Controlled Versus Uncontrolled Resistant Hypertension: Are They in the Same Bag?

PURPOSE OF REVIEW: Resistant hypertension (RHTN) is a condition in which besides the antihypertensive therapy using at least three different drugs (including a diuretics), brachial blood pressure does not reach the target (e.g., 140/90 mmHg). RECENT FINDINGS: Despite the diversity of clinical presentations, we divide RHTN in two major groups according to blood pressure and number of drugs taken: controlled (C-RHTN) and uncontrolled (UC-RHTN) resistant hypertension, with refractory hypertension (RfHTN) included in the latter subgroup. Both C-RHTN and UC-RHTN are heterogenic and complex syndromes. To better approach this matter, the some pathophysiological mechanisms (increased volemia, hyperactivity, plasma cortisol, adipocitokines, and other pro-inflammatory factors), have a pivotal clinical role. Some features (African ethnic, obesity, age > 60, LV hypertrophy, and vascular stiffness) increase the risk of refractoriness as well as worst prognosis. Based on increased target organ damage, cardiovascular risk and events will be addressed in this review. Our conclusion is that although both C-RHTN and UC-RHTN are extreme phenotypes of hard-to-control BP, some mechanisms of the disease and clinical expressions are distinct. According to these differences, "UC-RHTN and C-RHTN are not in the same bag."

Quality of first trimester risk prediction models for pre-eclampsia: a systematic review.

BACKGROUND: There is an increasing interest in first trimester risk prediction models for pre-eclampsia. OBJECTIVES: To systematically review and critically assess the building and reporting of methods used to develop first trimester risk prediction models for pre-eclampsia. SEARCH STRATEGY: Search of PubMed and EMBASE databases from inception to July 2013. SELECTION CRITERIA: Logistic regression model for predicting the risk of pre-eclampsia in the first trimester, including uterine artery Doppler among independent variables. DATA COLLECTION AND ANALYSIS: We extracted information on study design, outcome definition, participant recruitment, sample size and number of events, risk predictors and their selection and treatment, model-building strategies, missing data, overfitting and validation. MAIN RESULTS: The initial search identified 80 articles. A total of 24 studies were eligible for review, from which 38 predictive models were identified. The median number of study participants was 697 [interquartile range (IQR) 377- 5126]. The median number of cases of pre-eclampsia per model was 37 (IQR 19-97). The median number of risk predictors was 5 (IQR 3.75-7). In 22% of the models, the number of events per variable was fewer than the commonly recommended value of 10 events per predictor; this proportion increased to 94% in models for early pre-eclampsia. Treatment and handling of missing data were not reported in 37 models. Only three models reported model validation. CONCLUSIONS: We found frequent methodological deficiencies in studies reporting risk prediction models for pre-eclampsia. This may limit their reliability and validity.

Somatopause: state of the art.

Aging is associated with decay in the somatotroph axis, that has been considered to cause many of the catabolic sequelae of normal aging. The physiological changes that the human body undergoes during aging are similar to those observed in GH deficiency (GHD). Changes of aging are represented by increased fat mass, increased cardiovascular risk, reduced muscle mass, reduced exercise tolerance, decreased strength and impaired quality of life. Some authors conjecture that the elderly could be GH deficient and would benefit from GH treatment. However, the endocrine pattern of aging is distinct from the decrease of GH/IGF-I levels associated with hypopituitarism, although there is not sufficient evidence for a clear therapeutic role of GH treatment during somatopause. So, further studies are needed to evaluate the real benefit of somatotropic treatment in aging. This review is focused on the effects of the somatopause and summarize the potentials for a therapeutic role of the recombinant human GH (rhGH) or of GH secretagogues in aging.

Final height in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: the Italian experience.

OBJECTIVE: To investigate the influence of target height (TH), gender, phenotype, glucocorticoid formulation and age at onset of treatment on final height (FH) in patients with 21-hydroxylase deficiency (21OHD). PATIENTS: Clinical data of 93 patients--46 simple virilizing (SV), 35 salt-wasting (SW) and 12 late onset (LO)--were collected in six pediatric endocrinology units in Italy. RESULTS: FH and TH were always below the mean height of the general population (mean FH, SDS: SW patients -1.3 +/- 1.2, SV patients -1.8 +/- 0.9, LO patients -1.7 +/- 1.1; mean TH, SDS: SW patients -0.6 +/- 0.8, SV patients -0.7 +/- 0.9, LO patients -1.4 +/- 1.3). FH was significantly below TH in patients with classic form (SW and SV, p <0.001), but not in LO patients. In classic form, TH seems to be related to FH, followed by age at onset of therapy and by steroid formulation, these variables explaining 30% of FH variance. CONCLUSIONS: In the classic form, substitutive therapy started before 21 months of age improved the long-term outcome. Lower TH in LO patients could be due to undiagnosed non-classic 21OHD in some of their parents. FH in LO patients seems not to benefit from corticosteroid therapy, even if late diagnosis may partly account for this result.

Mutational analysis of GNAS1 in patients with pseudohypoparathyroidism: identification of two novel mutations.

Pseudohypoparathyroidism (PHP) refers to two major variants that generally coexist in the same family, PHP type Ia (PHP Ia), in which both PTH resistance and a constellation of physical features, termed Albright's hereditary osteodystrophy (AHO), are present, and pseudopseudohypoparathyroidism (PPHP), in which AHO occurs without PTH resistance. Most patients with PHP Ia show a partial deficiency (50%) of Gs activity, due to loss of function mutations in Gsalpha gene (GNAS1). The present study reports clinical, biochemical, and molecular data of 8 unrelated families with PHP Ia and PPHP. The 13 exons of GNAS1 were screened for mutations by PCR and direct sequencing of the amplified products. We detected heterozygous mutations in the affected members of the 4 families in which PHP Ia was present. In 2 families 2 previously reported deletions in exons 5 and 7 were found, whereas in the other 2 families, 2 novel frameshift deletions were identified in exons 1 and 11, causing a premature stop codon in the mutant allele. No mutation was detected in the families in which PPHP was the only clinical manifestation. In conclusion, we report the first mutational analysis of Italian patients with PHP Ia and PPHP, and we describe two novel deletions in GNAS1. Furthermore, we confirm that these mutations cannot be detected in families with isolated PPHP, suggesting that these forms of AHO are genetically distinct from PHP Ia.

Lack of effects of recombinant human growth hormone in a child with a complex cardiovascular malformation and dilated cardiomyopathy.

Recent studies have suggested the beneficial effects of GH treatment in patients with dilated cardiomyopathy. We have treated with recombinant human growth hormone (rhGH) a 6-year-old female with a complex congenital heart defect (severe tricuspid hypoplasia and malposition of the great arteries), who developed a progressive dilated cardiomyopathy of unknown etiology. rhGH treatment (0,1 U/kg/day, for 3 months) did not improve cardiac function, nor clinical symptoms, although we have no clear explanations for this. However, a trial with rhGH may be offered to children with dilated cardiomyopathy and waiting for heart transplantation.

17alpha-hydroxylase/17,20-lyase deficiency as a model to study enzymatic activity regulation: role of phosphorylation.

Cytochrome P450 17alpha-hydroxylase (CYP17) is a single gene-encoded protein with two activities: 17alpha-hydroxylase and 17,20-lyase. The two catalytic activities are differentially regulated in health and disease. We took advantage of naturally occurring human mutations to understand the molecular bases of this differential regulation. We identified eight novel mutations in the CYP17 gene, different in nature and spread throughout the gene. As posttranslational modifications appear to be important for activity control, we investigated the phosphorylation state of wild-type and mutant CYP17 proteins. Although phospholabeled protein was seen when the wild-type and most mutant proteins were expressed, no phosphorylation was detected for the F417C mutant. F417C is the only 17,20-lyase deficiency case confirmed at the molecular level and represents the first phosphorylation CYP17-deficient mutant. In search of the physiological agents involved in this process, the effect of cAMP was tested on activity and phosphorylation state of our mutant CYP17 proteins. cAMP stimulates activity and phosphorylation in all cases, except in the F417C and R35L mutants. The lack of response to the physiological second messenger might explain the different phenotypes. The F417C mutant protein, which is already shown to be associated with the lack of electron transfer, provides for the first time a link between the electron transfer system and the phosphorylation state of the CYP17 enzyme in the control of 17,20-lyase activity.

Point mutations in Italian patients with classic, non-classic, and cryptic forms of steroid 21-hydroxylase deficiency.

Seventy-three Italian patients affected by steroid 21-hydroxylase deficiency were studied by a PCR-allele-specific oligonucleotide protocol in order to evaluate the presence of eight known point mutations. The majority of chromosomes were found to carry point gene conversions normally present in the pseudogene. Within the classic form, the most common mutations were the splicing mutation A/C-655 to G in intron 2 (34.2%), the nonsense mutation C-1993 to T in exon 8 (10.8%), and the missense mutation T-999 to A in exon 4 (10%). Within the non-classic form, the missense mutation G-1683 to T was the most common (57.7%). Other mutations were either absent, such as the three clustered missense mutations T-1380, T-1383, T-1389 to A in exon 6, or very rare, like the 1761 + T in exon 7 and the C-2108 to T in exon 8. Family genotyping revealed the presence of ten asymptomatic parents carrying mutations in both chromosomes, thus identifying the gene defect in cryptic subjects. Interestingly, the same mutations were found in both symptomatic and asymptomatic forms.

[Endocrinologic problems of the male adolescent]. / Le problematiche endocrinologiche dell'adolescente di sesso maschile.

The male adolescent may present several endocrinological problems, the most frequent of which is the retardation or absence of puberty due to constitutional delay of growth and development. This form does not require therapy and must be distinguished from other forms of hypogonadism (primitive or secondary) by endocrine tests (LHRH test, nightly pulses LH secretion, plasmatic basal level of testosterone and after HCG, cerebral NMR). Hypogonadism treatment consists of replacement therapy with testosterone or testes stimulation with HCG or LHRH. Another frequent disease is gynecomastia, usually due to physiological enlargement of mammary gland during pubertal development, sometimes it may be secondary to hypogonadism, tumors, liver function abnormalities. Severe or psychologically disturbing gynecomastia can be corrected by reductive mammoplasty. Very often, adolescents may present diseases related to incorrect food habits. Obesity is common and anorexia is becoming an important problem also in males.

CAG triplet analysis in families with androgen insensitivity syndrome by capillary electrophoresis in polymer networks.

The potential use of capillary zone electrophoresis in polymer networks (linear polymers above the entanglement threshold, added to the background electrolyte for sieving purposes) for analysis of DNA fragments amplified by a polymerase chain reaction, is shown. In typical runs, the capillary is filled with Tris-borate-EDTA buffer, at pH 8.3, containing 6% linear polyacrylamide as a dynamic sieving matrix. Such formulations allow replenishing the capillary with fresh sieving solution when resolution decays after prolonged use (typically > 30 injections per capillary are obtained). The DNA fragments are detected by their intrinsic absorbance at 254 nm. This system has been applied to the analysis of CAG triplet polymorphism in families carrying the androgen insensitivity syndrome. While easy separation is obtained for fragments 139 base pairs (bp) and 160 bp (in families carrying a difference of 7 CAG repeats) even more difficult cases (such as those of families exhibiting fragments of 136 and 139 bp, thus differing by only one CAG repeat) are resolved with precision and diagnostic value.

Adrenarche does not occur in treated patients with congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency.

OBJECTIVE: There have been few studies of adrenarche in patients with congenital adrenal hyperplasia (CAH). We have therefore sought to detect the onset of adrenarche in CAH patients and to investigate whether its evolution was influenced by the severity of the disease, the age at the onset of substitution therapy, or both. DESIGN AND PATIENTS: Sixteen female CAH patients were studied longitudinally for 4-11 years. They were all given substitution therapy and treatments were well controlled as judged by repeated hormonal evaluations. The patients were divided into two groups: group A consisted of 10 girls with a severe classic (congenital) form, while group B included 6 girls presenting with a non-classic form. MEASUREMENTS: Circulating levels of dehydroepiandrosterone sulphate (DHEAS), were determined as an indicator of adrenarche. Hormonal assessments included measurements of 17-hydroxyprogesterone (17-OHP), testosterone, ACTH and plasma renin activity. All were estimated by conventional specific assays. RESULTS: Mean levels were analysed in consecutive two-year age periods. In group A, DHEAS levels were significantly lower at any age than in control subjects, and lower than in patients with non-classic CAH. DHEAS levels showed no increment with age. In group B, plasma DHEAS levels were surprisingly high for the age at the time of diagnosis, declining gradually on substitution therapy, although they remained somewhat higher than in group A. CONCLUSIONS: The high DHEAS levels observed in untreated girls of group B are probably the result of chronic hypersecretion of ACTH. Under well controlled, non-suppressive substitution therapy, patients with congenital adrenal hyperplasia showed no rise in DHEAS levels at the physiological age of adrenarche whatever the degree of the enzyme defect and whatever the age at onset of therapy.

[Endocrinological problems in male adolescents]. / Le problematiche endocrinologiche dell'adolescente di sesso maschile.

The male adolescent may present several endocrinological problems, the most frequent of which is the retardation or absence of puberty due to constitutional delay of growth and development. This form does not require therapy and must be distinguished from other forms of hypogonadism (primitive or secondary) by endocrine tests (LHRH test, nightly pulses LH secretion, plasmatic basal level of testosterone and after HCG, cerebral NMR). Hypogonadism treatment consists of replacement therapy with testosterone or testes stimulation with HCG or LHRH. Another frequent disease is gynecomastia, usually due to physiological enlargement of mammary gland during pubertal development, sometimes it may be secondary to hypogonadism, tumors, liver function abnormalities. Severe or psychologically disturbing gynecomastia can be corrected by reductive mammoplasty. Very often, adolescents may present diseases related to incorrect food habits. Obesity is common and anorexia is becoming an important problem also in males.

[Growth and puberal development in males with adreno-genital syndrome]. / Accrescimento e sviluppo puberale nel maschio con sindrome adreno-genitale.

Growth patterns of eleven male subjects affected by congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency were studied and correlation with treatment was evaluated. All patients had completed their growth and were divided into two groups according to the age of diagnosis; group A: treated before 6 months of age (5 patients), group B: treated after 3 years of age (6 patients). Besides the pattern of growth, mean parental age, genetic target, onset and completion of puberty were considered. Regardless of the age at diagnosis, the patients of both groups had an anticipated and stunted final height vs. general population, but correlated with mean parental height. In all patients pubertal spurt failed and height velocity slowed down after twelve years of age. We conclude that pattern of growth of patients with CAH is deeply influenced by genetic and constitutional factors and by negative effects of glucocorticoid therapy. Actually an excellent glucocorticoid treatment of CAH is not available as yet and careful clinical and laboratory evaluations are necessary to minimize negative influences on growth.