David Strich

The Histrelin Implant: A Novel Treatment for Central Precocious Puberty

Objective. Standard treatment of central precocious puberty (CPP) consists of intramuscular or subcutaneous administration of a gonadotropin-releasing hormone (GnRH) agonist (GnRHa) at 3- to 4-week intervals. Although generally effective in suppressing clinical and laboratory parameters of puberty, GnRHa injections are painful, and the need for monthly clinic visits may contribute to poor compliance. Recently, a subcutaneous implant was developed that releases the GnRHa histrelin at an average rate of 65 μg/day. The aims of this study were to determine if a histrelin implant would suppress gonadotropin and estradiol (E2) in girls with CPP for 1 year and to compare the suppression to standard treatment. Methods. We studied 11 girls with CPP to determine if the histrelin implant can maintain long-term gonadotropin suppression. Mean age at diagnosis was 6 years (range: 2–9 years). GnRH (100 μg intravenously) stimulation tests (GnRH-STs) showed peak luteinizing hormone and follicle-stimulating hormone responses of 23 ± 28 (mean ± SD) and 20 ± 25 mIU/mL, respectively. All subjects were initially treated with depot intramuscular GnRHa triptorelin embonate. Implants were inserted subcutaneously under local anesthesia, and depot GnRHa treatment was discontinued. Six girls were followed for 15 months after insertion (group A). For the remaining 5 girls, the implant was removed after 9 months, and a new implant was inserted at the same incision site (group B). GnRH-STs were performed before depot GnRHa treatment, immediately before implant insertion, at the 6- and 9-month visits for each patient and the 12- and 15-month visit for those girls followed for 15 months. Results. In all girls, breast development regressed, growth velocity decreased, and bone-age advancement was slowed. Basal gonadotropins and their responses to GnRH-STs and E2 levels were suppressed. Peak luteinizing hormone and follicle-stimulating hormone responses to GnRH-STs at preinsertion versus 9 months were 1.30 ± 1.34 vs 0.25 ± 0.08 and 1.68 ± 1.08 vs 1.13 ± 0.55 mIU/mL, respectively. Basal and stimulated gonadotropin levels and E2 level remained suppressed in all 6 patients followed for 15 months after implant insertion. Patients and parents reported less pain and discomfort and less interference with school activity and work with the implant compared with standard monthly injections. Conclusions. The histrelin implant consistently suppresses clinical and laboratory parameters of puberty for 1 year and is a promising new technique for treating CPP without the pain and inconvenience of monthly injections.

Time to menarche and final height after histrelin implant treatment for central precocious puberty

OBJECTIVE To compare final height, change in body mass index (BMI), and time from end of treatment until menarche in girls with central precocious puberty treated with the histrelin implant versus depot gonadotropin releasing hormone agonist injections. STUDY DESIGN Chart review, interview, and final height measurements of 2 groups of girls with central precocious puberty; triptorelin depot (TD) group: 23 girls were treated from age 8.4 ± 0.3 with monthly injections of TD, for 26.7 ± 2.5 months; histrelin implant group: 11 girls were treated from age 8.7 ± 0.3 years for 28.4 ± 3.7 months, of whom 9 initially received monthly TD injections for 1.5-39 months. Final height, BMI (pretreatment vs recent), and time between either implant removal or last injection to menarche were compared. RESULTS Time between removal of implant or last injection and menarche was 9.3 ± 1.5 (histrelin implant group) versus 16.1 ± 1.7 (TD group) months (P = .02). Predicted height at implant insertion was 156.8 ± 2.6 cm, and final height was 161.1 ± 2.0 cm (not significant [NS]). Predicted height for TD was 155.2 ± 1.9 cm and final height was 157.9 ± 1.7 cm (NS). Change from onset of treatment to final BMI-SDS for histrelin implant was -0.41 ± 0.3, and for TD was -0.03 ± 0.2 (NS). CONCLUSIONS Menarche occurred sooner after implant removal. There was no difference in final height or BMI outcomes between the 2 treatment modalities.

TSH enhancement of FT4 to FT3 conversion is age dependent

OBJECTIVE We previously reported increasing free T3 (FT3) to free T4 (FT4) ratios as thyroid-stimulating hormone (TSH) increases within the normal range in children. It is not known if this phenomenon is age-related among humans, as previously reported in rats. This study examines the relationships between TSH and FT3/FT4 ratios in different ages. DESIGN Retrospective examination of thyroid tests from patients without thyroid disease from community clinics. METHODS Free T3, free T4, and TSH levels from 527 564 sera collected from patients aged 1 year or greater were studied. Exclusion criteria were the following: missing data, TSH greater than 7.5mIU/L, and medications that may interfere with thyroid hormone activity. A total of 27 940 samples remaining after exclusion were stratified by age. Samples with available anthropometric data were additionally stratified for body mass index (BMI). Correlations of TSH to FT4, FT3, and FT3/FT4 ratios by age group were examined. RESULTS Up to age 40, for each increasing TSH quartile, FT3 and the FT3/FT4 ratio increased and FT4 decreased significantly (for both FT3, FT4 and FT3/FT4 ratio, P<0.05 for every TSH quartile when compared with the 1st quartile, except FT3 in the 30-40 age group). In older age groups, increasing TSH was not associated with increased FT3/FT4 ratio. CONCLUSION As TSH levels increase, FT3/FT4 ratios increase until age 40, but this differential increase does not occur in older age groups. This may reflect a decrease in thyroxine (T4) to triiodothyronine (T3) conversion with age, which may be part of the aging process.

Persistent hyperthyrotropinemia in congenital hypothyroidism: successful combination treatment with levothyroxine and liothyronine.

Abstract Background: Some children with congenital hypothyroidism (CH), have persistent hyperthyrotropinemia despite good compliance with levothyroxine. Objective: To evaluate combination therapy of liothyronine (cytomel®) with levothyroxine in CH with persistent hyperthyrotropinemia. Patients and methods: Files were reviewed retrospectively. Eight female patients with persistently high levels of TSH and upper normal FT4 levels were given either 6.25 or 12 μg liothyronine and the levothyroxine dose was reduced appropriately. Pre- and post-intervention hormone levels and drug doses were evaluated. Results: TSH decreased in 8/8 and normalized in 6/8 patients. FT4 and free tri-iodothyronine (FT3) remained normal. The levothyroxine-equivalent dose on the combination was 5.0±0.3 μg/kg/day in infants and 3.4±0.4 μg/kg/day in children above 2.5 years. Infants required higher liothyronine doses compared with older children (0.66±0.01 vs. 0.3±0.05 μg/kg/day). Conclusions: Combined therapy can achieve normal TSH levels with normal FT4 and FT3. Further long-term research is required to investigate effects on neurodevelopmental outcome.

Free α-Subunit Is the Most Sensitive Marker of Gonadotropin Recovery after Treatment of Central Precocious Puberty with the Histrelin Implant

BACKGROUND Gonadotropin free alpha-subunit (FAS) levels paradoxically increase during GnRH agonist (GnRHa) treatment of central precocious puberty (CPP). The histrelin implant suppresses gonadotropins and estradiol (E(2)) levels for 1 yr, but effects on FAS have not been described. OBJECTIVES We aimed to determine whether FAS levels remain elevated during treatment with the implant, to assess the dynamics of FAS after removal, and to ascertain the reliability of FAS for monitoring gonadotropin secretion. METHODS Ten girls with CPP were studied. In eight, monthly im GnRHa preparations were given until implant insertion. Two naive girls did not receive prior GnRHa. Duration of implant treatment ranged from 18-63 months with repeated implant removals and insertions of new implants. LH, FSH, E(2), and FAS were measured before implant insertion in the two naive patients and during treatment, and in all girls before and after implant removal. RESULTS FAS levels were 0.2 and 0.4 ng/ml (normal, <0.6 ng/ml) in the two naive girls and increased to 2.4 and 5.1 ng/ml within 2-5 d of insertion. FAS level (mean +/- SD) in all 10 girls during histrelin implant treatment was 1.19 +/- 0.49 ng/ml and rapidly decreased to 0.31 +/- 0.12 ng/ml within 1 wk of implant removal (P < 0.03). In contrast, significant increases in LH (P < 0.05) and FSH (P < 0.02) were observed at 3 wk and E(2) (P < 0.05) at 6 wk after implant removal. CONCLUSIONS Compared to LH, FSH, and E(2), FAS responds more rapidly to implant removal and represents the most sensitive indicator of gonadotropin recovery after histrelin implant treatment.

Current normal values for TSH and FT3 in children are too low: evidence from over 11,000 samples.

Abstract Background: Current pediatric normal values for thyroid function tests are based on data from relatively few patients. Objective: To develop new normal pediatric values based on a large sample of children. Patients and methods: Data were collected from a computerized database in Jerusalem, Israel, of thyroid function tests taken in community pediatric clinics. Samples from patients with antithyroid peroxidase antibodies and/or antithyroglobulin antibodies and from those treated with levothyroxine, methimazole, propylthiouracil, thyrotropin, lithium, phenobarbital, or glucocorticoids were excluded. The analysis included over 11,000 samples tested for TSH, free triiodothyronine (FT3), and free thyroxine (FT4) with the ADVIA® Centaur™ system. Results: The upper normal limit (UNL) for TSH increased by about 1 mIU/L and the lower normal limit (LNL) for FT3 increased by 0.5–2 pmol/L in different age groups. There was no significant change in FT4 values. Conclusions: These reference data should replace current normal values.

The arginine stimulation test: timing of peak is not a helpful parameter in the diagnosis of growth hormone deficiency.

Abstract Background: A typical peak timing in the glucagon stimulation test has been reported as an indication of growth hormone (GH) deficiency. Other stimulation tests have not been evaluated. Objective: To evaluate the clinical usefulness of peak timing in the arginine stimulation test (AST) for growth hormone deficiency. Methods: Retrospective review of 199 ASTs from one center. Outcomes included correlation of peak times with (a) frequency of deficient peak; (b) growth velocity standard deviation scores (GVSDSs); (c) other evidence of pituitary pathology; (d) results of confirmatory clonidine test; and (e) response to GH treatment. Results: The peak in 83/109 (76.14%) sufficient tests occurred at typical times vs. 45/72 (62.5%) deficient tests (p<0.05). GVSDS on GH treatment was greater among patients with typical timing in the AST compared with atypical timing (2.67±0.59 vs. 0.46±1.17, p=0.021). No other variable correlated significantly with AST timing. Conclusions: Timing of peak in the AST is not a clinically useful parameter.

FT3 IS HIGHER IN MALES THAN IN FEMALES AND DECREASES OVER THE LIFESPAN

OBJECTIVE Normal changes in free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) levels over the lifespan and differences between sexes are not well documented, mainly because even the largest-scale studies available include relatively small cohorts. The aim of this study was to define age-related trends including sex differences based on reliable data. METHODS A large database including serum thyroid tests drawn in community clinics was studied. FT3, FT4, and TSH levels from 527,564 sera samples taken from patients age 1 year or greater were included. After highly extensive exclusion criteria applied to remove all samples that may have been taken from unhealthy people, 27,940 samples remained. These were stratified by decades of age and by sex. RESULTS FT3 decreases throughout life, significantly more so among females, with equalization between sexes with greater age. FT4 declines to a lesser extent, also more among females than among males. Among the very old, females have higher levels of FT4. In contrast, TSH declines until age 50 and then increases slightly in both sexes. CONCLUSION This study provides reliable data regarding trends in hormonal levels by age and sex, with the major finding being higher FT3 in males throughout life except in the very young and very old. These results have important implications for diagnosing and treating thyroid conditions. ABBREVIATIONS ANOVA = analysis of variance; BMI = body mass index; FT3 = free triiodothyronine; FT4 = free thyroxine.

Triptorelin depot stimulation test for central precocious puberty

Abstract Background: Acute gonadotropin responses following depot leuprolide acetate injection are useful for monitoring therapeutic efficacy in central precocious puberty. Similar monitoring of therapy in patients treated with another widely used GnRH agonist, depot triptorelin, has not yet been reported. Objective: The objective of this study was to test the use of gonadotropin levels after therapeutic injections of depot triptorelin for evaluating efficacy of therapy. Patients and methods: Thirty-two patients (29 girls and three boys) were treated with triptorelin depot, 3.75 mg per vial, between 2006 and 2010. Treatment was initiated at 8.27±1.76 years (range, 4.6–11.6 years). Blood was drawn before and at variable times between 30 min and 2 h after injections. Clinical tests were retrospectively collected. Results: After the first injection, the 60-min mean luteinizing hormone (LH) level was 21.6.1±18.0 IU/L and the follicle-stimulating hormone (FSH) was 13.5±3.6 IU/L. After subsequent injections, for those who showed clinical suppression, the standard deviations above the mean were 3.6 IU/L for FSH and 2.1 IU/L for LH. The LH levels of two patients who did not suppress sufficiently were at these limits or higher. Conclusions: Sixty-minute postinjection depot triptorelin levels of LH can be successfully used to evaluate the efficacy of treatment with this agent. Limits for suppressed levels have been determined.

CLONIDINE STIMULATION TEST FOR GH DEFICIENCY: A NEW LOOK AT SAMPLE TIMING

OBJECTIVE In the glucagon stimulation test (GST), the occurrence of peak growth hormone (GH) levels at typical times is an indication of normal secretion. This has not been studied for the clonidine stimulation test (CST). The 120-minute time is rarely the peak, and previous reports suggest it can be omitted. This study aimed to evaluate the meaning and utility of peak time in the CST and the significance of shortening the test. METHODS CSTs performed on 250 consecutive subjects in a single center were evaluated for results (GH sufficient or deficient) and result of confirmatory GST with respect to the peak time of the CST. RESULTS Peak GH occurred typically at 30, 60, and 90 minutes (91.6% of tests, versus 60% expected) (P<.001). A total of 132 of 155 (85.15%) sufficient tests occurred at typical times, versus 66 of 97 (68%) deficient tests (P<.05). Typicality of timing did not follow in the confirmatory GST and did not predict the final result of testing. Removal of the 120-minute sample affected the final result in 0.4% of evaluations. CONCLUSION The timing of the GH peak is not useful when interpreting the CST. The CST is equally effective when terminated at 90 minutes from stimulation.