br Discussion The measurement of gonadotropins FSH LH is

Discussion The measurement of mitoxantrone (FSH, LH) is critical in the evaluation and assessment of 46,XX females presenting with primary amenorrhea and lack of pubertal development. A serum level of FSH higher than 40 U/L is diagnostic of ovarian failure (6), as seen in the present case. The most common causes of ovarian failure are gonadal agenesis, gonadal dysgenesis (7), ovarian enzymatic deficiency (17α-hydroxylase, 17,20-lyase) (2), premature ovarian failure secondary to injury (mumps oophoritis, radiation, chemotherapy), resistant ovary syndrome (8), autoimmune disease (9), and metabolic disease (galactosemia) (10). Some of these causes can be excluded by a careful history (e.g., chemotherapy, radiotherapy), karyotype, and measurement of urinary reducing substances and ovarian antibodies. However, abdominal pelvic ultrasound or abdominal pelvic magnetic resonance imaging is a useful initial step in evaluating primary ovarian failure, and the presence of large cystic ovaries in this patient pointed to a disorder of steroidogenesis rather than ovarian dysgenesis/agenesis or resistant ovary syndrome (due to FSH receptor mutations) (8), where the ovaries are typically small or cannot be detected. In patients with isolated 17,20-lyase deficiency, it has been proposed that the 17-hydroxyprogesterone/Δ4-androstenedione ratio is the most useful parameter to confirm the diagnosis (11). In the present case, ACTH stimulation resulted in a normal increase in P, 17-hydroxyprogesterone, and cortisol, but there were no significant responses in DHEA and androstenedione levels. The17-hydroxyprogesterone/Δ4-androstenedione ratio was 0.37 at baseline, however, the 17-hydroxyprogesterone/Δ4-androstenedione ratio was found to be 2.42 after the ACTH stimulation test. The hCG test showed similar characteristic changes in steroid hormone levels, which supported the diagnosis of an isolated deficiency of 17,20-lyase activity. Furthermore, steroid hormone levels in follicular fluid obtained from a cyst reflected isolated 17,20-lyase deficiency: P and 17-hydroxyprogesterone were normal whereas androstenedione, T, and E2 were extremely low. Two reports of steroid hormone levels in follicular fluid from patients with isolated 17,20-lyase deficiency have shown similar findings (12, 13). Thus, a combined biochemical approach using basal and stimulated steroid hormone analysis in serum and basal steroid hormone analysis in follicular fluid can be useful in reaching a diagnosis of isolated 17,20-lyase (desmolase) deficiency. Isolated 17,20-lyase deficiency can usually be differentiated from combined 17α-hydroxylase/17,20-lyase deficiency as patients with the latter condition have reduced cortisol levels and evidence of mineralocorticoid excess (2). Since the first description by Zachmann et al. (14), at least 23 cases of isolated 17,20-lyase deficiency diagnosed on biochemical profiling have been reported (2, 3, 12). Only three of them are 46,XX female, so it is likely that this condition is underdiagnosed in patients with delayed puberty and amenorrhea. In patients, a biochemical diagnosis of isolated 17,20-lyase deficiency has been confirmed genetically after analysis of the CYP17 gene. A limited number of point mutations have been described in ten karyotypically 46,XY patients with this condition (15, 16, 17). Detailed molecular analysis of DNA from this patient failed to reveal any mutations in these critical domains or throughout the CYP17 gene. It is possible that alternate mechanisms or interactions with alterative cofactors could be responsible for the apparent 17,20-lyase deficiency in this patient. Alternatively, an as yet undetermined molecular link between this steroidogenic defect and pituitary dysfunction could exist. This report highlights that isolated 17,20-lyase deficiency is an important diagnosis to consider in any girl with hypergonadotropic hypogonadism and cystic ovaries on ultrasound. Careful and detailed biochemical evaluation is necessary. Furthermore, appropriate induction of puberty with estrogen is important not only to induce breast development and uterine growth, but also to suppress the high gonadotropins that cause cystic ovarian changes (12, 18). This therapy can be combined with GnRH analogs to suppress the ovarian cysts (12, 19). Despite low intrafollicular E2 concentrations, successful IVF of a 46,XX female with 17α-hydroxylase deficiency has been reported (20, 21), highlighting the importance of appropriate diagnosis and early treatment in these patients.