Classical Adrenal Hyperplasia Research Articles

Journey with classical adrenal hyperplasia. Expectations and reality of treatment

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

POR polymorphisms are associated with 21 hydroxylase deficiency

PurposeGenotype–phenotype correlation in congenital 21 hydroxylase deficiency is strong but by no means absolute. Indeed, clinical and hormonal features may vary among patients carrying similar CYP21A2 mutations, suggesting that modifier genes may contribute to the phenotype. Aim of the present study was to evaluate whether polymorphisms in the p450 oxidoreductase (POR) gene may affect clinical features in patients with 21 hydroxylase deficiencyMethodsSequencing of the POR gene was performed in 96 patients with 21 hydroxylase deficiency (49 classic, 47 non-classic) and 43 control subjects.ResultsPrevalence of POR polymorphisms in patients with 21 hydroxylase was comparable to controls and known databases. The rs2228104 polymorphism was more frequently associated with non-classic vs classic 21 hydroxylase deficiency (allelic risk 7.09; 95% C.I. 1.4–29.5, p < 0.05). Classic 21 hydroxylase-deficient carriers of the minor allele in the rs2286822/rs2286823 haplotype presented more frequently the salt-wasting form (allelic risk 1.375; 95% C.I. 1.138–1.137), more severe Prader stage at birth (allelic risk 3.85; 95% C.I. 3.78–3.92), higher ACTH levels, and younger age at diagnosis.ConclusionsPolymorphisms in the POR gene are associated with clinical features of 21 hydroxylase deficiency both as regards predisposition to classic vs non-classic forms and severity of classic adrenal hyperplasia.

A Case of Lean Idiopathic Hirsutism not Having Insulin Resistant Unresponsive to Conventional Treatment for Hirsutism-A Case Report

Hirsutism is the presence of terminal (coarse) hairs in females in a male like pattern, which affects 5-10% of women of the sex steroids androgens are the most important in determining the type and distribution of hairs over the human body. Under the influence of androgens hair follicles that are producing vellus type hairs can be stimulated to begin producing terminal hairs. The activity of local 5 alpha reductase (5 alpha RA) determines to a great extent the production of dihydrotestosterone (DHT) and consequently the effects of androgens on hair follicles. The commonest cause is an ovulation, secondary to PCOS, a fairly common disorder, affecting 6-10% of women of reproductive age group. Besides PCOS other hormonal causes like thyroid hormone deficiency, growth hormone deficiency or hyperprolacinaemia, or hyperinsulinemia or IR may act on their own or synergistically increasing adrenal androgens. A serum T (Testosterone) over 2ng/ml warrants exploring for an androgen secreting tumor. Other causes include non classical adrenal hyperplasia. Occasionally it may not be because of any these causes when it is termed idiopathic hirsutism (IH). Normally these patients of IH respond to 5 alpha reductase inhibitors. Recently high incidence of association of IR has been reported in lean IH. We report a case of lean IH not having IR and very unresponsive to treatment although we are trying to follow her up before undertaking any type of eflornithine cream or laser therapy.

Blood Pressure in a Large Cohort of Children and Adolescents With Classic Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency.

Data on blood pressure (BP) in children and adolescents with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are conflicting in the literature. BP data of n = 716 children and adolescents (aged 3-18 years) from a national CAH database were analyzed. BP data were adjusted for height and compared to contemporary national reference data. A systolic and diastolic BP above the 95th centile was defined as hypertensive. Overall prevalence of hypertension was 12.5%. Prevalence of hypertension was higher in younger children than in adolescents (18.5% vs. 4.9%). Until 8 years of age, fludrocortisone dose/m(2)/day correlated significantly with BP in regression analysis (P < 0.0001). BP correlated significantly with body mass index standard deviation score (BMI-SDS) (P < 0.0001), but not with hydrocortisone dose. In patients with salt-wasting CAH, BMI-SDS and BP were significantly higher compared to patients with simple virilising CAH, P < 0.01. Especially young CAH children seem to be at risk for-most likely transient-hypertension, since the prevalence of hypertension decreases with age. In children up to 8 years of age, the used fludrocortisone dose is a significant risk factor for hypertension. Therefore we recommend accurate measurement of BP and careful fludrocortisone dosing in children with CAH.

FACTOR OVÁRICO ENDOCRINO

Se conoce como factor ovárico endocrino en endocrinología reproductiva al conjunto de alteraciones hormonales que se originan en el ovario o afectan la función ovárica y que pueden condicionar un trastorno de la fertilidad en la mujer. El ovario es regulado por mecanismos neuroendocrinos en los cuales participan fundamentalmente el hipotálamo y la hipófisis, en coordinación con otras glándulas como la tiroides y las suprarrenales, y con la regulación adicional proveniente del páncreas y el tejido adiposo. Los principales trastornos endocrinos en las pacientes con problemas de la fertilidad son: síndrome de ovario poliquístico, hiperprolactinemia, hiperplasia suprarrenal no clásica, amenorrea hipotalámica, falla ovárica prematura y enfermedad tiroidea. Se estudia estos trastornos con base en su sintomatología particular, principalmente su efecto sobre el ciclo menstrual, y con la determinación de diferentes hormonas. El tratamiento de cada trastorno está enfocado a su corrección causal específica y a la inducción de la ovulación, en el caso de que ello sea posible. Con excepción de la falla ovárica prematura, el pronóstico para la fertilidad es favorable para los otros trastornos, lográndose aproximadamente 80% de embarazos en los dos primeros años de tratamiento.

Effect of Vitamin D in a Patient With Classical Adrenal Hyperplasia due to 11-Hydroxylase Deficiency

Both classical and non-classical CAH, like PCOS, are characterized by insulin resistance (IR) and are also ameliorated by measures which reduce IR. Vitamin D supplementation reduces IR and ameliorates PCOS in Vitamin D deficient/insufficient (VDDI) patients-raising the question: would Vitamin D replacement also ameliorate CAH? Our patient is a 47 year old man with Type 2 diabetes (Type 2 DM) and hypertension hospitalized for cellulitis, abscess, osteomyelitis, and gangrene of the left foot. He was not taking any known insulin sensitizers, and denied any history of acne or hyperpigmentation. The patient has no progeny and never had intercourse due to issues concerning his phallus size. He had hypospadias and micropenis at birth. The former was surgically corrected in childhood. His BMI = 36.45 kg/m 2 with a central fat distribution. On physical examination there was no acanthosis nigricans or hyperpigmentation. He had a stage IVa Hamilton male pattern alopecia that started during his early 20s. He had micropenis (or clitoromegaly), measuring 1.5 - 2cm when flaccid; scrotum (or scrotalized labia majora) was normal in size. Testes is measured 3.4 cm in their long diameter and were firm. On 12-4-2012 his serum 11-deoxycortisol by liquid chromatography tandem mass spectrometry (LC MS/MS) was 2024 ng/dL ( less than or equal to 76) while his serum 25-OH-vitamin D by LC MS/MS was 12 ng/mL( greater than or equal to 30), and his 1,25 (OH)2-Vitamin D3 by LC MS/MS was less than or equal to 8 pg/mL (18 - 72). Supplementation was begun with ergocalciferol 50,000 units orally weekly. Nine days later his serum 11-deoxycortisol fell to 425 ng/dL, while serum 25-OH-Vitamin D rose to 23 ng/mL, and serum 1,25-(OH)2-Vitamin D3 remained ? 8 pg/mL. Seventeen days later his serum 11-deoxycortisol was 194 ng/dL, while his serum 25-OH-Vitamin D was 27 ng/mL, and his 1,25-(OH)2-vitamin D3 remained less than or equal to 8 pg/mL. 28 days after starting supplementation with ergocalciferol the 11-deoxycortisol was < 20ng/dL. The laboratory lost the corresponding sample for Vitamin D metabolites. His lymphocyte karyotype was XY. He refused any biopsies, which might have disclosed mosaicism.Vitamin D might be a means of treating classical 11-hydroxylasedeficiency in patients with a VDDI co-morbidity and suggest that it may work by reducing IR. doi: http://dx.doi.org/10.4021/jmc1352w

Effect of Vitamin D in a Patient With Classical Adrenal Hyperplasia due to 11-Hydroxylase Deficiency

Effect of Vitamin D in a Patient With Classical Adrenal Hyperplasia due to 11-Hydroxylase Deficiency

Clinico-investigative profile of patients of hirsutism in a tertiary level institution

Introduction:Hirsutism has a significant impact on the quality of life and serves as a marker of underlying hormonal and systemic conditions. The aim of this study was to study the clinical, biochemical characteristics of these patients and other associations.Materials and Methods:Fifty (n=50) consecutive newly diagnosed patients of hirsutism were assessed during a period from August 2009 to July 2010 using modified Ferriman Gallwey (mF-G) score.Results:Idiopathic hirsutism (IH) was found in 30 (60%) patients followed by polycystic ovarian syndrome (PCOS) in 19 (38%) patients. Other causes included late-onset classic adrenal hyperplasia in two (4%) and hypothyroidism in four (8%) patients. The mean age at presentation was 23.8±6.657 years. Total (T) and free testosterone (fT), 17-hydroxyprogesterone was significantly higher in PCOS than IH.Conclusion:The present data show IH as the commonest cause of hirsutism in our study population. Face, chest, and lower abdomen have a higher impact on the hirsutism score while upper back, abdomen, and lower back are rarely involved.

Precocious pubarche: experience in 173 cases

Precocious pubarche (PP), defined as the development of sexual pubic hair before 8 years of age in females and before 9 years in males, is usually a benign condition but it can also be the first sign of an underlying disease. To analyze the etiology and perform a short term follow up in a cohort of patients with PP. A group of 173 patients (158 females) consulted for PP with a mean age of 7.4+/-0.1 years. These patients were followed between 15 to 60 months. Anthropometric measurements, bone age, serum levels of total testosterone, 17 OH progesterone (17 OHP) and dehydroepiandrosterone sulphate (DHEAS) were evaluated. Mean birth weight and length was 3024.1+/-50.5 g and 48.5+/-0.3 cm, respectively. Ten percent of children were small for gestational age at birth. Bone age was accelerated by 1.1+/-0.01 years. One hundred and twelve patients were classified as having idiopathic PP (64.7%; 105 females), 29 as central precocious puberty (16.8%; only females), 16 as exaggerated adrenarche (EA 9.2%; 13 females) and 16 as non classical adrenal hyperplasia (9.2%; 11 females). PP represents a common and usually benign sign. However, 26% of cases had a pathologic underlying condition. Therefore, all children with PP should be evaluated by a pediatric endocrinologist. Low birth weight was not frequent in this cohort and these patients did not show EA .

Pubarquia precoz: Experience in 173 cases

Background: Precocious pubarche (PP), defined as the development of sexual pubic hair before 8 years of age in females and before 9 years in males, is usually a benign condition but it can also be the first sign of an underlying disease. Aim: To analyze the etiology and perform a short term follow up in a cohort ofpatients with PP. Material and methods: A group of 173patients (158 females) consulted for PP with a mean age of 7.4+0.1 years. These patients were followed between 15 to 60 months. Anthropometric measurements, bone age, serum levels of total testosterone, 17 OH progesterone (17 OHP) and dehydroepiandrosterone sulphate (DHEAS) were evaluated. Results: Mean birth weight and length was 3024.1+50.5 g and 48.5+0.3 cm, respectively. Ten percent of children were small for gestational age at birth. Bone age was accelerated by 1.1+0.01 years. One hundred and twelve patients were classified as having idiopathic PP (64.7%; 105 females), 29 as central precocious puberty (16.8%; only females), 16 as exaggerated adrenarche (EA 9.2%; 13 females) and 16 as non classical adrenal hyperplasia (9.2%; 11 females). Conclusions: PP represents a common and usually benign sign. However, 26% of cases had a pathologic underlying condition. Therefore, all children with PP should be evaluated by a pediatric endocrinologist. Low birth weight was not frequent in this cohort and these patients did not show EA .

Reproductive Outcome of Women With 21-Hydroxylase-Deficient Nonclassic Adrenal Hyperplasia

Many women with 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) carry at least one allele containing a severe mutation of CYP21, and as such are at risk for giving birth to an infant having classic adrenal hyperplasia (CAH). Infants with NCAH typically are asymptomatic at birth, in contrast to those with CAH, but they do develop symptoms of hyperandrogenism later in childhood or as adults. This international multicenter study, conducted both retrospectively and prospectively, was an attempt to determine how often mothers with 21-OH-deficient NCAH bear infants having CAH or NCAH. The 101 women entering the study had a total of 203 pregnancies that could be evaluated. Fourteen tertiary referral centers in nine countries participated in the study. The diagnosis of 21-OH-deficient NCAH was based on a baseline or post-ACTH level of 17-hydroxyprogesterone exceeding 10 ng/mL. Where feasible, the offspring underwent genotypic analysis. Nearly half the women with NCAH presented with oligomenorrhea, and four had primary amenorrhea. More than two-thirds of pregnancies took place before the mother was diagnosed as having NCAH. Spontaneous miscarriages occurred in one-fourth of 138 pregnancies before NCAH was diagnosed but in only four of 65 pregnancies occurring after the diagnosis (6%). The incidence of CAH in 162 live births was 2.5%. Twenty-four children (15%) have been diagnosed as having NCAH. Five other female infants developed signs of hyperandrogenism but did not meet hormonal criteria for a diagnosis of NCAH. Three of the four live-born CAH children were White Jewish or Hispanic, as were two of three NCAH mothers giving birth to a CAH child. In this international study, a woman with NCAH had a 2.5% chance of giving birth to a child having CAH and a 15% chance of having a child with NCAH. Preconception screening for 21-OH-deficient NCAH is especially important for hyperandrogenic or oligoovulatory women who wish to become pregnant. Glucocorticoid therapy before conception and/or before birth may favorably influence the outcome.

P-891: Clinical profile of insulin resistant PCOS subjects. Characterization of a Latin American population

To determine the clinical and laboratory profile of those subjects having the more elevated levels of insulin resistance according to the homeostasis model assessment (HOMA) in a population of Latin American PCOS subjects. Prospective descriptive clinical trial. Thirty three (33) consecutive subjects with diagnosis of PCOS were prospectively recruited. All patients had, at least, 12 weeks without any hormonal treatment and normal levels of thyroid-stimulating hormone, and prolactin before entering the study protocol. The diagnosis of PCOS was established by the exclusion of other conditions chronic anovulation with associated hyperandrogenism: 21-OH-deficient-non classic adrenal hyperplasia, ovarian-adrenal tumors, and Cushing’s syndrome. A detailed physical examination was performed and registered. We measured Body Mass Index (BMI), Ferriman Galwey score (FG), Waist to Hip ratio (W/H), ovarian volume (OV) by ultrasound and menstrual cycle length. Additional laboratory assessment was obtained including fasting glucose and insulin, and plasminogen activator inhibitor 1 (PAI-1). Serum samples for measuring androgens at the end of recuitment period were also collected and were frozen at -20 °C. Statistical analysis was performed using KwikStat-4 Statistical Data Analysis Program (TexaSoft, Cedar Hill, TX). We did obtain a mean HOMA value for entire study population; we then classified those subjects having HOMA values above the mean as insulin resistant and those with HOMA values below the mean as non insulin resistant. A total of 24 subjects completed the clinical and laboratory protocol. The mean HOMA value for the entire study population was 2.43. Ten from 24 (41.6%) subjects had values higher than the general mean, and constituted the insulin resistant group. Mean age of insulin resistant group was higher compared to non insulin resistant subjects (28.8 vs 24.62) but without reaching statistical significance. Overall, the insulin resistant group had a more severe clinical condition as it is suggested by the fact that they had statistically significant higher values of BMI (30.52 Kg/m2 vs 24.40 Kg/m2), W/H ratio (0.84 vs 0.78), menstrual cycle length (72.50 days vs 49.64 days), PAI (18.13 ng/mL vs 10.39 ng/mL), and A4 (4.11 ng/mL vs 3.33 ng/mL). Of note insulin resistant women had significantly lower values of DHEAS (154 ug/dL vs 208 ug/dL) In this population of Latin American PCOS women, we have demonstrated that PCOS subjects with higher insulin resistant state have a more severe disease, being older, with a major degree of obesity, elevated levels of PAI-1 and poorer menstrual function. Unexpectedly, adrenal androgens were lower in the insulin resistant group.

Reproductive Outcome of Women with 21-Hydroxylase-Deficient Nonclassic Adrenal Hyperplasia

Because many women with 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) carry at least one allele affected by a severe mutation of CYP21, they are at risk for giving birth to infants with classic adrenal hyperplasia (CAH). Our objective was to determine the frequency of CAH and NCAH infants born to mothers with 21-OH-deficient NCAH. We conducted an international multicenter retrospective/prospective study. The outcome of 203 pregnancies among 101 women with 21-OH-deficient NCAH was reviewed. The diagnosis of 21-OH-deficient NCAH was established by a basal or post-ACTH-stimulation 17-hydroxyprogesterone level of more than 10 ng/ml (30.3 nmol/liter). When possible, genotype analyses were performed to confirm CAH or NCAH in the offspring. Of the 203 pregnancies, 138 (68%) occurred before the mother's diagnosis of NCAH and 65 (32%) after the diagnosis. Spontaneous miscarriages occurred in 35 of 138 pregnancies (25.4%) before the maternal diagnosis of NCAH, and in only four of 65 pregnancies (6.2%) after the diagnosis (P < 0.002). Four (2.5%; 95% confidence interval, 0.7-6.2%) of the 162 live births were diagnosed with CAH. To date, 24 (14.8%; 95% confidence interval, 9.0-20.6%) children, 13 girls and 11 boys, have been diagnosed with NCAH. The distribution of NCAH children and their mothers varied significantly by ethnicity (P < 0.0001, for both). The risk of a mother with 21-OH-deficient NCAH for giving birth to a child affected with CAH is 2.5%; at least 14.8% of children born to these mothers have NCAH.

Time Androgens and Sexual Hormone Binding Globulin (SHBG) Take to Return to Baseline Levels Following Discontinuation of Oral Contraceptives Pills (OCP), in Women With Polycystic Ovary Syndrome (PCOS), A Prospective Study

To determine the time that it takes for androgens and SHBG in women with PCOS to return to their pretreatment levels, following discontinuation of therapy with an OCP containing drospirenone and ethinyl-estradiol. Prospective descriptive clinical trial. Eight (8) subjects with diagnosis of PCOS were assigned to receive a combination OCP containing drospirenone 3 mg and ethinyl-estradiol 30 μg for 12 weeks. After this treatment period, subjects discontinued OCP and were followed up during 8 weeks. All patients had, at least, 12 weeks without hormonal treatment and normal levels of thyroid-stimulating hormone, and prolactin before entering the study protocol. The diagnosis of PCOS was established by the exclusion of other conditions that can cause chronic anovulation with associated hyperandrogenism: 21-OH-deficient-non classic adrenal hyperplasia, ovarian-adrenal tumors, and Cushing’s syndrome. Serum samples were collected prior to and at week 12 of treatment, and also 4 and 8 weeks after discontinuation of OCP. Samples were frozen at -20 °C. We measured total (TT) and free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), and SHBG levels, by ELISA and RIA. Statistical analysis was performed using KwikStat-4 Statistical Data Analysis Program (TexaSoft, Cedar Hill, TX). A total of 7 PCOS subjects completed the study. Mean age was 26.29 years. Mean body mass index (BMI) at basal conditions and end of treatment period were 24.35 and 24.29 kg/m2, respectively (p = 0.86). Ferriman-Gallwey score decreased during treatment period, but change did not reach significance (mean baseline and post-treatment values were 4.14 and 3.86; p = 0.36). Mean initial and after 12 weeks of treatment levels for TT, FT, DHEAS, and SHBG were 4.14 nmol/L (119 ng/dL) and 1.9 nmol/L (54.86 ng/dL); 0.01 nmol/L (0.28 ng/dL) and 0.004 nmol/L (0.11 ng/dL); 4.4 μmol/L (164 μg/dL) and 2.84 μmol/L (105 μg/dL); 59 nmol/L and 311 nmol/L, respectively. Following discontinuation of OCP androgen levels increased progressively, at 4 and 8 weeks. Levels of TT (3.72 nmol/L = 107.3 ng/dL) and DHEAS (3.81 μmol/L = 140 μg/dL) at week 4 were not significantly different from those measured at baseline. Alternatively, FT (0.008 nmol/L = 0.22 ng/dL) and SHBG (54.4 nmol/L) returned to levels not significantly different from baseline values, only at week 8 post discontinuation of OCP. In this population of PCOS women, discontinuation of an OCP containing drospirenone 3 mg and ethinyl estradiol 30 μg was followed by return of TT and DHEAS to baseline levels in 4 weeks. On the other hand, levels of FT and SHBG returned to basal values only 8 weeks after discontinuation of OCP. These observations are pertinent when measuring androgens and SHBG in subjects suspected of having PCOS, who are currently taking OCP.

The 21-hydroxylase-deficient adrenal hyperplasias: More than ACTH oversecretion

Twenty-one hydroxylase (21-OH)-deficient classic adrenal hyperplasia (CAH) and nonclassic adrenal hyperplasia (NCAH) are two of the most common genetic disorders known to man, yet the mechanism(s) resulting in steroid excess remains unclear. Overactivation of the hypothalamic-pituitary-adrenal (HPA) axis and increased ACTH secretion appear to be important mechanisms resulting in steroid excess in untreated patients, at least in the classic forms of the disorder. Nonetheless, most NCAH patients do not demonstrate overactivity of the HPA axis. A few of these patients may demonstrate a mild degree of ACTH hyper-responsiveness to corticotropin-releasing hormone stimulation, and up to 40% have radiologic evidence of adrenocortical hyperplasia and/or isolated adenomas, suggesting that some degree of chronic ACTH excess is present. Another mechanism resulting in adrenocortical excess in adrenal hyperplasia, and primarily in NCAH, follows the alteration in enzyme kinetics resulting from the mutation of 21-OH. The mutated enzyme product is less efficient than the wild type, resulting in an increased precursor to product ratio, independent of ACTH levels. Hence, progesterone (P4) and 17-hydroxyprogesterone (17-HP) levels in these patients may remain above normal even in the presence of excess glucocorticoid administration. Overactivity of the renin-angiotensin system may also be important in stimulating adrenocortical steroidogenesis in patients with salt-wasting and in some with simple virilizing CAH. Alterations in ovarian and gonadotropic function, with the appearance of a polycystic ovary-like picture, also contribute to the androgen excess of these patients. Functional ovarian abnormalities in patients with CAH or NCAH may relate to a number of causes, including prenatal masculinization of the hypothalamic-pituitary-ovarian (HPO) axis by adrenal androgens, continued disruption of the HPO axis by persistently elevated P4 or androgen levels, and/or a direct glucocorticoid effect. Finally, these data suggest that the measurement of P4 or 17-HP may not be the most accurate marker of therapeutic efficacy, and suppression of both the ovaries and adrenals may be necessary for optimum steroidogenic control.

Congenital Adrenal Hyperplasia

The incidence of congenital adrenal hyperplasia in Saudi Arabia and the frequency of the carrier rate are not well known. Both figures should be high, considering the commonness of first-degree consanguinity in this part of the world. We present 25 cases of congenital adrenal hyperplasia, most of them due to a defect of the 21 hydroxylase enzyme, diagnosed and followed over three years at Suleimania Children's Hospital in Riyadh. There were ten boys and 15 girls exhibiting all degrees of masculinization, mostly Grade III (53%) and Grade IV and V (13.3% each). The degree of masculinization of the external genitalia in the girls (46XX) was sufficiently pronounced in seven patients to lead to sex identity errors at birth. This aggravated the psychological reactions in the families, particularly before the surgical correction. The frequency of neonatal deaths in the patients' families related to a similar disorder was high (12%). The mean age at onset of the salt-losing crises in affected infants was 9 days in females and 25 days in males and this was the most common clinical presentation of the disorder (80%). Systemic neonatal screening and intrauterine diagnosis in at risk families must be done to provide hormonal intervention and thus prevent the formation of ambiguous genitalia and avoid the resulting plastic surgery that must be performed in female patients.