Treatment of Girls and Boys with McCune-Albright Syndrome with Precocious Puberty - Update 2017

The most common endocrinopathy associated with McCune-Albright Syndrome (MAS) is peripheral precocious puberty (PP) which occurs far more often in girls than in boys. We will discuss the latest advancements in the treatment of precocious puberty in MAS that have been achieved during the past 10 years. However, due to the rarity of the condition and the heterogeneity of the disease, research in this field is limited particularly in regards to treatment in boys. In girls, a period of watchful waiting is recommended prior to initiating therapy due to extreme variability in the clinical course. This article will review in detail current pharmacologic treatment in girls, which typically consists of either inhibiting estrogen production or blocking estrogen action at the level of the end-organ. The two treatments with the most evidence at this time are Tamoxifen (which is an estrogen receptor modulator) and Letrozole (which is a 3rd generation aromatase inhibitor). This article will also review the current treatment strategies in boys which typically include using an androgen receptor blocker and an aromatase inhibitor. Due to the rarity of the condition, large multicenter collaborative studies are needed to further investigate efficacy and safety with the goal of establishing the gold standard for treatment of PP in children with MAS

How often are clinicians performing genital exams in children with disorders of sex development?

Background: We sought to determine the frequency with which genital exams (GEs) are performed in children with disorders of sex development (DSD) and ambiguous genitalia (AG) during routine visits to the pediatric endocrine clinic. Methods: Medical records of children with DSD and AG seen at one large academic center since 2007 were reviewed. Data analyzed included diagnosis, sex of rearing, age, initial or follow up visit, number of individuals present and sex of the pediatric endocrinologist. Repeated measures analysis was performed to evaluate associations between GEs and patient/physician factors. Results: Eighty-two children with DSD and AG who had a total of 632 visits were identified. Sex of rearing was female in 78% and the most common diagnosis was congenital adrenal hyperplasia (CAH) (68%). GEs were performed in 35.6% of visits. GEs were more likely in patients with male sex of rearing (odds ratio [OR] 17.81, p=0.006), during initial vs. follow-up visits (OR 5.99, p=0.012), and when the examining endocrinologist was female (OR 3.71, p=0.014). As patients aged, GEs were less likely (OR 0.76, p<0.0001). Conclusions: GEs were performed in approximately one-third of clinic visits in children with DSD and AG. Male sex of rearing, initial visits and female pediatric endocrinologist were associated with more frequent GEs

Treatment of Central Precocious Puberty

Long-acting analogs of GnRH (GnRHas) have been the gold-standard treatment of central precocious puberty (CPP) worldwide and have an enviable track record of safety and efficacy. Recent years have witnessed much growth in the availability of longer-acting and sustained-release forms of GnRHas. Although all available agents appear promising, limited long-term follow-up and/or comparative data are available. In this review, important issues pertaining to the treatment of children with CPP are discussed. In addition to an assessment of the newer extended-release GnRHa formulations, a delineation of factors essential in determining which children should be treated is offered. Outstanding uncertainties in clinical management are highlighted and areas in need of future research identified. Literature searches for this review were performed in PubMed and OVID, with a focus on English-language publications using the terms "central precocious puberty" and "treatment.

Experience with the Histrelin Implant in Pediatric Patients

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

Central Precocious Puberty: Update on Diagnosis and Treatment

Central precocious puberty (CPP) is characterized by the same biochemical and physical features as normally timed puberty but occurs at an abnormally early age. Most cases of CPP are seen in girls, in whom it is usually idiopathic. In contrast, ~50 % of boys with CPP have an identifiable cause. The diagnosis of CPP relies on clinical, biochemical, and radiographic features. Untreated, CPP has the potential to result in early epiphyseal fusion and a significant compromise in adult height. Thus, the main goal of therapy is preservation of height potential. The gold-standard treatment for CPP is gonadotropin-releasing hormone (GnRH) analogs (GnRHa). Numerous preparations with a range of delivery systems and durations of action are commercially available. While the outcomes of patients treated for CPP have generally been favorable, more research about the psychological aspects, optimal monitoring, and long-term effects of all forms of GnRHa treatment is needed. Several potential therapeutic alternatives to GnRHa exist and await additional investigation

Treatment of Peripheral Precocious Puberty

There are many etiologies of peripheral precocious puberty (PPP) with diverse manifestations resulting from exposure to androgens, estrogens, or both. The clinical presentation depends on the underlying process and may be acute or gradual. The primary goals of therapy are to halt pubertal development and restore sex steroids to prepubertal values. Attenuation of linear growth velocity and rate of skeletal maturation in order to maximize height potential are additional considerations for many patients. McCune-Albright syndrome (MAS) and familial male-limited precocious puberty (FMPP) represent rare causes of PPP that arise from activating mutations in GNAS1 and the LH receptor gene, respectively. Several different therapeutic approaches have been investigated for both conditions with variable success. Experience to date suggests that the ideal therapy for precocious puberty secondary to MAS in girls remains elusive. In contrast, while the number of treated patients remains small, several successful therapeutic options for FMPP are available

Experience with the once-yearly histrelin (GnRHa) subcutaneous implant in the treatment of central precocious puberty

In 2007, a hydrogel histrelin implant was approved for the treatment of children with central precocious puberty (CPP). Children with CPP commonly have reduced height potential due to premature closure of the epiphyseal growth plates from exposure to sex steroids. Gonadotropin-releasing hormone analog (GnRHa) treatment halts puberty and allows for improvement of adult height. A hydrogel implant delivery system utilizing the potent GnRHa, histrelin, was first developed for use in men with prostate cancer. A once yearly histrelin subcutaneous implant was subsequently developed for the treatment of children with CPP. Studies to date have demonstrated safety, tolerability, and effectiveness of this treatment option in patients treated up to 2 years. The most common adverse effects of the implant relate to implant site pain or bruising. Cost of this treatment seems comparable to somewhat higher than the commonly used GnRHa treatment option, depot leuprolide. While long term studies are needed to establish continued efficacy and safety beyond 2 years of treatment, the histrelin implant appears to be an attractive option for GnRHa treatment in patients with CPP

Central precocious puberty: From genetics to treatment

Central precocious puberty (CPP) results from early activation of the hypothalamic - pituitary -gonadal (HPG) axis and follows the same sequence as normal puberty. While many factors involved in pubertal initiation remain poorly understood, the kisspeptin system is known to play a key role. Currently, mutations in the kisspeptin system, MKRN3, and DLK1 have been identified in sporadic and familial cases of CPP. The diagnosis is based on physical exam findings indicating advancing puberty and on laboratory tests confirming central HPG axis activation. GnRH analogs are the mainstay of treatment and are used with the goal of height preservation. Newer extended release formulations continue to be developed. Currently there is no evidence of long-term complications associated with treatment. However, many areas remain to be explored such as targeted therapies and aspects of clinical management. Further investigation into psychological effects and additional data regarding long-term outcomes, particularly in males, is needed

Update on central precocious puberty: from etiologies to outcomes

Introduction: Precocious puberty (PP) is one of the most common reasons for referral to pediatric endocrinologists. Gonadotropin-releasing hormone analogs (GnRHas) are the gold standard for the treatment of central precocious puberty (CPP) and have an impressive record of safety and efficacy. However, ongoing refinements in diagnosis and management continue to lead to important advancements in clinical care. Areas covered: The aim of this review is to cover current considerations and controversies regarding the diagnosis of CPP, as well as new findings in regards to etiology and treatment modalities. Expert opinion: There is emerging evidence of monogenic etiologies of CPP and significant progress in the expansion of newer formulations of GnRHas. Despite these exciting developments, areas of uncertainty in the diagnosis and treatment of CPP remain. While long-term outcomes of patients treated for CPP are encouraging, only short-term follow-up is available with respect to the newer extended release GnRHa preparations, and how they compare with historically used formulations is unknown. A particular shortage of information exists pertaining to CPP in boys and regarding the psychological implications of PP in girls, and more research is needed. Continued investigation will yield new insights into the underlying genetics and optimal treatment strategies for CPP