Serum Luteinizing Hormone Rises Within Minutes After Depot Leuprolide Injection: Implications for Monitoring Therapy

Suruchi Bhatia, MD; E. Kirk Neely, MD; and Darrell M. Wilson, MD

ABSTRACT. Objective. To find the time of the serum treated, precocious puberty can result in short stat- gonadotropin peak after depot leuprolide injection in ure and significant social problems for children un- children and to show that depot leuprolide therapy can dergoing sexual maturation years before their be monitored by measuring serum luteinizing hormone peers.1,2 Pulsatile secretion of endogenous gonado- (LH) immediately after injections. tropin-releasing hormone (GnRH) results in luteiniz- Study Design. We measured concentrations of leuprolide, LH, and follicle-stimulating hormone (FSH) at mul- ing hormone (LH) and follicle-stimulating hormone tiple time points before and after the first dose of depot (FSH) release from the pituitary and progression of leuprolide in 14 pubertal children beginning therapy. puberty,3 whereas the tonic stimulus of a long-acting Gonadotropins and sex steroids were measured again GnRH analog causes an initial surge of gonadotropin after the fourth dose. release, followed by suppression of pituitary gonad- Results. Serum leuprolide, LH, and FSH levels rose otropin production and release.4,5 Depot leuprolide rapidly after initial injection, reaching sustained eleva- (Depot-Lupron, TAP Pharmaceuticals, Deerfield, IL), tions at 30 to 120 minutes. The median LH level increased a commonly used long-acting GnRH analog, is given from 2.1 mIU/mL at baseline to a peak of 27.5 mIU/mL at 45 minutes, and FSH increased from 5.2 to 16.5 mIU/mL. by monthly intramuscular (IM) injection and is After 3 months on therapy, median serum LH after depot slowly released into the circulation to provide such leuprolide injection was only 0.83 mIU/mL, similar to tonic suppressive levels. levels observed after intravenous or subcutaneous gona- Depot leuprolide consists of leuprolide encased in dotropin-releasing hormone stimulation in comparable microspheres of a glycolic and lactic acid copolymer. subjects on depot leuprolide. Free leuprolide is also present in the preparation6 Conclusion. Our pharmacokinetic data demonstrate and is absorbed into the circulation within minutes that free leuprolide present in a depot leuprolide injec- of injection, while the microspheres slowly release tion is equivalent to gonadotropin-releasing hormone in stimulating a rapid rise in serum gonadotropin concen- leuprolide, providing steady, suppressive levels. trations. We propose that a single serum sample for LH Pharmacokinetic data in adults receiving therapy for 4,5 7 obtained 30 to 60 minutes after depot leuprolide injection prostate and breast cancer show that free leupro- in children provides a convenient and accurate assess- lide in the depot preparation rapidly enters the se- ment of treatment efficacy. Pediatrics 2002;109(2). URL: rum, peaking at 45 to 60 minutes. In these studies in http://www.pediatrics.org/cgi/content/full/109/2/e30; pu- adult cancer patients, a rise in serum LH and FSH berty, leuprolide, luteinizing hormone, follicle-stimulating was documented 12 hours after injection but was not hormone, gonadotropin, gonadotropin-releasing hormone. studied at earlier time points. Pharmacokinetic data for depot leuprolide in children have not been pub- ABBREVIATIONS. CPP, central precocious puberty; GnRH, gona- lished. dotropin-releasing hormone; LH, luteinizing hormone; FSH, folli- Dosage of depot leuprolide varies widely in clini- cle-stimulating hormone; IM, intramuscular; IV, intravenous; SQ, cal practice in children, ranging from 3.75 to 15 mg at subcutaneous. 2- to 4-week intervals. Insufficient doses can be coun- terproductive, as the waxing and waning of hormone entral precocious puberty (CPP) is the early levels may actually mimic the stimulatory GnRH onset of pubertal development attributable to pulses that advance puberty.8,9 Frequent testing to premature gonadotropin release by the pitu- ensure adequacy of therapy and to optimize the dose C 3 itary. Most commonly idiopathic, CPP can also result is important in monitoring treated patients. from central nervous system trauma or tumors. Un- Patients receiving depot leuprolide therapy are monitored clinically, through assessment of linear From the Department of Pediatrics, Division of Endocrinology and Diabe- growth, sexual maturation, and bone age. However, tes, Stanford University, Stanford, California. these parameters may correlate poorly with the de- This work was presented, in part, at the Western Society for Pediatric gree of suppression of gonadotropins. In addition, Research; February 2000; Carmel, CA; at the National Cooperative Growth Study; September 22, 2000; San Francisco, CA; and at the Society for there is considerable lag time in bone age advance- Pediatric Research; July 8, 2001; Montreal, Canada. ment as well as significant variability in bone-age Received for publication Jun 13, 2001; accepted Oct 22, 2001. readings among examiners.10 Because estradiol is Address correspondence to E. Kirk Neely, MD, Division of Pediatric Endo- difficult to assay accurately, measurement of LH is crinology and Diabetes, Stanford University, S-302 Medical Center M/C the key biochemical assessment of pubertal status. 5208, Stanford, CA 94305-5208. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- Spontaneous or unstimulated LH concentrations, al- emy of Pediatrics. though potentially useful in diagnosis of CPP, have http://www.pediatrics.org/cgi/content/full/109/2/Downloaded from www.aappublications.org/newse30 PEDIATRICSby guest on September Vol. 10927, 2021 No. 2 February 2002 1of6 not proven precise in monitoring pubertal suppres- estradiol or testosterone were obtained during the course of ther- sion.11 Therefore, GnRH-stimulated LH has been the apy 40 to 60 minutes after the fourth depot leuprolide dose (3 mainstay of treatment monitoring. An IV GnRH months). (Factrel, Wyeth-Ayerst, St Davids, PA) stimulation Assays test, involving multiple serum samples for LH before All serum samples were analyzed for LH and FSH at Esoterix and after an intravenous (IV) dose of GnRH, has Endocrinology (formerly Endocrine Sciences), Calabasas Hills, been commonly used12 to ensure suppression of pi- California, by immunochemiluminometric assay, which has a sen- tuitary gonadotropin release during therapy, and sitivity of 0.02 mIU/mL and an interassay variability of 10.7% for Eckert et al13 showed the utility of a single-sample LH and a sensitivity of 0.02 mIU/mL and an interassay variability of 9% for FSH.14 Samples drawn at Ϫ10 minutes were assayed at subcutaneous (SQ) GnRH stimulation test. However, Esoterix Endocrinology for estradiol by radioimmunoassay after persistent lack of availability of GnRH has made extraction and LH20 column chromatography, with a sensitivity these tests impractical. of 0.5 ng/dL and an interassay variability of 14%, or for testoster- We hypothesized that depot leuprolide contains one, with a sensitivity of 3 ng/dL and an interassay variability of enough free leuprolide to cause a rapid rise in serum 8% to 15%. Plasma was assayed for leuprolide concentration by liquid chromatography followed by mass spectroscopy at North- gonadotropin concentrations in unsuppressed pa- west Bioanalytical, Salt Lake City, Utah. This assay has a sensitiv- tients. If true, measurement of gonadotropins after ity of 0.05 ng/mL and an interassay variability of Ͻ16.5%. therapeutic injection could prove to be useful in the monitoring of treatment efficacy. Historical Data Because GnRH was unavailable, IV or SQ GnRH stimulation STUDY DESIGN could not be performed in study participants. For comparative Participants purposes historical data showing LH concentrations in response to IV and SQ GnRH stimulation tests at diagnosis and during depot All children starting depot leuprolide therapy to halt gonado- leuprolide therapy have been included. Some of these data, com- tropin-mediated pubertal development were invited to participate paring IV and SQ GnRH testing in the diagnosis of CPP, were in this study. Enrollment criteria included clinical and laboratory previously published.13 Previously unpublished data for patients evidence of central puberty in both girls and boys. Fifteen patients on therapy include LH concentrations after standard IV GnRH of 16 starting depot leuprolide therapy between February 1999 stimulation performed at the 3-month follow-up visit and LH after and August 2000 agreed to be part of the study. No samples were SQ GnRH stimulation between 3 to 6 months. obtained from 1 participant because of venous access difficulties. Written informed consent was obtained from the parents of each Statistics participant before enrollment, as well as written assent from all children over 7 years of age. The study was approved by the All data are graphed as a concentration of each analyte, LH or Stanford University Administrative Panel on Human Subjects in FSH, versus time relative to the injection. The median value is Medical Research. shown on each graph. Correlations between body weight and peak leuprolide concentration and between peak leuprolide con- Procedures centration and peak LH and FSH were calculated according to the Spearman method (SAS, Cary, NC). Median peak LH after depot Participants received their first dose of 7.5 mg of depot leupro- leuprolide and median peak LH after IV and SQ GnRH stimula- lide IM in the General Clinical Research Center. An IV catheter tion tests were compared by Wilcoxon rank-sum test. P values of was placed in an antecubital vein after EMLA cream (lidocaine less than 0.05 were considered significant. and prilocaine 2.5%) had been applied to minimize discomfort. Blood was withdrawn through the IV catheter at times Ϫ10, Ϫ1, ϩ7.5, ϩ15, ϩ30, ϩ45, ϩ60, ϩ90, and ϩ120 minutes before and RESULTS after the injection. The 7.5-minute time point was added after Participants initial results on the first 4 participants were obtained. The samples were immediately processed and serum and plasma were The participants, 12 girls and 2 boys, ranged in age frozen and stored at Ϫ20°C until analysis for LH, FSH, sex steroid, from 5.7 to 14.4 years at onset of therapy. Of the 14 and leuprolide concentrations. Subsequently, serum LH, FSH, and participants, 11 were treated for precocious puberty

TABLE 1. Subject Characteristics Study Age Gender Diagnosis Weight Tanner LH at Diagnosis* ID (Year) (kg) (BG/P/A) (mlU/mL) 01 8.9 F CPP 32 3/4/2 2.3 02 8.1 F CPP, autism 32.9 2/1/1 4.1† 03 7.1 F CPP, mild cerebral palsy 26.5 2/2/1 2.5 04 8.8 F CPP, Russell-Silver 19.4 2/3/1 6.7† syndrome 05 14.4 F Hypothyroidism, short 20.3 3/1/1 3 stature 06 7.9 M CPP, seizures 41.3 3/2/2 2 07 8.8 F CPP 43.7 4/3/1 2.9 08 9.3 F CPP, Williams syndrome 30 3/2/1 0.7 09 10.3 M Astrocytoma, short stature 31.6 3/2/1 4.6 10 12.1 F Ex-premature infant, short 38 5/4/2 3.9 stature 11 8.2 F CPP 30.1 2/1/1 1.3 12 8.3 F CPP 42.8 4/3/1 0.34 13 8.3 F CPP 30.3 2/2/2 1.5 14 5.7 F CPP 26.7 3/1/1 2.8 BG/P/A indicates breasts or genitalia/pubic hair/axillary hair. * Spontaneous LH by immunochemiluminometric assay. † LH after SQ GnRH stimulation.

2of6 RISE OF SERUMDownloaded LUTEINIZING from www.aappublications.org/news HORMONE AFTER DEPOT by guest LEUPROLIDE on September 27, 2021 and had onset of pubertal changes before 8 years of age (Table 1). The 3 oldest participants (05, 09, and 10) were pubertal and began therapy with depot leuprolide in an effort to slow bone maturation and allow for additional linear growth. Participant 09 had an elevated baseline concentration of FSH.

Serum Leuprolide Serum leuprolide concentration showed an imme- diate rise after IM injection of depot leuprolide, with levels detectable at the first time point of 7.5 minutes (Fig 1). The median leuprolide level peaked at 60 minutes (44.8 ng/mL) and then declined. There was an inverse correlation between participant body weight and maximal serum leuprolide after IM injection (r ϭϪ0.53, P ϭ .0492, Spearman).

Serum Gonadotropins

Both LH (Fig 2) and FSH (Fig 3) showed a rapid Fig 2. Serum LH concentration (mIU/mL) versus time (minutes) rise after IM depot leuprolide injection. The median after depot leuprolide IM injection. Data for 14 participants; me- LH level at baseline was 2.1 mIU/mL and promptly dian in closed circle. rose to 5.9 mIU/mL at 7.5 minutes. Median peak LH increased to 12 and 23 mIU/mL at 15 and 30 minutes, respectively, and reached a plateau of approx- imately 26 mIU/mL at all time points from 45 to 120 minutes. FSH rose less rapidly than LH, from a median value of 5.2 mIU/mL at baseline to 5.8 mIU/mL at the first time point, and to 8.9 and 12.5 mIU/mL at 15 and 30 minutes, respectively. In contrast with the plateau of LH levels, peak FSH continued to rise gradually throughout the time course, from 13.5 mIU/mL at 45 minutes to 16.5 mIU/mL at 120 minutes. Peak leuprolide concentration did not correlate with peak LH (r ϭϪ0.015, P ϭ .96, Spearman) or peak FSH (r ϭ 0.15, P ϭ .61), suggesting that the amount of leuprolide in serum is far in excess of the amount needed to fully stimulate gonadotropin release. Comparison of peak LH at onset of therapy with historical controls: Maximal LH concentrations after Fig 3. Serum FSH concentration (mIU/mL) versus time (minutes) after depot leuprolide IM injection. Data for 14 participants; median in closed circle.

the first dose of depot leuprolide were compared with those seen after either IV or SQ GnRH stimulation in historical controls at the time of diagnosis (Fig 4). The median peak LH level after depot leuprolide (27.5 mIU/mL) was similar to that after IV GnRH (27.2 mIU/mL, P ϭ .98, Wilcoxon) or SQ GnRH (22 mIU/mL, P ϭ .54).

Serum Gonadotropins During Therapy At the 3-month follow-up visit 13 of 14 participants had a history and clinical examination consis- tent with adequate suppression of puberty. Partici- pant 07 presented to the follow-up visit with complaints of cyclical abdominal pain and breast tenderness and showed clinical evidence of pubertal progression. Laboratory data at that time included Fig 1. Serum leuprolide concentration (ng/mL) versus time (min- an FSH of 7 mIU/mL and estradiol of 1.1 ng/dL. Her utes) after depot leuprolide IM injection. Data for 14 participants; LH of 5.1 mIU/mL after the fourth dose of depot median in closed circle. leuprolide was substantially higher than the LH con-

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/109/2/ by guest on September 27, 2021 e30 3of6 ulation tests after similar durations of therapy (Fig 5). The median LH values after depot leuprolide, IV GnRH (P ϭ .17), and SQ GnRH (P ϭ .22) were similar (0.83, 0.6, and 0.54 mIU/mL, respectively).

DISCUSSION A reliable laboratory method of monitoring therapeutic efficacy is needed for children receiving GnRH agonists. The dose needed to adequately suppress puberty varies considerably.8,15 Inadequate therapy can lead to clinical progression and continued advancement of bone maturation.8,9 On the other hand, excessive dosing is costly: recent phar- macy retail pricing at our hospital shows that a 3.75-mg dose of depot leuprolide costs a patient $643, Fig 4. Peak stimulated LH concentrations (mIU/mL) in untreated participants: data for study participants receiving their first dose 7.5 mg costs $855, and 11.25 mg costs $1598. More of depot leuprolide (column 1; N ϭ 14) compared with historical importantly, overtreatment may suppress endoge- data for girls with precocious puberty tested with IV GnRH (col- nous growth hormone secretion and decrease umn 2; N ϭ 16) and/or SQ GnRH (column 3; N ϭ 14) stimulation growth velocity and bone density accrual below that tests. Bar marks median values. expected in the prepubertal period.3 A convenient and reliable method of monitoring could help the centrations for all the other, clinically well-sup- practitioner to avoid undertreatment of patients with pressed, participants. Her dose of depot leuprolide CPP and also might permit judicious lowering of was increased to 11.25 mg IM every 4 weeks, and depot leuprolide dosage in well-controlled patients, repeat testing after 3 months on the higher depot with subsequent testing performed to confirm puber- leuprolide dose showed a postinjection LH of 0.94 tal suppression at the lower dose. mIU/mL. Although highlighted in Fig 5, her values Clinical scoring systems have been devised in an were excluded for the calculation of median values attempt to standardize assessment of CPP patients for treated participants. For all other participants, on therapy,16 but most continue to rely on subjective median serum LH after the 7.5 mg depot leuprolide measures such as change in bone age.10 Although injection was 0.83 mIU/mL. Median FSH was 2.2 careful clinical assessment is crucial in follow-up of mIU/mL. these patients, an objective and prompt laboratory measure of treatment success or failure is needed. Comparison of LH During Therapy With Historical The GnRH stimulation test provides just such a mea- Controls sure. IV administration remains the standard, but SQ Median LH after dose 4 for the study group was GnRH testing is reliable and more convenient.13 compared with a group of patients on therapy for However, availability of GnRH has been severely CPP previously assessed with IV or SQ GnRH stim- restricted in recent years, and GnRH testing requires an additional injection for the child. Other laboratory measures for assessing therapy have been proposed. Cook et al9 reported that over- night LH sampling detects treatment failure. This method is expensive and time-consuming, and therefore is not likely to be performed as frequently as might be desirable in treatment monitoring. Twenty- four-hour urine collection for gonadotropins has not proven reliable in discerning treatment failure.17 An ultrasensitive estradiol assay has been very promis- ing18 but has proven to be technically difficult. Sal- erno et al19 have reported serum sampling for gonadotropins and estradiol 12 hours after dosing with depot-triptorelin, another GnRH analog. Although this method also relies on the stimulatory effect of free GnRH agonist particles in the depot preparation, sampling 12 hours after the treatment dose is incon- venient as well as unnecessary. Finally, short-acting Fig 5. Stimulated LH concentrations (mIU/mL) in treated participants at dose 4 (3 months): data for participants receiving their GnRH analogs, such as nafarelin (nasal delivery) and fourth dose of depot leuprolide (column 1; N ϭ 13), compared SQ leuprolide, can be used as substitutes for GnRH with historical data for girls with precocious puberty tested with in testing,20,21 but neither therapeutic standards nor IV GnRH (column 2; N ϭ 10) and SQ GnRH (column 3; N ϭ 12) time of peak response have been established, and an stimulation tests after 3 to 6 months on depot leuprolide therapy. Bar marks median values. Participant 07 highlighted because of additional medication is still required. treatment failure and not included in calculation of median for In our study, we have shown to our knowledge the suppressed patients. first pharmacokinetic data of serum leuprolide and

4of6 RISE OF SERUMDownloaded LUTEINIZING from www.aappublications.org/news HORMONE AFTER DEPOT by guest LEUPROLIDE on September 27, 2021 gonadotropin concentrations after IM depot leupro- after depot leuprolide appears to suffice for treat- lide in children. Serum leuprolide, LH, and FSH ment monitoring. Some clinicians may wish to concentrations all rise very rapidly after a 7.5-mg continue using GnRH-stimulation tests for initial dose of depot leuprolide in pubertal children. The monitoring to establish satisfactory suppression. free leuprolide available in IM depot leuprolide func- However, given our intermittent difficulties in ob- tions interchangeably with GnRH in stimulation of taining GnRH and the relative laboriousness of other pituitary LH release, and in a rapid time course tests, the depot leuprolide stimulation test is a rea- comparable with that induced by IV GnRH. Peak LH sonable solution for long-term monitoring of depot levels 10-fold higher than basal levels are sustained therapy. Its convenience allows the test to be used from 30 to 120 minutes after depot leuprolide injec- spontaneously and frequently, facilitating more care- tion, allowing a single sample obtained at any time ful management of children with CPP. point in this range to accurately represent the maximal postdepot concentration. ACKNOWLEDGMENTS Excluding the 1 transient treatment failure, the The investigation was supported, in part, by Human Health median peak LH after the fourth injection of depot Service grant M01-RR00070, General Clinical Research Centers, leuprolide was 0.83 mIU/mL, indicating nearly com- National Center for Research Resources, National Institutes of plete suppression of pituitary LH release. This value Health, Child Health Research Fund, and TAP Pharmaceutical is similar to those observed after IV and SQ GnRH Products Inc. stimulation testing in patients during depot leuprolide therapy (Fig 5). We cannot exclude the possibil- REFERENCES ity that LH concentrations stimulated by depot leu- 1. Ehrhardt AA, Meyer-Bahlburg HF. Psychosocial aspects of precocious prolide during therapy are slightly higher than those puberty. Horm Res. 1994;41(suppl):30–35 stimulated by GnRH, as has been observed in com- 2. Graber JA, Brooks-Gunn J, Warren MP. The vulnerable transition: pu- parison of 500 ␮g SQ leuprolide and 100 ␮g IV GnRH berty and the development of eating pathology and negative mood. at the time of diagnosis of CPP.21 However, this Womens Health Issues. 1999;9:107–134 3. Lee PA. Central precocious puberty. An overview of diagnosis, treat- argument is undermined by the indistinguishable ment, and outcome. 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