Menstrual problems and development of polycystic ovarysyndrome (PCOS)-like phenotype in long-term follow-up in female cases with congenital adrenal hyperplasia (CAH),

Introduction: Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disease caused by the deficiency of one of the 5 enzymes required for the synthesis of cortisol from cholesterol. 90-95% of CAH cases are related to the deficiency of the 21-hydroxylase (21-OHase) enzyme. In 21-OHase deficiency, the clinical picture varies depending on the degree of deficiency in the enzyme. The disease manifests itself in two clinical forms: "classical" and "non-classical". The classical type is divided into two types, salt wasting and simple virilizing type, based on the level of aldosterone deficiency. While 2/3 of the classical cases are caused by salt-losing CAH, 1/3 are caused by simple virilizing CAH, which is not salt-losing. In these cases, hyperandrogenism leads to increased bone age, menstrual irregularities, short stature, and PCOS. During treatment, the aim is to reduce ACTH secretion and therefore adrenal androgen production by glucocorticoid and mineralocorticoid hormone replacement. A picture similar to polycystic ovary syndrome may occur in women with CAH who do not receive adequate treatment. Although menstrual problems may be observed in girls with CAH due to 21-OHase deficiency, the number of studies on this subject is very few. Although menstrual disorders are often said to be a feature of congenital adrenal hyperplasia (CAH), little is known about the mechanism of this symptom. Purpose: The aim of our study is to determine the frequency of menstruation problems and polycystic ovary syndrome like phenotype in long-term follow-up in girls with CAH due to 21-OHase deficiency and to investigate the possible causes of menstruation problems and PCOS. Patients and method: Research The files of 53 female patients who were followed up and treated with the diagnosis of classical CAH due to 21-OHase deficiency at Hacettepe University İhsan Doğramacı Children's Hospital Endocrinology Polyclinic were examined. The study included female cases who were followed up with the diagnosis of classical CAH due to 21-OHase deficiency at Hacettepe University İhsan Doğramacı Children's Hospital Department of Pediatric Endocrinology between January 1, 2004 and December 31, 2023 (in the last 20 years), and those who had 2 years or more passed since their first menstrual bleeding. The files of these patients were examined retrospectively, and the results of the analysis of their clinical, hormonal and radiological characteristics were collected during the application and follow-up period. The data were analyzed with the SPSS 23 package program. Results: The average age of a total of 53 cases participating in the study was 22.1±6.4 years. Forty-one (77.4%) cases were diagnosed with classical salt-wasting CAD, while 12 (22.6%) cases were diagnosed with simple virilizing CAD. The average age at menarche was calculated as 13.3±2.4 (11-19) years, and the average time after menarche was calculated as 8.6±3.2 (2-20) years. The average age at which the cases were evaluated for menstrual irregularity was 16.1±2.1 (13-20) years. While 23 (43.4%) of the cases had regular menstruation, 20 (37.7%) had oligomenorrhea, 8 (15.1%) had amenorrhea, 3 (5.7%) had hypomenorrhea, and 2 (3.8%) had polymenorrhea and 1 (1.9%) patient had hypermenorrhea. Hirsutism was detected in 49,1% (26/53) of the cases. The median Ferriman-Gallwey score was 9 (3-22). When evaluating the cases in terms of menstrual irregularity, hormonal evaluation was performed at the 3rd-5th day of menstruation, and pelvic ultrasonography was performed on the following day. The average hormone levels measured at this time were determined as follows: DHEAS level 52.8±27.2 (25.6-998) mcg/dL, testosterone level 105.8±39.2 (34.2-1546) ng/dL, SHBG level 27.6±13.1 (10.8-60.2) nmol/L, FSH level 4.9±1.6 (1.9-11.1) mIU/mL, LH level 6.4±2.7 (1.4-21) mIU/mL, estradiol level 50.4±16.5 (20.8-156.2) pg/ml, fasting insülin 18,1±8,2 µIU/ml (5,1-48,5), postprandial insülin 89,2±29,1 µIU/ml (42,4-258,3). The average annual 17 (OH) progesterone level of the cases measured during the evaluation was 85.9±51.3 (10.5-845.1) ng/mL, and the annual average androstenedione level was 4.3±2.1 (0.8-30, 0) ng/mL, and the median annual mean ACTH level was 85.2±23.5 (5.9-1190) pg/mL. Pelvic ultrasonography revealed median right ovary volume as 4.9±2.5 (1.2-28.0) ml and left ovary volume as 5.6±2.1 (1.2-23.6) ml. While nineteen (35.8%) had <6 follicular cysts, 6-11 follicles were detected in 18 cases (34%), and >12 follicles were detected in 16 cases (30.2%). The ovarian volume was >10 ml in 24.5% (13/53) of the cases. The average largest follicle diameter was 8.7±3.2 mm. When demographic, clinical, laboratory and ultrasonographic features are compared between cases with regular menstruation and cases with menstrual irregularity, BMI-SDS, hirsutism ratios and median Ferriman-Galwey scores were higher in cases with menstrual irregularities compared to cases with regular menstruations (p=0,010, p<0,001 ve <0,001, respectively). The mean age of menarche in cases with menstrual irregularity was significantly higher than in cases with regular menstruation [14.3±2.7 years vs. 11.9±1.8 years, p=0.003]. Among the tests taken during the evaluation; mean DHEAS, testosterone, LH, fasting and postprandial insulin and annual mean 17-OH-progesterone and androstenedione levels were observed to be significantly higher in cases with menstrual irregularities compared to those with regular menstruation (p<0,001, <0,001, <0,001, 0,008, <0,001, <0,001 ve p=0,014, respectively). In pelvic ultrasonography, the average right and left ovarian volumes of cases with menstrual irregularities were larger than those with regular menstruations (p=0.026 and p=0.035, respectively). Cases with menstrual irregularities were more likely to have a higher follicle count (>12 follicles) and an ovarian volume of >10 ml than cases with regular menstruation (p=0.009 and p=0.010, respectively). The average largest follicle diameter of the cases with menstrual irregularity was larger than the cases with regular menstruation (10.3±4.8 mm vs. 5.9±2.4 mm). There was no significant difference between the groups in terms of mean annual steroid dose. A total of 20 (37.8%) cases were diagnosed with a PCOS-like phenotype according to the Rotterdam diagnostic criteria. Cases with PCOS-like phenotype had higher BMI-SDS, higher hirsutism ratios, higher median Ferriman-Galwey scores, and later age at menarche compared to those without PCOS-like phenotype (p<0.001, <0.001, <0.001, and <0.001, respectively). The average DHEASO4, testosterone, LH, fasting and postprandial insulin levels of the cases diagnosed with a PCOS-like phenotype were determined to be significantly higher than those of without a PCOS-like phenotype (sırasıyla p=0,010, <0,001, <0,001, <0,001 ve <0,001, respectively). Similarly, the annual average 17(OH)Progesterone, androstenedione and ACTH levels of cases with PCOS-like phenotype measured during evaluation were determined to be significantly higher than those of cases without PCOS-like phenotype (p<0.001, p=0.010 and p=0.048, respectively). In pelvic ultrasonographic measurements, the average right and left ovarian volumes of cases with a PCOS-like phenotype were larger than those without a PCOS-like phenotype (p<0.001 and p<0.001, respectively). Cases with a PCOS-like phenotype were more likely to have a higher follicle count (>12 follicles) and an ovarian volume of >10 ml than cases without a PCOS-like phenotype (p<0.001 and p<0.001, respectively). The average largest follicle diameter of cases with PCOS-like phenotype was larger than cases without PCOS-like phenotype (13.1±5.3 mm vs. 6.0±3.4 mm, p=0.003). Conclusion: In female cases followed up with the diagnosis of classical CAH due to 21-OHase deficiency, menstrual problems and a picture similar to polycystic ovary syndrome may develop at high rates during long-term follow-up. This may be due to insufficient suppression of androgen hormone levels, usually due to inadequate glucocorticoid treatment. Irregular menstrual cycles can be seen together with clinical and laboratory findings of hyperandrogenemia. Excess androgens with hyperinsulinemia play a role in the development of polycystic ovary. Therefore, in female cases with classic CAH, excessively secreted adrenal hormones should be adequately suppressed by replacement with adequate and appropriate doses of glucorticoid and mineralocorticoid therapy. In these cases, close monitoring is required for menstrual irregularity and PCOS-like phenotypes that may develop in the long term. Key words: Classic type Congenital Adrenal Hyperplasia, 21-hydroxylase deficiency, PCOS, Menstrual irregularities