bluuebunny/crossref_metadata_2025 huggingface dataset:
Tension Pneumocranium, a Rare Complication of Transsphenoidal Pituitary Surgery: Mayo Clinic Experience 1976–1998
Authors: Sawka Anna M. , Aniszewski Jaroslaw P. , Young William F. , Nippoldt Todd B. , Yanez Paulino , Ebersold Michael J.
Published: January 2014

We describe four cases of symptomatic pneumocranium, a rare, potentially life-threatening complication of transsphenoidal pituitary surgery. Symptomatic pneumocranium manifested as impaired mental status, headaches, and grand mal seizures, early in the postoperative course after transsphenoidal pituitary surgery. Furthermore, a Cushing response, including systemic hypertension and bradycardia (secondary to intracranial hypertension) was seen, which has not been previously described in association with symptomatic pneumocranium. We describe a previously unreported risk factor for tension pneumocranium, untreated obstructive sleep apnea. Other factors predisposing to tension pneumocranium in our patients included: cerebrospinal fluid leaks, postoperative positive-pressure mask ventilation, large pituitary tumors, and intraoperative lumbar drainage catheters. Surgical drainage of the pneumocranium and repair of any coexistent cerebrospinal fluid leak markedly improved neurologic status.

Symptomatic pneumocranium occurring early in the postoperative course after transsphenoidal pituitary surgery is rare, but prompt recognition and treatment of this condition can be life-saving.
The Effects of Anorexia Nervosa on Bone Metabolism in Female Adolescents1
Authors: Soyka Leslie A. , Grinspoon Steven , Levitsky Lynne L. , Herzog David B. , Klibanski Anne
Published: January 2014

Osteopenia is a frequent, often persistent, complication of anorexia nervosa (AN) in adolescent girls and occurs during a critical time in bone development. Little is known about bone metabolism in this patient population. Therefore, we measured bone density (BMD) and body composition by dual energy x-ray absorptiometry, nutritional status, bone turnover, calcium, and hormonal status in 19 adolescent girls with AN (mean ± sem, 16.0 ± 0.4 yr) and 19 bone age-matched controls. The mean duration of AN was 19 ± 5 months. Spinal (L1–L4) osteopenia was common in AN. Lumbar anterioposterior BMD was more than 1 sd below the mean in 42% of patients, and lateral spine BMD was more than 1 sd below in 63% of patients compared with controls. Lean body mass significantly predicted lumbar bone mineral content (r = 0.75; P < 0.0001) in controls only. In AN, duration of illness was the most significant predictor of spinal BMD (lumbar: r = −0.44; P = 0.06; lateral: r= −0.59; P = 0.008). AN adolescents with mature BA (15 yr and greater) were hypogonadal [estradiol, 16.2 ± 1.9 vs. 23.3 ± 1.6 pg/mL (P = 0.01); free testosterone, 0.70 ± 0.17 vs. 1.36 ± 0.14 pg/mL (P = 0.01)] although dehydroepiandrosterone sulfate and urinary free cortisol levels did not differ. Leptin levels were reduced in AN (2.9 ± 2.1 vs. 16.5 ± 1.8 ng/mL; P < 0.0001). Insulin-like growth factor I (IGF-I) was reduced in AN to 50% of control levels (219 ± 41 vs. 511 ± 35 ng/mL; P < 0.0001) and correlated with all measures of nutritional status, particularly leptin (r = 0.80; P < 0.0001). Surrogate markers of bone formation, serum osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), were significantly (P = 0.02) reduced in AN vs. controls (OC, 39.1 ± 6.4 vs. 59.2 ± 5.2 ng/mL; BSAP, 27.9 ± 4.0 vs. 40.6 ± 3.4 U/L). The majority of the variation in bone formation in AN was due to IGF-I levels (OC: r2 = 0.72; P = 0.002; BSAP: r2 = 0.53; P = 0.01) in stepwise regression analyses. Bone resorption was comparable in patients and controls. These data demonstrate that bone formation is reduced and uncoupled to bone resorption in mature adolescents with AN in association with low bone density. Lean body mass was a significant predictor of BMD in controls, but not AN patients. The major correlate of bone formation in AN was the nutritionally dependent bone trophic factor, IGF-I. Reduced IGF-I during the critical period of bone mineral accumulation may be an important factor in the development of osteopenia in adolescents with AN.
Serum Cytokines in Thyrotoxicosis1
Authors: Siddiqi A. , Monson J. P. , Wood D. F. , Besser G. M. , Burrin J. M.
Published: January 2014

Overproduction of thyroid hormones promotes bone resorption in vivo and in vitro, and we have evaluated whether mediators of such effects could include the osteotropic cytokines. Previous studies have demonstrated raised serum interleukin (IL)-6 in thyrotoxic patients, but differentiating the contribution of the elevated thyroid hormones from that of the autoimmune inflammation present in Graves’ disease (GD) has been difficult. We undertook a longitudinal study of 34 patients (19–45 yr old) with GD, toxic nodular goiter (TNG), or a history of thyroid carcinoma but no evidence of disease recurrence, receiving sufficient T4 to suppress TSH. Controls were 12 euthyroid females. The following measurements were made basally and for 6 months after carbimazole treatment: serum free T4, T3, bone-specific alkaline phosphatase (b-ALP), IL-6, IL-8, IL-1β, tumor necrosis factor-α, IL-11, and urinary deoxypyridinoline (Udpd). Compared with controls (IL-6, 1.1 ± 0.3 ng/L; IL-8, 3.2 ± 0.8 ng/L), untreated patients with GD and TNG had elevated IL-6 (GD, 7.11 ± 0.88 ng/L; TNG, 7.30 ± 0.77 ng/L; P < 0.001) and IL-8 (GD, 10.3 ± 1.23 ng/L; TNG, 9.81 ± 1.27 ng/L; P < 0.001). These levels fell after treatment and were then indistinguishable from those in control subjects. Thyroid carcinoma patients on TSH suppressive therapy also had significantly raised levels of IL-6 (2.5 ± 0.42 ng/L) and IL-8 (4.4 ± 0.63 ng/L). When data from all the patients were pooled, the levels of IL-6 and IL-8 correlated with serum T3 and free T4 but not with Udpd or b-ALP. IL-1β, IL-11, and tumor necrosis factor-α were not raised in any patient.

The elevations in serum IL-6 and -8 that occur in hyperthyroidism seem to result from the chronic effects of thyroid hormone excess rather than the accompanying autoimmune inflammatory condition produced by Graves’ thyroid or eye disease. The site of the presumed increased production of IL-6 and -8 is most likely from bone osteoblasts, despite the inability of bone markers (such as Udpd and b-ALP) to correlate with acute changes in thyroid hormone status produced by antithyroid therapy.
Maintenance of Serum Calcium by Parathyroid Hormone-Related Peptide During Lactation in a Hypoparathyroid Patient
Authors: Mather K. J. , Chik C. L. , Corenblum B.
Published: January 2014

We describe the changes in calcium homeostasis seen in a hypoparathyroid woman during the third trimester and with lactation following her second pregnancy. During lactation her need for supplemental calcium and calcitriol abated, and in fact she was transiently hypercalcemic and hypophosphatemic. This change was associated with a rise of serum parathyroid hormone-related peptide (PTHrP) released systemically during lactation. This is the first documentation of the time course of serum PTHrP levels from the late third trimester throughout lactation in a hypoparathyroid woman. In this context PTHrP may have sufficient biological activity to compensate for parathyroid hormone deficiency.
Resistance of Hypogonadic Patients with Mutated GnRH Receptor Genes to Pulsatile GnRH Administration
Authors: Caron Philippe , Chauvin Stéphanie , Christin-Maitre Sophie , Bennet Antoine , Lahlou Najiba , Counis Raymond , Bouchard Philippe , Kottler Marie-Laure
Published: January 2014

We have studied a kindred with three siblings with isolated hypogonadotropic hypogonadism caused by compound heterozygote mutations in the GnRH receptor gene. The disorder was transmitted as an autosomal recessive trait. The R262Q mutation in intracellular loop 3 of the receptor was associated with a mutation in the third transmembrane domain of the receptor, A129D, that has never been described before. This A129D mutation results in a complete loss of function, indicated by the lack of inositol triphosphate (TP3) 3 production by transfected Chinese hamster ovary (CHO) cells after GnRH stimulation. The two brothers had microphallus and bilateral cryptorchidism and were referred for lack of puberty, whereas their sister had primary amenorrhea and a complete lack of puberty. Their basal gonadotropin concentrations were below the reference range, and their endogenous LH secretory patterns were abnormal, with a low-normal frequency of small pulses or no apparent LH pulse. Pulsatile GnRH administration (10 μg/pulse every 90 min for 40 h) resulted in increased mean LH without any significant changes in testosterone levels in the two brothers, whereas the LH secretory profile of their sister remained apulsatile. Larger pulses of exogenous GnRH (20 μg every 90 min for 24 h) caused the sister to produce recognizable low amplitude LH pulses. The concentrations of free α-subunit significantly increased in all patients during the pulsatile GnRH administration. Thus, these hypogonadal patients are partially resistant to pulsatile GnRH administration, suggesting that they should be treated with gonadotropins to induce spermatogenesis or ovulation rather than with pulsatile GnRH.
An Intronless Homolog of Human Proto-Oncogene hPTTG Is Expressed in Pituitary Tumors: Evidence for hPTTG Family
Authors: Prezant Toni R. , Kadioglu Pinar , Melmed Shlomo
Published: January 2014

A novel proto-oncogene, PTTG (Pituitary Tumor Transforming Gene), was isolated in our laboratory by virtue of its increased expression in rat pituitary tumor cell lines. Cells which overexpress human or rat PTTG form tumors in athymic mice. hPTTG is highly expressed in cancer cell lines, pituitary adenomas and in normal testis, suggesting that hPTTG protein has different tissue-specific interactions in normal cells and in cancer. Alternatively, different hPTTG gene family members may be functional in normal development and in tumorigenesis. While mapping the chromosomal location of hPTTG to 5q33, we discovered a second gene, hPTTG2, which is intronless and maps to chromosome 4p12. Using gene-specific oligonucleotide hybridization in a PCR-ELISA assay, we determined that hPTTG2 is expressed in both normal and tumorous pituitary. However, high levels of hPTTG mRNA in cancer cell lines are due to increased expression of hPTTG1. Thus, this family of proto-oncogenes appears to differentially participate in tumor-specific pathogenesis.
Success Rate of Radioiodine Therapy in Graves’ Disease: The Influence of Thyrostatic Medication
Authors: Sabri Osama , Zimny Michael , Schulz Gernot , Schreckenberger Mathias , Reinartz Patrick , Willmes Klaus , Buell Udalrich
Published: January 2014

There is controversy whether simultaneous thyrostatic medication influences the outcome of radioiodine (131I) therapy in Graves’ disease by reducing the absorbed energy dose of 131I when delivering a standard dose. We therefore sought to ascertain whether the outcome of ablative 131I therapy is in any way affected by simultaneous thyrostasis (carbimazole) by aiming for a constant absorbed dose of 200–250 Gy. We prospectively studied 207 patients with Graves’ disease (106 with and 101 without simultaneous carbimazole at the time of 131I therapy). All patients were reexamined 3, 6, and 12 months after 131I therapy. The 101 nonthyrostatic patients showed a highly significantly greater success rate (93%) than the 106 thyrostatic patients (49%). Stepwise logistic regression demonstrated that failure was related to the administration of carbimazole during 131I therapy (P < 0.00005) and the absorbed dose (P < 0.025), but was not related to free T3, free T4, TSH receptor antibodies, or thyroid volume. The success rate was 100% in 93 nonthyrostatic patients with absorbed doses of 200 Gy or more, but was only 12.5% (1 of 8) for absorbed doses less than 200 Gy. Correlation between success and absorbed dose was significantly higher for nonthyrostatic than for thyrostatic patients (r = 0.93 vs. r = 0.24). Sixteen patients who discontinued thyrostasis 1–3 days before 131I therapy showed 94% successes.

Simultaneous thyrostasis is the decisive factor against a successful 131I therapy even if the significantly reduced 131I uptake/half-life values under thyrostasis are compensated with a higher delivered dose to ensure a comparable absorbed dose, possibly due to the additionally effective radioprotective properties of carbimazole. Therefore, if clinically feasible, we recommend discontinuing thyrostasis at least 1 day before beginning 131I therapy, because even in hyperthyroid nonthyrostatic patients the success rate was 100%.
Characterization of Human Iodothyronine Sulfotransferases1
Authors: Kester Monique H. A. , Kaptein Ellen , Roest Thirza J. , van Dijk Caren H. , Tibboel Dick , Meinl Walter , Glatt Hansruedi , Coughtrie Michael W. H. , Visser Theo J.
Published: January 2014

Sulfation is an important pathway of thyroid hormone metabolism that facilitates the degradation of the hormone by the type I iodothyronine deiodinase, but little is known about which human sulfotransferase isoenzymes are involved. We have investigated the sulfation of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3′-diiodothyronine (3,3′-T2) by human liver and kidney cytosol as well as by recombinant human SULT1A1 and SULT1A3, previously known as phenol-preferring and monoamine-preferring phenol sulfotransferase, respectively. In all cases, the substrate preference was 3,3′-T2 >> rT3 > T3 > T4. The apparent Km values of 3,3′-T2 and T3 [at 50 μmol/L 3′-phosphoadenosine-5′-phosphosulfate (PAPS)] were 1.02 and 54.9μ mol/L for liver cytosol, 0.64 and 27.8 μmol/L for kidney cytosol, 0.14 and 29.1 μmol/L for SULT1A1, and 33 and 112 μmol/L for SULT1A3, respectively. The apparent Km of PAPS (at 0.1μ mol/L 3,3′-T2) was 6.0 μmol/L for liver cytosol, 9.0μ mol/L for kidney cytosol, 0.65 μmol/L for SULT1A1, and 2.7μ mol/L for SULT1A3. The sulfation of 3,3′-T2 was inhibited by the other iodothyronines in a concentration-dependent manner. The inhibition profiles of the 3,3′-T2 sulfotransferase activities of liver and kidney cytosol obtained by addition of 10 μmol/L of the various analogs were better correlated with the inhibition profile of SULT1A1 than with that of SULT1A3. These results indicate similar substrate specificities for iodothyronine sulfation by native human liver and kidney sulfotransferases and recombinant SULT1A1 and SULT1A3. Of the latter, SULT1A1 clearly shows the highest affinity for both iodothyronines and PAPS, but it remains to be established whether it is the prominent isoenzyme for sulfation of thyroid hormone in human liver and kidney.
A Prospective Randomized Trial Comparing Low Dose Flutamide, Finasteride, Ketoconazole, and Cyproterone Acetate-Estrogen Regimens in the Treatment of Hirsutism
Authors: Venturoli S. , Marescalchi O. , Colombo F. M. , Macrelli S. , Ravaioli B. , Bagnoli A. , Paradisi R. , Flamigni C.
Published: January 2014

Sixty-six hirsute women were randomized and treated with 1) flutamide (n = 15), 250 mg/day; 2) finasteride (n = 15), 5 mg/day; 3) ketoconazole (n = 16), 300 mg/day; and 4) ethinyl estradiol (EE)-cyproterone acetate (CPA; n = 20), 0.01 mg EE/day for the first week, 0.02 mg EE/day for the second week, and 0.01 mg EE/day for the third week, followed by a pause of 7 days, then 12.5 mg CPA/day added during the first 10 days of every month for 12 months. Hirsutism was evaluated by the Ferriman-Gallwey score, and hair diameter and hair growth rate were determined by a special image analysis processor in basal conditions and after 90, 180, 270, and 360 days of treatment. All treatments produced a significant decrease in the hirsutism score, hair diameter, and daily hair growth rate: flutamide, −55 ± 13%, −21 ± 14%, and −37 ± 18%; finasteride, −44 ± 13%, −16 ± 12%, and− 27 ± 14%; ketoconazole, −53 ± 18%, −14 ± 12%, and −30 ± 21%; and EE-CPA, −60 ± 18%, −20 ± 11%, and −28 ± 21%.

Some differences existed among treatments with regard to effectiveness; EE-CPA and flutamide seem to be the most efficacious in improving hirsutism. For the hirsutism score, a greater decrease was seen with EE-CPA (−60 ± 18%) than with finasteride (−44 ± 13%; P < 0.01) and a greater decrease was seen with flutamide (−58 ± 18%) than with finasteride (−44 ± 13%; P < 0.05). Flutamide is the fastest in decreasing hair diameter; EE-CPA is the fastest in slowing down hair growth, even though at the end of the treatment there was a significant difference between flutamide and finasteride only (−41 ± 18% vs.− 27 ± 14%; P < 0.05).

Flutamide, ketoconazole, and EE-CPA induced a significant decrease in total and free testosterone, 5α-dihydrotestosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione plasma levels. During the EE-CPA treatment, gonadotropins were suppressed, and the sex hormone-binding globulin level increased. Finasteride induced a decrease in dehydroepiandrosterone sulfate and 5α-dihydrotestosterone and an increase in testosterone levels.

Very few side-effects were observed during treatment with low doses of flutamide, EE-CPA, and particularly finasteride. Flutamide induced a decrease whereas EE-CPA induced an increase in triglycerides and cholesterol, showing higher values within the normal range. Ketoconazole induced several side-effects and complications, and several people dropped out of the study.

Despite different modalities of action and significantly different effects on androgen levels, low doses of flutamide, finasteride, and EE-CPA constitute very satisfactory alternative therapeutic regimens in the treatment of hirsutism.
Restoration of Reproductive Potential by Lifestyle Modification in Obese Polycystic Ovary Syndrome: Role of Insulin Sensitivity and Luteinizing Hormone1
Authors: Huber-Buchholz M.-M. , Carey D. G. P. , Norman R. J.
Published: January 2014

Weight reduction and exercise have been shown to help with menstrual disturbance and infertility in obese women with polycystic ovary syndrome. We studied the relationship between insulin sensitivity and ovulation patterns in 18 infertile anovulatory obese polycystic ovary syndrome (PCOS) women (NO) with normal glucose tolerance, aged between 22–39 yr with a body mass index of 27–45 kg/m2, before and after a 6-month diet and exercise program. This program promotes healthy lifestyle factors, but does not lead to rapid weight loss. The anthropometric, metabolic, and endocrine factors of these subjects were compared to those of 10 age- and weight-matched PCOS women with regular monthly ovulation (RO).

Before lifestyle modification, the anovulatory subjects had greater central obesity than regular ovulators, as assessed by percent central fat (NO, 45.7 ± 0.8%; RO, 42.2 ± 1.6%; P < 0.05), higher glucose increment after glucose challenge (NO, 10.1 ± 1.0 mmol/L; RO, 6.4 ± 1.1 mmol/L; P < 0.02), lower insulin sensitivity index (NO, 1.2 ± 0.2; RO, 2.8 ± 0.6 μmol/kg·min/pmol/L; P < 0.005), higher plasma LH (NO, 8.9 ± 0.9; RO, 4.6 ± 0.9 IU/L; P < 0.005), and lower plasma sex hormone-binding globulin (NO, 18.0 ± 2.5; RO, 27.8 ± 5.7 nmol/L; P < 0.05].

Anovulatory subjects were classified as responders (R) to the intervention if they regained ovulation during the study. As a result of intervention, R showed an 11% reduction in central fat, a 71% improvement in insulin sensitivity index, a 33% fall in fasting insulin levels, and a 39% reduction in LH levels. None of these parameters changed significantly in nonresponders (NR). At the end of the study, R had lower fasting insulin (R, 13.6 ± 1.7; NR, 23.0 ± 3.5 mU/L) and LH levels (R,5.0 ± 1.7; NR, 7.4± 1.4 IU/L), but similar androgen levels compared to NR.

We conclude that lifestyle modification without rapid weight loss leads to a reduction of central fat and improved insulin sensitivity, which restores ovulation in overweight infertile women with PCOS. Lifestyle modification is the best initial management for obese women seeking to improve their reproductive function.
Functional and Molecular Characterization of a Muscarinic Receptor Type and Evidence for Expression of Choline-Acetyltransferase and Vesicular Acetylcholine Transporter in Human Granulosa-Luteal Cells1
Authors: Fritz S. , Föhr K. J. , Boddien S. , Berg U. , Brucker C. , Mayerhofer A.
Published: January 2014

Previously, we provided evidence for the presence of a class of muscarinic receptors on human luteinized granulosa cells (human GC) that is linked to transient increases in intracellular free calcium levels, but not to steroid production. The precise nature of the receptor is not known, and neither its function nor the source of its natural ligand acetylcholine (ACh) is clear. To address these issues we used RT-PCR approaches and isolated complementary DNAs corresponding to the M1 receptor subtype from reverse transcribed human GC messenger ribonucleic acids. M1 receptors were further shown by immunocytochemistry, using a M1 receptor antiserum. Single cell calcium measurements showed that the M1 receptor was functionally active and linked to acute increases in intracellular free calcium, as the M1 receptor specific antagonist pirenzepine blocked the Ca2+-mobilizing effect of oxotremorine M (a muscarinic agonist). An unexpected consequence of M1 receptor activation was evidenced by the ability of muscarinic agonists to stimulate the proliferation of human GC within 24 h. In vivo, ACh, the natural ligand of these receptors is thought to be contained in cholinergic nerve fibers innervating the ovary. Surprisingly, the prerequisite for the synthesis of ACh, the enzyme choline-acetyltransferase (ChAT), is also expressed by human GC, as shown by Western blotting and immunocytochemistry. In addition, these cells express another marker for ACh synthesis, namely the gene for the vesicular acetylcholine transporter, as evidenced by RT-PCR cloning, Western blotting, and immunocytochemistry. In conclusion, our data identify the M1 receptor in human GC and point to a novel, trophic role of the neurotransmitter ACh. Furthermore, the presence of the prerequisites of ACh synthesis in human GC indicate that an autocrine/paracrine regulatory loop also exists in the in vivo counterparts of these cells in the ovary, i.e. in the cells of the preovulatory follicle and/or of the young corpus luteum.
Protective Effect of Insulin against Hypoglycemia-Associated Counterregulatory Failure
Authors: Fruehwald-Schultes Bernd , Kern Werner , Deininger Eva , Wellhoener Peter , Kerner Wolfgang , Born Jan , Fehm Horst L. , Peters Achim
Published: January 2014

Antecedent hypoglycemic episodes reduce the counterregulatory neuroendocrine response to hypoglycemia. The role of insulin in the mechanism responsible for the antecedent hypoglycemia causing subsequent counterregulatory failure has not been elucidated. We performed antecedent hypoglycemic clamps (56 mg/dL) lasting 2 h with differing degrees of hyperinsulinemia, which were followed by 6-h stepwise hypoglycemic clamps (76–66–56–46 mg/dL) on the next day. Experiments were carried out in 30 young, healthy men. Fifteen of these subjects were tested on 2 occasions. On 1 occasion the antecedent hypoglycemia was induced by insulin infusion at a rate of 1.5 mU/min·kg (low insulin-ante-hypo); on the other occasion the insulin infusion rate was 15.0 mU/min·kg (high insulin-ante-hypo). Both sessions were separated by at least 4 weeks, and their order was balanced across subjects. The remaining 15 subjects (control group) received the same stepwise hypoglycemic clamp as the other subjects, but without antecedent hypoglycemia. During the stepwise hypoglycemic clamp, the counterregulatory increases in ACTH, cortisol, and norepinephrine were significantly blunted after the low insulin-ante-hypo (P < 0.01, P< 0.05, and P < 0.05, respectively) but not after the high insulin-ante-hypo (P = 0.12, P = 0.92, and P = 0.19, respectively) compared to that in the control group. The cortisol, norepinephrine, and glucagon responses were greater after the high than after the low insulin-ante-hypo (all P < 0.05). In conclusion, the present study clearly demonstrates that even a single episode of mild hypoglycemia reduces neuroendocrine counterregulation 18–24 h later. Insulin has a moderate protective effect on subsequent counterregulation.
Serum Levels of Insulin-Like Growth Factor I in 152 Patients with Growth Hormone Deficiency, Aged 19–82 Years, in Relation to Those in Healthy Subjects1
Authors: Hilding Agneta , Hall Kerstin , Wivall-Helleryd Inga-Lena , Sääf Maria , Melin Anna-Lisa , Thorén Marja
Published: January 2014

Serum insulin-like growth factor I (IGF-I) levels within normal range for age have been reported to be common in adults with GH deficiency (GHD). Therefore, serum IGF-I levels were determined in 152 consecutive patients (71 women and 81 men) with evidence of hypothalamic-pituitary disorders or previous cranial radiation, who fulfilled the presently used criteria for GHD i.e. peak GH response below 3μ g/L at stimulation test. Patients treated for acromegaly were excluded. Forty-three patients, aged 19–63 yr, had childhood onset GHD, and 109, aged 23–82 yr, had adult-onset GHD. Their IGF-I levels were expressed in sd scores in relation to normal reference values based on 448 healthy subjects, aged 20–96 yr (247 women and 201 men). In healthy subjects a linear inverse correlation, without gender difference, was found between logarithmic transformed IGF-I levels and age (r = −0.774; P < 0.001). In contrast, no age dependency was found in GHD patients. All patients with childhood-onset GHD had IGF-I values below −2 sd, significantly lower than those in adult-onset GHD patients (−6.2± 0.3 vs. −3.2 ± 0.2 sd score; P < 0.001). In patients with adult-onset GHD, 34% of the IGF-I levels were within normal range, increasing to 40% in the subgroup above 60 yr of age, in whom 86% were diagnosed with hypothalamic-pituitary tumors. Normal IGF-I was more common in men than in women, but no difference was observed between patients with panhypopituitarism and those with partial pituitary insufficiency. High frequencies of IGF-I levels within the normal range were found in GHD patients with pituitary tumors (20 of 57 nonsecreting pituitary adenomas, 5 of 15 prolactinomas, 6 of 12 Cushing’s disease, and 4 of 25 craniopharyngiomas), but in only 2 of 43 patients with GHD due to other causes.

In conclusion, an IGF-I level below −2 sd seems to be of diagnostic value in GHD with onset in childhood or early adulthood, whereas values within normal range are common in patients over 60 yr of age, especially those with pituitary tumors. The outcome of GH replacement therapy may reveal whether the addition of IGF-I as a diagnostic criterion is of predictive value in older patients.
Identification of a Potent Phytoestrogen in Hops (Humulus lupulus L.) and Beer
Authors: Milligan S. R. , Kalita J. C. , Heyerick A. , Rong H. , De Cooman L. , De Keukeleire D.
Published: January 2014

The female flowers of the hop plant are used as a preservative and as a flavoring agent in beer. However, a recurring suggestion has been that hops have a powerful estrogenic activity and that beer may also be estrogenic. In this study, sensitive and specific in vitrobioassays for estrogens were used for an activity-guided fractionation of hops via selective solvent extraction and appropriate HPLC separation. We have identified a potent phytoestrogen in hops, 8-prenylnaringenin, which has an activity greater than other established plant estrogens. The estrogenic activity of this compound was reflected in its relative binding affinity to estrogen receptors from rat uteri. The presence of 8-prenylnaringenin in hops may provide an explanation for the accounts of menstrual disturbances in female hop workers. This phytoestrogen can also be detected in beer, but the levels are low and should not pose any cause for concern.
[18F]-2-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography Localizes Residual Thyroid Cancer in Patients with Negative Diagnostic 131I Whole Body Scans and Elevated Serum Thyroglobulin Levels
Authors: Wang Weiping , Macapinlac Homer , Larson Steven M. , Yeh Samuel D. J. , Akhurst Timothy , Finn Ronald D. , Rosai Juan , Robbins Richard J.
Published: January 2014

Progressive dedifferentiation of thyroid cancer cells leads to a loss of iodine-concentrating ability, with resultant false negative, whole body radioactive iodine scans in approximately 20% of all differentiated metastatic thyroid cancer lesions. We tested the hypothesis that all metastatic thyroid cancer lesions that did not concentrate iodine, but did produce thyroglobulin (Tg), could be localized by [18F]2-fluoro-2-deoxy-d-glucose (FDG)-positron emission tomography (PET). We performed FDG-PET on 37 patients with differentiated thyroid cancer after surgery and radioiodine ablation who had negative diagnostic 131I whole body scans during routine follow-up. Serum Tg, Tg autoantibodies, neck ultrasounds, and other clinically indicated imaging procedures were performed to detect residual disease. In those with elevated Tg levels, FDG-PET localized occult disease in 71%, was false positive in one, and was false negative in five patients. The majority of false negative FDG-PET occurred in patients with minimal cervical adenopathy. Surgical resections, biopsies, 131I therapy, and differentiation therapy were performed based on the PET results. The FDG-PET result changed the clinical management in 19 of the 37 patients. In patients with elevated Tg levels, FDG-PET had a positive predictive value of 92%. In patients with low Tg levels, FDG-PET had a negative predictive value of 93%. No FDG-PET scans were positive in stage I patients; however, they were always positive in stage IV patients with elevated Tg levels. An elevated TSH level (i.e. hypothyroidism) did not increase the ability to detect lesions. FDG-PET is able to localize residual thyroid cancer lesions in patients who have negative diagnostic 131I whole body scans and elevated Tg levels, although it was not sensitive enough to detect minimal residual disease in cervical nodes.
Leptin Binding Activity Changes with Age: The Link between Leptin and Puberty1
Authors: Quinton N. D. , Smith R. F. , Clayton P. E. , Gill M. S. , Shalet S. , Justice S. K. , Simon S. A. , Walters S. , Postel-Vinay M.-C. , Blakemore A. I. F. , Ross R. J. M.
Published: January 2014

The timing of the physical transition from child to adult is determined by a biological clock that switches off the pituitary gonadal axis during infancy until puberty. Body composition (and in particular, fat mass), through leptin, are critical signals to this clock. However, no direct relationship between leptin and puberty has been demonstrated. Leptin is bound in the circulation by a high-affinity binding protein, which has been identified as a soluble leptin receptor. We found circulating levels of leptin binding activity (LBA) to be low at birth, to be high in the prepubertal years, to fall through puberty, and then to remain stable during adult life. LBA correlated with pubertal status in both boys and girls. We postulate that the fall in LBA, associated with increasing age and puberty, reflects a reduction in expression of truncated leptin receptors, and leptin is then available to the full-length receptor, which transmits the biological signal for leptin. The high levels of LBA occur during the years when the pituitary gonadal axis is quiescent. Thus, the change in LBA could explain how leptin regulates puberty.
Inhibition of Sham Feeding-Stimulated Human Gastric Acid Secretion by Glucagon-Like Peptide-2
Authors: Wøjdemann Morten , Wettergren Andre , Hartmann Bolette , Hilsted Linda , Holst Jens J.
Published: January 2014

Glucagon-like peptide (GLP)-2 is formed from proglucagon in the intestinal L cells and is secreted postprandially in parallel with the insulinotropic hormone GLP-1, the latter of which, in addition, acts to inhibit gastric secretion and motility by inhibiting central parasympathetic outflow. We now studied the effect of GLP-2 on gastric secretion stimulated by sham feeding to test the hypothesis that also GLP-2 acts as an enterogastrone. Eight healthy volunteers were studied twice on separate days. They were sham fed with and without GLP-2 infused iv at a rate of 0.8 pmol/kg·min. Gastric contents were aspirated continuously by a nasogastric tube for determination of acid secretion, volume, and osmolarity. Sham feeding increased gastric acid secretion nearly 5-fold. Infusion of GLP-2 reduced incremental acid secretion by 65 ± 6%, compared with saline infusion (Δ8.75 ± 0.37 vs. Δ3.04± 0.47 mmol × 60 min; P < 0.01). Plasma concentrations of GLP-2 rose from a basal mean of 3.3 ± 0.9 to a mean of 115 ± 8 pmol/L (range, 57–149 pmol/L) during infusion of GLP-2 and remained at basal level during saline infusion. Plasma concentrations of GLP-1, gastrin, cholecystokinin, and secretin remained low and unchanged on both study days. We conclude that GLP-2 is a powerful inhibitor of gastric acid secretion in man. Further investigations will show to what extent GLP-2 contributes to the inhibitory effects on gastric secretion exerted by hormones from the distal small intestine, under physiological circumstances.
Cisapride Versus Placebo for 8 Weeks on Glycemic Control and Gastric Emptying in Insulin-Dependent Diabetes: A Double Blind Cross-Over Trial1
Authors: Stacher Georg , Schernthaner Guntram , Francesconi Mario , Kopp Hans-Peter , Bergmann Helmar , Stacher-Janotta Giselheid , Weber Ute
Published: January 2014

In insulin-dependent diabetes mellitus, slow gastric emptying may make absorption unpredictable and foster glycemic instability. Cisapride accelerates emptying, but controlled long term studies are scarce, and effects on glycemic control unknown. We investigated, in patients with insulin-dependent diabetes mellitus and unstable glycemia, the effects of 10 mg cisapride 4 times daily for 8 weeks vs. placebo on glycemic control and gastric emptying under random, cross-over, double blind conditions. In 14 patients with delayed and 9 with nondelayed emptying, blood glucose variability over 2 8-week treatment periods separated by a 4-week wash-out and gastric emptying of a semisolid 1168-kJ meal immediately after the treatment periods were assessed. Cisapride did not affect glycemic control [sd of within-patient mean blood glucose, 4.2 mmol/L ± 0.1 (±sem) vs. 4.0 ± 0.1 mmol/L after placebo; hemoglobin A1c, 8.3 ± 0.2% vs. 8.5 ± 0.2%]. Emptying was faster after cisapride than after placebo in 8 of 14 patients with delayed vs. 7 of 9 with nondelayed emptying (P = NS) and in 11 of 15 without vs. 4 of 8 with cardiovascular autonomic neuropathy (P = NS). Autonomic neuropathy prevailed in 7 of 14 patients with delayed and 1 of 9 with nondelayed emptying. Blood glucose immediately before and during assessment of emptying was unrelated to the emptying rate, whereas blood glucose increases over fasting levels were greater with faster emptying (P< 0.002). In conclusion, cisapride’s effects were not different from those of placebo on glycemic control and gastric emptying, it did not differently affect patients with delayed vs. nondelayed emptying, and it slightly accelerated emptying (P = NS) in patients without, but not in those with, cardiovascular autonomic neuropathy. Blood glucose levels before and during assessment of emptying did not affect emptying, but the glucose rise over fasting levels was greater with faster emptying.
5α-Reductase Activity in Women with Polycystic Ovary Syndrome1
Authors: Jakimiuk Artur J. , Weitsman Stacy R. , Magoffin Denis A.
Published: January 2014

The recent demonstration of high concentrations of 5α-androstane-3,17-dione in the follicular fluid of polycystic ovaries suggests a potential role for 5α-reduced androgens in the etiology of polycystic ovary syndrome (PCOS). The purpose of the present study was to determine whether there is increased 5α-reductase activity or messenger ribonucleic acid (mRNA) expression in polycystic ovaries. 5α-Reductase 1 and 5α-reductase 2 mRNAs were measured in thecal (TC) and granulosa (GC) cells from individual follicles of 18 women with PCOS and 26 regularly cycling control women. Both 5α-reductase 1 and 2 mRNA expression was higher in GC than in TC, and 5α-reductase 2 mRNA levels were approximately 3-fold higher than 5α-reductase 1 mRNA. 5α-Reductase 1 and 2 mRNA expression were similar in GC from PCOS and control women, but 5α-reductase mRNA was decreased in TC from PCOS follicles. In control women, 5α-reductase 2 mRNA was highest in GC from 3- to 5-mm follicles and decreased to undetectable levels in GC from 7-mm follicles. A similar pattern of expression was present in GC from PCOS follicles, but detectable levels of 5α-reductase 2 mRNA were present in GC from 7-mm follicles. 5α-Reductase activity was measured in whole follicles by measuring the conversion of radiolabeled testosterone to dihydrotestosterone. Kinetic analysis of total 5α-reductase activity at physiological pH revealed a Km of 1.46 μmol/L and a maximal velocity of 0.31 nmol/min·mg protein, indicating predominantly type 1 activity. The total 5α-reductase activity was approximately 4-fold higher in PCOS follicles than in control follicles. These data demonstrate elevated 5α-reductase activity in polycystic ovaries and support the hypothesis that 5α-reduced androgens may play a role in the pathogenesis of PCOS.
Leptin and Leptin Receptor Expression in Normal and Neoplastic Human Pituitary: Evidence of a Regulatory Role for Leptin on Pituitary Cell Proliferation1
Authors: Jin Long , Burguera Bartolome G. , Couce Marta E. , Scheithauer Bernd W. , Lamsan Jesse , Eberhardt Norman L. , Kulig Elzbieta , Lloyd Ricardo V.
Published: January 2014

Leptin is a circulating hormone secreted by adipose and a few other tissues. The leptin receptor consists of a single transmembrane-spanning polypeptide that is present as a long physiologically important form as well as in several short isoforms. Recent studies have suggested that the anterior pituitary may have a role in the regulatory effects of leptin in animal models. To test this possibility in human pituitaries, we examined the expression of leptin and OB-R in normal and neoplastic pituitaries, and the possible functions of leptin in the pituitary were also analyzed. Leptin was present in 20–25% of anterior pituitary cells and was expressed in most normal anterior pituitary cells, including ACTH (70% of ACTH cells), GH (21%), FSH (33%), LH (29%), TSH (32%), and folliculo-stellate cells (64%), but was colocalized with very few PRL cells (3%), as detected by double labeling immunohistochemistry with two different antileptin antibodies. In addition, leptin expression was detected by RT-PCR in some pituitary tumors, including ACTH (three of four), GH (one of four), null cells (two of four), and gonadotroph (one of four) tumors as well as in normal pituitary. Immunohistochemical staining showed greater immunoreactivity for leptin in normal pituitaries compared to adenomas. Treatment of an immortalized cultured anterior pituitary cell line, HP75, with leptin stimulated pancreastatin secretion in vitro. Leptin also inhibited cell growth in the human HP75 and in the rat pituitary GH3 cell lines. Both long (OB-Rb) and common (OB-Ra) forms of the leptin receptor messenger ribonucleic acid and leptin receptor protein were expressed in normal and neoplastic anterior pituitary cells. These findings show for the first time that leptin is expressed by most human anterior pituitary cell types and that there is decreased leptin protein immunoreactivity in pituitary adenomas compared to that in normal pituitary tissues. We also show that OB-Rb is widely expressed by normal and neoplastic anterior pituitary cells, implicating an autocrine/paracrine loop in the production and regulation of leptin in the pituitary.
A One-Tube Polymerase Chain Reaction Protocol Demonstrates CC Chemokine Overexpression in Graves’ Disease Glands
Authors: Ashhab Yaqoub , Dominguez Orlando , Sospedra Mireia , Roura-Mir Carme , Lucas-Martín Anna , Pujol-Borrell Ricardo
Published: January 2014

An adaptation of mixed oligonucleotide primed amplification of complementary DNA to detect the profile of CC chemokines in biological samples is presented. By introducing normalization, two correction coefficients, performing a single amplification reaction, and five parallel hybridizations, intrasample and intersample comparisons can be reliably made. This protocol of single tube PCR CC chemokine profiling was applied to tissue samples from an autoimmune thyroid condition, Graves’ disease, and from a nonautoimmune condition, multinodular goiter. Results demonstrate overexpression of CC chemokines in Graves’ disease, statistically significant for macrophage inflammatory protein-1α and -1β, which correlated with the aberrant human leukocyte antigen class II expression by thyrocytes, as assessed by flow cytometry. Overexpression of CC chemokines probably plays a major role in determining the characteristics of the lymphocytes migrating to the thyroid gland and influences the course of the disease. The study of chemokine profile should be more informative than the study of isolated chemokines and cytokines, and as it can be applied to fine needle aspiration biopsies, it may be useful to clinical research.
Profiles of Endogenous Circulating Cortisol and Bone Mineral Density in Healthy Elderly Men1
Authors: Dennison E. , Hindmarsh P. , Fall C. , Kellingray S. , Barker D. , Phillips D. , Cooper C.
Published: January 2014

Exogenous glucocorticoids are known to increase the risk of osteoporosis. However, the contribution made by endogenous circulating cortisol concentrations to adult skeletal status remains unknown. We examined this issue in a sample of 34 healthy men, aged 61–72 yr. Venous blood samples were obtained under standard conditions every 20 min over a 24-h period. Measurements were made of serum cortisol and cortisol-binding globulin. Bone mineral density was measured at the lumbar spine and proximal femur using dual energy x-ray absorptiometry. Measurements were made at baseline and 4 yr later. There was a weak negative association between integrated cortisol concentration and lumbar spine bone density (r = −0.37; P < 0.05); similar relationships (P < 0.05) existed at three of five proximal femoral sites. There were also statistically significant positive associations between the trough cortisol concentration and bone loss rate at the lumbar spine (r = 0.38; P < 0.05), femoral neck (r = 0.47; P < 0.001), and the trochanteric region (r = 0.41; P = 0.02) over the 4-yr follow-up period. The cross-sectional relationships between cortisol concentration and bone density were removed by adjustment for body mass index, but the influence on bone loss rate remained significant after adjusting for adiposity, cigarette smoking, alcohol consumption, dietary calcium intake, physical activity, and serum testosterone and estradiol levels. These observations suggest that the endogenous cortisol profile of healthy elderly men is a determinant of their bone mineral density and their rate of involutional bone loss.
Gonadotropins, Prolactin, Inhibin A, Inhibin B, and Activin A in Human Fetal Serum from Midpregnancy and Term Pregnancy
Authors: Debieve F. , Beerlandt S. , Hubinont C. , Thomas K.
Published: January 2014

Using specific enzyme-linked immunosorbent assays we measured inhibin A, inhibin B, and activin A in relation to LH, FSH, and PRL in normal human fetal midpregnancy serum obtained by in utero cord venipuncture (n = 25) and compared these results to those in fetal serum from term pregnancies (n = 23). We also tested serum from fetuses with intrauterine growth retardation (n = 6) or trisomy 21 (n = 6). We found no measurable inhibin A, except in three midpregnancy males (3 of 14). Inhibin B, however, was detected in midpregnancy male fetuses (167 ± 67 pg/mL) and was higher than that in females (16 ± 12 pg/mL). It was present in male term fetuses (125 ± 32 pg/mL), but not in females. The activin A levels did not significantly differ between term and midpregnancy males and females.

LH and FSH were detected in midpregnancy male fetuses (4.4 ± 3.3 and 0.77 ± 0.49 mIU/mL, respectively), with higher levels in females (33.0 ± 23.2 and 54.4 ± 27.7 mIU/mL, respectively), and were suppressed at term. PRL did not exhibit sexual difference, but showed a higher level at term (322.4 ± 113.8 ng/mL) than at midpregnancy (33.0 ± 26.1 ng/mL). Comparison of inhibin B with FSH levels showed correlation coefficients of −0.565 at midpregnancy vs. +0.445 at term. Serum from fetuses with intrauterine growth retardation or trisomy 21 did not show any different hormonal profiles.

These data suggest that inhibin B is probably an additional factor in FSH inhibition at midpregnancy, whereas activin A is not associated with any change in the different studied populations. We speculate that inhibin A could be a method to detect maternal blood contamination in cord venipuncture.
17β-Hydroxysteroid Dehydrogenase Type 1 and 2 Expression in the Human Fetus1
Authors: Takeyama Junji , Suzuki Takashi , Hirasawa Gen , Muramatsu Yasunari , Nagura Hiroshi , Iinuma Kazuie , Nakamura Junji , Kimura Ken-ichi , Yoshihama Makoto , Harada Nobuhiro , Andersson Stefan , Sasano Hironobu
Published: January 2014

The present study investigates the expression patterns of 17β-hydroxysteroid dehydrogenase (17βHSD) isozymes in human fetal tissues to understand how estrogenic activity is regulated in the human fetus. Using enzyme assay, high 17βHSD activity was detected in the placenta and liver, and low levels of 17βHSD activity were also present in the gastrointestinal tract and kidney. After Northern blot analysis, we detected the messenger ribonucleic acid for 17βHSD type 1 (17βHSD1) only in the placenta, whereas that for 17βHSD type 2 (17βHSD2) was detected in the placenta, liver, gastrointestinal tract, and urinary tract at 20 gestational weeks. In RT-PCR analysis of the messenger ribonucleic acid transcripts, 17βHSD1 was predominantly expressed in the placenta, brain, heart, lung, and adrenal, whereas 17βHSD2 expression was predominantly detected in the liver, gastrointestinal tract, and kidney. In addition, we detected 17βHSD2 immunoreactive protein in surface epithelial cells of the stomach, absorptive epithelial cells of the small intestine and colon, hepatocytes of the liver, and interstitial cells surrounding the urinary tubules of the renal medulla. 17βHSD2 in these tissues may be functioning in the prevention of in utero exposure of the fetus to excessive estradiol from the maternal circulation and amniotic fluids.
The Effects of Hormone Replacement Therapy and Raloxifene on C-Reactive Protein and Homocysteine in Healthy Postmenopausal Women: A Randomized, Controlled Trial1
Authors: Walsh Brian W. , Paul Sofia , Wild Robert A. , Dean Robert A. , Tracy Russell P. , Cox David A. , Anderson Pamela W.
Published: January 2014

C-Reactive protein and homocysteine are independent risk factors for the development of cardiovascular disease. This study compared the effects of hormone replacement therapy (HRT) and raloxifene on serum C-reactive protein and homocysteine levels as markers of cardiovascular risk in healthy postmenopausal women. Healthy postmenopausal women (n = 390) were enrolled in a double blind, randomized, placebo-controlled, 6-month trial at eight out-patient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive protein and homocysteine were measured in baseline and 6-month serum samples. HRT increased C-reactive protein levels by 84% (P < 0.001), whereas raloxifene (60 and 120 mg/day) had no significant effect (−6% and −4%, respectively; P > 0.2). Raloxifene (60 and 120 mg/day) significantly lowered serum levels of homocysteine by 8% (P = 0.014) and 6% (P = 0.024), respectively, similar to the 7% (P = 0.014) reduction obtained with HRT.

We conclude that HRT and raloxifene lower serum homocysteine levels to a comparable extent in postmenopausal women. Whereas cardiovascular risk predicted by C-reactive protein in healthy postmenopausal women is not influenced by raloxifene, the relationship between elevated C-reactive protein levels with HRT and cardiovascular disease events requires further study.