Use of the Subcutaneous Triptorelin Stimulation Test for Diagnosis of Central Precocious Puberty.

BACKGROUND: The gold standard gonadotropin-releasing hormone (GnRH) stimulation test uses the response to intravenously injected gonadorelin to diagnose central precocious puberty (CPP). However, gonadorelin is not always readily available. OBJECTIVE: This study investigated the diagnostic efficacy of the subcutaneous triptorelin test and the optimal blood sampling time for diagnosis of CPP. METHODS: This study retrospectively examined the medical records of 220 girls who had undergone either the triptorelin or gonadorelin test and compared their clinical characteristics. We retrospectively compared clinical parameters between girls diagnosed with CPP (n = 111) and idiopathic premature thelarche (IPT) (n = 109) using three different diagnostic methods: the gonadorelin, triptorelin 120 min, and triptorelin 180 min tests. The diagnostic ability of the stimulated luteinizing hormone (LH) concentration in the triptorelin test for CPP was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The CPP group exhibited higher basal and peak gonadotropin levels, more advanced bone age, and a lower body mass index standard deviation score than the IPT group. In the gonadorelin test group, all girls with CPP exhibited a peak LH response 30-60 min after intravenous gonadorelin injection. In the triptorelin test group, most girls with CPP exhibited a peak LH response 60-180 min after subcutaneous triptorelin injection (n = 68). On the ROC curve, a peak LH concentration of ≥ 4.52 IU/L at 120 min had the highest CPP diagnostic accuracy, with sensitivity and specificity of 100% and 95.83%, respectively.

Regulation of RhoA GTPase and novel target proteins for ROCK.

Rho GTPases play significant roles in cellular function and their activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), providing activation and inactivation of these GTPases, respectively. Active GTP-bound form of RhoA activates its effector proteins while the inactive GDP-bound form of RhoA exists in a RhoA-RhoGDI (guanine nucleotide dissociation inhibitor) complex in the cytosol. In particular, IκB kinase γ IKKγ/NF-κB essential modulator (NEMO) plays a role as a GDI displacement factor (GDF) for RhoA activation through binding to RhoA-RhoGDI complex. Meanwhile, prion protein inactivates RhoA despite RhoA/RhoGDI association. Novel target proteins for Rho-associated kinase (ROCK) such as glycogen synthase kinase (GSK)-3ß and IKKß are recently discovered. Here, we elaborate on a post-translationally modified version of RhoA, phosphorylated at Tyr42 and oxidized at Cys16/20. This form of RhoA dissociates from RhoA-RhoGDI complex and activates IKKß on IKKγ/NEMO, thus providing possibly a critical role for tumourigenesis.

Regulation of RhoA GTPase and various transcription factors in the RhoA pathway.

RhoA GTPase plays a variety of functions in regulation of cytoskeletal proteins, cellular morphology, and migration along with various proliferation and transcriptional activity in cells. RhoA activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and the guanine nucleotide dissociation factor (GDI). The RhoA-RhoGDI complex exists in the cytosol and the active GTP-bound form of RhoA is located to the membrane. GDI displacement factors (GDFs) including IκB kinase γ (IKKγ) dissociate the RhoA-GDI complex, allowing activation of RhoA through GEFs. In addition, modifications of Tyr42 phosphorylation and Cys16/20 oxidation in RhoA and Tyr156 phosphorylation and oxidation of RhoGDI promote the dissociation of the RhoA-RhoGDI complex. The expression of RhoA is regulated through transcriptional factors such as c-Myc, HIF-1α/2α, Stat 6, and NF-κB along with several reported microRNAs. As the role of RhoA in regulating actin-filament formation and myosin-actin interaction has been well described, in this review we focus on the transcriptional activity of RhoA and also the regulation of RhoA message itself. Of interest, in the cytosol, activated RhoA induces transcriptional changes through filamentous actin (F-actin)-dependent ("actin switch") or-independent means. RhoA regulates the activity of several transcription regulators such as serum response factor (SRF)/MAL, AP-1, NF-κB, YAP/TAZ, ß-catenin, and hypoxia inducible factor (HIF)-1α. Interestingly, RhoA also itself is localized to the nucleus by an as-yet-undiscovered mechanism.