Precocious puberty: diagnosis and management

Precocious puberty is commonly defined as puberty that starts before age 8 years in girls and 9 years in boys. The causes of it may range from a variant of normal development to various pathologic conditions. The etiology of precocious puberty is classified by the underlying pathogenesis into gonadotropin dependent central precocious puberty and peripheral precocious puberty which is independent of gonadotropin but due to different other causes. Variants of precocious puberty include premature thelarche, premature puberche and isolated premature menarche which imply onset of isolated changes without any other signs of sexual development. Precocious puberty might have an impact on final stature owing to premature epiphyseal fusion and also it has got influence on psychosocial wellbeing. Evaluation includes a detailed history, physical examination, biochemical testing and imaging directed towards suspected etiology. Gonadotropin releasing hormone (GnRH) analogues are effective for treatment of central precocious puberty. Treatment of peripheral precocious puberty should be based on the specific cause. Pubertal variants are usually non-progressive and need no treatment but should be monitored carefully. BIRDEM Med J 2022; 12(1): 62-69

An Update on Pituitary Neuroendocrine Tumors Leading to Acromegaly and Gigantism

An excess of growth hormone (GH) results in accelerated growth and in childhood, the clinical manifestation is gigantism. When GH excess has its onset after epiphyseal fusion at puberty, the overgrowth of soft tissue and bone results in acromegaly. Persistent GH excess in gigantism also causes acromegalic features that become evident in the adult years. The causes of GH excess are primarily lesions in the pituitary, which is the main source of GH. In this review, we provide an update on the clinical, radiological and pathologic features of the various types of pituitary neuroendocrine tumors (PitNETs) that produce GH. These tumors are all derived from PIT1-lineage cells. Those composed of somatotrophs may be densely granulated, resembling normal somatotrophs, or sparsely granulated with unusual fibrous bodies. Those composed of mammosomatotrophs also produce prolactin; rare plurihormonal tumors composed of cells that resemble mammosomatotrophs also produce TSH. Some PitNETs are composed of immature PIT1-lineage cells that do not resemble differentiated somatotrophs, mammosomatotrophs, lactotroph or thyrotrophs; these tumors may cause GH excess. An unusual oncocytic PIT1-lineage tumor known as the acidophil stem cell tumor is predominantly a lactotroph tumor but may express GH. Immature PIT1-lineage cells that express variable amounts of hormones alone or in combination can sometimes cause GH excess. Unusual tumors that do not follow normal lineage differentiation may also secrete GH. Exceptional examples of acromegaly/gigantism are caused by sellar tumors composed of hypothalamic GHRH-producing neurons, alone or associated with a sparsely granulated somatotroph tumor. Each of these various tumors has distinct clinical, biochemical and radiological features. Data from careful studies based on morphologic subtyping indicate that morphologic classification has both prognostic and predictive value.

Final Height in Pubertal Short Stature Boys Treated with GH Combination with Letrozole: A retrospective study

BackgroundThe growth potential of pubertal short stature boys is limited by the effect of estrogen on epiphyseal fusion. This study aims to identify the efficacy and safety of growth hormone (GH) combination with letrozole on final adult height (FAH) in pubertal short stature boys. MethodsThis is a retrospective study. Among pubertal short stature boys who treated with GH and letrozole were be followed up in our hospital, 20 cases reached FAH. ResultsBaseline chronological age were 12.12±1.14yr, bone age were 13.00±0.93yr. The treatment duration was 1.94±0.67yr. The height standard deviation score for bone age was increased from -1.46±0.51 to -0.12±0.57 (p<0.000). The predicted FAH before treatment, predicted FAH after treatment, FAH, and genetic target height were 161.02 ±4.12 cm, 172.11±4.20 cm, 172.67±2.72cm and 167.67±3.56 cm, respectively. There was significant differences between predicted FAH before treatment and after treatment (p<0.000), as well as predicted FAH before treatment and genetic target height (p<0.000).The predicted FAH after treatment was higher than that of genetic target height (p<0.001), as well as FAH and genetic target height (p<0.000). ConclusionsThe GH combination with letrozole can enhance the FAH in pubertal short stature boys. No significant side effects were observed.

Anastrozole Improves Final Adult Height in Severe Hypothyroidism With Rapid Pubertal Progression

Severe prolonged hypothyroidism due to Hashimoto thyroiditis may lead to rapid pubertal progression and compromised adult height after initiation of levothyroxine (LT4) therapy. There are no reports of aromatase inhibitor use to augment height in these patients. We describe a patient with severe hypothyroidism and growth failure who experienced rapid pubertal and bone age maturation on initiation of LT4 therapy. Anastrozole was added after 2 years to delay epiphyseal fusion. A boy aged 12 years and 1 month presented to the endocrine clinic with short stature and a markedly delayed bone age of 6 years. Brain magnetic resonance imaging showed a 1.5 × 1.0 × 1.2-cm enlarged lobular anterior pituitary. On examination, his height was –3.5 SD score (SDS) and weight was –2.87 SDS. Laboratory studies showed elevated thyrotropin (TSH) 850.6 μIU/mL, low free thyroxine 0.25 ng/dL, and elevated antithyroid antibodies. LT4 was initiated with normalization of TSH after 6 months. After 2 years of treatment he demonstrated catch-up growth with rapid bone age maturation, and his predicted adult height was compromised at 164.6 cm vs a midparental target height of 175.4 cm. Anastrozole 1 mg once daily was initiated. After 1.5 years of anastrozole treatment, the rate of his bone age advancement had slowed and his linear growth remained robust. The patient’s near-final height (167 cm) was 2.4 cm taller than his height prediction prior to starting anastrozole. Anastrozole slowed the rate of bone age advancement in a patient with severe hypothyroidism and rapidly progressive puberty during treatment with LT4, leading to improvement in near-final height.

Height outcomes in children with growth hormone deficiency and idiopathic short stature treated concomitantly with growth hormone and aromatase inhibitor therapy: data from the ANSWER program

Background Treatment of children with growth hormone deficiency (GHD) or idiopathic short stature (ISS) using GH is only effective for bone growth prior to epiphyseal fusion. Aromatase inhibitor therapy (AIT) blocks estrogen production, thereby delaying epiphyseal fusion. The current study analyzed baseline characteristics and longitudinal data of male patients with GHD or ISS who were treated with GH and concomitant AIT. Methods Data were obtained from the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program, which collected efficacy and safety data of patients treated with Norditropin®. A longitudinal cohort approach compared patient characteristics, including chronologic age, bone age, and height standard deviation score (HSDS), in GH-treated males before and after AIT initiation. Results A total of 142 GH-naïve patients with GHD (n = 115) or ISS (n = 27) with mean (± SD) baseline chronological ages of 12.10 ± 3.00 and 10.76 ± 3.07 years, respectively, were analyzed. The majority were classified at advanced Tanner stages II to V. Patients with GHD had mean HSDS of − 1.97 ± 0.78 at baseline and − 0.99 ± 0.88 prior to AIT initiation, while corresponding values for patients with ISS were − 2.15 ± 0.72 and − 1.04 ± 0.79, respectively. In patients evaluated after 2 years of concomitant AIT, mean HSDS had decreased to − 0.40 ± 1.16 and − 0.65 ± 0.52 for patients with GHD and ISS, respectively. Patients with GHD had a mean bone age/chronological age ratio (BA/CA) of 0.91 ± 0.11 at baseline and 0.97 ± 0.10 prior to AIT initiation, while corresponding values for patients with ISS were 0.85 ± 0.16 and 0.99 ± 0.10, respectively. In patients evaluated after 2 years of concomitant AIT, mean BA/CA values were 0.95 ± 0.10 and 0.96 ± 0.06 for patients with GHD and ISS, respectively. Conclusions In this real-world analysis, use of AIT with GH in males appeared to be associated with ongoing growth over 2 years, and AIT likely augmented growth potential as indicated by continued HSDS increase with decreased BA/CA after AIT initiation. Trial registration This trial was sponsored by Novo Nordisk and is registered with ClinicalTrials.gov (NCT01009905). Registered November 11, 2009; retrospectively registered

Coming of age: morphometric variation in the hand skeletons of juvenile and adult Lesser Treeshrews (Scandentia: Tupaiidae: Tupaia minor Günther, 1876)

Morphometric analyses of the manus skeleton have proven useful in understanding species limits and morphological divergence among tupaiid treeshrews (Scandentia: Tupaiidae). Specimens in these studies are typically limited to mature individuals with fully erupted permanent dentition, which eliminates potentially confounding variation attributable to age, but also can exclude rare taxa and small island populations that are poorly represented in systematic collections. To determine the real limits associated with including immature animals in such studies, we used multivariate analyses to study sexual and age variation of the manus skeleton in two allopatric populations of the Lesser Treeshrew (Tupaia minor Günther, 1876) from the Malay Peninsula and from Borneo that we treated as separate samples. Individuals were aged using dental eruption of the permanent dentition. We also recorded the degree of epiphyseal fusion of the bones of the manus based on x-rays of study skins. We then tested our ability to distinguish the two populations using a series of discriminant function analyses of hand measurements from samples that included varying proportions of immature individuals and adults. We found no evidence of sexual dimorphism in hand proportions, permitting us to combine females and males in our samples. Epiphyseal fusion of the metacarpals and phalanges typically occurs by the time the third molars have completely erupted, and fusion of the distal epiphyses of the radius and ulna typically occurs by the time the permanent fourth premolars are in place. There is occasional asynchrony between dental age and epiphyseal fusion. In both populations, the hands of most infants and subadults provide morphometric values within the range of variation of adults, although they are typically distributed in the lower part of the adult range and have the potential to bias the sample toward lower mean size. The inclusion of infants and subadults when attempting to discriminate between two taxa generally results in lower rates of correct classifications, although the rates increase as the sample of immature individuals is limited to older subadults. As a general rule, we recommend that specimens of infants and subadults continue to be excluded from analyses when exploring taxonomic boundaries among treeshrews. In cases of extremely small sample sizes of adults, however, older subadults—in which the permanent third premolars are erupting or in place—can be used with appropriate caution.