Precocious Puberty and GnRH Analogs: Current Treatment Practices and Perspectives among US Pediatric Endocrinologists

Abstract

Introduction

Gonadotropin releasing hormone analogs (GnRHas) are used for treatment of precocious puberty. Over the last decade, several new formulations have been approved.

Methods

The Drugs and Therapeutics Subcommittee of the Pediatric Endocrine Society (PES) undertook a review to ascertain the current treatment options, prescribing behaviors, and practices of GnRHas among pediatric endocrinologists practicing within the USA. The survey consisted of four main subsections: (1) description of clinical practice; (2) self-assessment of knowledge base of pediatric and adult GnRHa formulations; (3) current practice for treating central precocious puberty (CPP); and (4) utilization of healthcare resources.

Results

There were 223 survey respondents. Pediatric endocrine practitioners were most familiar with the pediatric one-monthly preparation, the 3-month preparation, and the histrelin implant (Supprelin^®) (88%, 96%, and 91%, respectively), with lower familiarity for 24-week triptorelin intramuscular (Triptodur^®) (65%) and 6-month subcutaneous leuprolide (Fensolvi^®) (45%). Only 23% of the respondents reported being extremely familiar with the availability of adult formulations, and 25% reported being completely unaware of cost differences between pediatric and adult GnRHa preparations. The implant was the most preferred therapy (44%), but in practice, respondents reported a higher percentage of patients treated with the 3-month preparation. While family preference/ease of treatment (87%) was the key determinant for using a particular GnRHa preparation, insurance coverage also played a significant role in the decision (64%). Responses regarding assessment for efficacy of treatment were inconsistent, as were practices and criteria for obtaining an MRI.

Conclusions

The survey indicated there is more familiarity with older, shorter acting GnRHas, which are prescribed in greater numbers than newer, longer acting formulations. There is lack of consensus on the need for central nervous system (CNS) imaging in girls presenting with CPP between 6 and 8 years of age and use of laboratory testing to monitor response to treatment. Insurance requirements regarding CNS imaging and laboratory monitoring are highly variable. Despite having similar constituents and bioavailability, there are substantial cost differences between the pediatric and adult formulations and lack of evidence for safe use of these formulations in children. The survey-based analysis highlights the challenges faced by prescribers while reflecting on areas where further research is needed to provide evidence-based practice guidelines for pediatric endocrinologists.

Introduction and Historical Perspective

Gonadotropin releasing hormone analogs (GnRHa) have been used off-label for central precocious puberty (CPP) since the 1980s. In 1993, leuprolide, Lupron Depot^® (AbbVie Inc.), was the first GnRHa approved by the FDA for treatment of CPP, defined by the onset of secondary sexual characteristics before ages 8 years in girls and 9 years in boys. GnRHa is administered as an injection, implant, or intranasal spray. For 2 decades, monthly depot GnRHa was the only available formulation used by pediatric endocrinologists to treat CPP. In 2007, the FDA approved a long-acting GnRHa subcutaneous implant (Supprelin^® LA 50 mg). The implant is marketed for annual use but is often used safely and effectively clinically for up to 2 years, which reduces cost and the need for additional surgical procedures [1]. Other products have since been approved: first, a 3-month intramuscular leuprolide depot injection in 2011 (Lupron Depot-Ped^®), followed by approval of a 6-month intramuscular depot formulation (triptorelin, Triptodur^®) in 2017. In 2020, a subcutaneous formulation of leuprolide lasting 6 months (Fensolvi^®) was approved and in 2023, a 6-month leuprolide, Lupron^® intramuscular depot injection was approved. See Table 1 for information on 6 preparations approved at the time of this report.

Table 1.

US FDA approved pediatric formulations of GnRH analogs

GnRH analog	Preparation, manufacturer	Administration route	Available dosages	Year of US FDA approval
Leuprolide acetate	1-month Lupron Depot-Ped®, AbbVie (Chicago, IL)	Intramuscular	7.5 mg, 11.25 mg, 15 mg	1993
	3-month Lupron Depot-Ped®, AbbVie (Chicago, IL)	Intramuscular	11.25 mg, 30 mg	2011
	6-month Lupron Depot-Ped®, AbbVie (Chicago, IL)	Intramuscular	45 mg	2023
	6-month Fensolvi®, Tolmar Therapeutics (Fort Collins, CO)	Subcutaneous	45 mg	2020
Histrelin acetate	1-year Supprelin®, Endo Pharmaceuticals (Malvern, PA)*	Subdermal implant (requires surgical insertion and removal)	50 mg (65 μg/day)	2007
Triptorelin pamoate	6-month Triptodur®, Arbor Pharmaceuticals (Atlanta, GA)	Intramuscular	22.5 mg	2017

*Although histrelin is marketed as requiring annual replacement, reports indicate that it is effective for at least 2 years (Lewis 2013).

Methods

As newer GnRHa preparations have become available in the last decade, the Drugs and Therapeutics Subcommittee of the Pediatric Endocrine Society (PES) undertook a review to ascertain the current treatment options, prescribing behaviors, and practices of GnRHas among pediatric endocrinologists practicing within the USA. The committee proposed survey questions. A survey link was sent in October 2021 to all members of the PES. The survey was created using RedCAP, a browser-based HIPAA compliant database. As of 2021 the active PES membership included around 75% of all practicing pediatric endocrinologists. Total membership was 1,622 with 1,060 regular members, 77 advanced practice providers, 224 fellows in-training, 218 emeritus, and 23 associate members. No data are available on the gender, ethnicity, or sexual orientation of PES members. The survey consisted of 42 questions, took about 10 min to complete, and consisted of four main subsections: (1) description of clinical practice; (2) self-assessment of knowledge base of pediatric and adult GnRHa formulations; (3) current practice for treating CPP; and (4) utilization of healthcare resources. Questions had multiple choice options, with an opportunity to enter free text and 50% of the survey was Likert scale based. The study was approved by the Board of Directors and Research Affairs Committee of the PES.

Results

There were 223 survey respondents, the majority of whom were hospital/academic institution based (77%) and in an urban location (67%). When surveyed for familiarity of formulations, a high number of survey respondents reported being extremely familiar (as opposed to very, moderately, somewhat, or not at all familiar) with the pediatric one-monthly preparation, the 3-month preparation, and the histrelin implant (Supprelin^®) (88%, 96%, and 91%, respectively). The reported familiarity was lower for the two more recently approved preparations, with only 35% of respondents reporting being “extremely familiar” with 24-week triptorelin intramuscular (Triptodur^®) and 23% with 6-month subcutaneous leuprolide (Fensolvi^®). Only 23% of the respondents reported being extremely familiar with the availability of adult formulations, and 15% were completely unaware. 31% reported being extremely familiar with the cost differences between pediatric and adult GnRHa preparations, but 25% reported being completely unaware.

The implant was the most preferred therapy (44%), followed by the 3-month preparation (38%), and 6-month preparations (15%), with the 1-month injection being the least preferred therapy (3%). In practice, however, respondents reported a higher percentage of patients were treated with 3-month preparation, rather than implants. Nearly 1 in 10 respondents (n = 22) preferred using the monthly GnRHa preparation in very young patients (≤6 years) or those with a pathologic cause of CPP. While family preference/ease of treatment (87%) was the key determinant for using a particular GnRHa preparation, insurance coverage also played a significant role in the decision (64%) (shown in Table 2; Fig. 1). Insurance coverage was the main driver for prescribing behaviors, which are summarized in Table 2 and Figure 2.

Table 2.

Demographics and prescribing practices of PES survey responders (n = 223)

	Total, N (%)
Overall	223
Demographics
Region of USA
Northeast	79 (35)
Midwest	40 (18)
South	60 (27)
West	44 (20)
Practice setting
Solo	15 (7)
Faculty group practice	37 (17)
Hospital/academic institution	171 (77)
Location setting
Rural	9 (4)
Urban	149 (67)
Suburban	64 (29)
Years in practice (since fellowship)
<5	48 (22)
5–10	50 (22)
10–20	66 (30)
>20	59 (26)
Knowledge base of pediatric and adult GnRHa formulations
Familiarity with pediatric
a. Leuprolide monthly injections, 7.5, 11.25, 15 mg
Not at all familiar	0
Somewhat familiar	8 (4)
Moderately familiar	19 (9)
Very familiar/extremely familiar	196 (88)
b. Leuprolide 3-monthly injections (11.25 and 30 mg)
Not at all familiar	0
Somewhat familiar	1 (0.4)
Moderately familiar	9 (4)
Very familiar/extremely familiar	213 (96)
c. Triptorelin 6-monthly IM injection, Triptodur 22.5 mg
Not at all familiar	13 (6)
Somewhat familiar	21 (9)
Moderately familiar	44 (20)
Very familiar/extremely familiar	145 (65)
d. Leuprolide 6-monthly subcutaneous injection, Fensolvi 45 mg
Not at all familiar	21 (9)
Somewhat familiar	44 (20)
Moderately familiar	58 (26)
Very familiar/extremely familiar	100 (45)
e. Histrelin implant, supprelin 50 mg
Not at all familiar	0
Somewhat familiar	3 (1)
Moderately familiar	16 (7)
Very familiar/extremely familiar	204 (91)
Aware of equivalent adult preparations identical to above pediatric formulations
Not at all familiar	33 (15)
Somewhat familiar	31 (14)
Moderately familiar	63 (28)
Very familiar/extremely familiar	94 (42)
Aware of cost differences in pediatric versus adult preparations (2–5x cost)
Not at all familiar	56 (25)
Somewhat familiar	28 (13)
Moderately familiar	35 (16)
Very familiar/extremely familiar	104 (47)
Current practices for treating CPP
New patients with CPP evaluated per year
<10	35 (16)
10–20	101 (45)
>20	87 (39)
New patients with CPP treated per year
<10	96 (43)
10–20	86 (36)
>20	41 (18)
Prefer monthly GnRHs for children ≤6 or those with pathological cause of CPP
Yes	22 (10)
No	201 (90)
Preferred GnRHa
Monthly injections	7 (3)
3-monthly injections	84 (38)
6-monthly injections	33 (15)
Implants	99 (44)
Criteria used to decide which GnRHa to use (choose all that apply)
Child weight	40 (18)
Child age	109 (49)
Cause of CPP	47 (21)
Insurance	146 (64)
Family preference/ease of treatment	194 (87)
Rate of puberty progression	53 (24)
Bone age advancement	39 (17)
Predicted adult height much lower than mid	33 (15)
Other	8 (4)
How many factors did respondents choose
1 or 2	102 (46)
3 or 4	81 (36)
5, 6, or 7	23 (10)
Factors for deferring treatment (choose all that apply)
Child age	143 (64)
Child race	7 (3)
Parent preference	179 (80)
Insurance denial	88 (39)
Prohibitive cost	61 (27)
Patient lost to follow-up	101 (45)
Underlying pathology	33 (15)
Other	13 (6)
How many factors did respondents choose
1 or 2	92 (41)
3 or 4	112 (50)
5, 6, or 7	21 (9)
Before prescribing to you discuss
a. Possible deductibles, copays, insurance coverage
Always	62 (28)
Often	59 (27)
Sometimes	36 (16)
Rarely	44 (20)
Never	22 (10)
b. Prior authorizations
Always	48 (22)
Often	42 (19)
Sometimes	39 (18)
Rarely	42 (19)
Never	52 (23)
How often do you get denials for your preferred GnRHa
Always	1 (0.5)
Often	52 (23)
Sometimes	100 (45)
Rarely	57 (26)
Never	13 (6)
Utilization of healthcare resources
Do you order an MRI on every patient with CPP
Always	46 (21)
Only if under age 6 (girls with CPP)	85 (38)
Only for those I plan to treat	15 (7)
Only under age 6 (girls with CPP) and I plan to treat	34 (15)
Never	0
Other (sample or responses included rapidly progressing puberty, girls below age 7 years, menarche before 9, for insurance purposes)	43 (19)
How many follow-up visits per year for CPP patients?
<2	8 (4)
2–4	206 (92)
>4	9 (4)
When do you check GnRHa related labs?
Before dose, nadir level	68 (31)
After dose/mini stim test	69 (31)
Never/follow clinically only	53 (24)
Random	32 (14)
Preference for timing of repeat labs to evaluate pubertal suppression
1 month after therapy start	18 (8)
3 months after therapy start	105 (47)
6 months after therapy start	43 (19)
Never/follow clinically only	56 (25)
Injection administered by
Nurse/your office	137 (61)
Nurse/peds office	64 (29)
MD	11 (5)
Family	8 (4)
Visiting nurse	3 (1)
GnRHa implant procedure is performed
Outpatient	80 (35)
Inpatient	92 (41)
Either	51 (23)
There are no clear criteria (imaging, stim test) across insurances to assist in approval process
Strongly agree	67 (30)
Agree	88 (40)
Neutral	48 (22)
Disagree	17 (8)
Strongly disagree	3 (1)
Prescribing behaviors affected by
(1) Prescriber knowledge/comfort of formulations
Strongly agree	55 (25)
Agree	126 (57)
Neutral	23 (10)
Disagree	14 (6)
Strongly disagree	3 (1)
(2) Insurance
Strongly agree	91 (41)
Agree	78 (35)
Neutral	32 (14)
Disagree	16 (7)
Strongly Disagree	6 (3)
(3) Shortages of GnRHa
Strongly agree	98 (44)
Agree	97 (44)
Neutral	20 (9)
Disagree	7 (3)
Strongly disagree	0

Fig. 1.

Bar graph of criteria used by survey respondents to determine GnRHa prescription.

Fig. 2.

Insurance coverage and prior authorizations, respondent answers.

Survey participants were asked to report factors influencing their decisions to defer treatment for CPP. The most common factors were parental preference (80%) and age of patient (64%). When asked about practices and criteria for obtaining an MRI for patients with CPP, there was a large range of answers in provider practices with no clear consensus (Table 2). Responses indicated 70% agreed or strongly agreed that there were no standardized criteria.

The majority of survey respondents indicated they either “strongly agreed” or “agreed” that their prescribing behaviors were influenced by insurance preference and out-of-pocket costs (around 75%), availability/recent shortages of GnRHa (88%), and their knowledge/comfort using formulations (82%). Responses regarding assessment for efficacy of treatment were split between those checking hormone levels to monitor puberty before the next injectable dose or implant (“nadir level”) or shortly after a dose or implant (“mini-stim test”). Others did not check laboratory tests at all or tested without regard to timing of treatment (see Table 2). Respondents reported obtaining laboratory tests 1 month (8%), 2 months (47%), or 3 months (19%) after treatment initiation while 25% preferred to monitor clinically without additional testing after initiating GnRHa therapy.

Discussion

Our survey respondents mostly work in academic hospital settings, see an average of more than 20 patients with CPP each year, and initiate GnRH analogs in about 50% of patients evaluated for CPP. Survey results suggest the preferences and prescribing behaviors of the practicing pediatric endocrinologists vary across the USA. Regardless of practice setting or geographical location, family preference/ease of treatment, and insurance coverage were the most important factors in determining which GnRHa providers prescribe. Familiarity with the newest GnRHa formulations was lower than expected, and there was a high degree of variability in responses related to brain imaging and testing to monitor response to treatment. There was some familiarity with use of products in pediatric patients that are branded for adult use.

According to survey findings, newer 6-month formulations are not prescribed as often as 3-month formulations and the yearly implant. While the survey was not designed to determine why the newest GnRHa formulations are not being used as frequently, we speculate this may be due to their relatively recent FDA approval, as well as high cost and inconsistent insurance coverage. We also identified knowledge gaps among pediatric endocrinologists about the newer longer acting GnRHa formulations that may play a role in prescribing patterns.

There are few head-to-head pediatric studies of the six preparations (Table 1). Clinical trials investigating the 1-month versus 3-month leuprolide depot preparations demonstrated satisfactory clinical pubertal suppression for both; however, less LH suppression was noted with the 11.25 mg 3-month preparation [2]. Calcaterra et al. [3] compared 1-month (3.75 mg) versus 3-month (11.25 mg) leuprolide preparations in children, including patients less than 6 years of age. After 18 months and 30 months therapy, no difference in efficacy was found in pubertal suppression. The 3-month preparation has the advantage of requiring fewer injections and less frequent visits to the provider’s office, which lowers cost and is more convenient for patients and families [4, 5]. The efficacy for suppressing the hypothalamic-pituitary-gonadal axis has been reported to be similar for the histrelin implant, leuprolide 3-month depot intramuscular injection, leuprolide 6-month subcutaneous injection, and triptorelin 6-month intramuscular injection, but studies are limited by sample size and varied study designs (including assays and end-points), making direct comparisons challenging [6–11].

While theoretical reasons to prefer monthly dosing in younger children or ones with proven organic disease include faster suppression of puberty and earlier verification of suppression, evidence to support this is lacking. Only 10% of respondents indicated a preference for this approach; about 55% were from the northeast and 23% from the western USA.

The survey results indicate insurance coverage is one of the major drivers for providers’ prescribing behaviors. With the vast differences in the individual insurance policies related to coverage, copays, and deductibles charged, it is challenging for both providers and families to ascertain the relative costs of the formulations beforehand. Even though about half of the respondents reported discussing these costs with families before prescribing, only a small percentage voice their own opinion for formulation preference to the insurance carriers. This could be largely explained by the unpleasant experience of receiving frequent denials for the preferred formulation and the extra burden put on the prescribers to navigate insurance denials. As such, lack of inclusion of newer 6-month GnRHa formulations on insurance formularies may play a role in lower prescribing rates of these medications.

Several drugs in the GnRHa class that are approved for treatment of CPP in children have a biosimilar formulation (containing the same dose of active medication and vehicle) approved for adults. Yet, the pricing of pediatric formulations is generally two to three times, but sometimes up to four times, the price of comparable adult formulations (Table 3). The survey did not specifically address knowledge of various adult GnRHa products; however, the survey assessed awareness of adult preparations and their cost differences relative to the pediatric preparations. Survey responses highlighted pediatric endocrinologists’ unfamiliarity with adult preparations. As pediatric endocrinologists face challenges obtaining insurance approval of GnRHa for CPP and other off-label indications, such as gender dysphoria, cost awareness between formulations (pediatric vs. adult) is important. In some situations, GnRHa products approved for adults may need to be prescribed for children; i.e., if the cost of treatment is not covered by insurance or when there are shortages in pediatric formulations. In these cases, prescribers should disclose to families that they are using an adult formulation off-label.

Table 3.

Pediatric and adult preparations of GnRH analogs with estimated costs

	Pediatric preparations	Estimated cost	Adult preparations	Estimated cost
Leuprolide acetate	1-month		1-month Lupron depot
	Lupron depot-PED		3.75 mg	$
	7.5 mg	$	11.25 mg	$
	11.25 mg	$$	–	$
	15 mg	$$		–
Leuprolide acetate	3-month Lupron depot-PED		3-month Lupron depot
	11.25 mg	$$	11.25 mg	$
	30 mg	$$	22.5 mg	$
Leuprolide acetate	–	–	4-month Lupron depot: 30 mg	$$
Leuprolide acetate	6-month Fensolvi: 45 mg	20 × $	6-month Eligard: 45 mg	$
Triptorelin pamoate	6-month Triptodur: 22.5 mg	15 × $	6-month Trelstar: 22.5 mg	$
Histrelin	Annual supprelin LA: 65 μg/day	10 × $	Annual Vantas: 50 μg/day	$

Cost comparisons to be interpreted across each row and not within the columns. “$” symbol represents estimated relative cost. For example, if “$” is $10 then “$$” suggests $20. It is notable that active and inactive components of preparations can be similar, despite labeling for pediatric or adult use only. Cost comparisons to be interpreted across each row and not within the columns.

The vast majority (70%) of the respondents agreed or strongly agreed that there were no standardized criteria for insurance approval regarding diagnostic testing and imaging, emphasizing the need for guidelines regarding use of MRI for patients with CPP. Currently, brain MRI is recommended in all boys with CPP due to the high likelihood of having an intracranial pathologic cause for CPP, estimated to be as high as 40–75% [12, 13]. However, a more recent study suggests the prevalence of pathologic abnormalities in boys might be overestimated [14]. These authors reported a prevalence of central nervous system (CNS) lesions in 7% of boys with CPP who were otherwise healthy and did not have any neurological symptoms.

The need for a brain MRI in girls 6–8 years old continues to be an area of controversy. The survey indicated brain MRIs are ordered by the majority of pediatric endocrinologists for girls under 6 years, but there was greater variability regarding imaging for girls presenting after age 7 years. A study of 304 girls with CPP found that 18.4% had a CNS lesion, of which 9.9% were previously known abnormalities. In the 7 and up years age group, 7% had CNS lesions, including pituitary microadenomas, hypothalamic hamartomas, pineal arachnoid cysts, and enlarged cisterna magna [15]. Yoon et al. [16], found normal MRI findings in 91.8% of girls with CPP; the 8.2% with a finding were incidental and not pathologic, concluding that MRI may not be necessary in girls older than 6 who are neurologically asymptomatic. Another study evaluated 229 girls with CPP with a brain MRI and found that 6.3% had CNS lesions without any neurological symptoms. Girls with CNS lesions had higher basal LH compared to those with normal MRI [17]. A multicenter retrospective cohort of 770 girls with CPP found that 13.5% had a CNS lesion, of which only 3.8% were newly detected and related to the CPP diagnosis. Of these, only 0.25% (2/770) were neoplastic lesions (meningioma and low-grade glioma) [18]. A peak LH/FSH ratio >0.6 and breast development before 6 years of age were factors associated with a pathologic CNS lesion [18]. This finding was mirrored in Pedicielli’s study [19], who found that girls with hamartomas were all younger than age 6 at onset of puberty and had significantly higher mean baseline and stimulated LH values. Varimo et al. [20] found that among 60 asymptomatic and previously healthy 6–8 year old girls with CPP who had a brain MRI, only 1 girl (1.7%) had a pathologic tumor (craniopharyngioma) that required surgical intervention. When girls younger than 6 years old with CPP were included in the analysis, the prevalence of a CNS lesion was 6.4% [20].

A systematic review and meta-analysis collected data from 15 studies, including 1,853 girls with CPP [21]. The prevalence of a pathologic CNS lesion was 7%. The most common lesion identified was hypothalamic hamartoma. The incidence of tumors that needed intervention was 1.6%. In a subgroup analysis, the pooled prevalence of a CNS lesion was 25% in 173 girls less than 6 years and 3% in 514 girls 6–8 years old [21]. The authors concluded that the benefit of MRI over age 6 in females was unclear.

While the obvious advantage for performing an MRI of the brain is to identify a pathologic CNS lesion, the disadvantages include high medical costs, parental anxiety, a stressful experience for the child, and exposing the child to anesthesia for MRI sedation, and when contrast is used, gadolinium [22]. Identifying incidental lesions can lead to further imaging, evaluation by neurosurgery, parental anxiety, and medical costs [22]. Furthermore, the utility of a brain MRI in familial CPP cases (approximately 27% of CPP cases) is not very well established and should be re-evaluated [23]. As pointed out by the survey respondents, insurance companies have inconsistent criteria for brain MRI when approving GnRHa therapy. While the risk for a CNS lesion is low in 6–8 year old girls with CPP, it is not zero, and there are girls with CPP and no other neurologic symptoms who are found to have a CNS lesion. A consensus statement published in 2019 suggests that practicing providers can discuss with parents the advantages and disadvantages of performing an MRI and make an informed decision. This writing group concurs with this statement [24].

There was little agreement on the best approach to monitoring patients with CPP. Though some endocrinologists determine sufficiency of suppression solely by physical exam, for those who order laboratory tests, there was great variation in when and how to assess gonadotropin suppression. This is likely a reflection of the paucity of data on monitoring response to treatment. Lewis and Eugster [1] reported random LH levels remained elevated in more than half of patients treated for CPP with histrelin implant, warning that using a random elevated LH value in those with good clinical response should not be an indicator of treatment failure and, instead, could simply reflect that a child was further along in pubertal development when GnRHa therapy was initiated. Neely et al. [25], also reported the basal LH values frequently failed to suppress with the histrelin implant with 89% of children above a threshold of 0.3 mIU/mL. Similarly, Shubert et al. [26] reported that LH remained pubertal (defined as > 0.3 IU/L) during treatment with monthly GnRHa injections in those with clinical suppression (no breast advancement on Tanner staging, no bone age advancement, or increased growth velocity) and remained pubertal even after medical intensification, concluding that basal LH concentrations have poor specificity (12%) when compared with stimulation testing.

Bhatia et al. [27], introduced the idea that depot leuprolide contains enough free leuprolide to cause a rapid rise in serum gonadotropin concentrations in unsuppressed patients. Their study demonstrated a single serum sample obtained from a child 30–60 min after a depot suppressed LH to 0.5–1.0 mIU/mL after three doses of 7.5 mg monthly leuprolide. They proposed a cutoff of <3 mIU/mL for treatment adequacy based on their overall data, also consistent with prepubertal norms after GnRHa stimulation.

Lee’s 2016 study [28] tried to correlate these stimulatory levels to basal levels. Since there were patients who had treatment failure with GnRHas in their study group, they were able to deduce that a basal level cutoff of 0.6 IU/L on a third-generation immunochemiluminometric assay would correctly identify 80% of those who were suppressed on stimulation testing.

Notably, a 2009 consensus statement on GnRHa [29] did not provide guidelines about the routine use of random or stimulated gonadotropins or sex steroids for monitoring therapy, possibly because the practice of obtaining random levels was common and published data using sensitive LH assays were limited. The studies above suggest persistence of low-level tonic LH secretion on GnRHa therapy but nearly complete suppression of pulsatility. Thus, GnRHa-stimulated LH levels may be more useful for monitoring response to therapy. For the 45% of pediatric endocrinologists who currently obtain a random or pre-leuprolide dose level, it may be reasonable to use an LH result 0.6 mIU/mL found in Lee’s study [28], along with a thoughtful analysis of other clinical data (pubertal stage, growth rate, skeletal age) to decide whether GnRHa stimulation testing is necessary to determine if there is adequate suppression. GnRH stimulation testing may be necessary in girls with increasing breast tissue with concordant BMI increase, where ascertainment of breast staging may be deceptive and confounded by fat tissue.

The role in monitoring estradiol levels is less clear. While Freire et al. found estradiol (<14 pg/mL) assessment 24 h after depot triptorelin administration is a reliable indicator of ovarian suppression in CPP girls during treatment [30], others have not found that estradiol levels were concordant with stimulation test results [26, 31]. Thus, at this time, estradiol does not seem like an accurate indicator of suppression.

Interestingly, ultrasound evidence has also been studied as a way of evaluating efficacy of GnRHa therapy. One study of 122 girls with idiopathic CCP found the volume of the uterine body had the greatest discriminatory ability to separate patients with precocious puberty from girls without [32]. This was in agreement with past smaller studies showing that uterine dimensions were better indicators of adequate suppression than ovarian size [33]. However, other small studies found that ovarian volume changes can best reflect efficacy of treatment [34]. Ultimately more research is needed to elucidate how to best utilize non-invasive ultrasound for treatment monitoring.

Conclusions

The survey indicated there is greater provider familiarity with older, shorter acting GnRHas, which are prescribed in greater numbers than newer, longer acting formulations. There is lack of consensus on the need for CNS imaging in girls presenting with CPP between 6 and 8 years of age and use of laboratory testing to monitor response to treatment. Furthermore, insurance requirements regarding CNS imaging and laboratory monitoring are highly variable. Newer longer acting GnRHa formulations have the advantage of only twice-yearly dosing but may be under-utilized due to lack of insurance coverage and high price, particularly when compared to biosimilar medications approved for adults. Pre-authorization testing requirements and insurance restrictions have the potential to delay medication approval and prevent providers from offering the most appropriate treatment for individual patients. The adult equivalents of pediatric GnRHa formulations have not been studied in pediatrics. Despite having identical constituents and bioavailability, there are substantial cost differences between the pediatric and adult formulations. Under circumstances where a family may have to pay out of pocket, the provider should ensure that the families are made aware of the lack of studies regarding use in children. The survey-based analysis of the use of GnRHa in children with CPP highlights the challenges faced by prescribers while reflecting on areas where further research is needed to provide evidence-based practice guidelines for pediatric endocrinologists, including standardizing evaluation and management of CPP across the USA.

Acknowledgments

We thank the Research Affairs Committee of the PES, for supporting our vision for this project and survey, and the PES Drugs and Therapeutics Committee, of which all authors of this manuscript are members.

Statement of Ethics

The study was approved by the Board of Directors and Research Affairs Committee of the PES. Written Informed consent to participate was not directly obtained but inferred by filling the questionnaire-based survey that only involved e-mail contact with physicians.

Conflict of Interest Statement

R.M. has served as a consultant for NovoNordisk.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

P.C.B. conceived of the study, spearheaded design of the survey, provided supervision, and oversaw the manuscript. All co-authors (A.P.A., E.G., M.K.K., B.K., A.L., S.M., R.M., V.R., and A.K.K.) edited the survey questions. J.I. made the online survey link and analyzed the data. E.B., P.C.B., and M.R. led subsections of survey for interpretation and drafting work, which all co-authors contributed to writing. E.B., P.C.B., and A.K.K. made figures and tables. E.B. constructed and revised final version of manuscript critically, and received edits and final approval of version to be published by all co-authors.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

Table 2 is comprehensive of all our data; we are happy to supply raw data upon request to the corresponding author.