Dhiren Patel, PharmD, Robert Busch, MD, and Diana Issacs, PharmD, discuss recent advances in diabetes technology and their impact on patient care.

Pillars of Diabetes Care Technology

Data from a cross-sectional study carried out by investigators from in Asia suggests the team had developed a clinical risk score model to help stratify risk of central precocious puberty (CPP) in children.

Leveraging data from electronic medical records within the Children’s Hospital at Fudan University in Shanghai, China, investigators developed and tested a clinical risk score model, which consists of 4 items and a 33-point scale, they concluded had a moderate predictive performance that could help evaluate what patients require further diagnostic tests.

“GnRH stimulation test is the gold standard for CPP. But it is time-consuming and costly. In this study, we developed a risk score system containing information on age at the onset of puberty, basal luteinizing hormone concentration, and pelvic sonography for the prediction of CPP,” wrote investigators.

While gonadotropin-releasing hormone (GnRH) or GnRH analogs (GnRHa) stimulation tests may be the diagnostic standard for diagnosis CPP, investigators note the real-world use of the test can be time-consuming and expensive. With an interest in creating and validating new diagnostic criteria for determining presence of CPP in girls with precocious pubertal developments, a team led by Jingyu You, of Fudan University, designed the current cross-sectional study to assess the use of a clinical risk prediction model using pelvic ultrasonography and readily available clinical features.

Using the electronic medical record system of the Children’s Hospital at Fudan University, investigators obtained data related to the medical history, laboratory test results, physical examinations, treatment, and demographic information of all patients treated between January 2010 and August 2016. A total of 627 were deemed eligible for inclusion in the study. Of these, 314 were included in the training sample and 313 were included in the validation sample for the study.

For the purpose of analysis, variables associated with CPP in univariate analyses were subsequently introduced in a multivariable logistic regression model in the training sample. Additionally, the prediction model was selected using a forward stepwise analysis and the risk score model was built with scaled coefficients of the model and tested in the validation sample.

For inclusion, patients needed to be a female with a diagnosis of precocious puberty, be 8 years or less when diagnosed, have a hormone assay and pelvic ultrasonography performed the Children’s Hospital at Fudan University, and have pelvic ultrasonography perfumed within 1 week of the GnRHa stimulation test. Investigators pointed out those with secondary precocious puberty or ovarian cyst were not included in the study.

The mean age of patients included in the study was 7.5 years and the mean disease duration was 1.0 years. A diagnosis of CPP was received by 54.8% in the training sample and 55% of patients in the validation sample. Based on data from training sample the CPP risk score model developed by investigators, investigators included age at the onset of puberty, basal luteinizing hormone (LH) concentration, largest ovarian volume, and uterine volume.

Results of the investigators’ analysis suggested the C-index was 0.85 (95% CI, 0.81-0.89) in the training sample and 0.86 (95% CI, 0.82-0.90) in the validation sample. Investigators noted a pair of cut-off points were selected to stratify patients according to low-, median-, and high-risk groups, which were defined as less than 10 points, 10-19 points, and 20 or more points.

“Patients with high-risk score would be a major beneficiary of the risk score model. Based on the risk scores, high-risk patients could be diagnosed without GnRHa stimulation test; patients at medium-risk of CPP need diagnostic test promptly; patients at the low-risk category need to be followed up,” wrote investigators.

Investigators cautioned clinicians to consider the limitations within their study before overinterpretation of results. These limitations included inability to apply results to different populations, information on pubertal development being unavailable within the electronic medical record system, and the possibility that the study population does not repent to spectrum of precocious puberty.

Clinical risk score for central precocious puberty among girls with precocious pubertal development: a cross sectional study,

Articles

A cross-sectional study has returned results that suggest a risk score model could help identify patients with central precocious puberty without the need for more expensive and invasive stimulation tests.

Risk Score Model Could Provide Inexpensive CPP Diagnosis Tool

Data from a systematic review and meta-analysis assessing nearly 100 studies with more than 5000 patients is detailing the long-term efficacy and safety of gonadotropin-releasing hormone analog (GnRHa) treatment in children with idiopathic central precocious puberty (CPP).

Although results of the study provide insight into the effects of GnRHa treatment, including its effects on final adult height (FAH), body mass index (BMI), and risk of polycystic ovary syndrome (PCOS), investigators point out the need for more high-quality studies assessing long-term outcomes of GnRHa treatment in children with CPP.

“In this systematic review, we aimed to determine the long-term efficacy and safety of GnRHa treatment in children with ICPP. Current evidence is mainly focused on girls with ICPP, and the overall quality of evidence for each studied outcome was found to range from very low to moderate,” wrote investigators.

Together with a team of colleagues from the Tongji Medical College, Xiaoping Luo, MB, professor and chairman of the department of pediatrics at the Tongji Hospital of Tongji Medical College, designed the current study as a systematic review and meta-analysis to provide clinicians with an overview of the long-term efficacy and safety of GnRHa treatment. With this in mind, investigators queried the PubMed, EMBASE, and Cochrane Library databases from inception through November 2019 to identify studies for inclusion in their systematic review and meta-analysis.

Investigators had 3 specific inclusion criteria for the study, which were that studies needed to be prospective or retrospective comparative studies and single-arm studies, studies needed to include participants with ICPP with the onset of secondary sex characteristics before 8 years of age in girls and before 9 years of age in boys, and studies need to report long-term outcomes in participants who received GnRHa compared with participants who received no treatment/placebo or GnRHa plus growth hormone.

The primary outcomes of interest for the study included FAH, target height (TH), BMI, and incidence of PCOS among girls and androgen excess among boys. Secondary outcomes of interest included menstrual parameters, growth velocity (GV), IGF-1 level, BMD, glucose and lipid metabolism, insulin resistance parameters, and psychological state.

Investigators identified a total of 98 studies enrolling a population of 5475 participants for possible inclusion in the current study. Of these 18 were randomized comparative studies and 81 were single-arm studies. The sample size of studies ranged from 6 to 33 and 98.5% of the total population were women.

Upon analysis, investigators determined the overall risk of bias among eligible studies ranged from critical to moderate and the overall quality of evidence for each outcome ranged from very low to moderate. When assessing evidence-based comparative studies, results indicated GnRHa treatment was associated with increased FAH (mean difference=4.83 cm [95% CI, 1.32 to 7.34]; 

2=49%) and decreased BMI (MD=—1.01 [95%, -1.64 to -0.37]; 

=0%) in girls with idiopathic CPP compared with no treatment.

Additionally, incidence of PCOS did not appear to be significantly different with and without GnRHa therapy (RR, 1.21 [95% CI, 0.46 to 3.15]; 

2=48%). Investigators pointed out evidence for other long-term outcomes were very weak and contributed to an inability to deduce effects of GnRHa treatment on these outcomes. Investigators also pointed out limited evidence prevents these results from being applicable to populations of boys with idiopathic CPP.

“The current evidence indicates that GnRHa treatment improve the FAH of girls with ICPP, thus allowing them to meet or exceed their TH. GnRHa treatment also reduce the BMI levels of participants compared with BMI of those treated with placebo,” wrote investigators. “Furthermore, GnRHa did not appear to increase the risk of PCOS. However, evidence regarding other predefined key outcomes, such as infertility, malignancy and metabolic diseases, is very weak to indicate the benefits or side effects of GnRHa treatment.”

Long-term efficacy and safety of gonadotropin-releasing hormone analog treatment in children with idiopathic central precocious puberty: A systematic review and meta-analysis,

A systematic review and meta-analysis detail the effects of GnRHa therapy on final adult height, BMI, risk of PCOS, and more long-term outcomes among patients with idiopathic CPP. 

Influence of GnRHa on Long-Term Outcomes in Idiopathic Central Precocious Puberty

Editor's Note: Clicking in the center of a slide will redirect you to the article highlighted within that slide. 

Endocrine Month in Review: October 2021

Slideshows

October's endocrine month in review features stories on the new ADA and EASD type 1 diabetes guidance, a phase 2 trial examining oral PTH tablets for osteoporosis, and a 3-part panel discussion focusing on diabetes management in 2021. 

Patrick Campbell is the senior editor of Endocrinology Network, as well as its sister publication Practical Cardiology. Prior to joining these brands, he led coverage of cardiology and diabetes with HCPLive. Before joining parent company MJH Life Sciences in 2019, he spent time as a beat reporter with the Pocono Record in Stroudsburg, PA and Star News Group in Manasquan, NJ. He also touts experience in multimedia, having spent time as a freelance multimedia specialist with NJ Advance Media and multimedia coordinator at the Pocono Record. In his free time, he enjoys traveling, sports, and exploring the great outdoors. Follow him on Twitter @RealPatCampbell or reach him via email at PCampbell@mjhlifesciences.com.

New research from investigators at Brigham and Women’s Hospital and Harvard Medical School suggests use of SGLT2 inhibitors was not associated with an increased risk of fracture in older adults with 

A propensity score-matched analysis of data from a cohort of nearly 500,000 Medicare beneficiaries with type 2 diabetes and no history of fracture, results of the study demonstrate initiating treatment with an SGLT2 inhibitor was not associated with an increased risk of fracture compared to initiating treatment with a dipeptidyl peptidase 4 inhibitor (DPP-4i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA).

“In this nationwide Medicare cohort, initiating an SGLT-2i was not associated with an increased risk of fracture in older adults with T2D compared with initiating a DPP-4i or GLP-1RA, with consistent results across categories of frailty, age, and insulin use. These findings add to the evidence base evaluating the potential risks associated with SGLT-2i use for older adults outside of randomized clinical trials,” wrote investigators.

Although SGLT2 inhibitors have become the center of discussion for clinicians with an interest in cardiometabolic health in recent years, some have raised concerns over the safety profile of these agents in real-world settings. With former studies implicating a potential impact on bone health, a team of 9 Harvard Medical School-based investigators sought to investigate the effects of SGLT2 inhibitors on fracture risk in comparison to other therapies leveraging Medicare fee-for-service data.

Searching Medicare fee-for-service data from April 2013 to December 2017, investigators identified a cohort of 466,933 patients aged 66 years of age or older with type 2 diabetes and no history of fracture for potential inclusion in their study. For inclusion in the study, patients needed to be newly prescribed 1 of the 3 aforementioned therapy classes during the study period. Investigators noted 66 years was chosen as the lower cutoff for age so patients would have at least 1 year of Medicare eligibility before cohort entry.

Exposures of interest for the study were defined as new use of any SLGT2 inhibitor, GLP-1RA, or DPP-4i. The SGLT2 inhibitors included in the study were canagliflozin, dapagliflozin, and empagliflozin. The DPP-4 inhibitors included in the study were alogliptin, linagliptin, saxagliptin, and sitagliptin. The GLP-1 receptor agonists included in the study were albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide. The primary outcome of interest for the study was a composite of nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention within 30 days. Secondary outcomes of interest included incidence of falls, hypoglycemia, and syncope.

After the application of 3-way propensity score matching, investigates identified 45,889 matched sets of patients, including a total of 137,667 patients in the final study cohort. This population had a mean age of 72 (SD, 5) years and 47% were men. Investigators planned to use multivariable Cox proportional hazards regression models to estimate hazard ratios for SFGLT2 inhibitor use compared with DPP-4 inhibitors and GLP-1RA use. Additionally, Kaplan-Meier curves were used to visualize fracture risk over time.

Upon analysis, there were no differences observed in the risk of fracture for SGLT2 inhibitor users when compared to DPP-4i users (HR, 0.90; 95% CI, 0.73-1.11) or GLP-1RA users (HR, 1.00; 95% CI, 0.80-1.25). When assessing secondary outcomes, results indicated the risk of falls (HR, 0.82; 95% CI, 0.77-0.87) and hypoglycemia (HR, 0.75; 95% CI, 0.67-0.84) were lower in SGLT2 inhibitor users compared against matched DPP-4i users but no difference was observed for syncope. Investigators noted no difference in falls, hypoglycemia, or syncope for SGLT12 inhibitor users compared with GLP-1RA users.

Association of Sodium-Glucose Cotransporter–2 Inhibitors With Fracture Risk in Older Adults With Type 2 Diabetes

A propensity score-matched analysis comparing fracture risk associated with the initiation of SGLT2 inhibitors versus GLP-1RAs or DPP-4 inhibitors indicates use of SGLT2 inhibitors was not associated with an increase in risk of fractures in older patients with type 2 diabetes. 

No Increase in Fracture Risk from SGLT2 Inhibitor Use, Study Finds

 A female in her 40’s presents to the hospital for 3 days of generalized malaise and worsening left buttock pain with subjective fevers. She denies any abdominal pain but did vomit once. She denies chills, back pain or any other complaints.

 Vital signs were a bit soft: pulse 102, BP 92/51 with a shock index >1.0 (HR/SBP). Physical exam was otherwise normal except for a red swollen left buttock

Our latest emergency department quiz from Brady Pregerson, MD, features a woman in her 40’s presenting with 3 days of generalized malaise and worsening left buttock pain with subjective fevers. Check out the CT and see if you can determine the correct diagnosis.

Endocrine Case Report: Buttock Pain

A man in his mid-60’s with a history of diabetes and obesity presents to the hospital for one day of left groin pain that started in the morning and became severe after dinner followed by a syncopal episode

Vital signs are normal except for pulse of 48 and BP of 88/62. The physical exam is otherwise normal except for diminished left leg pulse (ALWAYS CHECK THE PULSE IN THE FOOT WITH ANY COMPLAINT INVOLVING THE LEG).

: CBC shows a WBC count of 13 and Hb of 12.2

Our latest endocrine case report features a man in his mid-60’s with a history of diabetes and obesity presenting with left groin pain followed by a syncopal episode. Check out the CT scan and determine the correct diagnosis.

Endocrine Case Report: Groin Pain and Syncope

New research from an imaging study assessing differences in brain volume among girls with idiopathic central precocious puberty (ICPP) against cohorts of healthy age-matched and normal puberty cohorts could provide insight into the neuroanatomical mechanisms on morphological variations associated with ICPP.

Results of the study, which included data from 15 girls with ICPP and matched controls, offer clinicians with an overview of the potential for volumetric differences in brain volume and correlations with differences in luteinizing hormone (LH) levels in patients with ICPP compared with those age-matched and normal puberty controls.

“These findings will be useful for understanding the neuroanatomical mechanisms on the specific morphological variations associated with ICPP,” wrote investigators.

Citing a lack of studies assessing differences in brain structure among patients with early puberty to other individuals, a team from Chonnam National University and Chosen University Hospital in Korea designed the current study to fill with apparent knowledge gap. Specifically, the study was designed to compare cerebral volume differences between ICPP girls, age-matched girls, and normal puberty girls using voxel-based morphometry as well as examining potential influence of LH on brain structure.

To do so, investigators created their 3 cohorts using patients recruited from the Department of Pediatrics at Chosun University Hospital. All individuals included in the study underwent anatomical imaging with 1.5 Tesla Avanto MR scanner and T1-weighted images were acquired with a T1 spin-echo sequence. Investigators compared volumes of total and regional brain using paired T-tests. Of note, luteinizing hormone levels were assessed through a correlation test.

The mean age of the ICPP group, age-matched group, and puberty group were 8.0±0.9 years, 7.8±0.9 years, and 11.9±0.9 years, respectively. Investigators noted the 15 girls with ICPP had advanced bone age and breast development. Investigators also noted peak LH levels stimulated by the gonadotropin-releasing hormone agonists (GnRHa) of ICPP girls were 15.9±14.9 mIU/mL. There were no significant differences in total intracranial volume observed among the cohorts, with TICV of 1194.6±122.4 ml for ICPP girls, 1139.0±75.5 ml for age-matched controls, and 1173.93±68.93 mL for normal puberty controls.

Investigators’ analyses indicated cerebral volumes in patients with ICPP were different from those of the age-matched cohorts. Specifically, ICPP was associated with a significant increase in gray matter (GM) volumes in the medial prefrontal cortex, superior parietal gyrus, supramarginal gyrus, angular gyrus, postcentral gyrus, superior occipital gyrus, cuneus, hippocampus, parahippocampal gyrus, posterior cingulate gyrus (PCgG), and cerebellar cortex (Cb) and in white matter (WM) volumes in the insular, caudate, and splenium of corpus callosum (

Investigators pointed out GM volumes of the PCgG (r=.57, 

=.04) were positively correlated with LH concentrations stimulated by GnRHa. However, investigators also pointed out there were no significant differences in GM volume observed when comparing the ICPP cohort to the normal puberty controls.

“Increased GM and WM volumes were observed in the whole cerebral area of ICPP girls compared to the age-matched control group. These observed brain regions were related to emotional and cognitive function, and correlated with the sex hormone additionally,” wrote investigators. “This suggests that the cerebral development pattern of ICPP is similar to that of normal puberty, and these local differences in cerebral volume may affect social and congenital changes.”

The Assessment of Brain Volume Differences in Idiopathic Central Precocious Puberty Girls; Comparison of Age-Matched Girls and Normal Puberty Girls

An imaging study of girls with idiopathic CPP and matched controls suggests idiopathic CPP was associated with increased gray matter and white matter volumes in the cerebral area. 

Study Assesses Brain Volume Differences in Girls with Central Precocious Puberty

An analysis of data from more than 50 women is providing insight into the potential for increased risk of polycystic ovary syndrome (PCOS) associated with exposure to gonadotropin-releasing hormone analogue (GnRHa) therapy among patients with endocrine disorders.

Conducted by investigators at the Hebrew University of Jerusalem, results of the study suggest use of GnRHa therapy was not associated with an altered prevalence of PCOS among patients with central precocious puberty (CPP).

“Some earlier work demonstrated a higher prevalence of PCOS in females who had precocious puberty. However, there is conflicting evidence regarding an association between GnRH analogue therapy and PCOS, though these studies either assessed for PCOS only two years after menarche or focused on clinical signs of hyperandrogenism without laboratory or sonographic evaluation for PCOS,” wrote investigators. “This study aimed to evaluate the prevalence of PCOS as defined by the widespread criteria, and other endocrine outcomes in females diagnosed with CPP according to GnRH analogue treatment, hypothesizing that the GnRH analogue treatment itself may affect its occurrence.”

Led by Gilad Karavani, MD, a senior physician in the Department of Obstetrics and Gynecology at Hebrew University Medical Center, and a team of colleagues, the current study was conducted with an interest in describing the association between GnRHa therapy and PCOS among patients with CPP. With this in mind, investigators designed the current study as a retrospective cohort study using data from women treated in a university-affiliated medical center from 1989 through 2011.

Investigators identified a cohort of 51 women for inclusion in their study, which included 24 who had been followed by a pediatric endocrinologist without medical treatment and 27 who had been treated with GnRHa therapy. The mean follow-up time for study participants was 10.9±3.8 years and the age at follow-up ranged from 15.1-38.8 years. Investigators noted age at follow-up was similar among those treated with GnRHa therapy (19.9±4.6 years) compared to those who did not receive GnRHa therapy (18.7±1.8) (

Among those treated with GnRHa, the mean age at initiation of treatment was 8.6±1.1 years, treatment was administered for a mean of 24.3±12.8 months. Investigators also pointed out the mean age at cessation of GnRHa treatment was 10.8±0.5 years and the mean time from its discontinuation to menarche was 10.0±3.5 months.

Upon analysis, results indicated the overall rate of PCOS diagnosis during the follow-up was 19.6%. Further analysis indicated PCOS occurred among 22.2% of the treatment group and 12.5% of the non-treatment group, but these results failed to reach statistical significance (

=.47). Investigators pointed out prevalence of oligomenorrhea or amenorrhea was 33.3% overall and similar rates were observed among both groups. Additionally, hyperandrogenism was reported among 29.6% of women in the GnRHa treatment group and 29.2% of those in the non-treatment group (

Investigators also noted a univariate analysis assessing factors associated with PCOS in adulthood was performed and none of the parameters included, such as age, BMI, and clinical signs of puberty at CPP diagnosis, were found to be significantly different among CPP patients diagnosed with PCOS compared to the rest of the cohort.

“We did not find any GnRHa treatment-associated difference in frequency of PCOS, two decades and more after the precocious onset of puberty. This data supports the overall safety of GnRHa therapy with regard to PCOS occurrence,” wrote investigators in their conclusion.

Gonadotropin releasing hormone analogue treatment of central precocious puberty is not associated with altered prevalence of polycystic ovary syndrome: a single center cohort study

Using data from more than 50 women, investigators determined exposure to GnRHa treatment was not associated with an increased risk of developing PCOS in women with CPP treated with GnRHa. 

GnRHa Not Associated with Increased PCOS Risk in Patients with Endocrine Disorders

A recent study by a team of European investigators is underlining the importance of an individualized approach in the management and treatment of central precocious puberty (CPP).

A translational study examining pathogenic and low-frequency variants in children with CPP, results of the study detail the incidence of rare sequence variants among 

 genes in a cohort of children, including girls and boys, with CPP.

“The results of the present study confirm the importance of the 

-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP,” wrote investigators in their conclusion.

A rare pubertal disorder with an apparent knowledge gap related to genetic determinants, the current study was designed by a team of investigators based in Greece and Cyprus with an interest in describing rare sequence variants among the 

The study population included in the analysis was a cohort of children, including 54 girls and 2 boys with CPP, referred for genetic investigation to the Department of Molecular Genetics, Function, and Therapy at the Cyprus Institute of Neurology and Genetics. All children included in the study met the criteria for CPP diagnosis, which was defined as presenting with breast development Tanner stage 2 before the age of 8 years in girls and presenting with testicular enlargement more than 4 ml in volume measured with Prader orchidometer before the age of 9 years in boys.

All children who were found negative for the 

gene underwent further investigation through whole exome sequencing. Results of whole exome sequencing among these children was compared against an in-house cohort of Cypriot children with CPP. Investigators pointed out the identified rare variants were initially examined by 

computational algorithms and subsequently comfier with Sanger sequencing. Investigators also pointed out a genetic network for the 

 gene, which replicated a holistic regulatory depiction of the crosstalk between MKRN3 and other genes, was designed for the purpose of analysis.

Upon analysis, 3 previously described pathogenic variants of the 

 gene were located in the coding region of the gene were identified in 12 girls with CPP. Specific mutations included the missense p.Gly312Asp was in 7 index girls, the frameshift p.Met268ValfsTer23 in 4 index girls,

and the nonsense p.Glu298Ter in 1 index girl with CPP. Investigators noted the most common pathogenic 

variant p.Gly312Asp was observed exclusively among patients within the Cypriot CPP cohort, which indicates a founder effect phenomenon.

In the cohort of 44 children who underwent whole exome sequencing, investigators identified 9 rare 

 variants among 11 girls, a pair of rare 

 variants among 6 girls, and a pair of rare 

 variants among 5 girls. Investigators also pointed out rs10407968 variant of the 

gene appeared to be less frequent in the cohort of patients with CPP.

“We confirmed the key role of the imprinted MKRN3 gene as the most common cause of monogenic CPP in the Cyprus cohort. The newly described p.Gly312Asp missense loss-of-function pathogenic variant was identified as the most prevalent among the tested Cypriot CPP cohort. This could be most likely due to the founder effect, a frequent phenomenon in the Cypriot population,” wrote investigators.

Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty

Results of a recent study provide insight into the prevalence of rare sequence variants among the MKRN3, DLK1, KISS1, and KISS1R genes in children with CPP. 

Study Details Prevalence of Genetic Variants in Central Precocious Puberty

A new study from investigators in the department of pediatric endocrinology at the Icahn School of Medicine at Mount Sinai is providing clinicians with an overview of factors that could negatively influence time to menarche following gonadotropin-releasing hormone agonist (GnRHa) in women with central precocious puberty (CPP).

Citing a dearth of research on the topic, investigators carried out a retrospective chart review of more than 3 dozen females with CPP and provide insight into multiple factors, including Tanner stage of breast development and change in bone age, that were negatively associated with the time interval to menarche.

“Few studies have evaluated auxological factors that can predict the time interval to menarche after treatment cessation. The aims of this study were to evaluate the time interval to menarche after GnRHa discontinuation and to identify factors that contribute to timing of menarche,” wrote investigators.

With GnRHa the most commonly used treatment for CPP, the current study was created by investigators described as a lack of studies detailing factors associated with a negative influence on time interval to menarche following treatment cessation. Led by Vickie Wu, MD, a pediatric endocrinologist at the Icahn School of Medicine at Mount Sinai, investigators designed their study as a retrospective chart review of records from women with idiopathic CPP treated with GnRHa from May 2005-November 2017 at an academic pediatric endocrinology clinic.

During this time period, 450 female patients were diagnosed with CPP. Of these, 67 were treated with GnRHa and had documented menarche in their medical record. After exclusion of patients with coexisting endocrinopathies and those with CPP and an identified etiology, 39 patients were identified for inclusion in the analysis. Of note, diagnostic criteria for CPP used min the study were breast development before 8 years of age, measurable pubertal luteinizing hormone (LH) and/or estradiol concentrations at baseline or in response to GnRH stimulation test, and significant bone age advancement.

The mean treatment duration for the 39 patients included in the study was 2.2±1.4 years. At the start of GnRHa treatment, the mean chronologic age of the cohort was 9.4±1.6 years, the mean bone age was 11.2±1.3 years, the mean height was 139.0±9.5 cm, and mean weight was 39.5±10.6 kg. At the end of treatment, the mean chronologic age was 11.6±1.2 years and the mean bone age was 12.5±0.9 years. The difference between bone age and chronologic age at the start of treatment was 1.8±1.4 years and the difference at the end of treatment was 0.9±1.2 years.

Results of the investigators’ analysis indicated menarche occurred at a mean of 12.6±1.1 years, which was a mean of 1.04±0.5 years following treatment discontinuation. Investigators noted 54% of patients reached menarche by 1 year after the end of treatment and 44% reached by 2 years. Further analysis suggested bone age at start of treatment, Tanner stage of breast development at start of treatment, and change in bone age from start to end of treatment were all negatively associated with time interval to menarche (

Investigators noted a greater change in bone age during treatment was significantly associated with a shorter interval to menarche after adjustment for initial bone age (β=-0.25; 95% CI, -0.44 to -0.07; 

=.009). Additionally, results incited advanced bone age and advanced Tanner stage prior to the start of treatment were associated with decreased time interval to menarche.

“In conclusion, the time from the end of treatment to menarche ranged from 0.5 to 1.5 years. The factors negatively associated with the time interval to menarche were Tanner stage of breast development at treatment onset, bone age at treatment onset, and change in bone age,” wrote investigators. “These data provide clinical correlates that assist providers during anticipatory guidance of patients after treatment of CPP with GnRHa.”

Investigators cautioned clinicians to consider the limitations of their study when interpreting the results. Limitations noted by investigators included the relatively small sample size and the lack of an untreated control group who could be followed until menarche.

Clinical findings influencing time to menarche post gonadotropin-releasing hormone agonist therapy in central precocious puberty

Annals of Pediatric Endocrinology & Metabolism.

Mount Sinai-led chart review provides insight into the influence of various factors on time to menarche among girls with central precocious puberty who received GnRHa treatment. 

Endocrine Case Report: Groin Pain and Syncope

Study Assesses Brain Volume Differences in Girls with Central Precocious Puberty

GnRHa Not Associated with Increased PCOS Risk in Patients with Endocrine Disorders

Study Details Prevalence of Genetic Variants in Central Precocious Puberty

Study Details Factors Negatively Impacting Time to Menarche in Central Precocious Puberty