All study subjects on histrelin implant therapy for CPP were clinically and biochemically suppressed using the standard outcome measures of peak LH returning to prepubertal levels, reduced sex steroid levels, cessation of advancement of Tanner stage, diminished growth velocity, and reduction in the rate of bone age advancement [6, 7]. In this multi-year study of 36 children treated with histrelin implants (20 naïve to treatment and 16 pretreated with another GnRHa), all peak LH values during implant therapy were < 2.5 mIU/mL, demonstrating that puberty in all subjects was unequivocally suppressed. Nonetheless, the random unstimulated LH value exceeded the 0.3 mIU/mL pubertal threshold for the Esoterix assay at 48.4% of the treatment visits, the value was sporadically > 1 mIU/mL in 7 different children, and the lack of suppression assessed by random LH was nearly universal, occurring in 89% of children, despite every other parameter indicating pubertal suppression.
In other words, stimulated LH returns to prepubertal norms during histrelin therapy, but random unstimulated LH levels do not, making the usefulness of random LH in therapeutic monitoring somewhat dubious. The physiologic reason for persistence of basal LH in the pubertal range is not understood. GnRH superagonist therapy might result in tonic LH secretion, but the observed decline over years of therapy would need to be explained. Alternatively, consistently low but measurable LH might be related to the circulating alpha subunits during therapy, although modern assays do not cross-react with those subunits.
Persistence of pubertal random LH values was reported in short-term depot leuprolide therapy nearly 2 decades ago when ultrasensitive LH assays became available [15, 16]. It was again recently noted during short-term histrelin therapy . That study was performed with a much smaller sample size, non-simultaneous random and stimulated LH testing, and a relatively insensitive LH assay, but the message is effectively the same. Nonetheless, random LH measurement is commonly performed and used as a criterion to confirm suppression. The persistent elevation in random LH and the temporal decline during the first years of therapy have also been observed during long-term depot leuprolide therapy . It is likely not coincidental that the mean random LH level in the previously treated group in our study was essentially unchanged by subsequent histrelin therapy. Persistent elevation of the random LH level is characteristic of both leuprolide and histrelin therapy, whereas a three-fold reduction in peak LH levels was seen following the change in our pretreated subjects from depot leuprolide to histrelin implant.
Unstimulated LH values trended lower during successive years of histrelin therapy, as did the GnRHa-stimulated LH levels . Our data confirm that random LH levels during GnRHa therapy correlate positively with stimulated LH levels. Nevertheless, a considerable percentage of random LH levels remained at or well above the pubertal threshold in the later years of histrelin treatment. The mean random LH of 0.35 mIU/mL during therapy remained approximately 10-fold higher than the prepubertal mean for this LH ICMA assay, 0.03 ± 0.03 mIU/mL , even in the later years of therapy. This extremely low prepubertal norm for random LH using an accurately performed ICMA has been corroborated by other assays .
In comparison with the continued elevation of random LH levels, the mean peak LH of 0.62 mIU/mL during therapy in the current study is markedly less than the normal mean prepubertal peak LH (2.0 ± 1.5 mIU/mL) for this ICMA assay . Mean GnRHa-stimulated levels in the later years of therapy fall to near-equivalence with random LH levels. These findings imply that chronic GnRH superagonist therapy results in low-level tonic LH secretion, but nearly complete suppression of pulsatility. As a consequence, only the GnRHa-stimulated LH level during therapy provides clear biochemical confirmation of suppression of the pubertal axis.
During histrelin therapy, assessment of peak LH requires an aqueous leuprolide injection, unlike GnRHa injection therapies in which the therapeutic injection itself can be used as the stimulating agent [4, 17, 18]. Thus, it is not surprising that some practitioners have been using unstimulated LH levels for convenience or cost savings in monitoring histrelin therapy, along with clinical features and random sex steroid levels. Some utilize 24-hour leuprolide-stimulated estradiol, which circumvents estradiol assay limitations but is likely more inconvenient to obtain than stimulated LH because of the necessity of a return visit. A consensus statement 5 years ago on pediatric uses of GnRHa  did not take a position on the utility of random LH for monitoring because the practice was common and published data using sensitive LH assays were at that time limited. Our findings clearly demonstrate that the practice of relying upon random LH for monitoring should be used cautiously, if at all.