or L-T4 therapy. The cross-sectional study showed that mean serum Crea concentrations were significantly reduced in overt hyperthyroid or subclinical hyperthyroid patients, while it was increased in overt hypothyroid patients, but not in mild hypothyroidism. Conversely, serum Cys C levels were significantly increased in overt hyperthyroid patients compared to controls (p<0.05), and significantly decreased in short-term, long-term and mild hypothyroids (p<0.05, p<0.05, p<0.01, respectively). However, 36 (62%) hyperthyroid patients and 50 (76%) hypothyroid patients had normal serum Cys C values. In the prospective study, restoration of euthyroidism by either methimazole or L-T4 therapy was associated with normalization of mean serum Cys C concentrations. In conclusion, thyroid dysfunction affects serum Cys C concentration, possibly influencing the production rate of the protein. However, the observation that hyper- or hypothyroid patients have normal serum Cys C levels limits its use as a marker of peripheral thyroid hormone effect.

Clinical aspects and therapeutic outcome in thyrotropin-secreting pituitary adenomas: a single center experience.

Background and aim: The management of pituitary adenomas secreting TSH has evolved considerably over the last decades. We report the clinical features, management, and outcome of a large monocentric series. Material and methods: A monocentric retrospective cohort of 26 patients admitted to our Department of Endocrinology between 1983 and 2007, followed for a period up to 204 months. The diagnosis of TSH-secreting adenoma was based on clinical and biochemical findings of central hyperthyroidism. Evaluation of basal and dynamic pituitary function, magnetic resonance imaging or computerized tomography scan were performed in all patients. Twenty-two patients, of whom 15 pre-treated by somatostatin analogs (SSA), underwent trans-sphenoidal surgery and were regularly re-evaluated. Results: The number of cases increased over the years. Age at diagnosis, micro- to macroadenoma ratio, and mean estimated latency between first symptoms and diagnosis did not appreciably change over time. Latency was significantly shorter in macroadenomas. Following surgery, 55% of patients obtained remission (success rate of 40 and 67% in macro- and microadenomas, respectively). SSA pre-treatment led to an apparent although not statistically-significant increase in success rate in micro- but not in macroadenomas. Conclusions: In a monocentric group of 26 TSH-secreting adenomas the high ratio between micro- and macroadenomas remained stable over time with a significantly shorter diagnosis latency in macroadenomas. A more precocious recognition of the tumors and possibly the use of presurgical SSA allowed a high remission rate. A varied combination of neurosurgery, SSA, radiotherapy, and thyroid ablation led to the control of the disease in all the patients studied.

Impairment of GH secretion in amyotrophic lateral sclerosis is not affected by riluzole treatment

Amyotrophic lateral sclerosis (ALS), the most common motor neurone disorder in human adults, is characterized by selective and progressive degeneration of upper and lower motor neurones in the central nervous system. The main currently available drug for ALS treatment is riluzole, a compound that acts through inhibition of glutamate release, postsynaptic receptor activation, and voltage-sensitive channel inhibition. GH secretion, evaluated by GHRH+arginine (ARG) test, has recently been reported to be impaired in most untreated ALS patients. The aim of the present study was to evaluate whether riluzole administration could interfere with GH secretion and therefore with the diagnosis of adult GH deficiency. Ten patients (6 males, 4 females, mean age 59±11 yr) were studied performing GHRH+ARG test before and 3 months after starting riluzole treatment (100 mg/day). Blood samples for GH were collected at baseline, at 30 and 60 min. Both before and during riluzole treatment, 5 patients showed GH deficiency and 5 patients had a normal GH response according to body mass index (BMI). Mean peak GH levels were similar before and during riluzole treatment (13.4±10 vs 14.2±10.1 μg/l, p=ns). No significant correlation was observed between GH concentrations and age, BMI, disease duration, severity or clinical (bulbar/spinal) form. In conclusion, the present data confirm that GH secretion is impaired in a new series of ALS patients and indicate that riluzole treatment does not interfere with GH secretion. Thus, evaluation of GH secretion in ALS patients can also be performed without withdrawing riluzole treatment.

Serum prostate-specific antigen concentration is increased in acromegalic women

Prostate-specific antigen (PSA) is a serine proteases produced by prostatic epithelial cells detectable in male serum and seminal plasma. PSA is also expressed in some female tissues and fluids and is increased in hirsute women showing a positive correlation with androgens. Accordingly, it has been suggested that PSA might be a marker of androgen action in women. The aim of this observational study was to assess serum PSA concentration in acro megalic women with active disease, in remission or during somatostatin analogs therapy. Forty-four acromegalic women, 15 with active disease, 10 in remission and 19 under longacting somatostatin analogs therapy were enrolled in the study; 273 normal women matched for age, body mass index, with no signs of hirsutism, served as controls. Serum PSA, 3a-androstanediol (3α-AG), total testosterone (T), DHEAS, LH, FSH and estradiol were assessed. No patient or control had been given estrogen or antiandrogen drugs; no acromegalic women had hyperprolactinemia or hypopituitarism. Serum PSA concentration was significantly higher in acromegalic patients than in control subjects (p<0.0001). Patients with active acromegaly or under somatostatin analogs therapy had significant higher serum PSA concentration than controls, while patients in remission after adenomectomy did not differ. Serum PSA was detectable in serum of 75% acromegalic women and 45% of controls. In addition 24% of acromegalic women had serum PSA concentrations higher than the mean±2SD of control subjects. Differences in serum PSA levels did not reach statistical significance in the different acromegalic subgroups possibly because of the small number of subjects, but patients with active acromegaly had higher serum PSA levels than patients under somatostatin analogs therapy or in remission. Acromegalic women had significantly higher serum PSA concentrations than controls both before and after menopause (p<0.01). 3α-AG (p<0.05) and T (p<0.01) were higher in acromegalic than in control subjects in pre-menopause (PM) but not in post-menopause (M). A correlation was found in the whole group of acromegalic patients between serum PSA and 3α-AG concentrations (r=0.3, p<0.01). In conclusion, acromegalic is associated with an increase in serum PSA concentrations as a group, although this increase is observed, at an individual level, in only 24% of cases. Patients whose disease is controlled by somatostatin analogs or has been cured by pituitary adenomectomy tend to have lower serum PSA levels than patients with active disease. M patients tend to have lower PSA values than PM women, consistent with the main androgen control of PSA production. However, the observation that M women still have higher serum PSA levels than controls suggest that in acromegaly PSA is regulated not only by androgens but also by the GH/IGF-I system itself.

Undetectable inferior petrosal sinus levels of PTH-related peptide (PTHrP) in patients with ACTH-dependent Cushing's disease

PTH-related peptide (PTHrP), a member of the PTH family, is widely expressed in foetal and adult tissues, and it has been found in benign and malignant tumors, including GH and PRL-secreting adenomas. Conflicting data are reported in literature on serum PTHrP concentrations in patients with Cushing’s disease. The aim of the present study was to further evaluate peripheral and inferior petrosal sinus (IPS) serum PTHrP concentrations before and after CRH, in a group of consecutive patients with ACTH-dependent Cushing’s disease. Nine patients with active ACTH-dependent Cushing’s disease (8 women and 1 man, age±SD 41±13 yr) were submitted to peripheral and IPS sampling under fluoroscopic control before and after iv administration of CRH. All patients were subsequently submitted to transsphenoidal surgery and an ACTH-secreting microadenoma was found in all cases. In all patients, serum IPS and peripheral ACTH measurement were in keeping with the diagnosis of ACTH-dependent Cushing’s disease. Serum PTHrP concentrations before and after CRH stimulation were below the sensitivity limit of the assay in all samples, and no gradient between IPS and peripheral sampling was observed. Our data, combined with others reported in literature, indicate that PTHrP release by ACTH-secreting tumors is not a common occurrence. Therefore, we conclude that IPS and peripheral PTHrP are of little clinical usefulness.

Effetti della terapia sostitutiva con GH sul sonno nei pazienti adulti con deficit di GH di origine ipofisaria

L.L. Morselli, A. Nedeltcheva, R. Leproult, K. Spiegel, E. Martino, J.J. Legros, R.E. Weiss, J. Mockel, E. Van Cauter, G. Copinschi Eur J Endocrinol 2013; 168: 763-770 La secrezione ipofisaria di GHRH non solo regola la produzione di GH da parte delle cellule somatotrope dell’ipofisi, ma influenza anche il sonno. In modo particolare, l’attività di GHRH è legata all’induzione degli stadi più profondi del sonno, caratterizzati dalla presenza all’elettroencefalogramma delle tipiche onde delta di ampio voltaggio e bassa frequenza (0,75-4 Hz). L’assenza di feedback negativo sulla regolazione dell’attività dei neuroni ipotalamici che rilasciano GHRH, come avviene nel deficit di GH (GHD) di origine ipofisaria, potrebbe quindi tradursi in una marcata stimolazione del sonno non REM profondo o sonno a “onde lente”. I pazienti con GHD non trattati riferiscono spesso sonnolenza diurna e una generale perdita delle proprietà rigeneranti del sonno, con conseguenti ripercussioni negative sulla qualità di vita. Recenti studi dimostrano infatti che il sonno in pazienti con GHD legato a cause ipofisarie si presenta frammentato, costituito da una attività delta o slowwave activity (SWA) preponderante rispetto ai soggetti sani. Lo scopo di questo studio è stato quello di valutare se la somministrazione di rhGH per 4 mesi fosse in grado di modificare l’eccessiva presenza di sonno ad onde lente nei pazienti adulti con GHD ipofisario. Lo studio ha coinvolto 13 pazienti adulti (età 22-77 anni) con diagnosi certa o presunta di GHD di origine ipofisaria formulata in base al riscontro di valori di GH <3 μg/l in risposta all’insulin tolerance test (ITT). I pazienti venivano suddivisi in maniera randomizzata in un gruppo che riceveva placebo e in uno a cui veniva somministrato rhGH. Al termine di 4 mesi di trattamento venivano acquisite informazioni sulla durata e sulla struttura del sonno nei due gruppi mediante registrazione polisonnografica e attraverso un sensore di movimento applicato al polso (wrist actigraphy). La somministrazione di rhGH ha determinato una riduzione della durata totale di sonno rispetto al placebo (479±11 vs 431±19 minuti; p=0,005). Questo dato riflette principalmente la tendenza al risveglio anticipato nei pazienti trattati con GH rispetto al placebo. Il trattamento ha provocato una riduzione del 27% dell’attività ad onde lente (stadio III e IV NREM) statisticamente non significativa. Tuttavia l’attività delta registrata durante le prime 6 ore di sonno è diminuita del 30% al termine del trattamento con rhGH rispetto al placebo (p=0,048). I dati polisonnografici registrati concordavano con le sensazioni riportate dai pazienti al termine del periodo di trattamento, con una riduzione del sonno (differenza di 24 minuti; p=0,002) e un risveglio anticipato (differenza di 46 minuti; p=0,007) rispetto al placebo. Questo studio, sebbene sia stato condotto in un campione esiguo di soggetti e per la maggior parte di età superiore ai 40 anni (l’attività delta tende a ridursi fisiologicamente con l’avanzare dell’età), dimostra che il trattamento con rhGH per 4 mesi può invertire alcuni dei disturbi del sonno osservati nei pazienti adulti con GHD. Questi risultati, inoltre, aggiungono una serie di prove del ruolo centrale svolto dal GHRH nel modulare la qualità del sonno nell’uomo.