Occult symptomatic bilateral pure Leydig cell tumors in a postmenopausal woman: a case report.

BACKGROUND: Pure Leydig cell tumors (LCTs) represent 0.1% of ovarian masses. Postmenopausal patients typically present with virilization. Although LCTs can be challenging to locate on conventional imaging, positron emission tomography (PET) has been demonstrated to be effective. CASE: A 64-year-old postmenopausal woman presented with alopecia, facial hirsutism, and clitoromegaly. Laboratory findings included elevated testosterone and androstenedione. Ultrasound, computed tomography, and magnetic resonance imaging showed no adnexal masses. PET did not demonstrate ovarian fludeoxyglucose-avidity. Histopathology after bilateral salpingo-oophorectomy revealed bilateral Leydig cell tumors. Her testosterone normalized 2 weeks postoperatively. CONCLUSION: We describe the occult, symptomatic, bilateral ovarian Leydig cell tumors, an occurrence that has not been described in the literature. Virilizing tumors must be considered in patients with evidence of hyperandrogenism, even without pelvic masses on imaging.

Local Backbone Flexibility as a Determinant of the Apparent pKa Values of Buried Ionizable Groups in Proteins.

Ionizable groups buried in the hydrophobic interior of proteins are essential for energy transduction. These groups can have highly anomalous pKa values that reflect the incompatibility between charges and dehydrated environments. A systematic study of pKa values of buried ionizable groups in staphylococcal nuclease (SNase) suggests that these pKa values are determined in part by conformational reorganization of the protein. Lys-66 is one of the most deeply buried residues in SNase. We show that its apparent pKa of 5.7 reflects the average of the pKa values of Lys-66 in different conformational states of the protein. In the fully folded state, Lys-66 is deeply buried in the hydrophobic core of SNase and must titrate with a pKa of ≪5.7. In other states, the side chain of Lys-66 is fully solvent-exposed and has a normal pKa of ≈10.4. We show that the pKa of Lys-66 can be shifted from 5.7 toward a more normal value of 7.1 via the insertion of flanking Gly residues at positions 64 and 67 to promote an "open" conformation of SNase. Crystal structures and nuclear magnetic resonance spectroscopy show that in these Gly-containing variants Lys-66 can access bulk water as a consequence of overwinding of the C-terminal end of helix 1. These data illustrate that the apparent pKa values of buried groups in proteins are governed in part by the difference in free energy between different conformational states of the protein and by differences in the pKa values of the buried groups in the different conformations.