Adiponectin expression in human fetal tissues during mid- and late gestation.

Adiponectin (ApN), an adipocytokine expressed in adipocytes with antidiabetic and antiatherogenic actions, has been detected in cord blood, suggesting a putative role in intrauterine fetal development. The aim of this study was to confirm the presence of ApN in the fetal circulation and directly investigate ApN expression in fetal tissues. The study showed high ApN levels in umbilical venous blood from fetuses [n = 44; 31.2 +/- 14.1 (sd) mg/liter in umbilical vs. 8.4 +/- 4.0 in maternal circulation (P < 0.0001)] that positively correlated with gestational age. By using RT-PCR, Western blotting, and immunohistochemistry, ApN was detected in several fetal tissues at mid- and late gestation (from 14 to 36 wk) but not in the placenta. ApN was expressed in tissues of mesodermic origin, i.e. brown and white adipocytes, skeletal muscle fibers of diaphragm and iliopsoas, smooth muscle cells of small intestine and arterial walls, perineurium and renal capsule, and tissues of ectodermal origin, i.e. epidermis and ocular lens. The distribution of ApN expression in nonadipose tissues showed a general decline during the progression of gestation. The unexpected pattern of ApN expression in the human fetus may account for the high ApN levels in cord blood and predicts novel roles for ApN during fetal development.

A study of the serum 3,5,3'-triiodothyronine sulfate concentration in normal and hypothyroid fetuses at various gestational stages.

We have studied T3 sulfate (T3S) levels, blindly, in coded plasma samples from 21 normal and 3 hypothyroid fetuses at different stages of gestation (19-42 weeks). Fetal plasma samples were obtained by cordocentesis. T3S was detectable in all samples studied, with values ranging from 50-294 (mean +/- SD, 130 +/- 62 pmol/L). Plasma T3S was low (< 45 pmol/L) in all 4 normal adult control subjects studied simultaneously; serum T3S ranged from less than 20 to 130 in another set of 18 control subjects (mean +/- SD, 63 +/- 32 pmol/L). Fetal T3S values were positively correlated with gestational age (r = 0.43; P < 0.05), but not with free T4 (FT4), FT3, or TSH values. In the 3 hypothyroid fetuses at 31, 38, and 40 weeks gestation, respectively, plasma TSH was elevated (26, 98, and 24 mU/L, respectively), FT4 was low (10, 6.7, and 7.5 pmol/L, respectively), and FT3 was normal or high (3.2, 8.2, and 2.2 pmol/L, respectively). However, T3S values in hypothyroid fetuses (88, 133, and 252 pmol/L, respectively) were similar to those in normal fetuses at corresponding gestational ages. We conclude that 1) T3S is detectable in fetal circulation from at least 19 weeks gestation, and its concentration increases with fetal-age; 2) plasma T3S concentrations in the fetus at 19-40 weeks gestation are at least comparable to but generally higher than those in the adult; and 3) plasma T3S levels in hypothyroid fetuses are similar to those in normal fetuses. Recent studies demonstrating the ability of some fetal rat tissues (e.g. cerebral cortex) to desulfate T3S to T3 have suggested a possible role of T3S as a source of T3. Normal T3S in fetal hypothyroidism suggests that T3S may contribute to attenuation of the effects of hypothyroidism during intrauterine life.

Maturation of hypothalamic-pituitary-gonadal function in normal human fetuses: circulating levels of gonadotropins, their common alpha-subunit and free testosterone, and discrepancy between immunological and biological activities of circulating follicle-stimulating hormone.

The recent availability of both cordocentesis, a low risk and effective technique for fetal blood sampling, and ultrasensitive/highly specific two-site immunofluorometric assays (IFMA) for pituitary and chorionic glycoprotein hormone (I-LH, I-FSH, and I-CG) measurement prompted us to study the maturation of hypothalamic-pituitary-gonadal function in 114 normal human fetuses (49 females and 65 males) from 17-40 weeks gestation. The subjects were selected from 216 consecutive cordocenteses carried out for rapid karyotyping and diagnosis of fetal infection or hematological disorders. In addition, FSH bioactivity (B-FSH) was measured by rat Sertoli cell aromatase induction assay, glycoprotein hormone alpha-subunit (alpha-SU) by RIA, and circulating free testosterone (fT) by direct analog technique. No significant cross-reactions were recorded in the different measurement methods. In particular, alpha-SU did not interfere in any IFMA, and CG cross-reactivity in LH IFMA was 0.5%. Circulating I-LH, I-FSH, and B-FSH levels at 17-24 weeks gestation were significantly higher in female than in male fetuses (I-LH, 48 +/- 4 vs. 6.3 +/- 0.7 U/L; I-FSH, 35 +/- 2 vs. 0.7 +/- 0.1 U/L; B-FSH, 131 +/- 17 vs. 43.4 +/- 5.4 U/L). During the last weeks of gestation, a significant decrease in I-LH and I-FSH levels was seen in both female and male fetuses (I-LH, 0.24 +/- 0.05 and 1.0 +/- 0.3 U/L; I-FSH, 0.45 +/- 0.1 and 0.5 +/- 0.1 U/L), while serum B-FSH remained elevated, but the previously recorded difference between sexes disappeared (54.3 +/- 7.2 and 58.7 +/- 7.3 U/L). Circulating I-CG and alpha-SU levels at midgestation were elevated in both female and male fetuses (I-CG, 117 +/- 29 and 191 +/- 44 U/L; alpha-SU, 143 +/- 16 and 105 +/- 9 micrograms/L, respectively) and decreased thereafter (I-CG, 42 +/- 9 and 26 +/- 6 U/L; alpha-SU, 60 +/- 15 and 37 +/- 6 micrograms/L). Serum fT levels at midgestation were significantly lower in females than in males (4.3 +/- 0.9 vs. 10.0 +/- 0.8 pmol/L) and increased until term, when the difference between sexes disappeared (16.2 +/- 1.8 vs. 17.6 +/- 1.6 pmol/L).(ABSTRACT TRUNCATED AT 400 WORDS)

Hyperthyroidism due to a pituitary adenoma composed of two different cell types, one secreting alpha-subunit alone and another cosecreting alpha-subunit and thyrotropin.

A 37-yr-old female presented with clinical signs and symptoms of mild hyperthyroidism, high serum levels of free T4 (24.2 pmol/L), free T3 (11.7 pmol/L), and sex hormone-binding globulin (157 nmol/L) as well as measurable (by immunofluorometric assay) serum TSH concentrations (1.9 mU/L) in the absence of any known methodological interference. The above finding indicated the presence of hyperthyroidism due to inappropriate secretion of TSH, whose neoplastic origin was documented by computed tomographic scan showing a 1-cm pituitary adenoma. The diagnosis was confirmed by elevated alpha-subunit levels (9.2 micrograms/L) and alpha-subunit/TSH molar ratio (25.2) as well as absent TSH suppression after T3 administration. TRH injection (200 microgram, iv) caused impaired TSH (from 3.0 to 4.8 mU/L) and unexpectedly exaggerated alpha-subunit (from 8.8 to 18.2 micrograms/L) responses. Such a discrepancy was also observed after other dynamic tests. Double gold particle immunostaining of the adenomatous tissue removed at surgery showed that all of the cells contained secretory granules positive for alpha-subunit, while very few cells were positive for TSH beta and alpha-subunit. In conclusion, the present study demonstrates the existence of TSH-induced hyperthyroidism due to a pituitary adenoma composed of two different cell types: one secreting alpha-subunit alone and another cosecreting alpha-subunit and TSH.

Effects of long-term treatment with the gonadotropin-releasing hormone analog nafarelin in patients with non-functioning pituitary adenomas.

The supposed origin of non-functioning pituitary adenomas (NFPA) from gonadotrophs prompted us to investigate the effects of the gonadotropin-releasing hormone (GnRH) analog nafarelin on hormonal and tumoral parameters in eight patients with NFPA, previously unsuccessfully operated and all hypogonadal. Nafarelin was administered intranasally for 1 year to all patients. Four patients received a dose of 1200 micrograms/day; the remaining four received 800 micrograms/day for 3 months, which was subsequently increased to 1200 micrograms/day. Basal gonadotrophin and alpha-subunit (alpha SU) levels were low-normal. In four patients (nos. 1,2,3,5) nafarelin significantly lowered luteinizing hormone (LH) levels, and also follicle-stimulating hormone (FSH) in three of them (nos. 1,2,3). Persistent FSH stimulation occurred in three patients (nos. 6,7,8), with a transient slight LH increase only in patient no. 8. In one patient (no. 7), alpha SU levels were persistently stimulated. Hormonal responses to an acute GnRH test during nafarelin administration were generally blunted when compared to the pretreatment responses. Immunofluorescence results, obtained before treatment in five adenomas (nos. 2,3,4,6,7), hae been as follows: positive for FSH-beta in all; negative for LH-beta in all, except a few positive cells in case no. 4; positive for alpha SU in three (nos. 2,3,7). No changes of visual field and tumor size occurred in any patient during treatment. However, one patient who showed a persistent increase in FSH levels exhibited left palpebral ptosis after 12 months of therapy and underwent a second transsphenoidal surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Maternal compound W serial measurements for the management of fetal hypothyroidsm.

OBJECTIVE: The diagnosis of fetal hypothyroidism is based at present on measurements of TSH and free thyroxine (FT4) in fetal blood samples obtained by cordocentesis. The measurement of maternal serum and urinary concentrations of compound W, immunologically similar to but chromatographically distinct from diiodothyronine sulfate (T2S), has been advocated as a new possible marker for fetal hypothyroidism. DESIGN: In this paper, we measured serum compound W levels in 84 pregnant women, 20 with and 64 without thyroid disorders before and during specific treatment. Compound W was also assessed in fetal blood obtained by cordocentesis from 49 normal fetuses and 4 fetuses with suspected hypothyroidism due to transplacental passage of propylthiouracil (PTU). Compound W levels were measured by T2S RIA in maternal and fetal serum. To assess the possible usefulness of 3, 5,3'-triiodothyroacetic acid (TRIAC) for therapy of fetal hypothyroidism we evaluated the transplacental passage of TRIAC by administering the drug to four pregnant women before therapeutic abortion. RESULTS: In normal pregnancies, both maternal and fetal compound W levels increased progressively during gestation with a significant direct correlation (P<0.001, in both mothers and fetuses). Moreover, a significant positive correlation was observed between fetal compound W and fetal FT4 values (P<0.005), whereas no correlation was observed between maternal serum compound W and maternal FT4 in either euthyroid or hyperthyroid women, suggesting the fetal origin of compound W. The hypothyroid fetuses of PTU-treated mothers showed low compound W levels, and maternal compound W values were in the low normal range and did not show the typical increase during progression of gestation. A significant increase of maternal compound W was observed when the PTU dose was reduced. TRIAC was documented to cross the placental barrier and the treatment of a hyperthyroid pregnant woman on PTU caused the high fetal TSH levels and goiter to normalize. CONCLUSIONS: Serial measurements of 3,3'-T2S crossreactive materials (compound W and 3, 3'-diiodothyroacetic acid sulfate) in maternal blood and the administration of TRIAC to the mother may represent a useful and safe alternative to invasive techniques for the diagnosis and therapy of fetal hypothyroidism.

Thyrotropin-secreting pituitary adenomas.

Normal or elevated thyrotropin (TSH) levels in hyperthyroid patients are characteristic of rare TSH-secreting pituitary adenoma (TSH-oma), which is easily detectable by computed tomographic (CT) scan or magnetic resonance imaging (MRI). Other diagnostic aids are an absent/impaired TSH response to thyrotropin-releasing hormone (TRH), discrepant TSH and alpha-subunit responses to TRH, high sex hormone-binding globulin (SHBG) levels, high alpha-subunit levels, and a high alpha-subunit/TSH molar ratio. Familial studies help rule out thyroid hormone resistance (RTH). Surgical removal of TSH-oma leads to clinical and biochemical remission in most patients. In surgical failures, radiotherapy and octreotide treatment have a high success rate. Undetectable TSH 1 week postsurgery suggests a definitive cure, backed up by tests for cosecreted hormones from the adenoma and dynamic tests of TSH suppression.

Resolution of hyperthyroidism in a pregnant woman with toxic thyroid nodule by percutaneous ethanol injection.

Overt hyperthyroidism was found in a 35-year-old pregnant woman at the 13th week of gestation who was referred to us for tachycardia, tremors, and weight loss. Clinical signs, symptoms, and laboratory findings led to the diagnosis of toxic thyroid nodule. She was treated with ultrasound guided percutaneous ethanol injection (PEI) and, after 2 weeks of treatment, the woman was completely euthyroid. These findings suggest that during pregnancy PEI appears to be a rapid and safe therapy for toxic nodular goiter and an effective alternative to the administration of antithyroid drugs.

Clinical and hormonal outcome after two years of triiodothyroacetic acid treatment in a child with thyroid hormone resistance.

We report here a new family with thyroid hormone resistance (RTH), with phenotypic variability among subjects. Particular emphasis is given to the clinical and hormonal outcome after 2 years of triiodothyroacetic acid (TRIAC) treatment in an affected child with peripheral thyrotoxic features (pituitary RTH [PRTH]). The genetic defect was a substitution in position 1642 (C to A) within the exon 10 of thyroid hormone receptor beta1 (TRbeta1) gene, resulting in the codon change P453T. The mutant receptor had a significantly reduced triiodothyronine (T3) binding affinity. Within this family, the child and the mother suffered from hyperthyroidism and were clinically classified as PRTH, while the maternal grandmother was clinically euthyroid, indicating a generalized form of the disease (GRTH). Rapid normalization of heart rate was initially obtained by the association of the cardioselective beta-blocker atenolol with TRIAC. Nevertheless, long-term TRIAC therapy, through its lowering action of serum thyrotropin (TSH) and thyroid hormone levels, maintained a normal heart rate after atenolol discontinuation and normalized the neurological disturbances and the clinical signs in the child, without any apparent side effect. In fact, growth velocity remained unchanged and no alteration of several parameters of thyroid hormone action at the tissue level was observed, whereas soluble interleukin-2 receptor levels improved significantly, confirming the safety and efficacy of long-term TRIAC therapy for PRTH also during childhood. We thus recommend testing the efficacy of TRIAC therapy in all RTH patients presenting with clinical features of hyperthyroidism.

Effects of thyroid hormones on cardiac structure: a tissue characterization study in patients with thyroid disorders before and after treatment.

Experimental evidence suggests an involvement of thyroid hormones in myocardial nonmyocyte component growth. We evaluated the possible role of thyroid hormones in myocardial remodeling by ultrasonic tissue characterization (videodensitometry) in 8 hyperthyroid patients, in 10 hypothyroid patients, and in 2 patients with thyroid hormone resistance syndrome (RTH), before, 60, and 120 days after treatment (T0, T60, T120), and in 10 age-matched euthyroids. According to a previously described procedure, the derived collagen volume fraction (dCVF%, an echocardiographic index estimating the collagen content) was predicted from the pixel-level frequency distribution width (broadband, Bb) of the selected echocardiographic images. Thyrotropin (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were assessed by immunometric method. QT interval dispersion (QTd) on basal electrocardiogram was measured as a marker of dyshomogeneous ventricular repolarization. At T0, Bb and dCVF% were normal in hyperthyroid and euthyroid patients, and slightly increased in RTH patients, whereas significantly higher values were found in hypothyroids. At T60, a significant reduction in Bb was observed in hypothyroids, with nearly normal dCVF% values. This trend was confirmed at T120 with complete normalization of echoreflectivity. No echoreflectivity changes were observed in hyperthyroid and RTH patients during treatment. QTd was significantly increased in hypothyroids at T0, while no significant differences were found among groups at T60 and T120. Because the different videodeonsitometric myocardial properties observed in hypothyroid versus hyperthyroid patients correspond to an increase of dCVF%, this study suggests that thyroid hormones exert an inhibitory effect on myocardial collagen synthesis in humans.

Circulating levels of inhibin A, inhibin B and activin A in normal and intrauterine growth restricted (IUGR) fetuses.

OBJECTIVE: To evaluate the relationships between circulating levels of inhibin A, inhibin B and activin A, and sex, gestational age and gonadotropins in normal and pathological fetuses. STUDY DESIGN: The study included 31 normal fetuses and 12 affected with intrauterine growth restriction (IUGR) of gestational age ranging 20-40 weeks. RESULTS: No gender difference in inhibin A and activin A levels were observed. Inhibin B levels were significantly higher in males than in females (P < 0.05). Fetuses with the highest levels of inhibin A and B were found in the IUGR group that also showed activin A levels significantly higher than normal. No correlations were observed between inhibin A, inhibin B, activin A and both gonadotropins. CONCLUSION: Plasma inhibin A, inhibin B and activin A are detectable in both genders during intrauterine life. The different gender pattern of inhibin B suggests that inhibin B may contribute to the assessment of the hypothalamic-pituitary-gonadal set-point at least in males.

Anti-iodothyronine autoantibodies in a girl with hyperthyroidism due to pituitary resistance to thyroid hormones.

In the present study, we report the uncommon case of a 9.6-yr-old girl with circulating anti-T3 autoantibodies (T3-Ab) and hyperthyroidism due to inappropriate secretion of TSH (IST). The diagnosis of IST was based on the findings of normal TSH levels (2.4 mU/L) in the presence of high free T4 (28.2 pmol/L) and free T3 (FT3) levels, as measured by direct measurement methods based on "one-step" analog tracer (28.0 pmol/L) and "two-step" Lisophase (13.3 pmol/L) techniques. The discrepancy between the two measurements suggested a methodological interference due to T3-Ab in "one-step" technique, being the "two-step" methodology unaffected by the presence of such autoantibodies. T3-Ab were documented by high nonspecific binding of serum to labeled T3 (38.0% vs 4.3 +/- 2.1% in controls). The clinical picture of hyperthyroidism, the qualitatively normal TSH responses to TRH and T3 suppression tests, the normal pituitary imaging and the values of some parameters of peripheral thyroid hormone action compatible with hyperthyroidism indicated that the patient was affected by pituitary resistance to thyroid hormones (PRTH). Chronic treatment with dopaminergic agent bromocriptine (7.5 mg/day) did not cause TSH secretion to be suppressed, while the administration of thyroid hormone analog TRIAC (1.4 mg/day) inhibited TSH release (from 2.4 to 0.2 mU/L). As a consequence, circulating thyroid hormone levels normalized and euthyroidism was restored. During TRIAC administration, FT3 levels, measured by "one-step" analog tracer technique, gave spuriously high values due to the methodological interference of T3-Ab (15.2 vs 4.3 pmol/L as measured by "two-step" Lisophase technique).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum FSH bioactivity and inhibin levels in patients with gonadotropin secreting and nonfunctioning pituitary adenomas.

It has been reported that serum FSH bioactivity and inhibin levels can be used as markers of the presence of true gonadotropin-secreting pituitary adenoma (Gn-oma). To verify this hypothesis, we have investigated the bioactivity of FSH and serum inhibin alpha-alpha and alpha-beta A levels in a series of patients with either Gn-oma or nonfunctioning pituitary adenoma (NFPA). Nine patients with Gn-oma (6 men and 3 women), 21 with NFPA (9 men and 12 women) and 30 normal subjects were included in the study. We studied FSH biological activity (FSH-B) by using Sertoli cell aromatase bioassay (SAB) and alpha-alpha and alpha-beta A inhibin levels by two noncompetitive immunometric assays (IEMA). In male patients with Gn-oma, serum immunoreactive FSH (FSH-I) and FSH-B levels ranged from 5.1 to 35.5 U/L and from 8.3 to 48 U/L, respectively, FSH B/I ratio being elevated in 2 (2.5 and 4.1; normal male range: 0.3-1.5), while female patients with Gn-oma had serum FSH-I and FSH-B levels ranging from 43.2 to 162 U/L and from 41.2 to 112.8 U/l, respectively, with a normal FSH B/I ratio. In male patients with NFPA, FSH-I and FSH-B levels ranged from 2.7 to 10.7 U/l and from 2.4 to 11.4 U/l while in females they ranged from 3.4 to 67.9 and from 4.6 to 60.8 U/l, respectively. FSH B/I ratio was elevated in 1 male (3.3) and normal in the remaining patients with NFPA. Serum alpha-alpha inhibin levels were normal or low in patients with Gn-oma and NFPA, while alpha-beta A inhibin concentrations were slightly elevated in 1 of 6 postmenopausal women (0.9; normal range < 0.7 U/ml). The present study confirms and extends previous reports indicating that male patients with Gn-oma may secrete FSH molecules with increased bioactivity. However, this abnormality was also observed in one male patient with NFPA. Moreover, the measurement of inhibin levels does not appear to be a reliable in vivo marker of pituitary tumors of gonadotroph origin, as it was normal or low in almost all patients with either Gn-oma or NFPA.

Prenatal treatment of fetal hypothyroidism: is there more than one option?

Following the diagnosis of fetal goitre at 22 and 24 weeks' gestation in two hyperthyroid pregnant women who underwent treatment with 400-500 mg of propylthiouracil in the first weeks of pregnancy, a total of seven fetal blood samplings were performed to evaluate thyroid function before and after the initiation of two different treatment regimens. L-Thyroxine (600 micrograms) was injected five times intra-amniotically in one woman and continuous maternal administration of the thyroid analogue 3, 5, 3'-triiodothyroacetic acid (Triac) was attempted in the other. Normalization of fetal thyroid function and reduction of fetal goitre were achieved in both fetuses and transplacental passage of Triac was indirectly demonstrated by high levels of free triiodothyronine in fetal blood. In cases of fetal hypothyroidism, direct or indirect prenatal therapy can be adopted successfully and safely.

Transplacental passage of anti-thyroid auto-antibodies in a pregnant woman with auto-immune thyroid disease.

We report the intra-uterine and postnatal thyroid status of a newborn, whose mother, affected with Hashimoto's thyroiditis superimposed on a previous Graves' disease, again became hyperthyroid during the third trimester of pregnancy. The mother had very high levels of anti-thyroid auto-antibodies, including TSH receptor auto-antibodies (TRAb) measured as TSH-binding inhibiting auto-antibodies (TBIAb). In order to exclude fetal thyroid dysfunction due to passive transplacental transfer of TRAb, fetal blood samples were obtained by cordocentesis at 21, 27 and 32 weeks of gestation. A transplacental transfer of TRAb was already seen at 21 weeks, but no alteration of fetal thyroid function was present at that time. In the following weeks, a rise in TRAb and circulating thyroid hormones was observed both in the fetus and mother, accompanied by overt hyperthyroidism in the mother and by growth retardation in the fetus. At birth, TRAb were shown to have stimulating activity both in the newborn and mother. This report documents the early transplacental passage of thyroid auto-antibodies and underlines the importance of close follow-up of pregnant women with auto-immune thyroid disorders.

Pituitary resistance to thyroid hormones.

Pituitary thyroid hormone resistance (PRTH) refers to a particular form of thyroid hormone refractoriness that is accompanied by peripheral hyperthyroidism, as only the TSH-secreting pituitary cells appear to be resistant to the effects of thyroid hormones. The presence of PRTH is suspected and diagnosed on the basis of the finding of high free thyroid hormone levels along with unsuppressed TSH, clinical signs and symptoms of hyperthyroidism and values of at least one of the parameters evaluating peripheral thyroid hormone action in the hyperthyroid range. However, most patients with PRTH present with clinical signs and symptoms of thyroid dysfunction, particularly goiter and tachycardia, overlapping those recorded in patients with generalized thyroid hormone resistance (GRTH), i.e. refractoriness to thyroid hormones at both pituitary and peripheral tissue level. Moreover, most of them display normal values of other parameters evaluating the peripheral effects of thyroid hormones and bear mutations in the gene encoding for T3 nuclear receptors similar to those found in patients with GRTH. These findings are questioning the existence of PRTH as a separate clinical entity and support the view that the various forms of thyroid hormone resistance may be part of a spectrum of disease with variable expression in different issues.

Fetal plasma leptin concentrations: relationship with different intrauterine growth patterns from 19 weeks to term.

The relationship between in utero fetal growth and fetal leptin concentrations was investigated between 19 and 41 wk in 40 normal (appropriate for gestational age, AGA) fetuses, in 25 intrauterine growth-restricted (IUGR) fetuses, and in 18 fetuses from gestational diabetic mothers (GDM), representing different intrauterine growth patterns. Umbilical venous plasma leptin concentrations were determined at the time of either in utero fetal blood sampling or delivery. Plasma leptin was measurable as early as 19 wk of gestation. A significant difference was observed between umbilical venous and arterial plasma leptin concentrations (0.6+/-0.6 ng/mL; p<0.01). In AGA and in IUGR fetuses, significant positive relationships were found between fetal leptin concentrations and both gestational age (p<0.001) and fetal weight (p<0.001). Leptin concentrations were significantly higher in AGA than IUGR only after 34 wk (p<0.05), but leptin per kilogram fetal weight (leptin/kg) was not significantly different. In IUGR with abnormal umbilical arterial Doppler velocimetry and fetal heart rate, leptin/kg significantly higher than in IUGR with normal biophysical and biochemical parameters was found (p<0.05). Both circulating plasma leptin and leptin/kg were significantly higher in GDM than in normal fetuses (p<0.001) and correlated with abdominal fat mass measured by ultrasound. No gender differences were observed in any group of fetuses. These findings indicate a clear relationship between fetal leptin concentrations and fetal fat mass. Data in severe IUGR suggest the presence of increased leptin concentrations associated with in utero signs of fetal distress.

Circulating levels of growth hormone, insulin-like growth factor-I and prolactin in normal, growth retarded and anencephalic human fetuses.

We measured growth hormone (GH), insulin-like growth factor-I (IGF-I), and both total and glycosylated prolactin (PRL) levels in 131 blood samples obtained by cordocentesis in normal and abnormal fetuses from 19 to 40 weeks of gestation. In normal fetuses, IGF-I and PRL levels showed a positive correlation and GH a negative correlation with gestational age. A negative relation between GH and IGF-I levels was observed, while PRL did not show any correlation with both GH and IGF-I concentrations. IGF-I increased from 5.6 +/- 3 (at 19-22 weeks) to 10.7 +/- 5 nmol/l at term; GH decreased from 31 +/- 10 to 7.7 +/- 4 micrograms/l and PRL increased from 16 +/- 18 to 139 +/- 76 micrograms/l. Glycosylated PRL accounted for about 15% of total PRL, a value similar to that found in normal adults. In 27 fetuses of 27-37 weeks with intra-uterine growth retardation, GH and PRL levels were higher and IGF-I levels lower than in normal fetuses matched for week of gestation. In 8 anencephalic fetuses of 19-26 weeks of gestation, both GH and IGF-I levels were lower, and PRL levels were higher than in matched controls. Altogether these data support the views that a) both GH and PRL secretion are under the hypothalamic control during fetal development, b) the serum GH decrease from midgestation to the end of pregnancy is mediated by the negative feed-back mechanism of increasing IGF-I levels and c) IGF-I production is mainly regulated by fuel supply and only partially by GH.

Thyrotropin-secreting pituitary tumors in hyper- and hypothyroidism.

Thyrotropin (TSH)-secreting pituitary tumors may be found in two opposite clinical situations: the hyperthyroidism secondary to thyrotroph adenomas, also called central hyperthyroidism, and the long-standing primary hypothyroidism which can be accompanied by a compensatory pituitary enlargement. TSH-secreting pituitary adenomas belong to the syndromes of "inappropriate secretion of TSH" (IST). The adjective "inappropriate" indicates the lack of the expected suppression of TSH secretion when free thyroid hormone levels are actually elevated, as in the other forms of thyrotoxicosis. Moreover, TSH-omas have to be differentiated from the non-neoplastic form of IST which is due to resistance to thyroid hormone. Differently, pituitary hyperplasia, which is reversible on thyroid hormone replacement, is the more frequent cause of a pituitary mass occurring in the context of untreated primary hypothyroidism. Failure or delay in the recognition of the above clinical situations may cause dramatic consequences, such as unnecessary pituitary surgery in hypothyroid patients or improper thyroid ablation in those with central hyperthyroidism. In contrast, early diagnosis and proper treatment of TSH-secreting pituitary tumors prevents the appearance of signs and symptoms of mechanical compression of the adjacent structures by the expanding tumor mass (visual field defects, headache and hypopituitarism).

Maturation of pituitary-thyroid function in the anencephalic fetus.

The recent availability of both cordocentesis and ultrasensitive/highly specific immunometric assays for TSH and its subunit determination along with direct "two-step" assays for free thyroid hormone measurement, prompted us to study the maturation of hypothalamic-pituitary-thyroid axis in normal and anencephalic human fetuses from 17 to 26 weeks of gestation. In addition, TSH bioactivity was measured as cAMP accumulation in CHO cells transfected with recombinant human TSH receptor and TSH carbohydrate structure was studied by lectin chromatography. In both normal and anencephalic fetuses, circulating TSH and FT4 levels significantly increased from 17 to 26 weeks of gestation. Circulating FT3 concentrations were very low (0.5-3.1 pmol/l), while alpha-SU levels were very high (20-417 mg/l). Both FT3 and alpha-SU levels did not change from 17 to 26 weeks of gestation and, again, no differences between normal and anencephalic fetuses were recorded. Circulating TSH from both normal and anencephalic fetuses showed an enhanced bioactivity and was more retained on the lectin column than adult TSH, thus indicating that molecules with different carbohydrate structure are circulating during fetal development. In conclusion, the present data demonstrate that the absence of the hypothalamus does not compromise the maturation of pituitary-thyroid function and that the mechanisms underlying the secretion of TSH molecules with elevated bioactivity and different structure of glycosylated chains are not dependent on hypothalamic neuroendocrine control.