2. Case Report
A 17-year-old girl (menarche at 12 y) presented with oligomenorrhea (menstrual cycles of 40–75 days) and hyperandrogenism observed for the last few years, since puberty. She suffered from persistent, severe acne, oily skin and hirsutism (modified Ferriman–Gallway score 11). Her weight was 57 kg, height 168 cm and body mass index (BMI) 20.2 kg/m2.
The patient was admitted to the Children’s Hospital at Poznan University of Medical Sciences. Written consent for routine diagnostic and treatment procedures is always taken on admission, together with consent for the use of all diagnostic or treatment results for scientific analysis and anonymous publication. Informed consent was obtained from the patient, aged 17 years old and from her legal representative, i.e., her mother. The approval of the Ethics Committee is not required for case reports as long as there is no experimental or out of label procedures applied. In the described case only routine procedures were performed and the value of our study relies upon meticulous analysis of all collected data.
Five months earlier she had been admitted into a gynecological ward where the diagnostic tests revealed slightly elevated levels of prolactin, 27.24 ng/mL (reference range: 4.79–23.30), and dehydroepiandrosterone sulfate (DHEA-S), 13.44 µmol/L (reference range: 1.77–9.99). Total testosterone (T) was 2.60 nmol/L (reference range: 0.2–2.80) and sex hormone binding globulin (SHBG), 103.1 nmol/L (reference range: 26.1–110.0). Free androgen index (FAI) was 2.5, and bioavailable testosterone was 0.50 nmol/L, i.e., 19.0%. In an abdominal ultrasound, the uterus size was estimated as 38 × 25 mm, endometrium 6 mm, while ovaries were not described at all. According to the patient’s statement, gynecological examination was not performed at that time. In an oral glucose tolerance test (OGTT) the fasting glucose was 106 mg/dL and in the 120th minute 145 mg/dL; while fasting insulin 14 IU/mL and 73 IU/mL at 120 min post glucose load. Based on these results, insulin resistance was diagnosed (homeostatic model assessment of insulin resistance, HOMA-IR 3.66) with borderline glycemia for impaired tolerance. Treatment with metformin was recommended; however, the patient has never started this therapy.
A few months later her hormonal diagnostic was extended in the pediatric endocrinology ward. The patient supplied her 24 h urine collection completed in the morning of admission (4th/5th day of follicular phase), which was sent for steroid profile evaluation. Thyroid function tests, including thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were all within the reference range. Other hormonal tests performed on the 6th day of the menstrual cycle revealed serum DHEA-S 11.39 µmol/L, i.e., close to the upper limit of normal, the luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio 9.8/6.3 mIU/mL, i.e., only slightly shifted towards LH, with the estradiol (E2) level 38 pg/mL, i.e., at the lower limit of the reference range. Morning plasma ACTH was 84.9 pg/mL (reference range up to 60 pg/mL) (Table 1
The OGTT was repeated with simultaneous estimations of frequently sampled glycemia, serum insulin and C-peptide levels. Its results were within the range of reference (HOMA-IR 1.58) and excluded glycemic-insulin disturbances in the patient (Table 2
Standard adrenocortical stimulation (on 7th day of cycle) with 250 μg intravenous Synacthen (an ACTH1–24
analogue) revealed normal secretory reaction of cortisol, 17OHP and androstenedione (ANDR) (Table 3
The results of steroid metabolites estimation in 24 h urine collection demonstrated an increased amount of 16α-OHDHEA (610.2 µg/24 h)—a dehydroepiandrosterone metabolite—and a marked increase in excretion of pregnanetriolone (PTN, 142.5 µg/24 h) (Table 4
In conclusion to their analysis, the steroid laboratory suggested excluding CAH in this patient. However, according to the clinical endocrinologist, the selective imbalance of excreted steroid metabolites was probably due to a mild restriction of 21α-hydroxylase (elevated PTN was suggestive of excess 17OHP). The contribution of the alternative pathway leading to enhanced production of DHT, with omission of T, was also suspected because of the discrepancy between severe skin symptoms and formerly reported normal serum testosterone level.
In the next step, a 3-day dexamethasone (0.5 mg orally every 6 h) suppression test was carried out. Its results (Table 5
) revealed initially elevated and then lowered serum values of DHEA-S (16.40 then 4.52 µmol/L), T (3.84 then 2.16 nmol/L) and ANDR (2.59 then 1.78 ng/mL). In the same series, a significantly elevated concentration of DHT (578 pg/mL) was observed and thereafter, upon dexamethasone, it returned to the reference range (337 pg/mL).
The abdominal ultrasound was also performed—no focal changes were found in the adrenal glands; both ovaries (LO: 33 × 24 × 21 mm, RO: 35 × 17 × 16 mm) were described as having normal solid/follicular architecture and the diameter of the largest follicle in the RO was 11 mm. We have revisited FAI again (for SHBG, 105.0 nmol/L and T, 3.84 nmol/L) and the result was 3.66, while T bioavailability 0.72 nmol/L, i.e., 18.8%. Hence, compared to previous estimations, FAI was slightly higher, however still within normal range.
Summarizing the patient’s medical history and her current clinical and biochemical results, we concluded that there were no convincing arguments to establish the diagnosis of polycystic ovary syndrome (PCOS), especially because adrenal source of hyperandrogenism was beyond doubt. The patient was discharged with the diagnosis of mild late-onset 21α-hydroxylase deficiency (steroid metabolites in urine) and hyperandrogenism due to enhanced “backdoor” androgen pathway. Furthermore, hormonal evaluation suggests a tendency for episodic stress-like reactions, manifested with higher ACTH and baseline cortisol concentrations close to the upper reference limit. However, 24 h urine cortisol excretion remained normal.
Our patient did not fulfill all standard criteria for PCOS diagnosis in adolescents [14
]. She presented irregular menstruation, clinical hyperandrogenism; however, biochemical indices of testosterone excess, as well as insulin resistance were not permanent or significant, and ovaries did not present morphology typical for PCOS. Moreover, the patient’s BMI was normal and stable. Nevertheless, an early stage of PCOS could not be totally excluded in the future besides the confirmed DHT excess of adrenal origin. Therefore, continued care of an endocrinologist-gynecologist was proposed, with the suggestion to start spironolactone treatment, combined with a two-component contraceptive pills comprising drospirenone for their antiandrogenic effects. A healthy lifestyle (diet, physical activity) was also advised as an essential method to avoid progression towards insulin resistance.