Female Congenital Adrenal Hyperplasia Research Articles

Landscape of congenital adrenal hyperplasia cases in adult endocrinology clinics of Türkiye-a nation-wide multicentre study.

Congenital adrenal hyperplasia (CAH) is a group of disorders that affect the production of steroids in the adrenal gland and are inherited in an autosomal recessive pattern. The clinical and biochemical manifestations of the disorder are diverse, ranging from varying degrees of anomalies of the external genitalia to life-threatening adrenal insufficiency. This multicenter study aimed to determine the demographics, biochemical, clinical, and genetic characteristics besides the current status of adult patients with CAH nationwide. The medical records of 223 patients with all forms of CAH were evaluated in the study, which included 19 adult endocrinology clinics. A form inquiring about demographical, etiological, and genetic (where available) data of all forms of CAH patients was filled out and returned by the centers. Among 223 cases 181 (81.16%) patients had 21-hydroxylase deficiency (21OHD), 27 (12.10%) had 11-beta-hydroxylase deficiency (110HD), 13 (5.82%) had 17-hydroxylase deficiency (17OHD) and 2 (0.89%) had 3-beta-hydroxysteroid-dehydrogenase deficiency. 21OHD was the most prevalent CAH form in our national series. There were 102 (56.4%) classical and 79 (43.6%) non-classical 210HD cases in our cohort. The age of the patients was 24.9 ± 6.1 (minimum-maximum: 17-44) for classical CAH patients and 30.2 ± 11.2 (minimum-maximum: 17-67). More patients in the nonclassical CAH group were married and had children. Reconstructive genital surgery was performed in 54 (78.3%) of classical CAH females and 42 (77.8%) of them had no children. Thirty-two (50.8%) NCAH cases had homogenous and 31 (49.2%) had heterogeneous CYP21A2 gene mutations. V281L pathological variation was the most prevalent mutation, it was detected in 35 (55.6%) of 21OHD NCAH patients. Our findings are compatible with the current literature except for the higher frequency of 110HD and 17OHD, which may be attributed to unidentified genetic causes. A new classification for CAH cases rather than classical and non-classical may be helpful as the disease exhibits a large clinical and biochemical continuum. Affected cases should be informed of the possible complications they may face. The study concludes that a better understanding of the clinical characteristics of patients with CAH can improve the management of the disorder in daily practice.

Ovarian reserve and fertility parameters in post-pubertal females with congenital adrenal hyperplasia: a case-control study.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder characterized by impaired activity of the enzyme required for cortisol and aldosterone production, resulting in increased adrenal androgen synthesis. Factors affecting fertility in CAH patients include ambiguous genitalia and their complications, excessive androgen secretion, adrenal progesterone hypersecretion, and various psychosocial factors. Serum anti-Müllerian hormone (AMH) level is used to assess ovarian reserve in women. A few data on serum AMH levels in CAH patients are available in the literature. The aim of the study was to evaluate ovarian reserve in a group of post-menarche females diagnosed with CAH by measuring serum AMH level and assessing the number of antral follicles sonographically. A case-control study was conducted on 17 post-pubertal CAH females and 17 age-matched healthy female controls; the mean age of the patient group was 15.09±3.55 years ranging from 11 to 24 years, while the mean age of the control group was 16.04±3.72 years ranging from 12 to 25 years, the mean post-menarchal age of the patients group was 3.29±1.37 years ranging from 1 to 6 years while the mean post-menarchal age of the control group was 4.13±1.62 years ranging from 1 to 9 years. The degree of hirsutism was compared between the two groups according to the modified Ferriman-Gallwey score, clitoral length was assessed using a digital caliber. Serum levels of adrenal androgens in addition to basal levels of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, and serum AMH were measured in both groups. Patients had smaller uterine volumes, and smaller ovarian volumes but a comparable number of antral follicles and comparable serum AMH levels relative to controls. Good compliance with treatment in patients with CAH results in good hormonal control, low risk of PCOS, good fertility parameters, and a good ovarian reserve.

The clinical characteristics and quality of life of 248 pediatric and adult patients with Congenital Adrenal Hyperplasia.

Congenital Adrenal Hyperplasia (CAH) is a chronic disease that requires lifelong treatment. Patients may face stigmatization, which may affect their quality of life (QoL). Therefore, we assessed the clinical characteristics and QoL of patients with CAH in the Middle East. This case-control study included patients with CAH aged >5 years from two tertiary centers (2020-2021). The patients were matched to a healthy control group and were then divided into pediatric and adult groups. Data were collected from their electronic medical records. Additionally, the EQ-5D-5L QoL questionnaire was completed by both the patients and control group to assess five domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The study included 248 patients with CAH (females: 58.8%), with a family history of the condition (57.3%) and/or parental consanguinity (68.1%). The most frequently reported gene defect was CYP21A2, while the most commonly reported symptoms/signs were ambiguous genitalia and obesity. Almost all female patients had received corrective surgery. The questionnaire response rate was 86.3% (n=214/248). The CAH patient group's mean total QoL score was 85.2 compared with 99.8 in the control. Further, CAH patients had lower QoL scores in all domains compared to those in the control group (p ≤ 0.0001-0.0023). The pain/discomfort and anxiety/depression domains were affected significantly more than the other domains were, with 47.7% and 44.4% participants, respectively, p<0.0001. Additionally, obesity was found to be a predictor of reduced mobility following a logistic regression analysis (p ≤ 0.04, OR (0.18-0.98)). Patients with CAH reported lower QoL overall, particularly in the pain/discomfort and anxiety/depression domains. Based on this, we recommend the early involvement of psychologists in a multidisciplinary team approach, pre-marital screening, and the implementation of awareness programs for people diagnosed with CAH in communities with high consanguineous mating.

Unexpectedly high mutation rate of cyp11b1 compared to cyp21a2 in randomly-selected turkish women: a large screening study.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders resulting from enzyme deficiencies associated with steroidogenesis. The clinical presentation of non-classic CAH (NCAH) in females is often indistinguishable from other hyperandrogenic disorders like polycystic ovary syndrome (PCOS). The data on the prevalence of NCAH in unselected women in the literature is scanty. The research aimed to evaluate the prevalence of NCAH, carrier frequencies, and the correlation between clinical symptoms and genotype in Turkish women. The study group comprised two hundred and seventy randomly-selected unrelated asymptomatic women of reproductive age (18-45). Subjects were recruited from female blood donors. All volunteers underwent clinical examination and hormone measurements. The protein-encoding exons and exon-intron boundaries of the CYP21A2, CYP11B1, HSD3β2 and CYP21A2 promoter were sequenced by direct DNA sequencing. After genotyping, seven (2.2%) individuals were diagnosed with NCAH. The heterozygous carrier frequencies of CYP21A2, CYP21A2 promoter, CYP11B1, and HSD3β2 genes with 34, 34, 41, and 1 pathologic mutation were determined at 12.6%, 12.6%, 15.2%, and 0.37% of volunteers, respectively. Gene-conversion (GC) frequencies between CYP21A2/CYP21A1P and CYP11B1/CYP11B2 were determined as 10.4% and 14.8%, respectively. Despite GC-derived higher mutation frequency determined in the CYP11B1 gene, the reason for the low frequency of NCAH due to 11OHD compared to 21OHD might be that gene-conversion arises with active CYP11B2 rather than an inactive pseudogene. HSD3β1 exhibits high homology with HSD3β2 located on the same chromosome; remarkably, it demonstrates low heterozygosity and no GC, most probably the outcome of a tissue-specific expression pattern.

Congenital adrenal hyperplasia in adolescence - a gynecological perspective.

Analysis of congenital adrenal hyperplasia (CAH) cases, gynaecological implications, referral reasons to gynaecologist and treatment. Retrospective, longitudinal, single-centre study with female CAH paediatric patients ≥ 10 years-old, followed between 1998-2018 in gynaecology and endocrinology departments at a public university tertiary hospital. 47 patients, 34.0% (n = 16) with classic, 66.0% (n = 31) with non-classic forms (NCAH), CYP21 deficit and 46,XX karyotype. We found a normal median menarche age (11.5 IQR 2 [6-15] years-old), but significantly earlier in NCAH (p = 0.003). Precocious puberty occurred in 48.9%, n = 23. Primary amenorrhea occurred in salt-wasting form (21.4%, n = 3). Oligomenorrhea and hirsutism were significantly more prevalent in NCAH (p = 0.018, p = 0.014 respectively) and acanthosis nigricans and virilization signs in classic forms (p = 0.05, p = 0.000 respectively). Sixteen patients (34.0%) were referred to gynaecology, mostly due to menstrual irregularities (50.0%, n = 8). Medical treatment with isolated or combined corticoids, oestrogen and progestogen were chosen in all but one case. Gonadotropin-releasing hormone analogues were used in 19.0% (n = 9). Surgery was performed in 34.0% (n = 16) patients, median age 2.0 IQR 2.5 (0.6-90) years-old. This paper highlights the importance of a multidisciplinary approach. Early treatment contributes to a phenotypical feminine differentiation and normalization of the hypothalamus-pituitary-ovarian axis, which is essential given the gynaecologic and obstetric consequences of untreated cases.

Growing up with clitoromegaly: experiences of North American women with congenital adrenal hyperplasia

To describe experiences of clitoromegaly in women with congenital adrenal hyperplasia (CAH). CAH females (46XX, ≥16 years old) from the United States and Canada were eligible for a cross-sectional online survey (2019-2020) if reporting clitoromegaly (life-long: "growing up with a larger than average clitoris," secondary: "clitoris grew over weeks or months"). A multidisciplinary team and women with CAH drafted questions assessing net effects of clitoromegaly on 10 activities and 10 life domains. Fisher's exact test was used to compare net effect (positive-negative) vs. no effect (Bonferroni p=0.05/10=0.005). Of 97 women with CAH enrolled, 53 women (55%, median age: 36 years, advocacy group recruitment: 81%) reported recognizing clitoromegaly at median 11-13 years old, with 21% identifying it in adulthood. There was no difference in self-reported timing or clitoral shape between life-long or secondary clitoromegaly (p≥0.06). There were no net positive effects of clitoromegaly. Rather, clitoromegaly had net negative effects on 7/10 activities (p≤0.003) and no net effect (neutral) on 3 (Table). Women were less likely to wear tight clothing, change clothes in public locker rooms and play group sports. Women reported net negative effects for most romantic activities (dating, any sexual activity, pain-free sexual activity, having a partner see their genitalia, p=<0.003), but did not report a net effect on pleasurable sexual activity (p=0.12). Clitoromegaly had net negative effects in 9/10 life domains (p<0.001) and neutral on job self-perception (p=0.25). Few women reported any positive impact (2-6%). However, 49-59% of women experienced poor self-esteem, anxiety, gender self-perception and body image, while 36% felt "down or depressed." Also, 21-23% experienced negative self-perception as friends and parents, 42-47% reported negative effects on plans for romantic and sexual relationships. Responses did not differ with advocacy group membership (p≥0.02). Our findings support qualitative and case series evidence that clitoromegaly has a negative psychological outcome on women with CAH. Clitoromegaly may add to the burden of living with a chronic endocrine disease. Women with positive and negative experiences had the same opportunity to participate. Since we could not assess objective clitoral size, baseline virilization and exact nature of any childhood clitoral procedures, these data cannot be used to estimate the impact of specific clitoral size or effectiveness of early clitoral treatments. Clitoromegaly appears to be common among women with CAH. While experiences of clitoromegaly vary between women, the overall experience is negative in multiple social, romantic, and emotional activities and domains.

Commentary to ‘Digital photography in the evaluation and management of female patients with congenital adrenal hyperplasia: A standardized protocol for quality improvement’

Smaller subspecialties, such as Pediatric Urology, can be late to develop best practices due to limited clinical trials and patient numbers. At the heart of clinical research, however, we still need patient outcomes. Earnest Codman pioneered this concept in surgery [1]. While true clinical outcome measures were not assessed in this study (such as medical anxiety from repeated exams or patient/parent comprehension of surgical goals), Cheng and colleagues [2] present pioneering research showing that digital photography improves the perioperative care of female congenital adrenal hyperplasia (CAH) patients by reducing opportunity costs related to travel and the number of clinical exams, as well as providers performing them.

PD02-11 WHEN AND HOW TO DISCLOSE GENITAL SURGERY TO GIRLS WITH CAH? EXPERIENCES AND PREFERENCES OF WOMEN WITH CAH

You have accessJournal of UrologyCME1 May 2022PD02-11 WHEN AND HOW TO DISCLOSE GENITAL SURGERY TO GIRLS WITH CAH? EXPERIENCES AND PREFERENCES OF WOMEN WITH CAH Ashley W. Johnston, Mimi S. Kim, Paul Kokorowski, Devon J. Hensel, Patrice M. Yasuda, and Konrad M. Szymanski Ashley W. JohnstonAshley W. Johnston More articles by this author , Mimi S. KimMimi S. Kim More articles by this author , Paul KokorowskiPaul Kokorowski More articles by this author , Devon J. HenselDevon J. Hensel More articles by this author , Patrice M. YasudaPatrice M. Yasuda More articles by this author , and Konrad M. SzymanskiKonrad M. Szymanski More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002517.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To describe experiences and preferences of disclosing childhood genital surgery to females with congenital adrenal hyperplasia (CAH). METHODS: We conducted an anonymous cross-sectional online survey of CAH females (46XX, ≥16 years [y] old), living in Canada and the United States, who underwent genital surgery before age 4y. Data included experiences and preferences of initial (“first time you were told”) and complete disclosure (“told all details of the surgery”). Non-parametric statistics were used. RESULTS: Median age of 59 participants was 37y. The 76% of women who received complete disclosure were younger (median age: 33y) and underwent surgery more recently (median decade of surgery: 1980s) than the 14% who received only initial disclosure (median: 47y, 1970s) and 10% without any disclosure (median: 61y, 1960s, p=0.0003). Median age of initial and complete disclosure was 7-10y and 11-13y years, respectively (Table). Disclosure was preferred by 58 (98%) women, with initial disclosure by age 14y and complete disclosure by 18y. Most disclosures were by women’s mothers (initial: 82%, complete: 64%). Doctors were more involved in the complete (47%) vs. initial disclosures (13%, p<0.001), coinciding with women’s preferences to include their mothers (72%) and doctors (43%) in the disclosure process. Complete disclosure had predominately neutral/mixed and positive effects, rather than negative, on relationships with parents (neutral/mixed: 68%, positive: 18%, negative: 7%, unknown: 7%) and doctors (neutral/mixed: 64%, positive: 21%, negative: 14%, unknown: 2%). CONCLUSIONS: Disclosure of childhood genital surgery to women with CAH has increased over time. Although timing of disclosures varied, women preferred disclosure, initiating it before age 14y and complete disclosure before age 18y. Disclosure may benefit relationships with parents and physicians. Source of Funding: Departmental research funding © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e39 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ashley W. Johnston More articles by this author Mimi S. Kim More articles by this author Paul Kokorowski More articles by this author Devon J. Hensel More articles by this author Patrice M. Yasuda More articles by this author Konrad M. Szymanski More articles by this author Expand All Advertisement PDF DownloadLoading ...

Cardiometabolic Health in Adolescents and Young Adults with Congenital Adrenal Hyperplasia.

Background and objectives: Data on long-term cardiometabolic consequences in patients with congenital adrenal hyperplasia (CAH) are controversial. The aim of our study was to evaluate body mass index (BMI), body composition, blood pressure (BP) and insulin sensitivity in adolescents and young adults with CAH in comparison with healthy controls. Methods: Thirty-two patients with classical CAH (13 males; mean of age 26.0 ± 7.1, years (14.0–37.3) were compared to 32 healthy sex and age-matched controls (13 males; mean of age 28.7 ± 4.6 years (14.1–37.2), p = 0.13). Body composition was evaluated in all subjects with DXA (Hologic Inc., Bedford, MA, USA). Elevated BP was defined as BP > 95th percentile in adolescents, and >140/90 mmHg in adults. Comparisons between the two groups were adjusted for age, gender, pubertal stage and height. An oral glucose tolerance test was performed, and fasting insulin levels were evaluated. Insulin sensitivity was determined using a homeostasis model assessment of insulin resistance index (HOMA-IR). Results: The median BMI was significantly higher in subjects with CAH (1.63 (0.3–2.4) SDS and 0.41 (−0.63–1.19) SDS, respectively, p < 0.001). Visceral adipose tissue (VAT) in grams was significantly higher in CAH females versus control females (467 (231–561) vs. 226 (164–295), p = 0.002). Elevated BP was identified in 34% of CAH patients (nine SW and two SV) and 12.5% (n = 4) of controls (p = 0.038). Impaired fasting glycemia was detected in one SW CAH patient and impaired glucose tolerance in three SV CAH patients; normal glucose tolerance was found in all controls. A strong positive correlation was found between median cumulative hydrocortisone (HC) dose equivalents and LDL-cholesterol and a negative association with lean body mass (r = −0.79, p = 0.036) in females with CAH. BMI, VAT, BP and HOMA-IR were not related to median cumulative HC dose equivalents. Conclusions: CAH patients had higher BMI, VAT and frequency of elevated BP compared to controls. Doses of glucocorticoids were related directly to LDL-cholesterol and inversely to lean body mass in CAH females, but not associated with body composition, insulin sensitivity and BP in the whole cohort of CAH patients.

Effect of Vitamin D Supplementation on Insulin Resistance Status in Pubertal Girls with Congenital Adrenal Hyperplasia

Introduction: Congenital adrenal hyperplasia (CAH) patients especially females are at increased risk for developing obesity and resistance to insulin (IR). Rising evidence indicate that insufficient vitamin D levels are associated with impaired function of β-cells of islets of Langerhans and IR, however, this finding hasn’t been investigated in patients with CAH. The aim was to identify the vitamin D levels and insulin resistance status in pubertal females with CAH, following up at Diabetes Endocrine and Metabolism Pediatric Unit, Abou ElRish Children’s Hospital, Cairo University. We also examined the association between vitamin D level &amp; insulin resistance and the impact of cholecalciferol administration on metabolic abnormalities.&#x0D; Subjects and Methods: Sixteen pubertal CAH females with deficient or insufficient Vitamin D levels were recruited. Follow up was done after a period of 6 months during which oral Vitamin D replacement therapy was prescribed.&#x0D; Results: The serum levels of 25-hydroxyvitamin D (25(OH)D3) were significantly raised following replacement therapy. Significant correlation was detected between HOMA-IR and serum levels of insulin, other IR indices both prior to and following vitamin D supplementation. However, HOMA-IR didn’t correlate with any of the following: 25(OH)D3 levels, 17 hydroxyprogesterone (17-OHP), or steroid dose either prior to or following replacement therapy.&#x0D; Conclusion: Vitamin D replacement therapy didn’t have favorable effects on IR in females with CAH. Future research using randomized controlled trials is required to examine the impact of Vitamin D on IR. This might influence the production of adrenal androgen, resulting in reduction of the therapeutic effect of glucocorticoids and evolution of metabolic derangements.

Polycystic Ovary Syndrome Among Female Adolescents With Congenital Adrenal Hyperplasia.

Objectives: Polycystic ovary syndrome is a common endocrine disease in adolescent females that is usually diagnosed based on clinical and hormonal abnormalities. Female adolescents with poorly controlled congenital adrenal hyperplasia are at increased risk of developing polycystic ovary syndrome. This study aimed to determine the prevalence of polycystic ovary syndrome and assess its relationship with hormonal control among adolescents with congenital adrenal hyperplasia.Methods: This retrospective descriptive study included 40 pubertal female adolescents aged between 12 and 20 years with at least two years after menarche diagnosed with classical congenital adrenal hyperplasia since birth who were screened routinely for polycystic ovary syndrome via pelvic ultrasonography between 2012 and 2020 at King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia. Serum adrenocorticotropic hormone, 17-hydroxy -progesterone, testosterone, dehydroepiandrosterone sulfate, luteinizing hormone, and follicle-stimulating hormone levels were measured.Results: Polycystic ovary syndrome was detected via routine pelvic ultrasonography in 12/40 (30%) females. The median age of the affected females was 16.6 years, with the youngest female aged 12.5 years. The bone age of the patients had advanced ≤3 years. Further, serum adrenocorticotropic hormone was determined to be an independent factor affecting polycystic ovary syndrome development, indicating poor hormonal control (P = 0.005).Conclusion: Polycystic ovary disease is likely a complication of poorly controlled congenital adrenal hyperplasia disease. Therefore, increasing the awareness of polycystic ovary disease among congenital adrenal hyperplasia females via routine ultrasonography screening is advisable to facilitate the early diagnosis and improve disease management.

The Spectrum of CYP21A2 Gene Mutations from 16 Families of Congenital Adrenal Hyperplasia: Genotype-Phenotype Correlation.

Aim:Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of the adrenal steroidogenic pathway. The most common form of CAH is due to 21-hydroxylase deficiency resulting from mutations in CYP21A2 gene. The present study aimed to identify CYP21A2 common gene mutations, phenotype correlation, and to analyze the segregation pattern in CAH patients, parents, and siblings.Materials and Methods:Sixteen families having at least one classic CAH child in each family, a total of 58 subjects were recruited. The presence of six most common gene mutations, namely, Intron 2 (c.293-13A/C>G), c.844G>T (p.Val282Leu), c.1019G>A (p.Arg340His), c.92C>T (p.Pro31Leu), c.955C>T (p.Gln319*), and c.518T>A (p.Ile173Asn) in CYP21A2 gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using specific primers.Results:Out of 16 classic CAH females analyzed, salt-wasting (SW) form was present in 12 (75%) and simple virilizing form in four (25%) children. Isolated clitoromegaly was the most common clinical presentation followed by ambiguous genitalia. The most common mutation observed in CAH patient population was Intron 2 (c.293-13A/C>G) (100%) followed by p.Pro31Leu (98%), p.Gln319* (93%), p.Val282Leu (91.4%), and p.Ile173Asn (19%). Although p.Arg340His mutation was not observed in this study. Interestingly, Intron 2 (c.293-13A/C>G) homozygous was observed in 31.3% of the entire study cohort and p.Ile173Asn mutation was found to be associated with SW form.Conclusions:Our results suggested a high prevalence of CYP21A2 gene mutations among CAH patients and heterogeneous mutation spectrum in their families of south Indian cohort. The outcomes afford valuable evidence for premarital and prenatal screening as well as planning suitable programs to prevent the development of CAH in Indian population.

Altered Gray Matter Structure and White Matter Microstructure in Patients with Congenital Adrenal Hyperplasia: Relevance for Working Memory Performance.

Congenital adrenal hyperplasia (CAH) has been associated with brain structure alterations, but systematic studies are lacking. We explore brain morphology in 37 (21 female) CAH patients and 43 (26 female) healthy controls, aged 16-33years, using structural magnetic resonance imaging to estimate cortical thickness, surface area, volume, subcortical volumes, and white matter (WM) microstructure. We also report data on a small cohort of patients (n = 8) with CAH, who received prenatal dexamethasone (DEX). Patients with CAH had reduced whole brain volume (4.23%) and altered structure of the prefrontal, parietal, and superior occipital cortex. Patients had reduced mean FA, and reduced RD and MD, but not after correcting for brain volume. The observed regions are hubs of the visuospatial working memory and default mode (DMN) networks. Thickness of the left superior parietal and middle frontal gyri was associated with visuospatial working memory performance, and patients with CAH performed worse on this task. Prenatal treatment with DEX affected brain structures in the parietal and occipital cortex, but studies in larger cohorts are needed. In conclusion, our study suggests that CAH is associated with brain structure alterations, especially in the working memory network, which might underlie the cognitive outcome observed in patients.

Phenotypic Variation of 46,XX Late Identified Congenital Adrenal Hyperplasia among Indonesians.

ObjectivesTo describe the phenotype variation in Indonesian 46,XX late-identified congenital adrenal hyperplasia (CAH) and the correlation between 17-hydroxyprogesterone (17-OHP) and genital virilization.MethodologyRetrospective study of 39 cases with five salt-wasting (SW) and 34 simple virilizing (SV) types.ResultsThe median age of the patients was 9.83 years (range, 0.58 to 44 years) with Prader score 2 to 5. Clitoromegaly (100%) and skin hyperpigmentation (87%) were the most common features. Lack of breast development (Tanner 1 to 2) and menstrual disorders occurred in 9 patients (teenagers and adults). Short stature (6), low voice (14), prominent Adam’s apple (9) and hirsutism (4) were found only in SV types. Rapid growth (7) and precocious puberty (8) were identified in children. Male gender on admission was found in 13 patients. The mean of 17-OHP level was 304.23 nmol/L [standard deviation (SD) 125.03 nmol/L]. There was no correlation between 17-OHP levels and virilization (r=0.19, p>0.05).ConclusionLate-identified CAH showed severe virilization and irreversible sequelae, with clitoromegaly and skin hyperpigmentation as the most commonly seen features. Masculinization of CAH females created uncertainty with regard to sex assignment at birth, resulting in female, male and undecided genders. There is no significant correlation between 17-OHP levels with the degree of virilization in CAH females.

Linking the degree of virilization in females with congenital adrenal hyperplasia to genotype.

Mutations of CYP21A2 variably decrease 21-hydroxylase activity and result in a spectrum of disease expressions in patients with congenital adrenal hyperplasia (CAH). We examined the association between CYP21A2 mutations and virilization (Prader score) in females with CAH. The study population included 187 CAH females with fully characterized CYP21A2 mutations. One hundred fifty-eight patients were sorted into groups by expected enzyme activity (percent of normal activity) of the less severely affected allele: (A) null, 0%; (B) I2G, 1%; (C) I172N, 2%; and (D) V281L, >2%. We observed an inverse relationship between virilization and residual enzyme activity (P < 0.001). Subjects in group A or B had a significantly higher likelihood (unadjusted odds ratio: 16; P < 0.001) of developing severe virilization compared with those in group C. Surprisingly, 24% of group D patients, whose mutation is usually associated with nonclassical (NC) CAH, had severe virilization. Among subjects with the NC P30L mutation, 66% expressed unexpected virilization. Virilization, usually leading to extensive reconstructive surgery, is highly likely in patients with null or I2G mutations; however, NC mutations (P30L/V281L) may also lead to unexpected virilization. These findings have implications for prenatal counseling and highlight the need for additional investigations into other factors that influence virilization in CAH.

Sexual orientation and medical history among Iranian people with Complete Androgen Insensitivity Syndrome and Congenital Adrenal Hyperplasia

ObjectiveTo report sexual orientation, relationship status and medical history of Iranian people with Differences of Sex Development (DSD) who were raised female. MethodsOur participants consisted of nineteen 46,XY individuals with Complete Androgen Insensitivity Syndrome (CAIS) and eighteen 46,XX individuals with Congenital Adrenal Hyperplasia (CAH) who were raised as females and older than 13years. As well as their relationship status and detailed medical history, an expert psychiatrist assessed their sexual orientation by a semi-structured psychiatric interview with them and, where applicable, their parents. ResultsFive percent of CAH participants and 42% of CAIS participants were in a relationship, which was significantly different. All CAH individuals had been diagnosed at birth; 89% of CAIS had been diagnosed after puberty and due to primary amenorrhea and 11% were diagnosed in childhood due to inguinal hernia. Genital reconstructive surgery had been performed in 100% of CAH participants and 37% of CAIS. Regarding sexual contact experiences and sexual fantasies (androphilic, gynephilic or both), no significant differences were found. However, CAH females had significantly more gynephilic dreams (P=0.045). ConclusionThis study, notable as one of the rare from a non-western culture, described sexual, medical and socioeconomic status of 46,XX CAH and 46,XY CAIS individuals living in Iran. Although broadly in line with previous findings from Western cultures, Iranian CAH individuals had fewer romantic relationships, but in contrast to previous studies their sexual orientation was only different from CAIS in the contents of sexual dreams.

Urinary continence outcomes following vaginoplasty in patients with congenital adrenal hyperplasia

Feminizing genitoplasty techniques have diversified to encompass the spectrum of atypical genitalia in 46,XX congenital adrenal hyperplasia (CAH) patients. However, long-term outcomes evaluating postoperative continence following complex vaginoplasty remain scarce. The aim was to review our surgical experience and assess postoperative urinary continence outcomes in CAH patients following complex, primary vaginoplasty. We retrospectively reviewed CAH patients who underwent complex, primary vaginoplasty at a single center by a single surgeon from 1996 to 2013. We collected data on clinical characteristics, surgical techniques and postoperative urinary continence outcomes. In patients who had reached toilet-training age, continence outcomes were reviewed. Twenty-four patients met the inclusion criteria. The median age at the time of surgery was 8 months (interquartile range [IQR] 1 year-6 months). The median length of follow up was 6 years (IQR 10 years-3 years). These patients required complex reconstruction because of more extensive virilization: total urogenital mobilization (TUM, 10), pull-through vaginoplasty (9), partial urogenital mobilization (3), or pull-through vaginoplasty with partial urogenital mobilization (2). After surgery, 15 out of 24 (62.5%) reported age appropriate toilet-training without further complaints. Seven (29.2%) patients reported daytime incontinence or enuresis that resolved with conservative management. Two patients reported day and night incontinence requiring urethral bulking procedures following TUM. Twenty-two (91.7%) of our patients achieved continence without further surgical intervention. Of these patients, the TUM patients had serious incontinence issues. Our study represents a review of clinically significant cases from the female CAH population. The limitations of our study include a relatively small sample size and retrospective design. Females with CAH and urogenital virilization most often achieved age appropriate toilet-training following vaginoplasty. Daytime incontinence and enuresis resolved without operative management in the vast majority of cases. TUM carries a risk of severe incontinence and may require further procedures to achieve urinary continence.

Should CAH in Females Be Classified as DSD?

Great controversies and misunderstandings have developed around the relatively recently coined term disorders of sex development (DSD). In this article, we question the wisdom of including XX individuals with congenital adrenal hyperplasia (CAH) in the DSD category and develop arguments against it based on the published literature on the subject. It is clear that females with CAH assigned the female gender before 24 months of age and properly managed retain the female gender identity regardless of the Prader grade. Females with CAH and low Prader grades have the potential for a normal sexual and reproductive life. Those with greater degrees of prenatal androgen exposure (Prader grades IV and V) raised as females also identify themselves as females but experience more male-like behavior in childhood, have a greater rate of homosexuality, and have greater difficulty with vaginal penetration and maintaining pregnancies. Improvement in surgical techniques, better endocrinological, psychological, and surgical follow-up may lessen these problems in the future. Given the fact that the term DSD includes many conditions with problematic gender identity and conflicts with the gender assigned at birth, it may be appropriate to exclude females with CAH from the DSD classification.

Carotid Intima-Media Thickness Is Associated with Increased Androgens in Adolescents and Young Adults with Classical Congenital Adrenal Hyperplasia

Background/Aims: Youth with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency develop cardiovascular disease (CVD) risk factors of obesity and hypertension. Carotid intima-media thickness (CIMT), a marker of CVD risk, is increased in CAH young adults. We examined CIMT and its relationship with androgens and obesity in adolescents/young adults with CAH. Methods: Twenty CAH subjects (age 16 ± 3.3 years, 50% female) and 20 matched controls were studied cross-sectionally. Eight additional obese patients with CAH were included in within-group comparisons. CIMT by high-resolution ultrasound, androgens, anthropometry, bone age (BA), and metabolic/inflammatory markers were assessed. Results: Within the CAH group, CIMT correlated with 17-hydroxyprogesterone (r = 0.48, p < 0.05) and androstenedione (r = 0.46, p < 0.05), and was greater in obese subjects. CIMT was greater in CAH males than females, but similar among CAH females with advanced BA, CAH males with normal BA, and control males. There was no difference in CIMT between CAH and controls, although high-density lipoprotein was inversely correlated with CIMT in both groups. Conclusion: CIMT is associated with increased androgens in CAH adolescents and young adults, with loss of sex differences in CAH females with excess androgen exposure. Our findings highlight the importance of hormonal control for CVD prevention in CAH.

Timing and Outcome Concerns regarding Feminizing Genitoplasty from the Perspective of Egyptian Families of Girls with Virilized External Genitalia

Background: Congenital adrenal hyperplasia in females leads to virilization of external genitalia and persistent urogenital sinus. There are controversies regarding the timing and outcomes of surgery. Deferring surgeries beyond childhood is difficult to implement in conservative societies, and may result in stigmatization and distress to individuals with disorders of sexual differentiation and their families. Methods: Thirty girls with virilization due to congenital adrenal hyperplasia were admitted for single-stage feminizing genitoplasty, between 2011 and 2014. We prospectively studied the concerns and input of the families represented by the mothers. After comprehensive counselling, the mothers completed a questionnaire to clarify their priorities and concerns related to surgery. Results: Surgeries were performed at a mean age of 22 months. Most cases ranged between Prader's degrees III and IV. Egyptian families believe that early surgical reconstruction is in the best interest of their girls. They are marginally more concerned about functional outcomes and future child bearing than external appearance and cosmetic outcomes. Conclusions: Social difficulties noticeably add challenges to the management plan within conservative societies. Early genital reconstructive surgery, when reasonably indicated, needs to remain a viable option. Comprehensive psychosocial support within a multidisciplinary approach is needed to defer feminizing genitoplasty in selected cases to adolescence.