A 25-year-old female was admitted to the Nephrology Department with a two-year history of unexplained fatigue and documented elevation in serum creatinine. Her past medical history was notable for atypical genitalia at birth. She was diagnosed with CAH at the age of 7, when she underwent penectomy and external genital reconstruction surgery. Postoperatively, she was treated with oral prednisone (dosage undocumented). Menarche occurred at age 12 but was followed by oligomenorrhea. Due to poor adherence, prednisone was discontinued at age 17, leading to the development of secondary amenorrhea, and she never returned for follow-up. She denied any history of residence at high altitudes or chronic comorbidities, including hypertension, cardiovascular disease, pulmonary disorders, diabetes mellitus, or autoimmune rheumatic diseases. In addition, the patient denied the use of exogenous androgens, anabolic drugs, and nephrotoxic medications.

To manage the severe polycythemia and underlying hormonal imbalance identified at baseline (Table 1), the patient initially underwent erythrocytapheresis and was initiated on Dexamethasone 0.75 mg daily. At the two-month follow-up, the suppression of the hypothalamic-pituitary-adrenal (HPA) axis was evident, with testosterone levels dropping slightly below the reference range. Consequently, the regimen was transitioned to oral Prednisone 5 mg daily. However, by the three-month follow-up, a significant clinical rebound occurred: ACTH surged to 645.4 pg/mL and testosterone rose to 2.65 ng/mL, indicating insufficient control by prednisone.

The therapy was subsequently optimized by reverting to Dexamethasone at a reduced dosage of 0.375 mg daily. This adjustment elicited a robust and sustained clinical response. Longitudinal follow-up (Figure 3) revealed a synchronized recovery of multi-organ functions compared to the initial baseline state. As illustrated in Figure 3A, the transient switch to prednisone at Month 3 caused a distinct spike in androgen activity, which was promptly suppressed upon the resumption of low-dose dexamethasone.

Parallel to these hormonal shifts, renal function showed marked and steady improvement (Figure 3B) from the initial insufficiency reported in Table 1. By the 20-month follow-up, serum creatinine had decreased to 70.7 μmol/L (reference range: 41–73 μmol/L), and the eGFR recovered to 101.8 mL/min/1.73m². The UACR also normalized to 9.5 mg/g, with clinical proteinuria becoming negative. Furthermore, secondary polycythemia remained resolved (Figure 3C); hemoglobin levels were consistently maintained below 150 g/L after the initial treatment, showing a significant reduction from the baseline value of 208 g/L (Table 1). These findings, summarized in Table 2, confirm the sustained efficacy of personalized low-dose dexamethasone in managing systemic complications and achieving long-term biochemical stability.

21-OHD is fundamentally characterized by impaired cortisol biosynthesis, which triggers compensatory ACTH hypersecretion via the HPA axis (8). This drive results in adrenal hyperplasia, the accumulation of steroid precursors (e.g., 17-OHP), and varying degrees of hyperandrogenemia. The SV form, associated with 2-10% residual 21-hydroxylase activity, typically presents with androgen excess—manifesting as virilization in females and precocious puberty in males—but usually spares patients from the life-threatening electrolyte disturbances seen in salt-wasting subtypes (9). However, while gonadal sequelae are well-documented, the systemic impact of chronic hyperandrogenemia on non-reproductive organs remains underappreciated.

Polycythemia, a rare clinical feature of CAH, was initially described in salt-wasting neonates and later in two adults with SV form. These three cases, including ours, shared the feature of chronic undertreatment, with markedly elevated androgen levels despite normal EPO (10–12). The marked elevation in RBC count and hemoglobin was driven by chronic hyperandrogenemia. Androgens stimulate erythropoiesis through multiple synergistic pathways: they directly upregulate erythropoietin (EPO) synthesis, enhance insulin-like growth factor-1 (IGF-1) activity, and facilitate iron incorporation into erythrocytes (13). In this patient, the EPO level was normal, suggesting that testosterone may increase the biological activity of erythropoietin without affecting its concentration (14). Previous studies have demonstrated a strong positive correlation between testosterone and hemoglobin levels, particularly in women with hyperandrogenic disorders (15). In our case, the normalization of hematological parameters following glucocorticoid therapy provides robust clinical evidence that the polycythemia was secondary to the hormonal imbalance.

The clinical implications of this secondary polycythemia are significant. Increased blood viscosity compromises microcirculation, predisposing patients to thrombotic events and organ ischemia. This risk was underscored by a reported case of a male patient with untreated CAH who suffered a stroke due to polycythemia (11). Similarly, in our patient, we postulate that hyperviscosity-induced renal hypoperfusion acted as a precipitating factor for renal dysfunction.

Polycythemia contributes to hyperuricemia via accelerated purine metabolism. The relationship between testosterone levels and uric acid levels remains controversial. Some studies have found that serum uric acid levels in adult males may be negatively correlated with serum testosterone levels (16). However, in a study of female-to-male transgender individuals with gender dysphoria, testosterone administration was associated with increased serum uric acid levels in a dose-dependent manner (17). This case corresponds to the latter mechanism, wherein androgen excess raises uric acid levels directly by accelerating purine catabolism and indirectly by promoting insulin resistance and central obesity.

There was a reported case of a newborn diagnosed with classic 21-OHD, who presented with acute renal insufficiency and hematuria. These manifestations were associated with factors such as dehydration, hyponatremia, and deep vein thrombosis (18). To our knowledge, chronic renal insufficiency has not been reported as a complication of 21-OHD. However, literature from sports medicine documents renal injury in bodybuilders using anabolic steroids, including focal segmental glomerulosclerosis (FSGS) and tubular atrophy (19). The temporal synchronization observed in our patient between androgen suppression and renal recovery (Figures 3A, B) provides strong clinical evidence for this mechanistic link. As the excessive testosterone was neutralized through optimized glucocorticoid therapy, the hemodynamic stress and metabolic burden on the kidneys appeared to alleviate concurrently. This is evidenced by the steady normalization of serum creatinine and the significant reduction in UACR over the 20-month follow-up period, reinforcing the hypothesis that hyperandrogenism acts as a reversible driver of renal impairment in female 21-OHD patients. We propose that the renal injury in this case resulted from a “triple-hit” mechanism:

Obesity is a recognized risk factor for glomerulopathy. While the patient’s BMI of 32 kg/m² could potentially contribute to renal stress, obesity-related nephropathy typically follows a slow, progressive course (24). In contrast, our patient exhibited a rapid and significant recovery of renal function (eGFR improved from 66.9 to 89.7 ml/min/1.73m²) and resolution of proteinuria within three months of hormonal control. Within three months of hormonal control. As illustrated in the long-term trend (Figure 3B), this recovery was not transient but sustained, with serum creatinine ultimately reaching a stable nadir of 70.7 μmol/L by Month 20. This sustained reversibility further distinguishes the androgen-mediated toxicity from the typically slow and progressive course of obesity-related glomerulopathy. This reversibility strongly suggests that testosterone-mediated toxicity, rather than obesity, was the primary driver of renal impairment, mirroring the reversible renal injury observed in bodybuilders upon steroid cessation (19). Based on the improvement in renal parameters, the patient declined renal biopsy. Nevertheless, the potential impact of obesity-related nephropathy warrants further investigation, particularly in patients with congenital adrenal hyperplasia who may harbor additional risk factors for chronic kidney disease. The patient’s refusal of a renal biopsy following clinical improvement represents a key study limitation, which prevented definitive histopathological classification.

Nephrocalcinosis is a rare complication of CAH, often accompanied by hypercalcemia and hypercalciuria, which can impact renal function. Studies have confirmed a higher incidence in male children. The patient’s age, gender, normal blood calcium levels, and absence of renal calcification deposits do not support a diagnosis of nephrocalcinosis (25, 26).

CAH is a relatively common genetic disorder, for which glucocorticoid therapy serves as an effective treatment option. In cases of salt-wasting 21-OHD, early diagnosis significantly reduces the risk of adrenal crisis. For patients with the SV form, early diagnosis helps prevent misassignment of female external genitalia, avoid psychological trauma associated with atypical sexual development, and allow timely initiation of glucocorticoid therapy, thereby effectively suppressing adverse outcomes caused by hyperandrogenism, such as accelerated growth and advanced bone age. Some countries recommend newborn screening for CAH. However, there is some controversy regarding the screening for the SV form. The potential benefits of early intervention for asymptomatic mild hyperandrogenemia remain uncertain, whereas long-term glucocorticoid treatment may pose metabolic and cardiovascular risks. As many individuals with the SV form of CAH have only mild adult symptoms, neonatal screening could lead to their over-medicalization. In resource-limited settings, incorporating the SV form into CAH screening may be cost-effective. Ethically, however, mandatory screening for this non-life-threatening variant is controversial, as it may infringe upon an individual’s future autonomy.

The clinical significance of personalized glucocorticoid titration is vividly illustrated by the ‘rebound phenomenon’ captured at Month 3 (Figure 3A). In our case, the transient switch from dexamethasone to prednisone resulted in an immediate escape of ACTH and testosterone from hormonal control, which was only reversed upon reinstating low-dose dexamethasone (0.375 mg daily). This fluctuation, clearly visualized in the longitudinal trend, underscores that for certain SV 21-OHD patients with extreme hyperandrogenemia and systemic complications, conventional prednisone doses may lack the necessary potency to stabilize the HPA axis. The superior suppressive effect of dexamethasone—when carefully titrated—offers a critical therapeutic window to achieve biochemical stability and prevent the recurrence of renal hemodynamic stress and polycythemia.