Long-term effects of oxandrolone treatment in childhood on neurocognition, quality of life and social-emotional functioning in young adults with Turner syndrome.

Turner syndrome (TS) is the result of (partial) absence of one X-chromosome. Besides short stature, gonadal dysgenesis and other physical aspects, TS women have typical psychological features. Since psychological effects of androgen exposure in childhood probably are long-lasting, we explored long-term psychological functioning after oxandrolone (Ox) therapy during childhood in adults with TS in terms of neurocognition, quality of life and social-emotional functioning. During the initial study, girls were treated with growth hormone (GH) combined with placebo (Pl), Ox 0.03 mg/kg/day, or Ox 0.06 mg/kg/day from the age of eight, and estrogen from the age of twelve. Sixty-eight women participated in the current double-blinded follow-up study (mean age 24.0 years, mean time since stopping GH/Ox 8.7 years). We found no effects on neurocognition. Concerning quality of life women treated with Ox had higher anxiety levels (STAI 37.4 ± 8.4 vs 31.8 ± 5.0, p=0.002) and higher scores on the depression subscale of the SCL-90-R (25.7 ± 10.7 vs 20.5 ± 4.7, p=0.01). Regarding social-emotional functioning, emotion perception for fearful faces was lower in the Ox-treated patients, without effect on interpersonal behavior. Our exploratory study is the first to suggest that androgen treatment in adolescence possibly has long-term effects on adult quality of life and social-emotional functioning. However, differences are small and clinical implications of our results seem limited. Therefore we would not recommend against the use of Ox in light of psychological consequences.

Safety and efficacy of oxandrolone in growth hormone-treated girls with Turner syndrome: evidence from recent studies and recommendations for use.

There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3­4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03­0.05 mg/kg/day starting from the age of 8­10 years onward scan be considered.

Ear and hearing problems in relation to karyotype in children with Turner syndrome.

The aim of the study was to report otologic and audiologic characteristics in a group of children with Turner syndrome (TS) and correlate these findings to karyotype. Additionally, we give recommendations for the otologic care of these children. Sixty children (age 1.7-21.2 years) were included in this retrospective study. Medical history and karyotypes were recorded and otologic and audiologic evaluation was performed. A history of recurrent otitis media was reported in 41/60 (68%) children and 3/60 (5%) had suffered from cholesteatoma. Audiometric data in 56 children revealed that normal hearing was only present in 33/112 (29%) ears. All other ears 79/112 (71%) were classified in five different audiometric categories for hearing loss. Hearing thresholds in general appeared to be about 10-11 dB worse in children with a monosomy 45,X or isochromosome (both have a total deletion of the short (p) arm of the X-chromosome) compared to those having a mosaicism or structural anomaly (partial deletion, or total deletion in only a few cells). Our findings support the hypothesis that hearing can be affected by loss of the p-arm of the X-chromosome. It is for the first time that a relation between hearing problems and karyotype is statistically confirmed in a large group of children with TS.

[Intraoperative parathyroid hormone measurement in patients with primary hyperparathyroidism; particularly valuable for suspected solitary parathyroid adenoma and re-operation]. / Intraoperatieve bepaling van parathormoon bij primaire hyperparathyreoïdie; vooral waardevol bij vermoeden van solitair bijschildklieradenoom en bij heroperatie.

OBJECTIVE: Analysis of the value of intraoperative parathormone (PTH) measurement in patients with primary hyperparathyroidism. DESIGN: Prospective study. METHOD: Evaluation of the value of intraoperative measurement ofPTH in 75 patients (including 19 patients with multiple endocrine neoplasia(MEN)-1 syndrome) who underwent parathyroidectomy in 2001-2005. RESULTS: The so-called Miami-criterion (PTH concentration 10 min after excision at least 50% below the value measured prior to the first incision) correctly predicted the success of the operation in 91% of the subjects. The success rate was correctly predicted as follows: in subgroups of patients with MEN-1 syndrome, 85%, patients after exclusion of MEN-1, 94%, and patients in whom a solitary adenoma was likely after preoperative localization studies, 97%. In 13% of the total number of operations, PTH-measurements led to further exploration, removal of additional parathyroid tissue and normocalcemia postoperatively. In patients without MEN-1 syndrome, in whom a solitary adenoma was likely on the basis of preoperative investigations, it was possible to limit the operation to a unilateral procedure in 87%. CONCLUSION: In the majority of patients with primary hyperparathyroidism, intraoperative PTH-measurement in combination with preoperative imaging studies leads to patients being cured with a unilateral instead of a bilateral operation.

[Turner syndrome in adulthood: the need for multidisciplinary care]. / Het syndroom van Turner op volwassen leeftijd: het belang van multidisciplinaire zorg.

Turner syndrome is the result of the complete or partial absence of one X-chromosome. As well as short stature and gonadal dysgenesis, a wide range of abnormalities which may not present themselves until adulthood, are seen in nearly every organ system. Adult women with this syndrome have a reduced estimated life expectancy due to the greatly increased risk of structural abnormalities of the heart and aorta, and of other cardiovascular disease. The latter is due to the higher prevalence of hypertension, type-2 diabetes mellitus and dyslipidaemia. Furthermore, Turner syndrome in adulthood is characterized by infertility and oestrogen substitution is often necessary. Due to the diverse and interconnected nature of these problems, women with Turner syndrome benefit from coordinated medical care provided by a multidisciplinary outpatient team including an internist-endocrinologist, a gynaecologist and a cardiologist. We advise a periodic medical screening of women with this syndrome.

[Determining aldosterone in the adrenal veins in order to establish uni- or bilateral aldosterone production in patients with primary hyperaldosteronism]. / Aldosteronbepaling in bijniervenen voor het vaststellen van enkel- of dubbelzijdige aldosteronoverproductie bij patiënten met primair hyperaldosteronisme.

In 3 patients, men aged 60, 55 and 60, respectively, with hypertension due to primary hyperaldosteronism, the aldosterone level in the adrenal veins was determined for the purpose of further diagnosis. In two patients, unilateral adrenal enlargement on the CT-scan was accompanied by overproduction ofaldosterone, in one case in a non-enlarged adrenal gland and in the other case in both adrenals. The first patient underwent adrenalectomy of the non-enlarged adrenal gland, while in the second patient surgery was decided against. The third patient had bilateral adrenal gland enlargement on the CT-scan with a surgically treatable, unilateral overproduction ofaldosterone. Now that determination ofthe aldosterone:renin ratio in plasma as a screening method in selected patients with hypertension is being used more often, primary hyperaldosteronism turns out to be more common than was previously thought. For differentiation between unilateral and bilateral overproduction of aldosterone, imaging of the adrenals, for example with CT, is insufficiently accurate. Aldosterone determination in the adrenal veins can distinguish between unilateral and bilateral overproduction of aldosterone with great accuracy, which has important therapeutic consequences.

COS-7 cells stably transfected to express the human ETB receptor provide a useful screen for endothelin receptor antagonists.

Endothelin acts via specific membrane-bound receptors through signal transduction pathways that include increases in intracellular free calcium and inositol triphosphate generation. Two endothelin receptors have been cloned. The ETA receptor is ET-1 selective, and the ETB receptor is isopeptide nonselective. Both receptor subtypes are widely distributed throughout the body, although ETA receptors predominate in vascular smooth muscle, whereas ETB receptors predominate in the brain. The presence of mixed receptor subtypes makes functional screening of subtype-specific analogues difficult. A eukaryotic expression vector was constructed by inserting the cloned coding region of the human ETB receptor downstream from the Rous sarcoma promoter. COS-7 cells were transfected with this construct, and cell lines were isolated with stably integrated copies of the relevant gene. One line, 1C7, was shown to specifically bind 125I-ET-1. Scatchard analysis indicated a Kd value of 8.8 pM and a Bmax value of 1.02 pM/mg. ET-1 stimulated phosphoinositide hydrolysis in a dose-dependent manner, as did ET-3, sarafotoxin 6c, and [1,3,13,15Ala]ET-1, whereas BQ123, a selective ETA receptor antagonist, did not inhibit the action of ET-1. The transfected receptor stimulates phosphoinositide (PI) hydrolysis via a pertussis-sensitive pathway. Pretreatment of the membrane from 1C7 cells with dithio-bis-nitrobenzoic acid (DTNB) a negatively charged, nonpenetrating agent capable of oxidizing sulfhydryl groups, and N-ethyl-maleimide (NEM), a penetrating agent that causes irreversible alkylation of sulfhydryl groups, significantly reduces Bmax but has no effect on Kd. In whole cells, DTNB pretreatment abolishes the ability of ET-1 to stimulate PI hydrolysis.