[Show abstract][Hide abstract] ABSTRACT: Prolactinomas, the most common type of pituitary tumor, are prevalent in women. Macroprolactinomas, which often present with misleading and polymorphic symptoms, occur mainly in men. We review the literature on pituitary prolactin-carcinomas in women, and include a case-report of a 27 year old woman who underwent radical trans-sphenoidal excision of a large invasive macroprolactinoma. Postoperative evaluation of pituitary function showed normal PRL levels associated to hypopituitarism. Three years later, PRL levels increased associated with gross visual defects and a second operation with radiotherapy was done. Bromocriptine normalized PRL levels, and no recurrence was seen on CT/MRI for seven years. When she was 37 years old, the patient became resistant to dopamine-agonists, and the adenoma recurred with invasion of the cavernous sinus and a left frontal mass. Surgical removal of the frontal PRL-secreting metastasis reduced PRL levels to normal associated with quinagolide treatment. Two years later, a progressive increase in PRL levels heralded further expansion of the pituitary mass. The patient underwent a surgical debulking procedure followed by gamma-knife radiosurgery. Two months later, sudden rhinorrhea and visual loss occurred followed by coma. New growth of the pituitary neoplasm was evident. Three months later she died of thromboembolic events. Various causes of resistance to dopamine agonists are known. We suggest that the sudden loss of sensitivity to chronic dopamine-agonist treatment is a sign of the malignant transformation of a macroprolactinoma.
Full-text · Article · Jan 2001 · The Endocrinologist
[Show abstract][Hide abstract] ABSTRACT: Pituitary apoplexy has been reported as a rare complication of dynamic testing used for the study of pituitary functional reserve. In 1993, a diagnosis of non-secreting macroadenoma with moderate functional hyperprolactinaemia was made in a 43-year-old woman. Soon after the start of therapy with bromocriptine up to 5 mg/die, the patient complained of nausea and postural hypotension. As the symptoms persisted even when the dose was reduced to 2.5 mg/die, the patient was transferred to therapy with quinagolide at the dosage of 37.5 microg/die. PRL levels quickly normalized (range 1.4-5.7 ng/ml) as well as menstrual cycles, and no side-effect was reported. In 1995 a sellar magnetic resonance imaging (MRI) showed no shrinkage of the known macroadenoma. In 1996, few hours after a gonadotropin-releasing-hormone (GnRH) test, which showed normal LH and FSH response and with baseline PRL levels in the normal range, the patient started complaining of severe frontal headache, nausea and vomiting. No gross visual defects were present. An emergency computed tomography (CT) showed no evident hemorrhagic infarction in the macroadenoma. The symptoms completely resolved in few days with steroidal and antiemetic therapy. A new MRI performed in 1998 showed a partial empty sella and PRL levels were in the normal range under dopaminergic treatment. The pituitary functional reserve proved normal on dynamic testing. The temporal association between the onset of symptoms and the GnRH test strongly suggests an association between the two events. No evident signs of pituitary apoplexy (either on emergency CT or hormonal evaluation) were detected. The authors suggest that GnRH can cause severe side-effects that mimic pituitary apoplexy without related morphological evidence and that, in our particular case, it can have caused the gradual disappearance of the non-secreting macroadenoma. Moreover, a causal role of the chronic dopaminergic treatment cannot be completely ruled out.
Full-text · Article · Mar 2000 · Journal of endocrinological investigation
[Show abstract][Hide abstract] ABSTRACT: Neurosurgery is still the first step in the treatment of thyrotropin (TSH)-secreting pituitary adenomas, although new perspectives are emerging from medical treatment with somatostatin analogs. We report the results of treatment with slow-release lanreotide in a woman who had undergone partial adenomectomy for a supposedly non-secreting pituitary adenoma, which proved to be a TSH-secreting adenoma, The treatment was effective in decreasing TSH and free thyroid hormone levels. Because TSH has an oligosaccharide structure, we also analyzed TSH isoform profiles before and during slow-release lanreotide treatment; this revealed a shift to a more acidic isoform profile, similar to that observed in healthy controls. Slow-release lanreotide treatment seems able to modify quantitative and qualitative TSH secretion.
No preview · Article · Jul 1999 · The Endocrinologist
[Show abstract][Hide abstract] ABSTRACT: Prolactin (PRL) possesses mitogenic and immunomodulatory properties. We evaluated the prevalence of ultrasonographic thyroid alterations and thyroid autoimmunity in hyperprolactinaemic (HPRL) women and correlated these with PRL levels. Furthermore, we studied the PRL binding in human benign nodular thyroid tissues. 133 HPRL patients (16-63 years) and 103 healthy female controls (16-63 years) with no known history of thyroid disease were studied. Blood samples were collected for PRL, FT3, FT4, TSH, thyroid peroxidase auto-antibodies (TPO Ab) and thyroglobulin auto-antibodies (Tg Ab) assays. All subjects underwent thyroid ultrasonography. PRL binding to thyroid membranes was determined by in-vitro radioreceptor assay in 5 human benign nodular thyroid fragments obtained from female patients. No difference in TSH levels was found, while FT3 (4.5 +/- 0.1 pmol/L) and FT4 (16.2 +/- 0.4 pmol/L) levels were significantly higher in controls than in HPRL (FT3: 3.8 +/- 0.1 pmol/L, p = 0.01, FT4: 15.4 +/- 0.2 pmol/L, p = 0.04). The prevalence of thyroid ultrasonographic alterations (simple goitre, uni-multinodular goitre, chronic thyroiditis) was significantly higher in HPRL (30.8%) than in controls (15.5%, p = 0.01) but did not correlate with mean initial and actual PRL levels or duration of the disease. The prevalence of autoantibodies was significantly higher in HPRL (29.6%) than in controls (14.3%, p = 0.04) but did not correlate with PRL levels. Very low specific PRL binding to thyroid membranes was detected. The high prevalence of thyroid ultrasonographic alterations and autoimmunity in HPRL suggests a possible role of PRL in the development of thyroid diseases. Clinical and instrumental thyroid screening may therefore be advisable in these patients.
[Show abstract][Hide abstract] ABSTRACT: Leptin may be a possible trigger for puberty. In normal males, it has been shown that leptin increases from the pre-pubertal to the early pubertal stage, and then declines in the late pubertal stage. We examined leptin levels in six male adolescents (mean age 16.3+/-0.6 yr; range 14.2-17.6 yr) with delayed puberty (constitutional delay of puberty no.=2; idiopathic hypogonadotropic hypogonadism no.=4) during 120 days of subcutaneous pulsatile GnRH administration. A group of subjects in pre-puberty (no.=11), early-puberty (n=10) and mid-puberty (no.=7) were evaluated as controls. Morning blood samples were taken for determination of leptin, testosterone, LH and FSH levels. In delayed puberty subjects blood samples were taken every 30 days after the start of GnRH administration. At each examination BMI and testicular volume were evaluated. A follow-up examination was performed in the 6 patients 1.3-7.5 yr after the end of the 120 days of GnRH therapy. At baseline evaluation in delayed puberty mean leptin levels were 11.3+/-2.0 microg/l (median 11.3 microg/l; range 4.7-17.3 microg/l) and were higher than those found in pre-puberty (p=0.04) and mid-puberty (p=0.001). During GnRH administration there was no change in BMI and leptin levels but there was an increase in gonadotrophin levels, testosterone and testicular volume. One hundred and twenty days after, mean serum leptin were 10.1+/-2.1 microg/l (median 9.1 microg/l; range 3.4-16.8 microg/l). At the end of the study, leptin levels were higher in delayed puberty than in mid-puberty (p=0.002). At the follow-up examination leptin levels were 4.3+/-1.3 microg/l (median 3.4 microg/l; range 1.4-9.1 microg/l) (p=0.03 vs end of 120 days GnRH therapy) while testosterone and BMI were not changed. In conclusion 120-day pulsatile GnRH administration induced in males with delayed puberty physiological-like pubertal changes but not the decline in leptin levels reported during the progression of puberty. Therefore, in males with delayed puberty an impairment in the phenomenon of leptin decline associated with progression of puberty could be suggested. However after retrospective diagnosis of pubertal delay and long-term therapy in subjects with idiopathic hypogonadotropic hypogonadism leptin levels declined. These data seem to indicate that time more than increase in testosterone levels and testicular volume is the determinant of leptin decline at puberty.
No preview · Article · Feb 1999 · Journal of endocrinological investigation
[Show abstract][Hide abstract] ABSTRACT: Hexarelin (Hex), a synthetic GH-releasing peptide, has recently been found to possess a weak PRL-releasing effect in normals. The aims of this study were to investigate the effect of Hex on GH and PRL secretion in 10 hyperprolactinemic women (HPRL) and 7 controls (C). All subjects underwent stimulus testing with placebo, bromocriptine (Br) (2.5 mg po at time -60), Hex (2 micrograms/kg/bw i.v.), and Br plus Hex. During placebo, HPRL showed a higher (p < 0.01) PRL area under curve (AUC) than C. Br significantly (p < 0.01) reduced PRL AUC both in HPRL and in C. Hex was able to induce a slight but significant (p < 0.05) PRL release in both groups. PRL response to Hex was abolished (p < 0.01 vs Hex) by Br priming in HPRL, while it was only blunted (p < 0.05 vs Hex) in C. Br induced a significant (p < 0.01) GH increase in both groups. However, GH AUC after Br was significantly higher (p < 0.01) in C than HPRL. Hex induced a significant (p < 0.01) GH release both in HPRL and in C. Br priming did not modify GH response to Hex in HPRL while it slightly (p < 0.05) increased GH response to Hex in C, suggesting that neuroendocrine modifications present in HPRL might, per se, be able to impair GH response to Br plus Hex, thus giving rise to receptor competition. Hex had a weak PRL-releasing effect in both groups studied, this was only blunted by Br priming in C but was abolished in HPRL, suggesting that oversensitivity to DA-ergic agents present in HPRL could be able to antagonize completely Hex action.
Full-text · Article · Mar 1998 · Recenti progressi in medicina
[Show abstract][Hide abstract] ABSTRACT: The Leydig cell function of adult male rats made hypothyroid with 6-propyl-2-thiouracil (6-PT, 0.1% w/v in drinking water for 1 month) was studied and compared with that of age-matched controls. After 6-PT treatment, a slight, non-significant decrease in serum testosterone was observed, but no changes in testis weight or number of Leydig cells were noted. The in vitro function of Leydig cells was therefore investigated during incubation for 3 h in the presence or absence of several stimuli: LH (30 mIU/mL), forskolin (FK 1 microM), isobutylmethylxanthine (IBMX, 100 microM), GnRH (100 nM) or FK 1 microM + IBMX 100 microM. Irrespective of the stimulus, cells from hypothyroid rats secreted less cyclic AMP, 17-hydroxyprogesterone, androstenedione and testosterone. No differences in LH receptors were noted between the groups. Prolonged incubation with triiodothyronine (5-250 ng/mL) or thyroxine (5-250 ng/mL) for 3, 16, 24 or 48 h did not affect testosterone secretion in either group; however, administration of IGF-I (8 ng/mL for 24 h) resulted in increased spontaneous and stimulated testosterone production in both groups. However, when hypothyroid animals were supplemented in vivo with thyroxine a full recovery of Leydig cell function in vitro was noted. In conclusion: (1) Leydig cells from rats made hypothyroid during adulthood produce less testosterone in vitro, both spontaneously and in response to cAMP and non-cAMP-mediated stimuli; (2) this is due to a reduction in cAMP production and in the activity of the enzymes in the androgen biosynthetic pathway, and not to changes in LH receptors; (3) direct administration of thyroid hormones did not improve testosterone secretion in either group, while incubation with IGF-I did.
No preview · Article · Nov 1997 · International Journal of Andrology
[Show abstract][Hide abstract] ABSTRACT: Previous studies have suggested that melatonin (MLT) acts directly on rat Leydig cells by modulating androgen production. In the present study, the site of action of MLT was investigated. The binding of 2-[125I]iodomelatonin (125I-MLT; 7-240 pmol/l) to Leydig cell membrane fragments was tested in the presence or absence of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S; 50 mumol/l). Saturation studies and Scatchard analysis revealed the existence of a high-affinity binding site with a Bmax of 46.70 +/- 3.50 fmol/mg protein and a Kd of 88.70 +/- 6.20 pmol/l; treatment with GTP-gamma-S reduced the concentration of 125I-MLT binding sites (Bmax 34.03 +/- 4.50), while increasing the Kd to 106.5 +/- 2.61 pmol/l. Pretreatment of the cells with pertussis toxin (PTX; 10 ng/ml for 16 h) resulted in a decreased binding of 125I-MLT and a lack of effect of GTP-gamma-S. Moreover, the effect of MLT on testosterone secretion induced by LH (30 mIU/ml), forskolin (1 mumol/l) and LHRH (100 nmol/l) was studied after 3-h incubation of cells which had been precultured with or without PTX. The inhibition of testosterone secretion due to MLT administration was eliminated by PTX pretreatment during forskolin and LH, but not during LHRH administration. However, 17-hydroxyprogesterone levels were higher in all groups incubated in the presence of MLT, irrespective of PTX pretreatment. Our data suggest that: (a) MLT receptors are present on the membranes of adult rat Leydig cells; (b) they couple through PTX-sensitive G-protein-coupled binding sites; (c) the mechanism by which MLT blocks 17-20 desmolase enzymatic activity (thus leading to increased 17-hydroxyprogesterone levels), and testosterone secretion during LHRH stimulation is likely to depend on one or more different mechanism(s) of action.
No preview · Article · Jul 1997 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Prolactin (PRL) circulates as multiple molecular weight variants: glycosylated phosphorylated, deamidated and sulphated forms. The profiles of the forms, as determined by isoelectrofocusing (IEF), differ in physiological and pathological conditions. The case of a 72-year-old woman affected by an invasive prolactinoma is described. The patient had undergone surgical treatment followed by radiotherapy at the age of 71 years. Bromocriptine therapy followed (up to 10 mg/die), but the PRL levels were still extremely high (over 13,000 micrograms/l as determined by IRMA, after dilution). We therefore treated the patient with quinagolide, at increasing dosages, from 150 micrograms/die on day 0 to 600 micrograms/die on day 220. This treatment progressively lowered PRL to 23.2 micrograms/l. In addition to a decrease in PRL levels, a progressive change in the IEF profile was also noted. Indeed, on day 0, the PRL isoforms were very acidic and during treatment they progressively shifted toward a more basic range. For purpose of comparison PRL profiles were also determined in 8 women with pathological hyperprolactinaemia (group A, aged 16-50 years, PRL levels: 25.1-170.4 micrograms/l), in 6 normal women (group B, aged 25-29 years, PRL levels: 3.4-7.9 micrograms/l) and in 5 normal women during a TRH test (group C, aged 17-52 years, PRL levels: 2.7-10.3 micrograms/l). The profiles observed in group A had a single major peak at isoelectric point (pI) 6.5, while the group B and C profiles were more heterogeneous displaying multiple minor peaks, the majority of the molecules being in a more basic range (pI 6.9 for group B and pI 7.5 for group C). During treatment, the profiles of our subject at first resembled those of group A; subsequently, when the PRL levels had normalised, the profile resembled those noted in group B. Altered (immature?, more glycosilated?, less bioactive?) PRL molecules could be secreted by the tumour. These data show that quinagolide successfully reduced PRL levels, while inducing secretion of forms more similar to those found in women affected by pathological hyperprolactinaemia or in normal women.
Full-text · Article · Jun 1997 · Journal of endocrinological investigation
[Show abstract][Hide abstract] ABSTRACT: LH isoform profiles were analyzed in sera resolved with isoelectrofocusing from 5 elderly men (age 70.6 +/- 2.95) and 5 young adult men (age 28.2 +/- 1.24), by using polyclonal antibodies (RIA), monoclonal antibodies directed against the beta-subunits (IRMA) and in vitro LH bioassay. Despite the fact that the elderly had lower testosterone levels than the young (293 +/- 38 vs 512 +/- 77 ng/dl, p < 0.05), no differences were noted in the isoforms detected by any of the assays, although each assay yielded a characteristic profile. Indeed, RIA showed most LH in the acidic range, while IRMA revealed LH profiles with a major peak in the basic range, thus resembling the profiles determined by means of the bioassay. In the elderly, the profiles were also analyzed on day 7 and day 14 of short-term pulsatile sc LHRH administration (150 ng/bw/120 min). Only the LH bioassay detected an LHRH-induced shift to more basic and bioactive forms; these changes accompanied an increased in testosterone levels on day 7 (396 +/- 83 ng/dl, p < 0.05 vs day 0) and on day 14 (320 +/- 58 ng/dl NS vs day 0). Our data suggest that: 1) the profiles obtained in young and elderly subjects are similar, irrespective of the antisera used; 2) as a result of treatment with LHRH in the elderly an increase in T levels occurs, possibly due to the observed changes in LH bioactivity; 3) the in vitro LH bioassay appears to be the most sensitive assay in detecting such changes, which consisted of an enrichment in more basic and bioactive glycoforms.
Full-text · Article · May 1997 · Journal of endocrinological investigation
[Show abstract][Hide abstract] ABSTRACT: The effects of melatonin (MLT; 4.3 pM to 4.3 microM) on rat Leydig cell steroidogenesis and cAMP production were investigated during 3-h LH (30 mIU/ml) stimulation. Having noted a dose-dependent inhibition of testosterone (T) release, we also tested MLT in the presence of the cAMP activator forskolin (1 microM), the phosphodiesterase inhibitor isobutylmethylxanthine (100 microM), a combination of these two, and LHRH (100 nM), a non-cAMP-mediated stimulus. Regardless of the stimulus, levels of T, androstenedione, and cAMP were reduced, whereas that of 17-hydroxyprogesterone was enhanced. Cells were also tested after prolonged exposure to MLT (215 nM for 16 h). When compared with data from cells not preincubated with MLT, cAMP and T levels were 30% higher during LH stimulation (30 mIU/ml); comparable during treatment with forskolin (1 microM), isobutylmethylxanthine (100 microM), or their combination; and reduced during LHRH (100 nM). Scatchard analysis did not reveal changes in LH receptors during prolonged MLT exposure. Our data show that MLT acutely reduces cAMP- and non-cAMP-stimulated T. This effect is linked in part to reduced cAMP production and in part to reduced 17-20-desmolase enzymatic activity, which, however, can occur even with non-cAMP-mediated stimulation. On the other hand, prolonged exposure to MLT results in sensitization of the LH-dependent adenylate cyclase activity.
[Show abstract][Hide abstract] ABSTRACT: Patients with beta-thalassemia major often have pubertal delay, the etiology of which has not been fully elucidated. We investigated the pituitary-gonadal response to short-term subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) administration (150 ng/kg body weight every 120 min for 7 days) in five young males (aged 13.6-19.0 years) affected by beta-thalassemia major and presenting signs of delayed puberty. Immunoreactive and bioactive gonadotropin levels were determined and their isoform profiles were examined, before and after GnRH treatment, in a pool of samples collected every 15 min for 240 min. Testosterone, androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone and 17 beta-estradiol were measured as markers of gonadal function on days 0, 1, 3, 5 and 7 of treatment. Five patients (aged 16.9-26.8 years) with confirmed diagnosis of idiopathic hypogonadotropic hypogonadism who were starting pulsatile GnRH therapy were also studied in the same protocol. Increased sex steroid levels were observed in both groups as a result of treatment. On day 7, the thalassemic patients had increased bioactive luteinizing hormone (LH) and follide-stimulating hormone (FSH), although immunoreactive LH and FSH were comparable to day 0. Moreover, fewer acidic and more basic immunoreactive and bioactive isoforms were noted in LH profiles on day 7. Similar results were observed in hypogonadal patients, who also had increased immunoreactive LH and FSH values. We suggest that the early stage of delayed puberty in thalassemia might be characterized by a neuroendocrine dysfunction resulting in an impaired hypothalamic GnRH release, which is inadequate for a proper pituitary stimulation. Pulsatile GnRH treatment seems to re-establish partially the correct pituitary-gonadal function.
No preview · Article · Aug 1995 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: In anorexia nervosa (AN) luteinizing hormone (LH) release is often impaired during opioid blockade. We investigated whether a restoration of the endogenous sex steroid milieu, together with a rise in central serotonergic tone, could increase LH responsiveness to Naloxone (NAL) in seven young women affected by AN. The spontaneous pulsatility of gonadotropins and their response to gonadotropin-releasing hormone (GnRH) and NAL challenges were tested before and after 13 days of pulsatile GnRH treatment and oral administration of L-5-hydroxytryptophan. Low and unpulsatile gonadotropin levels, responsive to GnRH, but not to NAL, were found before treatment. Pulsatile GnRH brought about a quasi-normal secretory pattern and 17 beta-estradiol increased to preovulatory levels in six of seven patients. On day 13 the lack of response to NAL administration was still present, however. A neuroendocrine disorder seems to be present in AN, which appears more complex than in other forms of hypothalamic amenorrhea.
No preview · Article · Dec 1994 · Biological Psychiatry