Basal Serum Luteinising Hormone Cut-Off, and Its Utility and Cost-Effectiveness for Aiding the Diagnosis of the Onset of Puberty in Girls With Early Stages of Breast Development

Somboon Wankanit; Pat Mahachoklertwattana; Oraluck Pattanaprateep; Preamrudee Poomthavorn

Disclosures

Clin Endocrinol. 2020;91(1):46-54. 

In This Article

Discussion

Owing to the fact that basal and peak LH levels are elevated with advanced stage of puberty, a mixed study population of girls with different Tanner stages could be a factor that has caused different basal and peak LH cut-offs and their diagnostic accuracy for diagnosing CPP.[3–5,9,10,18,21–25] Different Tanner stages of CPP girls might have different LH cut-offs for the diagnosis.

Our study demonstrated that basal LH level of 0.2 IU/L represented 95th percentile of PT girls with Tanner stage II breasts. However, basal LH of 0.3 IU/L has been proposed and widely adopted as the cut-off for diagnosing CPP in previous studies.[1,6,18,19] Basal LH levels of 0.3 IU/L or greater were also associated with peak LH levels of 8 IU/L or greater and were observed in normal girls with Tanner stages IV and V breasts.[6,18] Therefore, diagnostic accuracy of these 2 basal LH cut-offs was compared. Lowering basal LH cut-off from 0.3 to 0.2 IU/L in this study showed moderately increased sensitivity with acceptable specificity (95%) in CPP girls with Tanner stage II. The specificity of basal LH cut-off of 0.2 IU/L was not inferior to that of peak LH cut-off of 5 IU/L which has been widely used to indicate CPP in previous studies.[1,6,18,26] Hence, basal LH cut-off of 0.2 IU/L could effectively reflect an early activation of hypothalamic-pituitary-gonadal (HPG) axis and thus the onset of puberty. Our result was in agreement with a previous study which reported that none of PT girls had basal LH level exceeding 0.2 IU/L.[24] Additionally, a study of normal girls revealed that basal LH level of 0.2 IU/L was the upper limit for prepubertal girls.[7] A recent study also reported no pubertal progression during the 6-month follow-up in girls with premature breast development who had basal LH level of <0.2 IU/L.[22] Furthermore, basal LH concentration of greater than 0.2 IU/L was also proposed as the pubertal level for CPP diagnosis in a recent review.[26] Taken together, our study suggests using basal LH cut-off of 0.2 IU/L to indicate the onset of early or normal puberty in girls with Tanner stage II breasts.

In girls with Tanner stage III breasts, basal LH cut-off of 0.21 IU/L represented 95th percentile of PTIII girls in this study. Similar to Tanner stage II, the specificity of basal LH cut-off of 0.2 IU/L (94%) for Tanner stage III was not inferior to that of peak LH cut-off of 5 IU/L. Additionally, the sensitivity of the cut-off of 0.2 IU/L was better than that of 0.3 IU/L with acceptable specificity. Therefore, basal LH cut-off of 0.2 IU/L was also proposed to use as an indicator of HPG axis activation in girls with Tanner stage III breasts.

Peak LH levels of 5–8 IU/L have been widely adopted as pubertal level and used for CPP diagnosis[1,6,18,26] with sensitivity and specificity of 76%-98% and 90%-100%, respectively.[3–5,8–10,21,22] In agreement with the previously published data, peak LH of 5 IU/L was the most appropriate cut-off for diagnosing the onset of early or normal puberty in both girls with Tanner stages II and III breasts in our study (Table 2).

Peak LH:FSH ratio was proposed as an alternative for diagnosing CPP, although its sensitivity and specificity were lower than peak LH.[27] Peak LH:FSH ratio of 0.43 or greater achieved comparable specificity, but lower sensitivity as compared with peak LH cut-off of 5 IU/L in this study. The same cut-off ratio was also studied by Vestergaard et al[28] who described peak LH:FSH ratio below 0.43 in all prepubertal girls aged under 6 years. Therefore, our study proposed to use the ratio of 0.43 for defining the onset of early or normal puberty rather than the traditional ratio of 0.66[20] which had lower sensitivity.

GnRHa test is a labour-intensive, time-consuming and costly tool for diagnosing CPP when compared with a single blood sample for basal LH measurement. Using basal LH cut-off of 0.2 IU/L for diagnosing girls with CPP followed by GnRHa test only in those with negative basal LH level or basal LH level of <0.2 IU/L showed a significant reduction in diagnostic cost as compared with performing GnRHa test in all patients. Comparing with traditional basal LH cut-off of 0.3 IU/L, our proposed basal LH cut-off of 0.2 IU/L demonstrated significant cost-saving outcome in diagnosing the onset of early or normal puberty in girls with Tanner stages II and III breasts. Basal LH cut-off of 0.2 IU/L could thus be considered as a more practical and cost-effective tool than the basal LH cut-off of 0.3 IU/L for determining the onset of early or normal puberty before performing GnRHa test. Additionally, based on the results of our study which demonstrated a peak LH level as early as 60 minutes after the GnRHa administration, a simplified test with serum LH levels only measured at 60–90 minutes after GnRHa administration could be performed to further reduce the diagnostic cost.

Although blood tests are commonly performed to confirm the CPP diagnosis, acceleration of height velocity, advancement of bone age as well as ultrasound findings of pubertal-sized and pear-shaped uterus are still crucial for the diagnosis. Girls without the above-mentioned findings could be followed for the pubertal progression without performing the blood tests. To the best of our knowledge, this is the first study that determined basal and peak LH cut-offs for each of Tanner stage II and III breasts of CPP girls and compared the cost-effectiveness of different diagnostic approaches. The strength of the study was that it included a large number of patients. Tanner staging was only performed by two experienced paediatric endocrinologists (PM and PP), thus this limited the variability in the assessment. In addition, the diagnoses of CPP and PT were made based on the breast progression and clinical course.

We acknowledge the limitation of this study. Owing to a retrospective nature of the study, prepubertal controls (Tanner stage I) were not available.

In conclusion, basal serum LH cut-off of 0.2 IU/L could be a simple and cost-saving tool for initial diagnosis of onset of early or normal puberty in girls with Tanner stages II and III breasts before proceeding to GnRH testing.

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