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Raimo Voutilainen

Inhibins and activins (1, 2) belong to a group of structurally related proteins that includes transforming growth factor β (TGF-β), Müllerian inhibiting substance (MIS) and bone morphogenetic proteins (BMPs) (reviewed in Ref. 3). Ovarian granulosa cells and testicular Sertoli cells are the main source of circulating inhibins. Inhibins are composed of an α-subunit and one of two β-subunits (αA or βB), joined by disulfide bonds. Both inhibin A (αβA) and B (αβB) preferentially inhibit FSH release from the pituitary, but dimers of the β-subunits (activins) increase pituitary FSH secretion. Activin A is a homodimer ofβA-subunits (βAβA), while activin B is a homodimer of βB-subunits (βBβB), and activin AB a heterodimer of β-subunits (βAβB). Each of the subunits (α, βA, βB) is encoded by separate genes, and the primary translation products are processed further before they join to form mature inhibins or activins.

Follistatin (also known as FSH-suppressing protein) is a

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Pauliina Utriainen, Raimo Voutilainen, and Jarmo Jääskeläinen

Objectives

Premature adrenarche (PA), the early rise in adrenal androgen (AA) production, can manifest with different clinical signs of androgen effect. Premature pubarche defined as appearance of pubic hair before the age of 8/9 years in girls/boys, is the most prominent clinical sign of PA and often erroneously described as a synonym of PA. Our aim was to determine the association of circulating AA concentrations with different prepubertal signs of androgen action (SAA). Secondly, we tested whether adrenomedullary function is altered in children with SAA, as it is in congenital adrenal hyperplasia (CAH) also causing adrenal hyperandrogenism.

Design and methods

We examined 73 Finnish prepubertal children with any hyperandrogenic sign(s) having appeared before the age of 8/9 years (girls/boys) (35 with pubic and/or axillary hair=PAH; 38 without=nonPAH), and 98 age- and sex-matched controls. Circulating adrenal steroid and catecholamine concentrations were measured and correlated with clinical parameters.

Results

None of the children with SAA had CAH or virilizing tumor. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione concentrations overlapped between the SAA and control children, and they were lower in the nonPAH than PAH group (P<0.01). SAA children had similar plasma epinephrine but higher norepinephrine (NE) concentrations than their controls (mean (95% confidence interval) 1.61 (1.44, 1.77) versus 1.39 (1.30, 1.49) nmol/l, P=0.03).

Conclusions

PA forms a continuum with more pronounced increase in circulating androgens in children with PAH than in those without. Some children show SAA with fairly low androgen concentrations. The clinical significance of elevated NE concentrations associated with SAA needs to be confirmed in further studies.

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Jianqi Liu, Arvi I Kahri, Anna-Maija Teppo, and Raimo Voutilainen

Liu J, Kahri AI, Teppo A-M, Voutilainen R. Regulation of parathyroid hormone gene expression and peptide secretion in human parathyroid cells. Eur J Endocrinol 1994;130:394–401. ISSN 0804–4643

In cell cultures prepared from human parathyroid adenomas, parathyroid hormone (PTH) mRNA expression decreased slowly. During short-term incubations (less than 24), a low calcium concentration (0.5 mmol/l) and protein kinase C activator TPA (12-O-tetradecanoyl phorbol 13-acetate) (160 nmol/l) increased PTH secretion (60%; p <0.05), while a high extracellular calcium concentration (2.5 mmol/l) reduced PTH secretion (60%; p<0.05), The TPA could block the inhibitory effect of a high calcium level on PTH peptide secretion. All these agents had no effect on PTH mRNA accumulation in short-term experiments. In long-term cultures (more than 24 h), a low calcium level increased and a high calcium level reduced both PTH mRNA (85 and 34%; p <0.05) and peptide secretion (140 and 80%; p <0.05), respectively. The TPA reduced PTH mRNA accumulation down to 30% (p<0.05) and PTH secretion down to 14% (p<0.05) in a time- and dose-dependent fashion. The TPA also reversed the stimulatory effect of hypocalcemia on PTH mRNA accumulation and peptide secretion. Protein kinase C inhibitors staurosporine (100 nmol/l) and H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride) (50 μmol/l) had similar effects to TPA on PTH gene expression and peptide secretion in long-term cultures. The results support the hypothesis that extracellular calcium regulates PTH mRNA accumulation and PTH secretion via protein kinase C.

Raimo Voutilainen, Department of Pathology, PO Box 21 (Haartmaninkatu 3), SF-00014 University of Helsinki, Finland

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Satu Seppä, Tanja Kuiri-Hänninen, Elina Holopainen, and Raimo Voutilainen

Puberty is the period of transition from childhood to adulthood characterized by the attainment of adult height and body composition, accrual of bone strength and the acquisition of secondary sexual characteristics, psychosocial maturation and reproductive capacity. In girls, menarche is a late marker of puberty. Primary amenorrhea is defined as the absence of menarche in ≥15-year-old females with developed secondary sexual characteristics and normal growth or that in ≥13-year-old females without signs of pubertal development. Furthermore, evaluation for primary amenorrhea should be considered in the absence of menarche three years after thelarche (start of breast development) or five years after thelarce, if that occurred before the age of 10 years. A variety of disorders in the hypothalamus-pituitary-ovarian axis can lead to primary amenorrhea with delayed, arrested or normal pubertal development. Etiologies can be categorized as hypothalamic or pituitary disorders causing hypogonadotropic hypogonadism, gonadal disorders causing hypergonadotropic hypogonadism, disorders of other endocrine glands, and congenital utero-vaginal anomalies. This article gives a comprehensive review of the etiologies, diagnostics and management of primary amenorrhea from the perspective of pediatric endocrinologists and gynecologists. The goals of treatment vary depending on both the etiology and patient; with timely etiological diagnostics fertility may be attained even in those situations where no curable treatment exists.

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Sirpa Tenhola, Pirjo Halonen, Jarmo Jääskeläinen, and Raimo Voutilainen

Objectives: Our aim was to determine whether markers of growth hormone and insulin action differ between children born small for gestational age (SGA) and those born of an appropriate size for gestational age (AGA).

Design: Fifty-five SGA children and their 55 age- and sex-matched AGA control subjects were studied in a case-control setting at 12 years of age.

Methods: We examined serum concentrations of insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-1 and IGFBP-3, sex hormone binding globulin (SHBG), leptin, fasting insulin, and blood glucose. Insulin sensitivity was evaluated by the homeostasis model assessment for insulin resistance (HOMA-IR).

Results: The body mass index (BMI), sex, and puberty-adjusted mean serum IGF-I concentration was higher in the SGA than in the AGA children (303.4 vs 282.3 μg/l, P = 0.006). The mean serum concentrations of IGF-II, IGFBP-I, IGFBP-3, SHBG, fasting insulin, blood glucose and HOMA-IR did not differ between the SGA and the AGA group. The BMI, sex, and puberty-adjusted mean serum leptin concentration was lower in the SGA than in the AGA children (7.9 vs 10.1 μg/l, P = 0.037). In multiple logistic regression analysis, high HOMA-IR predicted high serum IGF-I levels in the SGA children (odds ratio 8.3; 95% confidence interval 1.7–41; P = 0.010), whereas in the AGA group HOMA-IR did not associate with the serum IGF-I level.

Conclusions: The BMI, sex, and puberty-adjusted mean serum IGF-I concentration was significantly higher and the leptin concentration was lower in the SGA than in the AGA children. No differences were found in the indices of insulin action or sensitivity between the SGA and AGA children at 12 years of age. However, HOMA-IR strongly associated with serum IGF-I levels in the SGA children.

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Jianqi Liu, Päivi Heikkilä, Raimo Voutilainen, Sirkka-Liisa Karonen, and Arvi I Kahri

Liu J, Heikkilä P, Voutilainen R, Karonen S-L, Kahri AI, Pheochromocytoma expressing adrenocorticotropin and corticotropin-releasing hormone; regulation by glucocorticoids and nerve growth factor. Eur J Endocrinol 1994;131:221–8. ISSN 0804–4643

A pheochromocytoma from a 59-year-old woman was found to be immunoreactive to adrenocorticotropin (ACTH), chromogranin, neurofilament-200, neuron-specific enolase and S-100 protein. Northern blot analysis showed that both proopiomelanocortin (POMC) and corticotropin-releasing hormone (CRH) genes were expressed in the pheochromocytoma but not in the surrounding adrenal cortex. In primary culture, the POMC and CRH mRNAs were increased by dexamethasone (500 μg/l for 3 days) up to 10- and 15-fold of the control, respectively. The secretion of ACTH also was stimulated eightfold with the same treatment. The stimulatory effect of dexamethasone on POMC gene expression was inhibited 70% by nerve growth factor (NGF, 200 μg/l), 30% by 12-O-tetradecanoyl phorbol 13-acetate (TPA, 160 nmol/l) (a protein kinase-C activator) and 30% by (Bu)2cAMP (1 mmol/ 1). On the other hand, NGF alone increased the CRH mRNA accumulation up to 10-fold, and further enhanced the stimulatory effect of dexamethasone on the CRH mRNA twofold, and TPA inhibited (30%) the dexamethasone-induced CRH mRNA accumulation. Furthermore, the conditioned medium of the pheochromocytoma cells increased secretion of corticosterone fourfold in the primary culture of rat fetal adrenal cells. Our results indicate abnormal expression and regulation of POMC and CRH genes in this pheochromocytoma.

Arvi I Kahri, Department of Pathology, PO Box 21 (Haartmaninkatu 3), FIN-00014 University of Helsinki, Finland

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Sirpa Tenhola, Raimo Voutilainen, Monica Reyes, Sanna Toiviainen-Salo, Harald Jüppner, and Outi Mäkitie

Objective

Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11.

Design

A three-generation family with seven members (3 adults, 4 children) presenting with ADH.

Methods

Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed.

Results

Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from −3.4 to −2.3 vs −0.5 in the unaffected children).

Conclusions

The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for Gα11 signaling besides calcium regulation.

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Päivi Nykänen, Taneli Raivio, Kirsti Heinonen, Olli A Jänne, and Raimo Voutilainen

Objective: Glucocorticoids are widely used before preterm delivery and in preterm infants may bear serious adverse effects. Better knowledge about the circulating glucocorticoid milieu after glucocorticoid treatment could improve treatment modalities. Therefore, we investigated the influence of exogenous glucocorticoids and clinical factors on serum cortisol (F) levels and circulating glucocorticoid bioactivity (GBA) in preterm infants.

Design: Eighty-nine infants (gestational age (GA) 23.6–33.1 weeks at birth) were enrolled in a prospective cohort study in two tertiary neonatal centres.

Methods: Cord, day of birth (D0), fourth day (D4) and 36 weeks postmenstrual age serum F and GBA levels were measured.

Results: The cord GBA was 5.8-fold and D0 GBA 2.3-fold higher in the infants exposed to antenatal steroids within 12 h before birth when compared with those unexposed or exposed >7 days before birth (95% CI 3.8–8.6; P<0.0001, and 1.8–3.0; P<0.0001 respectively). In the infants treated with early postnatal dexamethasone, D4 GBA was 1.7-fold (1.3–2.2; P<0.0005) higher when compared with levels in the infants without this treatment. Clinical factors indicating perinatal distress, such as Apgar scores <7 and low GA, were associated with higher cord, D0 and D4 serum F levels.

Conclusions: Both ante- and postnatally administered glucocorticoids increase circulating GBA not attributable to endogenous F. Perinatal distress and preceding glucocorticoid treatment need to be taken into account when circulating glucocorticoid milieu is evaluated in preterm infants. The GBA assay may prove to be a useful instrument in the development of new glucocorticoid treatment strategies.