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Purpose: This study aimed to evaluate the time interval to menarche after gonadotropin-releasing hormone agonist (GnRHa) treatment in females with central precocious puberty (CPP) and to identify factors contributing to timing of menarche.Methods: We retrospectively reviewed medical records of 39 females with CPP who reached menarche after GnRHa treatment (leuprolide or histrelin). CPP diagnostic criteria were breast development at

Managing social groups in zoos requires controlling reproduction in individuals that do not have a current breeding recommendation, while simultaneously maintaining social harmony and animal well-being. Contraceptives, such as gonadotropin releasing-hormone (GnRH) agonists, that suppress testosterone production, offer a potential solution. They achieve infertility by interrupting spermatogenesis and may ameliorate androgen-induced aggression. This study investigated the effects of two GnRH agonists, histrelin and deslorelin, on testosterone, testis size, body weight and sperm production in male lion-tailed macaques, along with subjective observations of aggressive behavior. Five trials at three institutions with 14 males demonstrated that 100 mg histrelin or 9 to 12 mg of deslorelin could at least temporarily reduce testosterone, but a lower 6 mg dose was ineffective. However, ability of deslorelin to produce azoospermia varied among males, even at the highest dose. In general, a higher dose was needed (1) to achieve than to maintain suppression of any measured parameter and (2) to suppress sperm production than testosterone concentration. Testosterone production was also more likely than sperm production to recover, suggesting possible damage to seminiferous tubules but not to Leydig cells. Aggressive behavior was reduced in all but the group receiving the lowest dose. This allowed social groups to be maintained for many years despite recovery of testosterone in some males, suggesting that new social roles had been learned and become independent of androgen influence.

Objectives Gonadotropin-releasing hormone analogs are the treatment of choice for central precocious puberty (CPP). This study characterizes patients treated with histrelin implant or leuprolide injection. Methods A US claims database was used to identify patients aged ≤20 years with ≥1 histrelin or leuprolide claim (index treatment) between April 2010 and November 2017 and continuous enrollment ≥3 months before and ≥12 months after the index treatment date. Results Overall, 4,217 patients (histrelin, n=1,001; leuprolide, n=3,216) were identified. The percentage of patients with CPP diagnosis was greater in the histrelin (96.5%) vs. leuprolide (68.8%; p50% of patients aged 6–9 years. Mean treatment duration was significantly longer for histrelin (26.7 ± 14.8 months) vs. leuprolide (14.1 ± 12.1 months; p Conclusions Patients with CPP treated with histrelin had a longer duration of treatment, lower rates of index treatment discontinuation, and lower annual treatment costs vs. those treated with leuprolide.

Purpose: Development of incongruent secondary sex characteristics in transgender youth can intensify or trigger the onset of gender dysphoria. Guidelines from professional organizations recommend gonadotropin-releasing hormone agonists, including histrelin implants (Vantas and SupprelinLA) to suppress endogenous puberty. Although Vantas does not have a pediatric indication, it is anecdotally being used in pediatric gender centers throughout the United States because of its substantially lower cost. This retrospective study aimed to determine if both implants were effective in suppressing the hypothalamic-pituitary-gonadal axis in early-to-mid pubertal youth with gender dysphoria. Methods: Youth with gender dysphoria receiving care at the Center for Transyouth Health and Development at Children's Hospital Los Angeles (CHLA) or participants from an ongoing observational trial with a histrelin implant placed for pubertal suppression at Tanner stage 2 or 3 were included. Sex steroid (testosterone or estradiol) and gonadotropin measurements at baseline (T0) and then 2 to 12 months following implant placement (T1) were abstracted from medical records. Results: Of the 66 eligible participants, 52% were designated female at birth. Most participants were white (60.6%). Twenty participants (30.3%) had a Vantas implant and 46 (69.7%) had a SupprelinLA implant. Mean age of insertion was 11.3 years. Gonadotropin and sex steroid levels were significantly decreased at T1 (2-12 months after insertion of implant), with no differences between implants. Conclusion: These results indicate that both implants are effective in suppressing puberty in early-to-mid pubertal youth with gender dysphoria. These data may inform decisions about insurance coverage of Supprelin and/or Vantas for youth with gender dysphoria.

Made available in DSpace on 2022-04-29T08:33:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-09-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The objectives of this study were: (1) to assess uterine features and serum progesterone concentrations of acyclic mares synchronized and resynchronized with intravaginal progesterone release device (IPRD), and (2) to compare pregnancy rates and losses of cyclic and acyclic embryo recipient mares treated with different synchronization protocols. In Experiment 1, mares (n = 12) received estradiol for 3 days (E2-3d), and then 24 h after the last injection, an IPRD was inserted and kept in place for 9 days. Three days after IPRD removal, mares were treated with E2-3d, and then a new IPRD was inserted and maintained for three days. Serum progesterone concentrations were assessed 2, 6, and 12 h after insertion and removal of IPRD, and then daily from the insertion of the first IPRD to one day after removal of the second IPRD. Experiment 2 was conducted with embryo recipient mares randomly assigned to four groups: (1) Cyclic: mares (n = 75) had ovulation confirmed after receiving a single dose of histrelin when a periovulatory follicle was first detected, (2) LAP4: acyclic mares (n = 92) were treated with E2-3d and then administered a single dose of LAP4 24 h after the last estradiol injection, (3) IPRD: acyclic mares (n = 130) were treated with E2-3d and an IPRD for 4–8 days, and (4) RE-IPRD: acyclic mares (n = 32) were synchronized as in the IPRD group but not used for embryo transfer (ET), then 8 to 15 days later, the mares were resynchronized with E2-3d and an IPRD for 4–8 days. In vivo-produced Day-8 embryos were collected and transferred 4–8 days after ovulation or progesterone treatments. Mares in IPRD and RE-IPRD groups had the intravaginal device removed immediately before ET, and then a new IPRD was inserted right after ET. Pregnancy diagnosis was performed at 5, 30, and 60 days after ET. Once pregnancy was confirmed, mares in the three acyclic groups received weekly injections of LAP4 (1.5 g) until 120 days of pregnancy. Mares in IPRD and RE-IPRD groups had the device removed three days after the first pregnancy diagnosis. In Experiment 1, progesterone concentrations increased rapidly starting 2 h after insertion of IPRD (p < 0.05); then, concentrations plateaued well above pregnancy maintenance until removal on days 9 and 3, respectively. Progesterone concentrations were reduced to baseline 24 h after IPRD removal (p < 0.05). For experiment 2, there was no difference in pregnancy rates across groups (65–74%) or pregnancy losses by 60 days of gestation (7–12%) (p > 0.05). In conclusion, the IPRD used herein resulted in a rapid increase and a sharp decline in progesterone concentrations upon its insertion and removal, respectively. Finally, our results demonstrated that IPRD could be a compatible alternative to LAP4 to synchronize and resynchronize acyclic embryo recipient mares. Department of Veterinary Surgery and Animal Reproduction School of Veterinary Medicine and Animal Science São Paulo State University UNESP Department of Veterinary Clinical Medicine College of Veterinary Medicine University of Illinois, 1008 W Hazelwood Drive Department of Veterinary Surgery and Animal Reproduction School of Veterinary Medicine and Animal Science São Paulo State University UNESP FAPESP: 2017/ 13883-9

Purpose To perform the largest review of the safety and clinical management practices of histrelin implantation in children. Methods A retrospective cohort study was performed including all patients (age ≤ 20) that underwent histrelin implant insertion, replacement, or removal by a single surgeon at a large pediatric tertiary care center (2008–2017). Data analyzed included patient demographics, procedure details, and complications. Results A total of 377 patients, with a mean age of 9.3 ± 2.4 years, underwent 866 unique procedures (352 insertions, 329 replacements, and 185 removals) for a diagnosis of either central precocious puberty (343 patients, 821 cases) or gender identity disorder (34 patients, 45 cases). There were 271 (72%) female patients, 72 (19%) male patients, and 34 (9%) children in gender transition. Procedures were performed in three settings: 415 (47.9%) in the outpatient clinic, 401 (46.3%) in a sedation unit, and 50 (5.8%) in the operating room. The preferred setting shifted over time to more clinic-based procedures (9.4% vs. 62.9% in the first five vs. second five years, respectively). Complications were rare (1% of cases). Conclusion Histrelin implantation in the pediatric population is safe, with minimal morbidity. Implantation and removal in the clinic setting are appropriate for the majority of patients. Level of evidence Treatment study; Level IV.

Objectives The purpose of this study was to review our success rate performing the histrelin implant procedure in clinic without sedation. Methods A retrospective study was performed for histrelin implant procedures done at our institution from 2008 to 2020. Wilcoxon rank-sum test or Fisher’s exact test was utilized to identify significant differences (p Results A total of 73 patients underwent 184 histrelin implant procedures from 2008 to 2020. In the past few years, there has been a decrease in procedures for precocious puberty and an increase for gender dysphoria. The majority of procedures were performed in clinic without sedation (82%). The only risk factor associated with requiring sedation was younger age (median 9 vs. 10 years; p Conclusions Procedural refinements and distraction therapy have enabled us to perform the majority of procedures in clinic without sedation. In our experience, procedural difficulty and complications appear to increase with prolonged implant duration. Histrelin implantation is increasingly being performed for gender dysphoria.

Aims: To compare treatment duration, healthcare resource utilization (HRU), and direct healthcare costs between patients with central precocious puberty (CPP) treated with leuprolide or histrelin, and between patients with Medicaid or commercial insurance. This information is important as it affects treatment choice and outcomes.Materials and methods: This retrospective cohort study identified commercial and Medicaid-insured CPP patients ≤12-years-old who were diagnosed between 1 January 2010 and 30 September 2014 and had ≥1 prescription for leuprolide or histrelin (first prescription = index date). Treatment patterns were measured for the duration of available data; whereas, all-cause and disease-monitoring HRU and all-cause costs were compared between treatment groups for the year following treatment initiation. Multivariable analysis was used to adjust healthcare costs for differences in baseline patient characteristics.Results: A total of 1,177 commercially-insured (907 leuprolide and 270 histrelin) and 658 Medicaid-insured (613 leuprolide and 45 histrelin) patients were identified. Mean age at treatment initiation ranged from 7.5-8.5-years-old, 11.1-20.5% of patients were male, and the mean treatment duration was over one year. Commercially-insured patients treated with histrelin used more services in general than those treated with leuprolide but had fewer office visits. Healthcare service utilization was similar between Medicaid-insured treatment groups. In both payer populations, costs were similar.Limitations: The number of Medicaid-insured patients who received a histrelin implant was low, and this may make the findings more sensitive to influence by outliers.Conclusions: Mean overall healthcare costs were similar between CPP patients treated with leuprolide and those treated with histrelin. Medicaid patients generally received less testing and were less likely to receive specialist care. Patients treated with histrelin had fewer office visits but also had a shorter overall treatment.

Background Costello syndrome (CS) is a rare RASopathy causing developmental delays, short stature and classically, delayed puberty. We present a patient with CS and central precocious puberty (CPP). Case presentation A female patient with CS presented at 6 years 10 months of age with breast development. CPP was biochemically confirmed at 7 years 1 month of age, no additional pituitary dysfunction was noted and puberty progressed at follow-up. Brain magnetic resonance imaging (MRI) revealed a Chiari I malformation with a syrinx, requiring surgical decompression. The patient was successfully treated with histrelin. Conclusions Although recent publications do not recommend routine brain MRI in girls with isolated CPP over 6 years of age, in those with CS actionable MRI findings are more likely and imaging should be performed. It is unclear whether the cerebral malformation in the patient contributed to CPP or was an incidental syndromic finding.

Background Children with congenital adrenal hyperplasia (CAH) because of 21 hydroxylase deficiency (21OHD) are at risk for early or precocious puberty and a short adult height compared to population means and midparental height. The effect of histrelin in suppressing puberty and improving growth in these children has not been reported. Methods Retrospective cohort analysis of all patients (age ≤ 20) at our institution who underwent histrelin implantation between 2008 and 2017. Treated patients with CAH (classic and nonclassic forms of 21OHD) were identified and their growth data analyzed. Results Fifteen children with CAH were treated with histrelin for a median of 3 years (range 2–5; age at first implantation 7.7 ± 1.5 years). Bone age (BA) to chronologic age (CA) decreased from 1.57 ± 0.4 to 1.25 ± 0.25 (P < .01), while predicted adult height (PAH) increased by 7.1 ± 6.6 cm (P < .01). A subgroup of 10 children reached adult height. Similar changes in BA/CA and PAH were observed with therapy (P = .02). Adult height z improved compared to pretreatment PAH z (–1.42 ± 0.9 vs. –1.96 ± 1.1 respectively, P < .01), but remained lower than midparental height z (P = .01). Conclusion In this retrospective cohort study of children with CAH due to 21OHD and early or precocious puberty, histrelin implantation resulted in a decrease in BA progression compared to CA and an improvement in PAH. In the subgroup who completed growth, adult height remained significantly lower than midparental. These results need to be confirmed with prospective controlled studies.

Made available in DSpace on 2022-04-28T17:20:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-03-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fazenda Experimental Gralha Azul (FEGA) of the Pontifical Catholic University of Parana (PUCPR), Curitiba, Brazil The study aimed to evaluate two hormonal protocols for oestrus and ovulation synchronisation for timed artificial insemination (TAI) and their effect on the embryo recovery rate (ERR) in horses. Eleven crossbreed mares were allocated in three groups, taking 3 different oestrus cycles per mare, during two breeding seasons, totalling 17 cycles followed per group, with 11 cycles in the first season and 6 cycles in the second season. Conventional follicular follow-up in the control group (CG; n = 17) was performed by transrectal palpation and ultrasound (US) examination; the ovulation was induced with 500 mu g histrelin (intramuscularly: IM) when the diameter of the follicles was >= 35 mm, the uterine oedema was grade 3 and cervical opening had begun. Artificial insemination with fresh semen (250 x 10(6) sperm cells) was performed 24 h after ovulation inductor administration, and embryos were collected eight days after ovulation (D8). The experimental groups had a progesterone-releasing intravaginal device (PRID) inserted for 9 (PRID9) or 11 days (PRID11). Day zero (D0) was defined as the day of TAI for both groups. The PRID was inserted at the beginning of the protocol (D-14 for PRID9 or D-16 for PRID11) plus US examination of the ovaries; the PRID was removed on D-5, 75 mu g prostaglandin were administered (PGF2 alpha; IM) and US was performed; 500 mu g (IM) of histrelin (ovulation inductor) was administered on D-1; after 24 h (D0), TAI was performed with fresh semen (250 x 10(6) sperm cells) plus US; nine days after TAI (D9), transcervical embryo collection was performed. After the embryo collection, a dose of prostaglandin F2 alpha was administered, with a delay of seven days before the start for the next group in order to desynchronise the mare's oestrus cycles between the protocols, so as not to interfere in the synchronisation results from one group to another. The order of submission of mares to protocols was randomly defined by sortition in each group. The groups were worked simultaneously: PRID11, PRID9 and CG in the first season and PRID11, CG and PRID9 in the second, during three consecutive months within the reproductive season. Treatment in both experimental groups (PRID9 and PRID11) was performed at any stage of the oestrous cycle. The administration of the protocols was applied to cyclical mares regardless of the US findings at the beginning of the study, and ovulation induction was performed regardless of the size of the follicle or uterine oedema. The US examinations of ovulations were only performed to verify whether they were early or late in relation to the protocol. Responsiveness (presence of preovulatory follicle diameter >= 30 mm on the day of ovulation induction D-1) for CG, PRID9 and PRID11 was 100 %, 58.8 % and 41.1 %, respectively (P > 0.05). The ERRs were 52.94 %, 29.41 % and 17.64 % for the CG, PRID9 and PRID11, respectively. There was a statistical difference only between the CG and PRID11 (P < 0.05). It was concluded that the hormonal protocol using PRID for nine days combined with histrelin administration four days after the PRID's removal showed promising results related to the ERR in mares, while reducing conventional follicular monitoring, the number of gynaecological examinations, animal management and visits to the properties. Because no statistical difference was detected between the PRID9 protocol and the CG, it could be used in large equine herds, reducing animal management and the number of visits by professionals. Effects such as early ovulations, the small size of preovulatory follicles at TAI, the interval between P4 removal and ovulation induction, and low ERR in treatment groups might be improved in future studies, aiming at the possibility using the method for commercial purposes under the acceptance of TAI protocols by veterinarians and breeders. Further studies about TAI in horses are recommended. Pontificia Univ Catolica Parana PUCPR, Sch Life Sci, Anim Sci Postgrad Program, Curitiba, Parana, Brazil Sao Paulo State Univ, Campus Botucatu, Sao Paulo, Brazil Sao Paulo State Univ, Campus Botucatu, Sao Paulo, Brazil CAPES: 001

Background The most common cause of precocious puberty is idiopathic central precocious puberty (CPP), which is usually treated with monthly injections. An alternative treatment of precious puberty is a subcutaneous implant that contains histrelin acetate, which is continuously released for more than 1 y and then removed or replaced with a new implant. Methods The aim of this study was to conduct a retrospective review of one surgeon's experience with the histrelin implant and to examine patient satisfaction. After obtaining institutional review board approval, the charts of all children who had undergone at least one implant were reviewed. Results Fifty-eight children, average age 8.4 y old (range 7–14), underwent at least one histrelin implant insertion for treatment of CPP. Parents of 44 patients were able to be reached by telephone for this study and rated the histrelin implant treatment highly. All implants were placed, replaced, or removed without significant difficulty, and there were no complications. Conclusions This study suggests that the use of a histrelin subcutaneous implant for control of CPP is a safe and effective method for the treatment of this condition.

Background Precocious puberty treatment traditionally meant anxiety-provoking monthly depot injections until the advent of the annually implanted histrelin capsule. This study is the first to evaluate the surgical and anesthetic aspects of histrelin implantation for precocious puberty. Methods All cases from one surgeon at a tertiary pediatric hospital were reviewed for patient age, anesthetic type, technical difficulties, and complications. Results From 12/2007 to 3/2013, 114 cases (49% implantations, 25% removals/re-implantations, 25% removals) were performed. Local anesthesia was employed in 100% of non-general anesthesia cases (n = 109, 96%), augmented by inhaled N2O in 49%. Five patients (4%) underwent general anesthesia: three neurologically-impaired and two coordinated with scheduled MRIs. Procedural difficulties (n = 18, 16%) included implant fracture during removal (n = 16/58 removals, 28%). Fracture never occurred during implantation. Three children (3%) suffered complications. One infection was treated with antibiotics, and two implants were removed for systemic allergic reaction. Six children (5%) had unscheduled post-operative checks for pain (n = 3, 3%), allergy to elastic dressing (n = 2, 2%), or rash (n = 1, 1%). Mean charges for general anesthesia were $10,188 ± 1292 versus $528 ± 147 for N2O or local alone (p Conclusion While histrelin implantation is straightforward, removal presents technical challenges. Local anesthesia, with possible N2O supplementation, is well-tolerated and introduces substantial resource and cost savings.

* Abbreviations: FDA — : US Food and Drug Administration GnRH — : gonadotropin-releasing hormone PAG — : pediatric and adolescent gynecology referral service PES — : pediatric endocrinology service Appropriate medical intervention along with an affirming environment has been shown to result in improved health outcomes for transgender and gender-nonconforming people.1,2 Youth whose natural pubertal development would be detrimental to their psychological and general well-being can be treated with “puberty blockers” to prevent irreversible phenotypic changes. In our experience, the most effective medications are the gonadotropin-releasing hormone (GnRH) agonist leuprolide injections (Lupron; AbbVie, Chicago, IL) or histrelin subcutaneous implant (Supprelin, Vantas; Endo Pharmaceuticals, Malvern, PA), and these have been recommended in both the Endocrine Society Guidelines and the World Professional Organization for Transgender Health Standards of Care.3,4 The safety and efficacy of these regimens have been reported in several populations.2,5 GnRH agonist pharmacotherapy can cost thousands of dollars per month. As a result, articles both in the media and in medical literature discuss the difficulty of obtaining insurance coverage for GnRH analogs used for this indication. As Dr Norman Spack stated, “Many, if not most, young adolescent American transgender patients who are deemed appropriate candidates for the recommended medical intervention . . . are unable to obtain the treatment due to insurance denial”; he estimated that insurance had covered blockers for $6000, … Address correspondence to Elyse Pine-Twaddell, 1111 N Charles St, Baltimore, MD 21201. E-mail: epine{at}chasebrexton.org

The histrelin implant (Supprelin LA) is an efficacious, safe and well tolerated medication for the treatment of central precocious puberty (CPP). Minor reactions such as bruising, redness, and pain at the implant site have commonly occurred, but only two cases of systemic allergic reaction leading to emergent removal of device have previously been reported. An otherwise healthy eleven-year-old female with CPP and no history of prior supprelin implantation, and a nine-year-old female with CPP and history of two prior supprelin implantations without complications, had a supprelin implant inserted on the same day. Within days of the procedure both presented with severe allergic reaction and underwent removal of the device. A few months after removal, both children had another supprelin implant placed without complications. It was determined that the device was not the cause of the allergic reaction, but rather the dressing material included in the implantation kit that was the offending agent. This report describes two patients with a severe systemic allergic reaction after histrelin implant necessitating urgent implant removal with resolution of allergic symptoms. It was later determined that the allergic reaction was caused by a substance in the self-adhering dressing wrap.

GnRH analogs represent the drug of choice for medical treatment of central precocious puberty (CPP). They provided prompt and reversible suppression of reproductive axis and several reports have shown that adult height is preserved in treated children.This review updates GnRH analog treatment in CPP by a search of the literature published on the topic since 1980.Monthly GnRH analogs are currently considered the 'gold standard' for the medical treatment of CPP, since a lot of experience is accumulated on their use in children. Differences in long-term outcome (in terms of adult height) are reported and they may be due to differences in selection criteria, treatment monitoring, criteria to stop of therapy, different biological activity of the various drugs and different genetic background of treated patients; altogether, these items remain poorly evaluated. Psychological indications for treatment and long-term psychological outcome of treated children should be better addressed. Comparative trials among the various GnRH analogs are very scarce. New very long-acting GnRH analogs (quarterly or yearly formulations) may improve compliance with therapy, but longer follow-up studies are needed. Medical treatment of CPP should be close to pediatric endocrinologists or tertiary pediatric endocrinology centers with documented experience in this field.

Study Type – Therapy (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Androgen deprivation therapy with a gonadotropin-releasing hormone agonist is an effective option for the palliative treatment of advanced prostate cancer. This study demonstrated the safety and efficacy of the histrelin acetate implant over successive one year treatment cycles for up to four years in an open-label extension trial. OBJECTIVE • To evaluate the efficacy and tolerability of a once-yearly histrelin implant during an open-label extension of a pivotal study. PATIENTS AND METHODS • Men with advanced prostate cancer and a clinical response to 52 weeks of treatment with the histrelin implant. • Implants were placed annually. The primary efficacy variable was achievement of serum testosterone levels of ≤50 ng/dL. Secondary efficacy variables were disease progression, analgesia use, performance status and tolerability of therapy. RESULTS • Of 104 patients enrolled, over 70% received three consecutive histrelin implants, and the longest, single treatment period was greater than 4 years. Serum testosterone was consistently suppressed below 50 ng/dL in all patients and mean testosterone levels were 13.1, 14.8 and 10.8 ng/dL after 104 weeks (year 2), 156 weeks (year 3) and 208 weeks (year 4) of treatment, respectively. • Most patients showed no clinical worsening of their disease, were able to continue normal daily activities, and did not require analgesic medication during the extension period. • Mean (sd) time to place the histrelin implant was 4.5 (6.2) min, with only three patients having insertions that were considered difficult. • Adverse events were reported in 100 (96.2%) patients. The eight deaths and 28 (26.9%) serious adverse events were judged as unrelated to the study drug. The most commonly reported drug-related adverse events was hot flashes in 67 (64.4%) patients. Most of these cases was judged as mild or moderate. CONCLUSIONS • The once-yearly histrelin implant maintained testosterone suppression for repeated treatment cycles and was generally well tolerated. • The histrelin implant provides a clinically attractive option for long-term androgen deprivation therapy in patients with advanced prostate cancer seeking fewer office visits and repeated injections.

Central precocious puberty is defined as puberty occurring prior to the age of 7.5–8 years in girls and 9 years in boys. The main goals of treatment include the arrest of pubertal progression and preservation of final adult height. In the USA, depot leuprolide has been the mainstay of treatment. It is a gonadotropin-releasing hormone agonist that is administered as an intramuscular injection every 4 weeks. Recently, a 1-year subcutaneous implant has been developed for continuous delivery of the gonadotropin-releasing hormone agonist histrelin. Initial prospective trials have demonstrated that it is efficacious, safe and well tolerated. It is an exciting alternative to painful monthly injections for the treatment of central precocious puberty.

GnRH analog (GnRHa) therapy for central precocious puberty (CPP) typically involves im injections. The histrelin implant is a new treatment that provides a continuous slow release of the GnRHa histrelin.The objective of the study was to investigate the safety and efficacy of the subdermal histrelin implant for the treatment of CPP in treatment naive and previously treated children.This was a phase III, open-label, prospective study of 1-yr duration.The study was conducted at nine U.S. medical centers.Girls ages 2-8 yr (naive) or 2-10 yr (previously treated) and boys 2-9 yr (naive) or 2-11 yr (previously treated) with clinical evidence of CPP and a pretreatment pubertal response to leuprolide stimulation were eligible.A 50-mg histrelin implant was inserted sc in the inner upper arm.Peak LH after GnRHa stimulation testing and estradiol (girls) and testosterone (boys) were the main outcome measures.Thirty-six subjects (20 naive) were enrolled. By 1 month, peak LH fell from 28.2 +/- 19.97 (naive) to 0.8 +/- 0.39 mIU/ml (P0.0001) and from 2.1 +/- 2.15 (previously treated) to 0.5 +/- 0.32 mIU/ml (P0.0056). Estradiol suppressed from 24.5 +/- 22.27 (naive) to 5.9 +/- 2.37 pg/ml (P = 0.0016) and remained suppressed in previously treated subjects, as did testosterone. Suppression was maintained throughout the study. No significant adverse events occurred.The subdermal histrelin implant achieves and maintains excellent suppression of peak LH and sex steroid levels for 1 yr in children with CPP. The treatment is well tolerated. Long-term studies are needed to confirm these results.

The histrelin implant has emerged as a therapeutic option for the treatment of central precocious puberty that has been favorably received by patients and providers. Inserted subcutaneously, the 50-mg implant provides continuous release of the potent gonadotropin-releasing hormone analog (GnRHa) histrelin. Profound suppression of the hypothalamic-pituitary-gonadal (HPG) axis occurs within 1 month of its placement resulting in pubertal arrest, attenuation of skeletal advancement and a progressive increase in predicted adult height. Although marketed for annual use, suppression lasting 2 years from a single implant has been demonstrated. Placing and removing the device is a minor outpatient procedure easily accomplished by a pediatric surgeon using local anesthesia. The major downside to the implant is a ∼25% rate of breakage upon removal. Information about the recovery of the HPG axis following histrelin explantation is limited but suggests an average time to menarche comparable with depot GnRHa formulations albeit with wide individual variation.

This study was the first to investigate the colonic stability of 17 peptide molecules (insulin, calcitonin, glucagon, secretin, somatostatin, desmopressin, oxytocin, Arg-vasopressin, octreotide, ciclosporin, leuprolide, nafarelin, buserelin, histrelin, [D-Ser(4)]-gonadorelin, deslorelin, and goserelin) in a model of the large intestine using mixed human faecal bacteria. Of these, the larger peptides - insulin, calcitonin, somatostatin, glucagon and secretin - were metabolized rapidly, with complete degradation observed within 5 min. In contrast, a number of the smaller peptides - Arg-vasopressin, desmopressin, oxytocin, gonadorelin, goserelin, buserelin, leuprolide, nafarelin and deslorelin - degraded more slowly, while octreotide, histrelin and ciclosporin were seen to be more stable as compared to the other small peptides under the same conditions. Peptide degradation rate was directly correlated to peptide lipophilicity (logP); those peptides with a higher logP were more stable in the colonic model (R(2)=0.94). In the absence of human faecal bacteria, all peptides were stable. This study highlights the impact of the colonic environment - in particular, the gut microbiota - on the metabolism of peptide drugs, and identifies potential peptide candidates for drug delivery to the colon.

Context and Objective: The histrelin implant has proven to be an effective method of delivering GnRH analog (GnRHa) therapy to children with central precocious puberty (CPP), yet there are limited data available regarding hormonal suppression and auxological changes during an extended course of therapy. Design: This was a phase 3, prospective, open-label study. Setting and Participants: Thirty-six children with CPP who participated in a phase 3, open-label study and required further GnRHa therapy were eligible to continue treatment receiving a new implant upon removal of the prior 12-month histrelin implant during a long-term extension phase. Outcome Measures: Hormone levels and auxologic parameters were measured periodically for up to 6 years of treatment and up to 1 year of posttreatment follow-up. Results: Hormonal suppression was maintained throughout the study in patients who had prior GnRHa therapy (n = 16) and in treatment-naive patients (n = 20). Bone age to chronological age ratio decreased from 1.417 (n = 20) at baseline to 1.18 (n = 8) at 48 months in treatment-naive children (P < .01). Predicted adult height in girls increased from 151.9 cm at baseline to 166.5 cm at month 60 (n = 6; P < .05), with a 10.7-cm height gain observed among treatment-naive children (n = 5). No adverse effect on growth or recovery of the hypothalamic-pituitary-gonadal axis was observed with hormonal suppression. The histrelin implant was generally well tolerated during long-term therapy. Conclusions: Long-term histrelin implant therapy provided sustained gonadotropin suppression safely and effectively and improved predicted adult height in children with CPP.

This open label, multicenter study was done to evaluate the efficacy and safety of the gonadotropin hormone-releasing hormone agonist histrelin acetate administered as a 50 mg subdermal implant in men with advanced prostatic cancer.The 3 cm x 3.5 mm histrelin implant was surgically inserted in the inner aspect of the upper nondominant arm of eligible patients under local anesthesia. Patients were evaluated weekly for the first 2 weeks after implant insertion and monthly thereafter. At week 52 the implant was removed and in most cases a new implant was inserted. Patient observation for safety and efficacy continued to week 60. Efficacy was determined by the proportion of patients who attained chemical castration (serum testosterone 50 ng/dl or less) at weeks 4 through 52.Of the 134 patients with week 4 testosterone levels available 100% achieved chemical castration. Testosterone suppression was maintained throughout the 52 weeks after implantation in more than 99% of patients. Significant LH and PSA suppression was also observed. By week 16 PSA had decreased an average of 90% from a baseline of 83.6 ng/ml (p = 0.0001). By week 60, 79% of patients had a complete PSA response (p0.0175). No testosterone or LH surge was observed with reimplantation. Additionally, the implant was safe and well tolerated.The gonadotropin hormone-releasing hormone agonist histrelin acetate provided in a unique implant delivery device is effective for treating men with advanced prostate cancer, as demonstrated by the suppression of testosterone and LH to castrate levels at 4 weeks and the maintenance of these levels during 52 weeks. PSA, a secondary end point for effectiveness, was also suppressed significantly from baseline.

Objective. Standard treatment of central precocious puberty (CPP) consists of intramuscular or subcutaneous administration of a gonadotropin-releas- ing 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 g/day. The aims of this study were to determine if a histrelin im- plant would suppress gonadotropin and estradiol (E2 )i n 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 gonado- tropin suppression. Mean age at diagnosis was 6 1 ⁄2 years (range: 2-9 years). GnRH (100 g intravenously) stimu- lation tests (GnRH-STs) showed peak luteinizing hor- mone 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 fol- lowed 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 be- fore depot GnRHa treatment, immediately before im- plant 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 lutein- izing hormone and follicle-stimulating hormone re- sponses 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 gonad- otropin 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 sup- presses 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. Pediatrics 2005;116:e798-e802. URL: www. pediatrics.org/cgi/doi/10.1542/peds.2005-0538; precocious puberty, gonadotropins, estradiol, GnRH agonists, histre- lin.