Endocrine Abstracts

Central hypogonadism (CH) is a syndrome that can be diagnosed in women with hypoestrogenic amenorrhea and a lack of normal response of gonadotropins to hypoestrogenemia in the absence of other reasons. To date, about 50 genes were reported as a possible reason for this condition, but the genetic basis is still unknown for approximately a half of CH cases.

Patients and Methods: Some of the CH-related genes are expressing in leukocytes of peripheral blood: GNRHR and GNRH1 (necessary for the adequate biological effect of GnRH); PROK2 and CHD7 (responsible for the GnRH neurons migration), WDR11 and DUSP6 (involved in normal sexual development). 15 female patients with CH (age from 18 to 50 y.o.) were examined; 6 of them have amenorrhea I and the rest 9 – amenorrhea II. Risk factors of amenorrhea II were: stress, excessive physical exercises, rapid weight loss, past use of oral contraceptives. The control group: 21 healthy women (age from 19 to 37 y.o.) with the regular ovulatory menstrual cycle, some of them have children.

A quantitative determination of mRNA expression of genes GNRHR, GNRH1, PROK2, CHD7, WDR11 and DUSP6 was completed in the fresh peripheral blood sample by PCR in real-time. Measurement results were normalized to the reference primer beta-actin expression.

Results: Expression patterns of examined genes differed from normal in each case of CH. Changes in neurodevelopmental genes PROK2, DUSP6 and WDR11 expression were statistically significant: U_emp = 75 vs U_cr = 83 for PROK2, 77 vs 88 for DUSP6 and 66 vs 77 for WDR11 (P < 0.05 for all genes; Mann-Whitney U-test). After ROC-analysis diagnostic clipping points were determined: PROK2 expression >0.009356 and DUSP6 expression >0.01478 showed sensitivity 60.0% and 60.0% and specificity 82.0% and 83.3%, respectively, for CH diagnosis. WDR11 expression > 0.002224 pointed to the central genesis of hypogonadism with sensitivity 66.7% and specificity 75.0%.

Conclusion: According to our results, quantitative mRNA expression measurement of neurodevelopmental genes PROK2, DUSP6, and WDR11 (which are responsible for CH) can be considered as diagnostic criteria for central hypogonadism with sensitivity 60.0%, 60.0%, 66.7% and specificity 82.0%, 83.3%, 75.0% respectively.