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Prolactin secretion before, during, and after chronic gonadotropin-releasing hormone agonist treatments in children
Prolactin secretion before, during, and after chronic gonadotropin-releasing hormone agonist treatments in children Francesco Massart, M.D., Ph.D.,a Roberta Parrino, M.D.,b Giulia Placidi, M.D.,a Ginevra Massai, M.D.,a Giovanni Federico, M.D.,a and Giuseppe Saggese, M.D.a a Pediatric Endocrine Center/Department of Pediatrics, University of Pisa, Pisa; and b Pediatric Clinic, University of Palermo, Palermo, Italy
Objective: To examine the effect of long-term administration of GnRH agonists (GnRHa) on PRL secretion in children affected by central precocious puberty (CPP) and growth hormone deficiency (GHD). Design: Prospective analysis of blood sampling before, during, and after GnRHa treatments. Setting: Pediatric endocrine center. Patient(s): One hundred nineteen and 93 children with a diagnosis of CPP and GHD, respectively. Intervention(s): Monthly depot injections of GnRHa drugs (leuprorelin acetate 3.75 mg [LA] and triptorelin 3.75 mg [TR]) administered to CPP and GHD patients for 40 and 24 months, respectively. Main Outcome Measure(s): Serum PRL levels at baseline and after 6, 12, 18, 24, 30, 36, and 40 months of treatment with GnRHa were compared between CPP and GHD groups. PRL levels at 6 and 12 months after GnRHa withdrawal were also examined. Result(s): Although serum PRL levels tended to be higher in TR- than in LA-treated patients, no significant difference in circulating PRL in basal condition and during GnRHa treatment was detected between the CPP and GHD groups. However, five children (3.8%) developed hyperprolactinemia during TR treatment. Conclusion(s): Although there are no general concerns about GnRHa treatment safety, careful PRL monitoring is required in GnRHa-treated children. (Fertil Steril威 2005;84:719 –24. ©2005 by American Society for Reproductive Medicine.) Key Words: Gonadotropin-releasing hormone agonist, growth hormone deficiency, leuprorelin acetate, precocious puberty, prolactin, triptorelin
Gonadotropin-releasing hormone agonists (GnRHa), such as leuprorelin acetate (LA) and triptorelin (TR), have been extensively used to treat a variety of endocrine-related disorders because of their suppressive effects on serum FSH, LH, and, subsequently, gonadal sex steroids, that is, androgens and estrogens. The use of these agents to treat uterine leiomyomata, endometriosis, breast cancer, and prostate disorders in adults is well documented (1–3). GnRHa are also used to delay the effects of premature awakening of the hypothalamic-pituitarygonadal axis in children with precocious puberty (4 – 6). On the other hand, there is evidence that slowing pubertal development by administering long-acting GnRHa for a limited time may improve final height in children with growth hormone deficiency (GHD) who do not properly respond to exogenous growth hormone (GH) treatment (7, 8). Although there are no general concerns about GnRHa treatment safety, reports on the relationship between GnRHa and serum prolactin (PRL) are rather controversial. Some investigators claim that GnRHa inhibits PRL secretion both in vitro and in vivo (9, 10); some report similar plasma PRL levels
Received November 19, 2004; revised and accepted March 16, 2005. Reprint requests: Francesco Massart, M.D., Ph.D., Pediatric Endocrine Center/Department of Pediatrics, University of Pisa, Via Roma 67, 56125 Pisa, Italy (FAX: 39-050-8311-768; E-mail: [email protected]).
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.03.041
before and after gonadal suppression by GnRHa (11); and others observe a transient increase in serum PRL levels after GnRHa treatment (12–14). In this regard, Golan et al. (10) suggested that GnRHa may reduce serum PRL in women with hyperprolactinemia, although GnRHa treatment did not lower PRL levels in subjects who were euprolactinemic. Sklar et al. (11) found no difference in unstimulated PRL secretion before and after leuprolide acetate treatment of 11 children with central precocious puberty (CPP). On the other hand, Kauschansky et al. (12) reported a significant increase in PRL levels in all 13 females who underwent TR treatment for CPP and who had normal circulating PRL before the treatment. In addition, these investigators found an overt hyperprolactinemia in some of the treated patients (12). In this study, we measured circulating levels of PRL before, during, and after monthly LA and TR administration to detect the potential adverse effects of prolonged GnRHa stimulation on the pituitary PRL function in children with CPP and GHD. MATERIALS AND METHODS To further assess the behavior of circulating PRL in GnRHatreated patients, we assayed serum PRL in 119 (105 females and 14 males) and 93 (83 females and 10 males) children affected by CPP and GHD, respectively. All subjects were
Fertility and Sterility姞 Vol. 84, No. 3, September 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
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attended as outpatients at the Pediatric Endocrine Center of the Department of Pediatrics, University Hospital of Pisa, Italy, between 1999 and 2003. After receiving local Institutional Review Board approval, informed consent was obtained from all parents of patients before the beginning of the study. At the time of GnRHa treatment, patients with CPP ranged in age from 5.5 to 9.0 years and had pubertal development in the second to third Tanner’s stage for breast, pubic hair, and genital development. Patients with CPP underwent GnRHa treatment by monthly IM injection of a depot preparation of the drug. They were randomly divided into two groups according to the different GnRHa administered; group 1 included 74 of 119 patients who took TR at a dosage of 3.75 mg (Ipsen Pharma Biotech, Toulon Cedex, France), while the remaining 45 of 119, group 2, were treated with LA at a dosage of 3.75 mg (Takeda Chemical Industries, Osaka, Japan). The treatment period lasted 40 months on average. Clinical CPP diagnosis was confirmed by the following laboratory criteria for females and males aged ⱕ8 years and ⱕ9 years, respectively: E2 ⫽ 25.0 pg/mL for females, T ⫽ 3.0 ng/dL for males, and GnRH-induced rise in LH and FSH blood levels ⬎6.9 IU/L and ⬎5.0 IU/L, respectively. All of these patients had idiopathic CPP. The 93 patients included in the present study fulfilled diagnostic criteria for GHD (15): they had GH peaks less than 5 g/L after two provocative pharmacological stimuli (levodopa and insulin tolerance test) and had reduced spontaneous 24-hour GH secretion (mean GH concentration ⬍3 g/L). They did not show any associated deficiency of other pituitary hormones at diagnosis or during treatment. They received recombinant human GH (rhGH) treatment at a dosage of 30 g/kg/day, which was given SC at bedtime six times weekly. GnRHa was added to GH treatment in those patients who did not make sufficient improvements in their predicted adult height during GH administration. As mentioned above for CPP subjects, 56 of 93 underwent TR therapy in 3.75 mg doses (Ipsen Pharma Biotech) in addition to rhGH (group 3), while the remaining 37 of 93 patients with GHD were given LA 3.75 mg (Takeda Chemical Industries) (group 4). The GnRHa treatment of GHD lasted 24 months on average. All the GHD patients were in early puberty (second Tanner’s stage for breast and pubic hair) when GnRHa treatment was started. Furthermore, GnRHinduced gonadotropin circulating levels were ⬎6.9 IU/L for LH and ⬎5.0 IU/L for FSH. GnRHa suppression of gonadotropin secretion was checked every 6 months by RIA for blood levels of LH, FSH, E2, and T in both CPP and GHD children. Serum circulating levels of PRL were assayed before and during GnRHa treatment at 6-month intervals (i.e., at baseline and at 6, 12, 18, 24, 30, 36, and 40 months for the CPP group and at baseline and at 6, 12, 18, and 24 months for the GHD group). In addition, in all subjects’ blood PRL was checked at 6 and 12 months after GnRHa therapy withdrawal. 720
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TABLE 1 Clinical data of central precocious puberty (CPP) and growth hormone deficiency (GHD) patients at the start of GnRHa administration. At start of GnRHa therapy
CPP (n ⴝ 119)
Sex (F/M) 105/14 Chronological age 7.8 ⫾ 1.4 (years) Pubertal stage, median (range) Breasts 2 (2–3) Pubic hair 2 (2–3) LH (IU/L) 1.8 ⫾ 1.6 FSH (IU/L) 2.7 ⫾ 0.9 27.8 ⫾ 2.1 E2 (pg/mL) (females) T (ng/dL) (males) 2.7 ⫾ 1.3 Leuprorelin acetate74 treated subjects Triptorelin-treated 45 subjects Therapy months 40
GHD (n ⴝ 93) 83/10 8.6 ⫾ 2.1
2 (2–3) 2 (2–3) 1.3 ⫾ 0.9 2.0 ⫾ 1.2 21.4 ⫾ 3.5 1.4 ⫾ 0.4 56 37 24
Note: P⬍.05. Massart. Child PRL secretion during GnRHa treatments. Fertil Steril 2005.
Circulating PRL values were assayed by an RIA kit (Schering S.p.A., Milan, Italy). The detection limit of the method was 0.1 ng/mL; the intra-assay and interassay coefficients of variation were 5.5% and 7.5%, respectively. All blood samples from each subject were analyzed in a single assay. Data are expressed as mean ⫾ standard deviation unless otherwise stated. Statistical analysis was performed using Student’s t-test, analysis of variance (ANOVA), and Fisher’s exact test. P⬍.05 was considered statistically significant. All statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS, Chicago, IL) for Windows version 9.0. RESULTS At the start of the GnRHa therapy the auxological characteristics of CPP and GHD subjects treated with TR or LA were similar (Table 1). During GnRHa treatment, downregulation of the pituitary gland was confirmed by suppressed levels of LH, FSH, E2, and T. Before GnRHa administration, levels of LH, FSH, E2 (for females), and T (for males) were 1.6 ⫾ 0.5 IU/L, 2.4 ⫾ 0.7 IU/L, 25.0 ⫾ 3.4 pg/mL, and 2.2 ⫾ 0.8 ng/dL in both the CPP and GHD groups. They fell significantly during GnRHa treatment, with serum values of 0.75 ⫾ 0.4 IU/L, 1.24 ⫾ 0.5 IU/L, 14.5 ⫾ 1.3 pg/mL, and 0.8 ⫾ 0.5 ng/dL, respectively (P⬍.001 for all four hormones as compared with their levels before treatment). No significant difference was found between the
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FIGURE 1 (A) Serum PRL levels (⫾SD) in CPP children during 40 months of LA (open diamonds) and TR treatment (full square). (B) Mean PRL release (⫾SD) in GHD children during 24 months of LA(open triangle) and TR treatment (full circle). (C) PRL levels (⫾SD) in all LA-treated (open diamonds) and TR-treated (full square) children. Full and open arrows indicate GnRHa therapy start and stop, respectively (* and °P⬍.05 vs. baseline for TR and LA, respectively; §P⬍.05 LA vs. TR series).
(P⬍.05 for both values vs. baseline) at 6 and 12 months after TR treatment was stopped. Similarly, the mean PRL level showed a steady and significant decline during LA treatment (group 2) from a pretherapy concentration of 9.9 ⫾ 4.6 to 6.0 ⫾ 3.6 and 6.6 ⫾ 2.1 ng/mL (P⬍.05 for both values vs. baseline) at 6 and 12 months after the end of treatment. These results were confirmed by ANOVA analysis (P⬍.05 vs. basal level). In the GnRHa-treated patients, circulating PRL values at 6, 12, 18, 24, 30, 36, and 40 months were 11.7 ⫾ 5.8, 13.8 ⫾ 4.6, 10.9 ⫾ 6.6, 11.1 ⫾ 4.3, 10.4 ⫾ 6.9, 12.3 ⫾ 8.0, and 12.5 ⫾ 4.1 ng/mL in TR-treated CPP subjects (group 1, P⬎.05 for any levels vs. pretherapy) and 9.7 ⫾ 4.5, 7.5 ⫾ 3.1, 7.0 ⫾ 5.2, 8.6 ⫾ 4.8, 8.1 ⫾ 2.9, 7.6 ⫾ 3.2, and 6.0 ⫾ 2.2 ng/mL in LA-treated CPP subjects (group 2, P⬎.05 for any levels vs. pretherapy), respectively. When comparing LA and TR treatments, circulating PRL was similar at baseline and at 6 and 12 months after GnRHa treatment (P⬎.05 for all three time points). However, TR induced higher PRL levels than LA at 12, 18, 36, and 40 months of GnRHa treatment (P⬍.05 for four time points). In patients with GHD, we failed to observe any significant changes in serum PRL levels before and during 24 months of GnRHa administration (Fig. 1B). Serum PRL levels at baseline and after 6, 12, 18, and 24 months of GnRHa were 10.3 ⫾ 8.4, 13.6 ⫾ 7.5, 12.0 ⫾ 5.7, 9.6 ⫾ 6.2, and 10.8 ⫾ 6.9 ng/mL for TR-treated GHD group 3 (P⬎.05 for any time points vs. untreated value) and 9.3 ⫾ 3.8, 9.2 ⫾ 3.6, 9.0 ⫾ 3.0, 7.3 ⫾ 2.6, and 6.8 ⫾ 3.5 ng/mL for LA-treated GHD group 4 (P⬎.05 for any time points vs. untreated value). PRL values were 7.8 ⫾ 3.4 (P⬎.05 vs. pretherapy) and 6.8 ⫾ 3.3 ng/mL (P⬍.05 vs. pretherapy) for the TR group and 6.2 ⫾ 3.0 and 6.2 ⫾ 2.3 ng/mL (P⬍.05 for both values vs. pretherapy) for the LA group at 6 and 12 months after GnRHa withdrawal, respectively. No difference was detected between the LA and TR GHD groups before, during, or after GnRHa treatment (P⬎.05 TR vs. LA). Also, none of the PRL levels were statistically different as assessed by ANOVA (P⬎.05).
Massart. Child PRL secretion during GnRHa treatments. Fertil Steril 2005.
CPP and GHD groups before and during GnRHa treatment (P⬎.05). Figure 1A shows circulating PRL levels (means ⫾ SD) of CPP patients at diagnosis (baseline) and during 40 months of LA and TR treatments and 6 and 12 months after its withdrawal. In the TR-treated CPP group (group 1), the mean PRL level rose from 10.1 ⫾ 6.0 ng/mL at untreated baseline to 13.8 ⫾ 4.6 ng/mL after 12 months of TR therapy, gradually declining thereafter to 7.0 ⫾ 2.8 and 6.9 ⫾ 2.9 ng/mL Fertility and Sterility姞
Although circulating PRL behaved quite similarly in both CPP and GHD patients in response to GnRHa administration, TR induced higher PRL levels than LA in both conditions (Fig. 1A, 1B). The same behavior was still present even after the results obtained in all the TR-treated patients were cumulated and compared with those found in the LA-treated ones (Fig. 1C). Serum PRL levels at baseline and after 6, 12, 18, and 24 months of GnRHa treatment were 10.2 ⫾ 7.0, 12.5 ⫾ 6.6, 13.0 ⫾ 5.1, 10.3 ⫾ 6.4, and 11.0 ⫾ 5.5 ng/mL in TR-treated subjects (group 1 plus 3; P⬎.05 for any time points vs. basal value) and 9.7 ⫾ 4.2, 9.5 ⫾ 4.1, 8.5 ⫾ 4.8, 7.1 ⫾ 4.2, and 7.8 ⫾ 4.0 ng/mL in patients treated with LA (group 2 plus 4; P⬎.05 for any time points vs. basal value). Although PRL levels were similar at basal levels and at 24 months (P⬎.05 for TR vs. LA series), TR-induced PRL was significantly higher than LA-induced PRL at 6, 12, and 18 months (P⬍.05 for TR vs. LA series). ANOVA analysis did 721
FIGURE 2 Mean PRL values (⫾SD) in CPP children during 40 months of LA (open diamonds) and TR treatment (full squares). Five CPP children with TR-induced hyperprolactinemia are indicated (full triangle; *P⬍.05 vs. both untreated baseline and TRinduced PRL mean). Full and open arrows indicate GnRHa therapy start and stop, respectively.
Massart. Child PRL secretion during GnRHa treatments. Fertil Steril 2005.
not detect any significant difference among LA and TR series (P⬎.05). Using a PRL level cutoff ⬎35 ng/mL, five of 130 TRtreated patients (3.8%) (Fig. 2) showed a steady and significant increase of circulating PRL levels from untreated baseline (12.5 ⫾ 3.7 ng/mL) to 38.6 ⫾ 3.8, 41.0 ⫾ 6.4, 43.5 ⫾ 4.0, 49.5 ⫾ 5.6, 36.9 ⫾ 5.2, 38.1 ⫾ 4.5, and 45.6 ⫾ 4.5 ng/mL after 6, 12, 18, 24, 30, 36, and 40 months of TR treatment, respectively (P⬍.05 vs. untreated baseline). However, these PRL values normalized after GnRHa withdrawal: 13.7 ⫾ 8.9 and 17.2 ⫾ 7.8 ng/mL at 6 and 12 months, respectively (P⬎.05 vs. untreated baseline). All five of these patients were TR-treated CPP females who did not show any typical clinical symptoms of hyperprolactinemia. Tumors, hypothyroidism, gonadotropin-independent puberty, and polycystic ovary syndrome were periodically excluded, and the patient’s magnetic resonance image was always normal during and after GnRHa treatment. No cases of hyperprolactinemia were found in our 82 LA-treated subjects. No difference was detected comparing LA and TR GHD groups before, during, or after GnRHa treatment (P⬎.05 TR vs. LA). Using Fisher’s exact test, no significant difference was detected among LA- and TR-treated groups compared with hyper and normal PRL values (P⬎.05). DISCUSSION Over the last 20 years, long-acting GnRHa has been widely used to induce gonadal suppression as treatment for a variety of endocrine diseases (1– 4). Chronic administration of GnRHa was found to inhibit release of LH and FSH by down-regulating the receptors for gonadotropins and leading in turn to reduced levels of sex steroids. These drugs may 722
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also affect the secretion of pituitary hormones other than gonadotropins such as GH (16). In this regard, GnRHa affects the GH-IGF1 function through its suppressive effect on the sex steroids, which are known to exert a stimulatory action on the GH-IGF1 endocrine axis (8, 11). However, specific mechanisms by which GnRHa may affect pituitary hormonal secretion other than gonadotropins are still unknown. With regard to thyroid-stimulating hormone (TSH), Chantilis et al. (17) found no alteration in basal or thyrotropin-releasing hormone (TRH)-stimulated TSH secretion in reproductive-age women chronically treated with GnRHa. These results were in agreement with those by Cedars and colleagues (18), who did not find any change in the free thyroxin index in women receiving chronic GnRHa. On the other hand, GnRHa did not seem to affect both basal and corticotropin-releasing hormonestimulated ACTH release (19). With regard to PRL secretion, most published studies focused on GnRHa-treated adults affected by endometriosis, uterine leiomyomata, and breast and prostate cancers, and several investigators did not find any significant difference in basal PRL levels in adult women chronically exposed to GnRHa (9, 10, 17, 20). Venturini et al. (20) followed up 32 adult women with endometriosis who were treated for 6 months with GnRHa goserelin acetate depot. These investigators concluded that there were no significant differences in basal serum PRL levels in comparison with those found during GnRHa administration. In addition, 15 adult euprolactinemic women treated with TR for uterine leiomyomata did not show any significant change in their serum PRL values during treatment, whereas one of them showing hyperprolactinemia had significant suppression of serum PRL during GnRHa administration (10). Chantilis et al. (17) reported that GnRHa did not significantly affect baseline or TRH-stimulated PRL levels in ovulatory adult women. On the contrary, other investigators (21, 22) observed that chronic GnRHa treatment may result in diminished serum PRL levels in comparison with controls; however, it should be considered that these contrasting results may reflect the higher E2 serum levels in the control group because estrogens are believed to augment PRL secretion in women (23). At present, sporadic data are available for children regarding GnRHa-induced PRL secretion. Sklar et al. (11) reported no difference in unstimulated PRL secretion before and after leuprolide acetate treatment of only 11 CPP children. In contrast, 13 girls aged 6.5–11 years with idiopathic CPP were all found to have a significant increase of serum PRL levels within the first 6 months of TR treatment (12). Indeed, all 13 CPP females had normal serum PRL values (5–20 ng/mL) before TR treatment initiation and all of them had increased PRL release (21.5 ⫾ 12.5 ng/mL), reaching hyperprolactinemia in five CPP patients (12). It is interesting to note that although GnRHa drugs are generally considered safe, data on potential long-term side effects are quite limited.
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All this information prompted us to examine possible adverse GnRHa effects on the PRL secretion in children. With this in mind, we compared two widely used GnRHa (i.e., TR and LA) treatments in CPP and GHD patients. Because of similar clinical outcomes of LA and TR, these GnRHa drugs were randomly chosen for treatment in CPP and GHD children. To our knowledge, this is actually the longest PRL monitoring study in CPP children. Also, the present study evaluated for the first time the possible GnRHa effects on the PRL secretion in GHD children in relation to different GnRHa drugs.
CPP and not for GHD too. Similarly, although LA did not seem to affect PRL secretion such as TR, larger studies are needed to verify this clinical finding.
In agreement with previous reports (11), we generally found no significant difference between basal and GnRHstimulated secretion of PRL, although PRL values were significantly lower after both LA and TR withdrawal. Furthermore, this trend was in both the CPP and the GHD groups. The major concern is that GnRHa treatment (i.e., LA and TR) did not generally affect hypothalamic PRL secretion during GnRHa treatment, although TR-treated subjects had slightly increased PRL levels in comparison with those we found in LA-treated CPP and GHD patients.
In summary, we analyzed the effects of long-term administration of two widely used GnRHa treatments such as TR and LA on the PRL release. For the most part, we found no alteration in basal or stimulated patterns of PRL secretion in children chronically treated with GnRHa for both CPP and GHD, although some TR-treated subjects developed hyperprolactinemia. Because the clinical importance of this observation is also unclear, we suggest a routine check of PRL secretion before, during, and after long-acting GnRHa treatment.
On the other hand (with regard to the PRL level cutoff of ⬎35 ng/mL), we observed stable hyperprolactinemia in five (3.8%) of our 130 TR-treated children, which suggests that TR therapy may rarely alter PRL secretion. In these five subjects, we cannot identify any factor (e.g., drug cotherapy, endocrine or other disorders, etc.) that could explain or contribute to the abnormal PRL response. Although no formal mechanism has been identified, our data agreed with those of Kauschansky et al. (12), who reported 5 of 13 CPP patients reaching hyperprolactinemia within 6 months of TR therapy. However, the investigators did not report PRL behavior after TR withdrawal. Of special interest, in our five hyperprolactinemic patients, PRL secretion normalized within 6 months of TR stop, supporting hyperprolactinemia as a transient adverse effect of TR treatment. Alternatively, it may be that in our patients TR administration simply disclosed the presence of such a small PRL-secreting adenoma that it was not resolved by magnetic resonance imaging. However, the latter hypothesis seemed unlikely because of the negative screening for PRL-related disorders and of normalized PRL values at 6 and 12 months after TR withdrawal. Therefore, the present data suggest that chronic TR treatment may induce a transient alteration in the PRL secretion but without clinical relevance for treated patients. Indeed, all five of our patients did not show any of the typical clinical symptoms of hyperprolactinemia during and after TR treatment. In our opinion, it is possible to continue TR treatment in these patients who developed hyperprolactinemia if there are no clinical symptoms of hyperprolactinemia. In this instance, careful patient monitoring is required. Although the five hyperprolactinemic children were treated by TR for CPP, our GHD population is too small to assume that TR-induced hyperprolactinemia is exclusive for Fertility and Sterility姞
Up to now, there is no consensus about monitoring PRL function in GnRHa-treated patients. However, we suggest obtaining PRL levels before initiation of GnRHa therapy and at 4 – 6 months of such therapy. Then, in our opinion, two examinations each year of circulating PRL values are a useful tool for monitoring the early development of hyperprolactinemia in GnRHa-treated children.
Acknowledgments: The authors thank Sara Galliano, M.D., Patrizia Gerini, pediatric nurse, and Teresa Vanacore, M.D., for their technical support.
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Child PRL secretion during GnRHa treatments
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Objective: To examine the effect of long-term administration of GnRH agonists (GnRHa) on PRL secretion in children affected by central precocious puberty (CPP) and growth hormone deficiency (GHD). Design: Prospective analysis of blood sampling before, during, and after GnRHa treatments. Setting: Pediatric endocrine center. Patient(s): One hundred nineteen and 93 children with a diagnosis of CPP and GHD, respectively. Intervention(s): Monthly depot injections of GnRHa drugs (leuprorelin acetate 3.75 mg [LA] and triptorelin 3.75 mg [TR]) administered to CPP and GHD patients for 40 and 24 months, respectively. Main Outcome Measure(s): Serum PRL levels at baseline and after 6, 12, 18, 24, 30, 36, and 40 months of treatment with GnRHa were compared between CPP and GHD groups. PRL levels at 6 and 12 months after GnRHa withdrawal were also examined. Result(s): Although serum PRL levels tended to be higher in TR- than in LA-treated patients, no significant difference in circulating PRL in basal condition and during GnRHa treatment was detected between the CPP and GHD groups. However, five children (3.8%) developed hyperprolactinemia during TR treatment. Conclusion(s): Although there are no general concerns about GnRHa treatment safety, careful PRL monitoring is required in GnRHa-treated children. (Fertil Steril威 2005;84:719 –24. ©2005 by American Society for Reproductive Medicine.) Key Words: Gonadotropin-releasing hormone agonist, growth hormone deficiency, leuprorelin acetate, precocious puberty, prolactin, triptorelin
Gonadotropin-releasing hormone agonists (GnRHa), such as leuprorelin acetate (LA) and triptorelin (TR), have been extensively used to treat a variety of endocrine-related disorders because of their suppressive effects on serum FSH, LH, and, subsequently, gonadal sex steroids, that is, androgens and estrogens. The use of these agents to treat uterine leiomyomata, endometriosis, breast cancer, and prostate disorders in adults is well documented (1–3). GnRHa are also used to delay the effects of premature awakening of the hypothalamic-pituitarygonadal axis in children with precocious puberty (4 – 6). On the other hand, there is evidence that slowing pubertal development by administering long-acting GnRHa for a limited time may improve final height in children with growth hormone deficiency (GHD) who do not properly respond to exogenous growth hormone (GH) treatment (7, 8). Although there are no general concerns about GnRHa treatment safety, reports on the relationship between GnRHa and serum prolactin (PRL) are rather controversial. Some investigators claim that GnRHa inhibits PRL secretion both in vitro and in vivo (9, 10); some report similar plasma PRL levels
Received November 19, 2004; revised and accepted March 16, 2005. Reprint requests: Francesco Massart, M.D., Ph.D., Pediatric Endocrine Center/Department of Pediatrics, University of Pisa, Via Roma 67, 56125 Pisa, Italy (FAX: 39-050-8311-768; E-mail: [email protected]).
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.03.041
before and after gonadal suppression by GnRHa (11); and others observe a transient increase in serum PRL levels after GnRHa treatment (12–14). In this regard, Golan et al. (10) suggested that GnRHa may reduce serum PRL in women with hyperprolactinemia, although GnRHa treatment did not lower PRL levels in subjects who were euprolactinemic. Sklar et al. (11) found no difference in unstimulated PRL secretion before and after leuprolide acetate treatment of 11 children with central precocious puberty (CPP). On the other hand, Kauschansky et al. (12) reported a significant increase in PRL levels in all 13 females who underwent TR treatment for CPP and who had normal circulating PRL before the treatment. In addition, these investigators found an overt hyperprolactinemia in some of the treated patients (12). In this study, we measured circulating levels of PRL before, during, and after monthly LA and TR administration to detect the potential adverse effects of prolonged GnRHa stimulation on the pituitary PRL function in children with CPP and GHD. MATERIALS AND METHODS To further assess the behavior of circulating PRL in GnRHatreated patients, we assayed serum PRL in 119 (105 females and 14 males) and 93 (83 females and 10 males) children affected by CPP and GHD, respectively. All subjects were
Fertility and Sterility姞 Vol. 84, No. 3, September 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
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attended as outpatients at the Pediatric Endocrine Center of the Department of Pediatrics, University Hospital of Pisa, Italy, between 1999 and 2003. After receiving local Institutional Review Board approval, informed consent was obtained from all parents of patients before the beginning of the study. At the time of GnRHa treatment, patients with CPP ranged in age from 5.5 to 9.0 years and had pubertal development in the second to third Tanner’s stage for breast, pubic hair, and genital development. Patients with CPP underwent GnRHa treatment by monthly IM injection of a depot preparation of the drug. They were randomly divided into two groups according to the different GnRHa administered; group 1 included 74 of 119 patients who took TR at a dosage of 3.75 mg (Ipsen Pharma Biotech, Toulon Cedex, France), while the remaining 45 of 119, group 2, were treated with LA at a dosage of 3.75 mg (Takeda Chemical Industries, Osaka, Japan). The treatment period lasted 40 months on average. Clinical CPP diagnosis was confirmed by the following laboratory criteria for females and males aged ⱕ8 years and ⱕ9 years, respectively: E2 ⫽ 25.0 pg/mL for females, T ⫽ 3.0 ng/dL for males, and GnRH-induced rise in LH and FSH blood levels ⬎6.9 IU/L and ⬎5.0 IU/L, respectively. All of these patients had idiopathic CPP. The 93 patients included in the present study fulfilled diagnostic criteria for GHD (15): they had GH peaks less than 5 g/L after two provocative pharmacological stimuli (levodopa and insulin tolerance test) and had reduced spontaneous 24-hour GH secretion (mean GH concentration ⬍3 g/L). They did not show any associated deficiency of other pituitary hormones at diagnosis or during treatment. They received recombinant human GH (rhGH) treatment at a dosage of 30 g/kg/day, which was given SC at bedtime six times weekly. GnRHa was added to GH treatment in those patients who did not make sufficient improvements in their predicted adult height during GH administration. As mentioned above for CPP subjects, 56 of 93 underwent TR therapy in 3.75 mg doses (Ipsen Pharma Biotech) in addition to rhGH (group 3), while the remaining 37 of 93 patients with GHD were given LA 3.75 mg (Takeda Chemical Industries) (group 4). The GnRHa treatment of GHD lasted 24 months on average. All the GHD patients were in early puberty (second Tanner’s stage for breast and pubic hair) when GnRHa treatment was started. Furthermore, GnRHinduced gonadotropin circulating levels were ⬎6.9 IU/L for LH and ⬎5.0 IU/L for FSH. GnRHa suppression of gonadotropin secretion was checked every 6 months by RIA for blood levels of LH, FSH, E2, and T in both CPP and GHD children. Serum circulating levels of PRL were assayed before and during GnRHa treatment at 6-month intervals (i.e., at baseline and at 6, 12, 18, 24, 30, 36, and 40 months for the CPP group and at baseline and at 6, 12, 18, and 24 months for the GHD group). In addition, in all subjects’ blood PRL was checked at 6 and 12 months after GnRHa therapy withdrawal. 720
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TABLE 1 Clinical data of central precocious puberty (CPP) and growth hormone deficiency (GHD) patients at the start of GnRHa administration. At start of GnRHa therapy
CPP (n ⴝ 119)
Sex (F/M) 105/14 Chronological age 7.8 ⫾ 1.4 (years) Pubertal stage, median (range) Breasts 2 (2–3) Pubic hair 2 (2–3) LH (IU/L) 1.8 ⫾ 1.6 FSH (IU/L) 2.7 ⫾ 0.9 27.8 ⫾ 2.1 E2 (pg/mL) (females) T (ng/dL) (males) 2.7 ⫾ 1.3 Leuprorelin acetate74 treated subjects Triptorelin-treated 45 subjects Therapy months 40
GHD (n ⴝ 93) 83/10 8.6 ⫾ 2.1
2 (2–3) 2 (2–3) 1.3 ⫾ 0.9 2.0 ⫾ 1.2 21.4 ⫾ 3.5 1.4 ⫾ 0.4 56 37 24
Note: P⬍.05. Massart. Child PRL secretion during GnRHa treatments. Fertil Steril 2005.
Circulating PRL values were assayed by an RIA kit (Schering S.p.A., Milan, Italy). The detection limit of the method was 0.1 ng/mL; the intra-assay and interassay coefficients of variation were 5.5% and 7.5%, respectively. All blood samples from each subject were analyzed in a single assay. Data are expressed as mean ⫾ standard deviation unless otherwise stated. Statistical analysis was performed using Student’s t-test, analysis of variance (ANOVA), and Fisher’s exact test. P⬍.05 was considered statistically significant. All statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS, Chicago, IL) for Windows version 9.0. RESULTS At the start of the GnRHa therapy the auxological characteristics of CPP and GHD subjects treated with TR or LA were similar (Table 1). During GnRHa treatment, downregulation of the pituitary gland was confirmed by suppressed levels of LH, FSH, E2, and T. Before GnRHa administration, levels of LH, FSH, E2 (for females), and T (for males) were 1.6 ⫾ 0.5 IU/L, 2.4 ⫾ 0.7 IU/L, 25.0 ⫾ 3.4 pg/mL, and 2.2 ⫾ 0.8 ng/dL in both the CPP and GHD groups. They fell significantly during GnRHa treatment, with serum values of 0.75 ⫾ 0.4 IU/L, 1.24 ⫾ 0.5 IU/L, 14.5 ⫾ 1.3 pg/mL, and 0.8 ⫾ 0.5 ng/dL, respectively (P⬍.001 for all four hormones as compared with their levels before treatment). No significant difference was found between the
Child PRL secretion during GnRHa treatments
Vol. 84, No. 3, September 2005
FIGURE 1 (A) Serum PRL levels (⫾SD) in CPP children during 40 months of LA (open diamonds) and TR treatment (full square). (B) Mean PRL release (⫾SD) in GHD children during 24 months of LA(open triangle) and TR treatment (full circle). (C) PRL levels (⫾SD) in all LA-treated (open diamonds) and TR-treated (full square) children. Full and open arrows indicate GnRHa therapy start and stop, respectively (* and °P⬍.05 vs. baseline for TR and LA, respectively; §P⬍.05 LA vs. TR series).
(P⬍.05 for both values vs. baseline) at 6 and 12 months after TR treatment was stopped. Similarly, the mean PRL level showed a steady and significant decline during LA treatment (group 2) from a pretherapy concentration of 9.9 ⫾ 4.6 to 6.0 ⫾ 3.6 and 6.6 ⫾ 2.1 ng/mL (P⬍.05 for both values vs. baseline) at 6 and 12 months after the end of treatment. These results were confirmed by ANOVA analysis (P⬍.05 vs. basal level). In the GnRHa-treated patients, circulating PRL values at 6, 12, 18, 24, 30, 36, and 40 months were 11.7 ⫾ 5.8, 13.8 ⫾ 4.6, 10.9 ⫾ 6.6, 11.1 ⫾ 4.3, 10.4 ⫾ 6.9, 12.3 ⫾ 8.0, and 12.5 ⫾ 4.1 ng/mL in TR-treated CPP subjects (group 1, P⬎.05 for any levels vs. pretherapy) and 9.7 ⫾ 4.5, 7.5 ⫾ 3.1, 7.0 ⫾ 5.2, 8.6 ⫾ 4.8, 8.1 ⫾ 2.9, 7.6 ⫾ 3.2, and 6.0 ⫾ 2.2 ng/mL in LA-treated CPP subjects (group 2, P⬎.05 for any levels vs. pretherapy), respectively. When comparing LA and TR treatments, circulating PRL was similar at baseline and at 6 and 12 months after GnRHa treatment (P⬎.05 for all three time points). However, TR induced higher PRL levels than LA at 12, 18, 36, and 40 months of GnRHa treatment (P⬍.05 for four time points). In patients with GHD, we failed to observe any significant changes in serum PRL levels before and during 24 months of GnRHa administration (Fig. 1B). Serum PRL levels at baseline and after 6, 12, 18, and 24 months of GnRHa were 10.3 ⫾ 8.4, 13.6 ⫾ 7.5, 12.0 ⫾ 5.7, 9.6 ⫾ 6.2, and 10.8 ⫾ 6.9 ng/mL for TR-treated GHD group 3 (P⬎.05 for any time points vs. untreated value) and 9.3 ⫾ 3.8, 9.2 ⫾ 3.6, 9.0 ⫾ 3.0, 7.3 ⫾ 2.6, and 6.8 ⫾ 3.5 ng/mL for LA-treated GHD group 4 (P⬎.05 for any time points vs. untreated value). PRL values were 7.8 ⫾ 3.4 (P⬎.05 vs. pretherapy) and 6.8 ⫾ 3.3 ng/mL (P⬍.05 vs. pretherapy) for the TR group and 6.2 ⫾ 3.0 and 6.2 ⫾ 2.3 ng/mL (P⬍.05 for both values vs. pretherapy) for the LA group at 6 and 12 months after GnRHa withdrawal, respectively. No difference was detected between the LA and TR GHD groups before, during, or after GnRHa treatment (P⬎.05 TR vs. LA). Also, none of the PRL levels were statistically different as assessed by ANOVA (P⬎.05).
Massart. Child PRL secretion during GnRHa treatments. Fertil Steril 2005.
CPP and GHD groups before and during GnRHa treatment (P⬎.05). Figure 1A shows circulating PRL levels (means ⫾ SD) of CPP patients at diagnosis (baseline) and during 40 months of LA and TR treatments and 6 and 12 months after its withdrawal. In the TR-treated CPP group (group 1), the mean PRL level rose from 10.1 ⫾ 6.0 ng/mL at untreated baseline to 13.8 ⫾ 4.6 ng/mL after 12 months of TR therapy, gradually declining thereafter to 7.0 ⫾ 2.8 and 6.9 ⫾ 2.9 ng/mL Fertility and Sterility姞
Although circulating PRL behaved quite similarly in both CPP and GHD patients in response to GnRHa administration, TR induced higher PRL levels than LA in both conditions (Fig. 1A, 1B). The same behavior was still present even after the results obtained in all the TR-treated patients were cumulated and compared with those found in the LA-treated ones (Fig. 1C). Serum PRL levels at baseline and after 6, 12, 18, and 24 months of GnRHa treatment were 10.2 ⫾ 7.0, 12.5 ⫾ 6.6, 13.0 ⫾ 5.1, 10.3 ⫾ 6.4, and 11.0 ⫾ 5.5 ng/mL in TR-treated subjects (group 1 plus 3; P⬎.05 for any time points vs. basal value) and 9.7 ⫾ 4.2, 9.5 ⫾ 4.1, 8.5 ⫾ 4.8, 7.1 ⫾ 4.2, and 7.8 ⫾ 4.0 ng/mL in patients treated with LA (group 2 plus 4; P⬎.05 for any time points vs. basal value). Although PRL levels were similar at basal levels and at 24 months (P⬎.05 for TR vs. LA series), TR-induced PRL was significantly higher than LA-induced PRL at 6, 12, and 18 months (P⬍.05 for TR vs. LA series). ANOVA analysis did 721
FIGURE 2 Mean PRL values (⫾SD) in CPP children during 40 months of LA (open diamonds) and TR treatment (full squares). Five CPP children with TR-induced hyperprolactinemia are indicated (full triangle; *P⬍.05 vs. both untreated baseline and TRinduced PRL mean). Full and open arrows indicate GnRHa therapy start and stop, respectively.
Massart. Child PRL secretion during GnRHa treatments. Fertil Steril 2005.
not detect any significant difference among LA and TR series (P⬎.05). Using a PRL level cutoff ⬎35 ng/mL, five of 130 TRtreated patients (3.8%) (Fig. 2) showed a steady and significant increase of circulating PRL levels from untreated baseline (12.5 ⫾ 3.7 ng/mL) to 38.6 ⫾ 3.8, 41.0 ⫾ 6.4, 43.5 ⫾ 4.0, 49.5 ⫾ 5.6, 36.9 ⫾ 5.2, 38.1 ⫾ 4.5, and 45.6 ⫾ 4.5 ng/mL after 6, 12, 18, 24, 30, 36, and 40 months of TR treatment, respectively (P⬍.05 vs. untreated baseline). However, these PRL values normalized after GnRHa withdrawal: 13.7 ⫾ 8.9 and 17.2 ⫾ 7.8 ng/mL at 6 and 12 months, respectively (P⬎.05 vs. untreated baseline). All five of these patients were TR-treated CPP females who did not show any typical clinical symptoms of hyperprolactinemia. Tumors, hypothyroidism, gonadotropin-independent puberty, and polycystic ovary syndrome were periodically excluded, and the patient’s magnetic resonance image was always normal during and after GnRHa treatment. No cases of hyperprolactinemia were found in our 82 LA-treated subjects. No difference was detected comparing LA and TR GHD groups before, during, or after GnRHa treatment (P⬎.05 TR vs. LA). Using Fisher’s exact test, no significant difference was detected among LA- and TR-treated groups compared with hyper and normal PRL values (P⬎.05). DISCUSSION Over the last 20 years, long-acting GnRHa has been widely used to induce gonadal suppression as treatment for a variety of endocrine diseases (1– 4). Chronic administration of GnRHa was found to inhibit release of LH and FSH by down-regulating the receptors for gonadotropins and leading in turn to reduced levels of sex steroids. These drugs may 722
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also affect the secretion of pituitary hormones other than gonadotropins such as GH (16). In this regard, GnRHa affects the GH-IGF1 function through its suppressive effect on the sex steroids, which are known to exert a stimulatory action on the GH-IGF1 endocrine axis (8, 11). However, specific mechanisms by which GnRHa may affect pituitary hormonal secretion other than gonadotropins are still unknown. With regard to thyroid-stimulating hormone (TSH), Chantilis et al. (17) found no alteration in basal or thyrotropin-releasing hormone (TRH)-stimulated TSH secretion in reproductive-age women chronically treated with GnRHa. These results were in agreement with those by Cedars and colleagues (18), who did not find any change in the free thyroxin index in women receiving chronic GnRHa. On the other hand, GnRHa did not seem to affect both basal and corticotropin-releasing hormonestimulated ACTH release (19). With regard to PRL secretion, most published studies focused on GnRHa-treated adults affected by endometriosis, uterine leiomyomata, and breast and prostate cancers, and several investigators did not find any significant difference in basal PRL levels in adult women chronically exposed to GnRHa (9, 10, 17, 20). Venturini et al. (20) followed up 32 adult women with endometriosis who were treated for 6 months with GnRHa goserelin acetate depot. These investigators concluded that there were no significant differences in basal serum PRL levels in comparison with those found during GnRHa administration. In addition, 15 adult euprolactinemic women treated with TR for uterine leiomyomata did not show any significant change in their serum PRL values during treatment, whereas one of them showing hyperprolactinemia had significant suppression of serum PRL during GnRHa administration (10). Chantilis et al. (17) reported that GnRHa did not significantly affect baseline or TRH-stimulated PRL levels in ovulatory adult women. On the contrary, other investigators (21, 22) observed that chronic GnRHa treatment may result in diminished serum PRL levels in comparison with controls; however, it should be considered that these contrasting results may reflect the higher E2 serum levels in the control group because estrogens are believed to augment PRL secretion in women (23). At present, sporadic data are available for children regarding GnRHa-induced PRL secretion. Sklar et al. (11) reported no difference in unstimulated PRL secretion before and after leuprolide acetate treatment of only 11 CPP children. In contrast, 13 girls aged 6.5–11 years with idiopathic CPP were all found to have a significant increase of serum PRL levels within the first 6 months of TR treatment (12). Indeed, all 13 CPP females had normal serum PRL values (5–20 ng/mL) before TR treatment initiation and all of them had increased PRL release (21.5 ⫾ 12.5 ng/mL), reaching hyperprolactinemia in five CPP patients (12). It is interesting to note that although GnRHa drugs are generally considered safe, data on potential long-term side effects are quite limited.
Child PRL secretion during GnRHa treatments
Vol. 84, No. 3, September 2005
All this information prompted us to examine possible adverse GnRHa effects on the PRL secretion in children. With this in mind, we compared two widely used GnRHa (i.e., TR and LA) treatments in CPP and GHD patients. Because of similar clinical outcomes of LA and TR, these GnRHa drugs were randomly chosen for treatment in CPP and GHD children. To our knowledge, this is actually the longest PRL monitoring study in CPP children. Also, the present study evaluated for the first time the possible GnRHa effects on the PRL secretion in GHD children in relation to different GnRHa drugs.
CPP and not for GHD too. Similarly, although LA did not seem to affect PRL secretion such as TR, larger studies are needed to verify this clinical finding.
In agreement with previous reports (11), we generally found no significant difference between basal and GnRHstimulated secretion of PRL, although PRL values were significantly lower after both LA and TR withdrawal. Furthermore, this trend was in both the CPP and the GHD groups. The major concern is that GnRHa treatment (i.e., LA and TR) did not generally affect hypothalamic PRL secretion during GnRHa treatment, although TR-treated subjects had slightly increased PRL levels in comparison with those we found in LA-treated CPP and GHD patients.
In summary, we analyzed the effects of long-term administration of two widely used GnRHa treatments such as TR and LA on the PRL release. For the most part, we found no alteration in basal or stimulated patterns of PRL secretion in children chronically treated with GnRHa for both CPP and GHD, although some TR-treated subjects developed hyperprolactinemia. Because the clinical importance of this observation is also unclear, we suggest a routine check of PRL secretion before, during, and after long-acting GnRHa treatment.
On the other hand (with regard to the PRL level cutoff of ⬎35 ng/mL), we observed stable hyperprolactinemia in five (3.8%) of our 130 TR-treated children, which suggests that TR therapy may rarely alter PRL secretion. In these five subjects, we cannot identify any factor (e.g., drug cotherapy, endocrine or other disorders, etc.) that could explain or contribute to the abnormal PRL response. Although no formal mechanism has been identified, our data agreed with those of Kauschansky et al. (12), who reported 5 of 13 CPP patients reaching hyperprolactinemia within 6 months of TR therapy. However, the investigators did not report PRL behavior after TR withdrawal. Of special interest, in our five hyperprolactinemic patients, PRL secretion normalized within 6 months of TR stop, supporting hyperprolactinemia as a transient adverse effect of TR treatment. Alternatively, it may be that in our patients TR administration simply disclosed the presence of such a small PRL-secreting adenoma that it was not resolved by magnetic resonance imaging. However, the latter hypothesis seemed unlikely because of the negative screening for PRL-related disorders and of normalized PRL values at 6 and 12 months after TR withdrawal. Therefore, the present data suggest that chronic TR treatment may induce a transient alteration in the PRL secretion but without clinical relevance for treated patients. Indeed, all five of our patients did not show any of the typical clinical symptoms of hyperprolactinemia during and after TR treatment. In our opinion, it is possible to continue TR treatment in these patients who developed hyperprolactinemia if there are no clinical symptoms of hyperprolactinemia. In this instance, careful patient monitoring is required. Although the five hyperprolactinemic children were treated by TR for CPP, our GHD population is too small to assume that TR-induced hyperprolactinemia is exclusive for Fertility and Sterility姞
Up to now, there is no consensus about monitoring PRL function in GnRHa-treated patients. However, we suggest obtaining PRL levels before initiation of GnRHa therapy and at 4 – 6 months of such therapy. Then, in our opinion, two examinations each year of circulating PRL values are a useful tool for monitoring the early development of hyperprolactinemia in GnRHa-treated children.
Acknowledgments: The authors thank Sara Galliano, M.D., Patrizia Gerini, pediatric nurse, and Teresa Vanacore, M.D., for their technical support.
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