Hydroxysteroid Dehydrogenase Deficiency Research Articles

Congenital adrenal hyperplasia due to 3 beta hydroxysteroid dehydrogenase deficiency About two cases

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

An Adult With Hair Loss! a Rare Case of Non-Classical 3β Hydroxysteroid Dehydrogenase (3β HSD) Deficiency

Introduction: Congenital adrenal hyperplasia (CAH) is the most frequent cause of adrenal insufficiency and ambiguous genitalia in newborn. Unlike 21-hydroxylase and 11β- hydroxylase deficiencies, classical 3β hydroxysteroid dehydrogenase (3β HSD) deficiency affects steroid biosynthesis in both the adrenals and the gonads. We present a rare case of suspected 3β HSD in an adult with hair loss. Case: 33 years old with female with no PMH/prior pregnancies was referred to endocrinology for low testosterone, male pattern hair loss and decreased libido for 2 years. At onset of symptoms, she was following an intensive exercise regimen for weight loss and was using Oxandrolone for 2 months to promote muscle mass. She now reports increased axillary and pubic hair growth but loss of scalp hair as well as fatigue. Menarche was at 14 years. Menstrual cycles are regular but with hypomenorrhea. Physical examination showed normal BP, signs of male pattern hair loss on scalp. light terminal hair growth over abdomen, middle thighs and around areola but without galactorrhea. Labs remarkable for normal sodium and potassium, A1c 5.2%, ACTH of 7.2, Cortisol of 8.2 (5–25 µg/dl), TSH of 1.43 (0.5–5.0 mIU/L), Free T4 of 1.28 (0.8–1.8 ng/dl), Estrone 102 (17–200 pg/ml), Normal DHEA 133, Total testosterone <3 (8–60 ng/dl), Free testosterone 0.4 (0.3–1.9 ng/dL), LH 7 (1.0–18.0 mIU/mL), FSH 9.6 (2.0–12.0 mIU/mL), Estradiol 45.9 (15–350 pg/mL),low 17-hydroxyprogesterone of 11 (<80 ng/dL), DHEA-S of 88 (31–228 µg/dL), low Androstenedione of 28 (80–240 ng/dL) and Dihydrotestosterone 6.3 (normal). MRI brain revealed a normal pituitary gland, slightly enlarged for age. Co-syntropin stimulation test has been delayed due to the pandemic. Discussion: 3β HSD converts delta-5 steroids (pregnenolone, 17-hydroxypregnenolone, DHEA, androstenediol) to delta-4 steroids (progesterone, 17-hydroxyprogesterone, androstenedione, testosterone) respectively. Delta-4 steroids were low in our patient. Increased ratio of delta 5 steroids: delta 4 is characteristic of 3β HSD. Most cases of 3β HSD deficiency present as neonates with hyponatremia, hyperkalemia, and ambiguous genitalia but a non-salt wasting form has occasionally been described in older patients. The non-classical form often manifests as menstrual irregularities and hirsutism along with possible male pattern hair loss of varying degrees in women. The normal levels of estradiol and estrone are likely due to peripheral conversion of androstenedione by aromatase. 3β HSD deficiency is usually treated with steroids which helps resolve most symptoms.

Congenital adrenal hyperplasia secondary to 3-beta hydroxysteroid dehydrogenase deficiency

Congenital adrenal hyperplasia secondary to 3-beta hydroxysteroid dehydrogenase deficiency

Human 3[beta]-hydroxysteroid dehydrogenase deficiency associated with a normal spermatic numeration despite a severe enzyme deficit, after an accomplished transition period

Human 3[beta]-hydroxysteroid dehydrogenase deficiency associated with a normal spermatic numeration despite a severe enzyme deficit, after an accomplished transition period

Imaging of disorder of sex development

BACKGROUND AND OBJECTIVESDisorders of sex development (DSDs), formerly termed ambiguous genitalia, are a group of conditions where the external genitalia appear abnormal. It represents a true medical and social emergency that needs a multidisciplinary team approach for elucidation. The pediatric radiologist plays an important role in defining the genital anatomy that remains one of the most important factors in sex determination, in addition to chromosomal analysis.DESIGN AND SETTINGSA retrospective study, conducted between January 1995 and December 2010.MATERIALS AND METHODSImaging studies (ultrasound, genitogram, and/or magnetic resonance imaging) were performed in patients with ambiguous genitalia, confirmed by chromosomal analysis and appropriate hormonal investigations.RESULTSThe sensitivity of ultrasound is 89.5%, while its specificity reaches 100%. Retrograde genitogram is more invasive and less sensitive, as the yield of determining the presence of a uterus ± vagina is 84.2%. However, magnetic resonance imaging (MRI) is more sensitive for gonadal tissue identification. Its specificity reaches up to 100% and can provide detailed internal structures (uterus, fallopian tubes, and gonads).CONCLUSIONUltrasound examination is still the main modality of choice for screening patients with ambiguous genitalia. It is cheap and readily available everywhere. In addition to elucidating the uterus in 89.5%, it can also give more information on the adrenal glands. However, genitography is good—84.2% in elucidating genital anatomy—but it gives no information of the gonads and it is time consuming and invasive. MRI is helpful in cases with equivocal ultrasound, reaches 100% in elucidating internal extractor, and therefore could be reserved for that.

Non-classic congenital adrenal hyperplasia. Clinical experience versus clinical guidelines

The ability to diagnose non-classic congenital adrenal hyperplasia (NC-CAH) has improved drastically over the past decade due to standardization of laboratory assays and refinement of molecular studies. However, the optimal clinical management for this patient population is still evolving. Thus, we describe the clinical presentation and diagnostic approach of children with non-classic congenital adrenal hyperplasia (NC-CAH). A retrospective chart review was done to identify all subjects diagnosed with late-onset CAH or NC-CAH at a single institution during the last decade. Eighteen subjects were identified. Fourteen were diagnosed as NC-CAH 21-hydroxylase deficiency and four with NC-CAH 3-beta hydroxysteroid dehydrogenase (3βHSD) deficiency. The approach to evaluation was different according to the provider. Re-evaluation of steroid hormone concentrations using updated diagnostic criteria revealed one patient had ACTH-stimulated hormone concentrations consistent with classic CAH (non-salting wasting variant) and four patients initially thought to have NC-CAH 3βHSD had steroid hormone concentrations consistent with premature adrenarche. Age and clinical presentation did not differentiate subjects with NC-CAH from those with premature adrenarche. Skeletal age was ≥ to 2 standard deviations advanced only in those patients with NC-CAH. Variations in the diagnostic approach to evaluate children for NC-CAH exist. We provide a practical algorithmic recommendation, incorporating the most recent diagnostic guidelines, to aid the clinician in the evaluation of this disorder.

Congenital adrenal hyperplasia: hospital based study

Background: Congenital adrenal hyperplasia is a family of autosomal recessive disorders of cortisol biosynthesis. Depending on the enzymatic step that is deficient, there may be signs, symptoms, and laboratory findings of mineralocorticoid deficiency or excess; incomplete virilization or premature puberty in affected males; and virilization or sexual infantilism in affected females. The most frequent is 21-hydroxylase enzyme deficiency, accounting for more than 90% of cases.Objectives: to review cases of congenital adrenal hyperplasia registered in children welfare teaching hospital- medical city- Baghdad.Patients and method: This study included all patients who were presented and registered in the endocrine clinic of the children welfare teaching hospital- medical city complex as a case of congenital adrenal hyperplasia from the 1st of January 1990 till the 1st of Jun 2009. Demographic informations together with epidemiological, clinical, diagnostic and therapeutic data of the patients were collected.Results: The total number of patients was 60 patients with mean age (6.321) +/- (3.996) SD and male to female ratio of 2:3. Seventy percent of patients presented within the 1st 6 months of life, 61.9% of them were females. Thirty-one (51.7%) patients were delivered in the hospital including 72% of those who were presented within the 1st month. Forty six (76.7%) patients were presented with ambiguous genitalia with or without other presentations, 8 (13.3%) patients presented with salt losing only and 6(10%) patients presented with pseudo precocious puberty with or without other presentations. Consanguinity between the parents was present in 86.7% of patients, 33.3% of patients had positive family history of similar condition, 36.7% of patients had positive family history of neonatal death due to dehydration or abortion and only 3.3% of patients had history of hormonal therapy during pregnancy. Twenty two (36.7%) patients were reared with false sex, 95.5% of them were females reared as males, 33.3% of them accept to change their names &amp; sex of rearing to definitive sex asfemales and one male (4.5%) patient reared as female had change his name and sex to male. Seventy percent of patients were diagnosed as 21 hydroxylase deficiency, both salt loser (71.4%) and non salt loser (28.6%), (10%) as 11 hydroxylase deficiency, (18.3%) as 3β hydroxysteroid dehydrogenase deficiency both salt loser (54.5%) and non salt loser (45.5%) and (1.7%) as17 hydroxylase deficiency.Conclusions: The commonest form of congenital adrenal hyperplasia in Iraq is 21 hydroxylase deficiencies. There was delay in the diagnosis in spite of hospital delivery, and this may lead to psycho-social problems for the patients and their families regarding changing the sex of rearing. Many patients having genital anomalies did not operate upon yet.

Clinical, hormonal, and molecular-genetic characteristics of two cases of abnormal sex formation (ASF) in 46XY subjects caused by type 3 17-beta hydroxysteroid dehydrogenase deficiency

Type 3 17-beta hydroxysteroid dehydrogenase (17HSD3) deficiency is a rare form of abnormal sex formation (ASF) in 46XY subjects in which the conversion of androstendione to testosterone is blocked; this defect results in compromised masculinization of the external genitalia during the intrauterine development. A distinctive feature of this form of sex development is masculinization at puberty due to the extragonadal conversion of androstendione to testosterone. Two clinical cases are reported: both girls were born with the female-type of external genitalia and 46XY karyotype, but progressive virilization in the pubertal period gave reason to suspect diagnosis of 17HSD3 deficiency. In both cases, this diagnosis was confirmed in molecular genetic studies (the following mutations were identified in the HSD17B3 gene: c.728-734delGATAACCp.1244fsX254/c.277+4A&gt;T and c.277+4A&gt;T). These two cases are the first reports of 17HSD3 deficiency in the Russian literature.

Gene- and Environment-Dependent Neuroendocrine Etiogenesis of Homosexuality and Transsexualism

Sexual brain organization is dependent on sex hormone and neurotransmitter levels occurring during critical developmental periods. The higher the androgen levels during brain organization, caused by genetic and/or environmental factors, the higher is the biological predisposition to bi- and homosexuality or even transsexualism in females and the lower it is in males. Adrenal androgen excess, leading to heterotypical sexual orientation and/or gender role behavior in genetic females, can be caused by 21-hydroxylase deficiency, especially when associated with prenatal stress. The cortisol (F) precursor 21-deoxycortisol (21-DOF) was found to be significantly increased after ACTH stimulation in homosexual as compared to heterosexual females. 21-DOF was increased significantly before and even highly significantly after ACTH stimulation in female-to-male transsexuals. In view of these data, heterozygous and homozygous forms, respectively, of 21-hydroxylase deficiency represent a genetic predisposition to androgen-dependent development of homosexuality and transsexualism in females. Testicular androgen deficiency in prenatal life, giving rise to heterotypical sexual orientation and/or gender role behavior in genetic males, may be induced by prenatal stress and/or maternal or fetal genetic alterations. Most recently, in mothers of homosexual men--following ACTH stimulation--a significantly increased prevalence of high 21-DOF plasma values and 21-DOF/F ratios was found, which surpassed the mean + 1 SD level of heterosexual control women. In homosexual men as well--following ACTH stimulation--most of the 21-DOF plasma values and 21-DOF/F ratios also surpassed the mean + 1 SD level of heterosexual men. In only one out of 9 homosexual males, neither in his blood nor in that of his mother increased 21-DOF values and 21-DOF/F ratios were found after ACTH stimulation. In this homosexual man, however, the plasma dehydroepiandrosterone sulfate (DHEA-S) values and the DHEA-S/1000 x A (A = androstenedione) ratio were increased before and after ACTH stimulation. Furthermore, highly significantly increased basal plasma levels of dehydroepiandrosterone sulfate were found in male-to-female transsexuals as compared to normal males, suggesting partial 3 beta-ol hydroxysteroid dehydrogenase deficiency to be a predisposing factor for the development of male-to-female transsexualism.

Infant with 3 beta hydroxysteroid dehydrogenase deficiency

The Journal is the primary organ of Continuing Paediatric Medical Education in Sri Lanka. The journal also has a website. Free full text access is available for all readers.The Sri Lanka Journal of Child Health is now indexed in SciVerse Scopus (Source Record ID 19900193609), Index Medicus for South-East Asia Region (IMSEAR), CABI (Centre for Agriculture and Bioscience International Global Health Database), DOAJ and is available in Google, as well as Google Scholar.The policies of the journal are modelled on the Committee on Publication Ethics (COPE) Guidelines on Principles of Transparency and Best Practice in Scholarly Publishing. Sri Lanka Journal of Child Health is recognised by the International Committee of Medical Journal Editors (ICMJE) as a publication following the ICMJE Recommendations.

Molecular aspects and treatment concepts of intersexuality

The increasing knowledge of the molecular pathogenesis of sexual differentiation have provided the basis for a more comprehensive diagnostic work-up and the therapeutic management of newborns with ambiguous external genitalia or external genitalia which contrasts the karyotype. The determination of the sex in mammals is governed by the development of the bipotential primordium into a testis or an ovary, which results in a female or male phenotype of the secondary sex characteristics through the production of hormones. The primary requirement for sexual differentiation are early growth and survival factors, e.g. WT1, that control the proliferation of the bipotential gonad The sry gene was identified as the primary genetic switch, which turns on the development of the gonadal primordium into a testis. Subsequently other downstream genetic factors (Dax1, Sox9) have been identified, which are essential for a normal testis development. Human mutations of these genetic factors, controlling the development of the bipotential gonad or the testis result in male pseudohermaphroditism. The most frequent causes of an impaired virilization of an embryo with a 46XY karyotype are molecular defects of androgen biosynthesis (e.g. 17β hydroxysteroiddehydrogenase deficiency) and action (androgen receptor defects). However in or than half of the newborns with an XY karyotype and ambiguous or female external genitalia the cause is still unknown. In patients with female pseudohermaphroditism the major differential diagnosis is congenital adrenal hyperplasia leading to a prenatal stimulation of fetal adrenal androgen production. Developmental defects of the female gonad into an ovary (e.g. in patients with Turner Syndrome) do not result in ambiguous external genitalia and therefore these diagnoses are not considered as intersexuality. The basic cellular and molecular research will help to understand the pathways that control testis and ovary development, but for the development of treatment concepts for affected newborns it is crucial to perform clinical studies which aim to define the impact of these genetic factors as well as of fetal and neonatal hormones on the development of a male or female gender identification. Regarding the increasing knowledge of genetic and molecular basis of intersexuality, it is no longer justified to assign a sex of rearing only according to the karyotype, the physical appearance and surgical possibilities.

The prevalence of late onset congenital adrenal hyperplasia in hirsute women from Central Anatolia.

Late onset congenital adrenal hyperplasia (LO CAH) can be seen in association with polycystic ovary syndrome (PCOS) or idiopathic hirsutism (IH). The study aimed to find out the prevalence of LO CAH in Central Anatolia among hirsute women. Sixty-three patients with hirsutism were evaluated to determine the frequency of LO CAH by comparing them with their age and body mass index matched 28 healthy controls. Of those 63 hirsute women, 43 were diagnosed as PCOS, and 20 were diagnosed as IH. Following basal hormonal evaluation, all subjects underwent ACTH stimulation test and ACTH stimulated 17-hydroxyprogesterone (17-OH P), 11-desoxycortisol (11-DOC), cortisol (F), and dehydroepiandrosterone sulfate (DHEA-S) levels were determined in all subjects. ACTH stimulated 17-OH P, 11-DOC, and DHEA-S levels did not differ between groups. However, stimulated F levels were found to be higher in hirsute women (p<0.001). Six out of 63 (9.52%) patients with hirsutism met the criterion for 21 hydroxylase deficiency. We found no subject presumed to have 11-beta hydroxylase deficiency, but one subject in control group (3.57%) and two patients among PCOS subjects (4.65%) had exaggerated DHEA-S response which was suggestive of mild 3-beta hydroxysteroid dehydrogenase deficiency. In conclusion, the most frequent form of LO CAH seems to be due to 21 OH deficiency among women with PCOS and IH in Central Anatolia. Mild 3-beta HSD deficiency may also be an underlying cause for hirsutism and it may be seen without any clinical presentation. Adrenal hyperactivity is likely to be the main reason of hyperandrogenemia in women with hirsutism.

Severe 46,XY virilization deficit due to 17beta-hydroxysteroid dehydrogenase deficiency

17beta hydroxysteroid dehydrogenase deficiency is a presumable rare cause for a severe virilization disorder in children with 46,XY karyotype due to a defect in the testicular testosterone biosynthesis from androstenedione. We report on a 14 year old child with 46,XY karyotype with a predominantly female phenotype. Hormonal analysis showed low values for androstenedione and testosterone before and after stimulation with human chorionic gonadotropin, however, the androstenedione/testosterone ratio was elevated. Molecular genetic analysis proved the diagnosis of 17beta-hydroxysteroid dehydrogenase deficiency due to a homozygous mutation (325+4 A-T) in the HSD17B3-gene, which leads to an aberrant splicing process. This case demonstrates that in addition to a meticulous steroid analysis a direct molecular genetic analysis can be helpful in the diagnosis of 17beta-hydroxysteroid dehydrogenase deficiency.

Newly Proposed Hormonal Criteria via Genotypic Proof for Type II 3 -Hydroxysteroid Dehydrogenase Deficiency

Newly Proposed Hormonal Criteria via Genotypic Proof for Type II 3 -Hydroxysteroid Dehydrogenase Deficiency

A Novel A10E Homozygous Mutation in the HSD3B2 Gene Causing Severe Salt-Wasting 3 -Hydroxysteroid Dehydrogenase Deficiency in 46,XX and 46,XY French-Canadians: Evaluation of Gonadal Function after Puberty

A Novel A10E Homozygous Mutation in the HSD3B2 Gene Causing Severe Salt-Wasting 3 -Hydroxysteroid Dehydrogenase Deficiency in 46,XX and 46,XY French-Canadians: Evaluation of Gonadal Function after Puberty

New Insight into the Molecular Basis of 3 -Hydroxysteroid Dehydrogenase Deficiency: Identification of Eight Mutations in the HSD3B2 Gene in Eleven Patients from Seven New Families and Comparison of the Functional Properties of Twenty-Five Mutant Enzymes

New Insight into the Molecular Basis of 3 -Hydroxysteroid Dehydrogenase Deficiency: Identification of Eight Mutations in the HSD3B2 Gene in Eleven Patients from Seven New Families and Comparison of the Functional Properties of Twenty-Five Mutant Enzymes

Urinary cortisol metabolites in the assessment of peripheral thyroid hormone action: overt and subclinical hypothyroidism.

Biological assessment of peripheral thyroid hormone action may be important in subclinical hypothyroidism, where decision-making is often difficult. The impairment of urinary cortisol metabolites in overt hypothyroidism reflects an acquired 11 beta hydroxysteroid dehydrogenase (11 beta OHSD) deficiency, and is assessed in terms of a reduction in the tetrahydrocortisone (THE)/tetrahydrocortisol (THF) ratio or THE/THE + alpha THF ratio; the alpha THF/THF ratio reflects 5 beta reductase activity. The aim of this study was to determine if urinary cortisol metabolite ratios are a good index of peripheral thyroid hormone action in subclinical hypothyroidism. the THE/THF, THE/THF + alpha THF and alpha THF/THF ratios were measured in 24 h urine samples from 3 groups of subjects: 1) 18 euthyroid subjects; 2) 25 patients with elevated serum TSH and low FT4 levels (overt hypothyroidism); and 3) 25 patients with increased serum TSH and normal FT4 levels (subclinical hypothyroidism. 7/25 overtly and 5/25 subclinically hypothyroid patients had a THE/THF + alpha THF ratio below the mean control value -2 SD, while respectively 20/25 and 11/25 patients had a THE/THF ratio below the mean control value -2 SD. The mean THE/THF + alpha THF, THE/THF and alpha THF/THF ratios were significantly different among the 3 groups (ANOVA) and were lower in the overtly hypothyroid group than in the other two groups (Fisher's test); daily urine sodium output was also significantly different between the three groups and lower in the overtly and subclinically hypothyroid groups than in the control group (Fisher's test). FT3 and FT4 both correlated with THE/THF + alpha THF in the overtly hypothyroid patients (r = 0.43; p < 0.05 and r = 0.40; p < 0.05, respectively). In the subclinically hypothyroid patients, TSH correlated with THE/THF + alpha THF (r = 0.44; p < 0.05) and THE/THF (r = 0.43; p < 0.05). FT3, FT4 and TSH levels correlated with THE/THF + alpha THF (p < 0.001), THE/THF (p < 0.001), alpha THF/THF (p < 0.001) and daily natriuresis (p < 0.05) in the whole population (patients + controls). In conclusion, urinary cortisol metabolites, although impaired in overt hypothyroidism, are not an accurate index of peripheral thyroid hormone deficiency in subclinical hypothyroidism. We also identified an increase in the alpha THF/THF ratio in overt hypothyroidism, which may be related to 5 beta reductase disturbances.

Transient virilization in early puberty

A case report of a patient in whom transient elevation of androgens during early puberty, presumably physiologic, resulted in significant clitoral enlargement is presented. ACTH stimulation showed elevated A5 pathway steroids. The findings are consistent with partial 3-β-ol hydroxysteroid dehydrogenase deficiency. However, the condition resolved spontaneously following puberty.

22 STEROID BIOSNTHESIS IN PATIENTS WITH MALE PSUDOHERMAFRODITISM. STUDIES PERFORMED IN LEYDIGG CELL MESENCHYMAL PRECURSORS IN CULTURE

Among the cause of male pseudohermafroditism(MPH), disorders of testicular function, which include enzymatic defects in the testosterone (T)biosynthesis, have been demonstrated. In a 8 1/2 years old patient with MPH (MG, 46 XY), with ambiguous genitalia and raised as a female, plasmatic levels of the following steroids were determined: Pregnenolone (P5), Progesterone (P4), Androstenedione (Δ 4), 17αhydroxyprogesterone (17αOHP4) and T. Values were found in the normal prepubertal range. Lack of response to acute hCG stimulation for these steroids was observed. After gonadectomy, Leydig cell mesenchymal precursors were isolated as previously described (Biol.Reprod.46:793, 1992). Cells were cultured for 6 days and T,P5,P4 17OHP4, Δ4 and dehydroepiandrosterone (DHA) levels were determined by RIA in the culture medium. Results were compared with those found in two other patients (PM, VT) bearing the androgen insensitivity syndrome. Levels of T (pg/h/ugDNA) were as follows, MG:0.35±0.06, PM:101±10 and VT: 141±15. Similar results in FSH or hCG stimulated cultures were obtained. The overall steroid production in the three patients was: MG: 108, PM; 184 and VT: 319 (pg/h/ugDNA). A marked modification of T/Δ 4 relationship was observed in MG (MG: 0.03, PM: 64 and VT: 3.97). These results suggest that MG male pseudohermafroditism is due to 17β hydroxysteroid dehydrogenase deficiency. This deficiency could not be demonstrated at the peripheral level but it was evident in Leydig cell mesenchymal precursors in culture.

Hypothalamic-pituitary-gonadal axis function in pubertal male and female siblings with glucocorticoid-treated nonsalt-wasting 3 beta- hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia

Hypothalamic-pituitary-gonadal axis function in pubertal male and female siblings with glucocorticoid-treated nonsalt-wasting 3 beta- hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia