Non-classic congenital adrenal hyperplasia (NCAH) is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline 17-hydroxyprogesterone measurement may be used for screening, but 17-hydroxyprogesterone measurement after ACTH stimulation is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOS-like picture and fertility issues. Many men with NCAH never seek medical attention and escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time, including fertility issues. Long-term treatment with glucocorticoids will improve the androgen symptoms but may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. The glucocorticoid doses should be kept low. However, complications seen in NCAH, assumed to be caused by the glucocorticoid treatment, may also be associated with long-term androgen exposure. Oral contraceptive pills are a common treatment option for young females with NCAH. Regular clinical monitoring to improve the clinical outcome is recommended. It is important to acknowledge that glucocorticoid treatment will lead to secondary cortisol insufficiency and the need for stress dosing. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted.
Anna Nordenström and Henrik Falhammar
Henrik Falhammar, Helena Filipsson Nyström, Anna Wedell, and Marja Thorén
Lifelong glucocorticoid therapy in patients with congenital adrenal hyperplasia (CAH) or the disease per se may result in increased cardiovascular risk. We therefore investigated cardiovascular and metabolic risk profiles in adult CAH males.
Subjects and methods
We compared CAH males (n=30), 19–67 years old, with age- and sex-matched controls (n=32). Subgroups of different ages (<30 years or older) and CYP21A2 genotypes (null, I2splice, and I172N as the mildest mutation) were studied. Anthropometry, fat and lean mass measured by dual-energy X-ray absorptiometry, lipids, liver function tests, homocysteine, lipoprotein-(a), glucose and insulin during an oral glucose tolerance test (OGTT), urine albumin, adrenal hormones, and 24 h ambulatory blood pressure measurements were studied.
CAH males were shorter. Waist/hip ratio and fat mass were higher in older patients and the I172N group. Heart rate was faster in older patients, the I2splice, and I172N groups. Insulin levels were increased during OGTT in all patients and in the I172N group. γ-glutamyl transpeptidase was increased in older patients and in the I172N group. Testosterone was lower in older patients. Homocysteine was lower in younger patients, which may be cardioprotective. The cardiovascular risk seemed higher with hydrocortisone/cortisone acetate than prednisolone. Urinary epinephrine was lower in all groups of patients except in I172N.
Indications of increased risk were found in CAH males ≥30 years old and in the I172N group. In contrast, younger CAH males did not differ from age-matched controls. This is likely to reflect a better management in recent years.
Henrik Falhammar, Helena Filipsson Nyström, Urban Ekström, Seth Granberg, Anna Wedell, and Marja Thorén
Fertility in males with congenital adrenal hyperplasia (CAH) is reported from normal to severely impaired. Therefore, we investigated fertility/fecundity, social/sexual situation, and pituitary–gonadal function in CAH males.
Subjects and methods
The patient cohort comprised 30 males, aged 19–67 years, with 21-hydroxylase deficiency. Their fertility was compared with age-matched national population data. For the evaluation of social/sexual factors and hormone status, age-matched controls were recruited (n=32). Subgroups of different ages (<30 years and older) and CYP21A2 genotypes (null (severe salt-wasting (SW)), I2splice (milder SW), and I172N (simple virilizing)) were also studied. Patients underwent testicular ultrasound examination (n=21) and semen analysis (n=14).
Fertility was impaired in CAH males compared with national data (0.9±1.3 vs 1.8±0.5 children/father, P<0.001). There were no major differences in social and sexual factors between patients and controls apart from more fecundity problems, particularly in the I172N group. The patients had lower testosterone/estradiol (E2) ratio and inhibin B, and higher FSH. The semen samples were pathological in 43% (6/14) of patients and sperm concentration correlated with inhibin B and FSH. Testicular adrenal rest tumors (TARTs) were found in 86% (18/21). Functional testicular volume correlated positively with the testosterone/E2 ratio, sperm concentration, and inhibin B. Patients with pathological semen had increased fat mass and indications of increased cardiometabolic risk.
Fertility/fecundity was impaired in CAH males. The frequent occurrence of TARTs resulting in testicular insufficiency appears to be the major cause, but other factors such as elevated fat mass may contribute to a low semen quality.
Hedi L Claahsen-van der Grinten, Nike Stikkelbroeck, Henrik Falhammar, and Nicole Reisch
Gonadal dysfunction is an adverse outcome in patients with congenital adrenal hyperplasia (CAH), which may become apparent already during puberty. Clinical consequences of gonadal dysfunction include menstrual disturbances in females and hypogonadism and impaired fertility in males and females. In males, gonadal dysfunction can be caused by primary gonadal failure due to testicular adrenal rest tumours (TART), and by secondary gonadal failure due to poor hormonal control. In females, gonadal dysfunction can result from an overproduction of adrenal androgens including 11-oxygenated C-19 androgens and progestins, and rarely from ovarian adrenal rest tumours. In all patients with CAH, optimal hormonal control is the key for adequate gonadal function. Therefore, regular measurements of adrenal steroids and/or their metabolites should be performed. In addition, markers of the hypothalamus-pituitary-gonadal axis need to be assessed. In females, the regularity of the menstrual cycle should be evaluated. In males, regular evaluation for TART using ultrasonography is recommended from the start of puberty or even earlier when poor hormonal control is present. When TART is present, counselling on cryopreservation of semen should be offered.
Henrik Falhammar, Helena Filipsson Nyström, Anna Wedell, Kerstin Brismar, and Marja Thorén
The aim of this study was to determine bone mineral density (BMD), markers of bone metabolism, fractures, and steroids reflecting hormonal control in adult males with congenital adrenal hyperplasia (CAH).
Subjects, methods, and design
We compared CAH males with 21-hydroxylase deficiency (n=30), 19–67 years old, with age- and sex-matched controls (n=32). Subgroups of CYP21A2 genotypes, age, glucocorticoid preparation, poor control vs overtreatment, and early vs late (>36 months) diagnosis were studied. BMD measured by dual energy X-ray absorptiometry and markers of bone metabolism and androgens/17-hydroxyprogesterone levels were investigated.
All, including older (>30 years), CAH patients had lower BMD in all measured sites compared with control subjects. The null group demonstrated lower BMD in more locations than the other groups. Osteoporosis/osteopenia was present in 81% of CAH patients compared with 32% in controls (≥30 years). Fracture frequency was similar, osteocalcin was lower, and fewer patients than controls had vitamin D insufficiency. IGF1 was elevated in the milder genotypes. In patients, total body BMD was positively correlated to weight, BMI, total lean body mass, and triglycerides, and negatively to prolactin. Patients on prednisolone had lower BMD and osteocalcin levels than those on hydrocortisone/cortisone acetate. Patients with poor control had higher femoral neck BMD. There were no differences in BMD between patients with an early vs late diagnosis.
CAH males have low BMD and bone formation markers. BMD should be monitored, adequate prophylaxis and treatment established, and glucocorticoid doses optimized to minimize the risk of future fractures.
Jun Ma, Sofia Nordman, Anna Möllsten, Henrik Falhammar, Kerstin Brismar, Gisela Dahlquist, Suad Efendic, and Harvest F Gu
The distribution of Leu7Pro polymorphism in the neuropeptide Y gene shows a geographical north to south gradient of decreasing frequency, suggesting that it may be a population-specific causal variant. This polymorphism is found to be associated with diabetic nephropathy (DN) and coronary heart disease in Finnish women with type 1 diabetes (T1D). The present study aims to evaluate the susceptibility of this polymorphism to the development of DN in two different populations.
One sample set consists of 174 (females 98 and males 76) Swedish T1D patients with DN and 249 (females 132 and males 117) patients without DN. Another sample set includes 597 (females 356 and males 241) American T1D patients without DN and 577 (females 264 and males 313) patients with DN, who were descents of European Caucasians and were from the Genetics of Kidneys in Diabetes (GoKinD) Study.
Genotyping of Leu7Pro polymorphism was performed by dynamic allele-specific hybridization.
The C allele frequencies of Leu7Pro polymorphism in T1D patients between Swedish and American GoKinD populations were significantly different (6.3 vs 4.0%; P=0.006). Particularly, the C allele frequency in Swedish female T1D patients with DN was significantly higher in comparison with T1D patients without DN (10.2 vs 4.2%; P=0.011, OR=2.614, 95% confidence intervals: 1.249–5.467). No significant association of this polymorphism with DN was observed in Swedish male T1D patients and the patients from GoKinD.
The present study provides further evidence that Leu7Pro polymorphism confers the susceptibility to the development of DN in Swedish female T1D patients.