Evaluation of basal sex hormone levels for activation of the hypothalamic–pituitary–gonadal axis

Yu Ding; Juan Li; Yongguo Yu; Peirong Yang; Huaiyuan Li; Yongnian Shen; Xiaodong Huang; Shijian Liu

doi:10.1515/jpem-2017-0124

Article Publicly Available

Evaluation of basal sex hormone levels for activation of the hypothalamic–pituitary–gonadal axis

Yu Ding , Juan Li , Yongguo Yu , Peirong Yang , Huaiyuan Li , Yongnian Shen , Xiaodong Huang and Shijian Liu

Published/Copyright: February 21, 2018

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 31 Issue 3

Abstract

Background:

This study aimed to identify the predictive value of basal sex hormone levels for activation of the hypothalamic–pituitary–gonadal (HPG) axis in girls.

Methods:

Gonadotropin-releasing hormone (GnRH) stimulation tests were performed and evaluated in a total of 1750 girls with development of secondary sex characteristics. Correlation analyses were conducted between basal sex hormones and peak luteinizing hormone (LH) levels ≥5 IU/L during the GnRH stimulation test. Receiver operating characteristic (ROC) curves for basal levels of LH, follicle-stimulating hormone (FSH), LH/FSH, and estradiol (E2) before the GnRH stimulation test were plotted. The area under the curve (AUC) and 95% confidence intervals (CIs) were measured for each curve.

Results:

The maximum AUC value was observed for basal LH levels (0.77, 95% CI: 0.74–0.79), followed by basal FSH levels (0.73, 95% CI: 0.70–0.75), the basal LH/FSH ratio (0.68, 95% CI: 0.65–0.71), and basal E2 levels (0.61, 95% CI: 0.59–0.64). The appropriate cutoff value of basal LH levels associated with a positive response of the GnRH stimulation test was 0.35 IU/L, with a sensitivity of 63.96% and specificity of 76.3% from the ROC curves when Youden’s index showed the maximum value. When 100% of patients had peak LH levels ≥5 IU/L, basal LH values were >2.72 IU/L, but the specificity was only 5.45%.

Conclusions:

Increased basal LH levels are a significant predictor of a positive response during the GnRH stimulation test for assessing activation of the HPG axis in most girls with early pubertal signs.

Keywords: diagnosis; gonadotropin-releasing hormone stimulation test; hypothalamic–pituitary–gonadal axis; precocious puberty; sex hormones

Introduction

Precocious puberty is a common disease in the field of pediatric endocrinology [1]. Most patients with precocious puberty suffer from inappropriate activation of the hypothalamic–pituitary–gonadal axis (HPG), which results in idiopathic central precocious puberty (CPP). Activation of the HPG is important in the diagnosis of CPP and is based on progressive sexual development, accelerated growth rate, and advanced bone maturation. In cases where the gonadal axis is not activated, peripheral precocious puberty (PPP) is considered. PPP can show similar clinical manifestations to CPP, although the pathogenesis, clinical outcomes, and treatment methods for PPP differ from those of CPP.

Measurements of peak luteinizing hormone (LH) following the gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for assessing early activation of the HPG axis in cases with clinical symptoms and signs of puberty [2], [3]. However, the GnRH stimulation test requires several blood samples over long time periods, with relevant technicians and facilities. This highlights the need for a simple measure that can be used as a screening test for assessing early activation of the HPG axis. Early in the activation of the HPG axis, amplitude and pulse frequency of serum LH and follicle-stimulating hormone (FSH) secretion are significantly increased. However, prepubertal and pubertal gonadotropin baseline values have some overlap [4]. With use of a third-generation gonadal hormone detection method, which uses an immunochemiluminometric assay, detection sensitivity has significantly improved compared with traditional detection methods. This has helped to differentiate between prepubertal and pubertal hormone levels [5]. Children with CPP were proposed to have higher basal FSH and LH levels than children with PPP in a cross-sectional study [6]. However, further studies are required to determine a more sensitive index for detecting gonadal axis activation and how to select the appropriate cutoff value.

Therefore, the present study aimed to identify the predictive value for activation of the HPG axis in girls. We analyzed basal LH and FSH levels, the ratio between LH and FSH (LH/FSH), and estradiol (E2) levels prior to the GnRH stimulation test.

Subjects and methods

Subjects

We studied a total of 1750 girls with breast enlargement before 8 years of age, who had a physical examination and breast ultrasound indicating breast development, with a breast of Tanner stage 2 or higher. These girls were diagnosed and treated in the Endocrinology Department of Shanghai Children’s Medical Center from January 2010 to June 2015. Patients with precocious puberty as a result of another etiology, such as a central tumor, infection, or cranial irradiation, were excluded from the study. Measurements included height, weight, bone age by X-ray photography, and ultrasonography of the uterus and ovaries. Bone age was measured by the Greulich-Pyle method [7]. The volumes of the uterus and ovary were calculated by multiplying the length by the width, thickness, and 3.14, and then dividing by six according to ultrasonography. GnRH stimulation tests were performed and evaluated. The girls were divided into two groups according to GnRH stimulation test results. Girls with peak LH values ≥5 IU/L were considered to have pubertal activation of the HPG axis. These girls were categorized into the positive GnRH stimulation test group. Girls with peak LH values <5 IU/L were considered to have inactivation of the HPG axis and were categorized into the negative GnRH stimulation test group. Informed consent was obtained from the participating children and their parents, and the study was approved by the Institutional Review Board of the Shanghai Children’s Medical Center. This study was in accordance with the tenets of the Helsinki Declaration.

Methods

The GnRH stimulation test was performed in the early morning after fasting for 10 h. Gonadorelin (AnhuiFengyuan Pharmaceutical Co., Anhui, China) was injected at a dose of 2.5 μg/kg, with a maximum dosage of 100 μg. Blood samples were drawn from an inserted intravenous cannula before and 30 and 60 min after GnRH injection. Previous studies have suggested that LH levels between 30 and 60 min are sufficient for diagnosis of activation of the HPG axis [8], [9], [10]. All samples were analyzed for LH and FSH levels. The maximal LH and FSH levels achieved at any time point of testing were considered to be the peak levels. Additionally, E2 levels were determined prior to GnRH administration. An electrochemiluminescence immunoassay (DxI800 automated chemiluminescence assay and commercial kit; Beckman Coulter, Inc., CA, USA) was used to determine hormone levels. The intra-assay coefficient of variation for LH was 3.6%–5.4%, with an inter-assay imprecision of 4.3%–6.4% and sensitivity of 0.2 IU/L. The calibration range of the assay was up to 250 IU/L. The intra-assay coefficient of variation for FSH was 3.1%–4.3% and inter-assay imprecision was 4.3%–5.6%. The sensitivity was 0.2 IU/L and the calibration range of the assay was up to 200 IU/L. E2 assay sensitivity was 20 pg/mL. The calibration range of the assay was up to 4800 pg/mL. The intra-assay coefficient of variation was 12%–21%.

Statistical analysis

The Student’s t-test was performed to compare the mean of subjects’ characteristics between groups, and normal distribution transformation was conducted on a 1/square. Correlation analyses were conducted between sex hormones and puberty status. The odds ratio was calculated according to basal test value between the positive GnRH test group and negative GnRH test group. Because the cutoff value was LHmax=5.0, the continuous variable LHmax was converted into a binary variable. The LHmax values were categorized as 0 or 1 if LHmax values were <5.0 or ≥5.0. Receiver operating characteristic (ROC) curves for basal levels of LH, FSH, LH/FSH, and E2 were plotted. The area under the curve (AUC) and 95% confidence intervals (CIs) were measured for each curve. Youden’s index (sensitivity+specificity−1) was used to determine the optimal gonadotropin cutoff point from the ROC. The test of equality of ROC areas was performed to compare the AUC between groups. ROC analysis for multiple comparisons was performed between different AUCs using the DeLong method [11]. If multiple comparisons were significant, every two AUCs were further compared. A p-value <0.05 was considered statistically significant. All statistical analyses were performed using Stata 13.0 (Stata Corporation, College Station, TX, USA).

Results

Clinical and hormonal characteristics in the patients

There were 1138 patients in the positive GnRH test group (mean age±standard deviation: 7.95±1.25 years) and 612 patients (7.16±1.59 years) in the negative GnRH test group. The difference between chronological age and bone age was 1.38 years in the negative GnRH test group and 1.43 years in the positive GnRH test group (p=0.671). There was no significant difference in body mass index between the two groups. Uterine volume and mean ovarian volume were larger in the positive GnRH test group than in the negative GnRH test group (both p<0.05). Basal LH levels, FSH levels, the LH/FSH ratio, and E2 levels were significantly lower in the negative GnRH test group than in the positive GnRH test group (all p<0.05). Peak LH levels, FSH levels, and the LH/FSH ratio were significantly higher in the positive GnRH test group than in the negative GnRH test group (all p<0.05, Table 1). The correlation coefficient of peak LH levels and bone age was 0.21, that of peak LH levels and the size of the uterus was 0.42.

Table 1:

Hormonal and clinical characteristics of participants.

Variables	GnRH test (−), n=612				GnRH test (+), n=1138				t-Test^a	p-Value^a
Variables	Mean±SD	Median	Range	Distribution	Mean±SD	Median	Range	Distribution	t-Test^a	p-Value^a
Age, year	7.16±1.59	7.46	4.91–10.08	Normal	7.95±1.25	8.17	5.12–10.33	Normal	−5.99	<0.001
Bone age–chronological age, year	1.38±1.000	1.38	−2.08 to 3.63	Normal	1.43±1.11	1.50	−3.03 to 4.47	Normal	−0.43	0.671
Height	126.91±11.49	129.00	108.00–158.40	Normal	131.15±9.85	132.60	109.00–163.50	Normal	−2.39	<0.001
Weight	27.72±6.79	27.70	18.50–48.00	Normal	29.48±6.14	29.00	18.50–50.50	Normal	−3.07	0.001
BMI, kg/m²	16.98±2.43	16.47	12.49–27.51	Normal	16.99±2.31	16.74	10.92–32.53	Normal	−0.06	0.475
Mean ovarian volume, mL^3b	1.88±0.93	1.75	0.10–6.16	Normal	2.05±0.94	1.90	0.08–7.04	Normal	2.41	0.016
Uterine size, mL³	2.61±1.83	2.23	0.22–21.30	Normal	3.75±2.21	3.22	0.15–16.12	Normal	−7.24	<0.001
Basal LH, IU/L	0.27±0.32	0.19	0.01–16.69	Normal	0.87±1.20	0. 52	0.01–16.31	Normal	4.74	<0.001
Basal FSH, IU/L	2.51±1.33	2.31	0.03–8.10	Normal	3.93±2.03	3.46	0.57–17.75	Normal	2.34	0.010
Basal LH/FSH ratio	0.17±0.56	0.08	0.01–12.0	Normal	0.22±0.28	0.15	0.01–4.35	Normal	3.96	<0.001
Basal E2, pg/mL	15.56±21.81	11.00	1.0–258.0	Normal	21.51±24.72	15.00	1.00–447.00	Normal	4.55	<0.001
Peak LH, IU/L	3.18±1.15	3.32	0.12–4.98	Normal	14.95±14.04	9.78	5.00–158.12	Normal	4.22	<0.001
Peak FSH, IU/L	13.73±5.26	13.48	0.14–33.71	Normal	15.98±5.96	14.98	1.56–46.37	Normal	2.39	0.017
Peak LH/FSH ratio	0.27±0.18	0.23	0.04–2.93	Normal	0.98±0.75	0.73	0.19–9.02	Normal	21.81	<0.001

GnRH test (−): peak LH values <5 IU/L during GnRH stimulation test. GnRH test (+): peak LH values ≥5 IU/L during GnRH stimulation test. ^at-Test based on 1/square transformation. ^bMean ovarian volume was calculated by dividing the sum of right and left ovarian volumes by two. SE, standard error.

Logistic regression analysis

The biochemical parameters that were considered to be related to the GnRH stimulation test results were adjusted using binary logistic regression analysis (Table 2). After regression analysis, basal LH levels were the most significantly and positively related to a positive response in the GnRH stimulation test (p<0.05).

Table 2:

Binary logistic regression analysis of hormones compared between GnRH test (+) group and GnRH test (−) group.

Variable	Odds ratio	95% CI	z-Value	p-Value
Basal LH	12.11	8.29–17.71	12.88	<0.001
Basal FSH	1.73	1.60–1.87	13.69	<0.001
Basal LH/FSH ratio	1.90	1.19–3.04	2.68	0.007
Basal E2	1.02	1.01–1.02	5.10	<0.001

GnRH test (−) group: peak LH values <5 IU/L during GnRH stimulation test. GnRH test (+) group: peak LH values ≥5 IU/L during GnRH stimulation test.

ROC analysis

ROC curves were plotted for basal LH levels, FSH levels, the LH/FSH ratio, and E2 levels (Figure 1). The AUC was measured for each curve (Table 3). A larger AUC represented a more positive rate of excitation. The maximum AUC was observed for basal LH levels, followed by basal FSH levels, the basal LH/FSH ratio, and basal E2 levels. This finding suggested that the basal LH value was best for predicting activation of the gonadal axis. The p-values of AUC comparisons was <0.05 between each AUC of basal hormone (Table 3). The appropriate cutoff value of basal LH levels associated with a positive response was 0.35 IU/L when Youden’s J index reached the maximum value. The sensitivity was 63.96% and specificity was 76.35% from the ROC curves. Therefore, a basal LH value that reached 0.35 IU/L suggested that gonadal axis activation was relatively high and further GnRH stimulation testing was required. A basal LH value that reached 2.72 IU/L (specificity was 100%, but sensitivity decreased to 5.45%) suggested a 100% peak LH level of ≥5 IU/L (Table 4).

Figure 1:

ROC curves of basal LH and FSH, basal LH/FSH ratio, and E2 value for predicting positive results following GnRH stimulation testing.

Table 3:

Comparison of AUCs for each basal hormone.

Variable	AUC	95% CI	p-Values^a
Variable	AUC	95% CI	AUC_(LH)	AUC_(FSH)	AUC_(LH/FSH)	AUC_(E2)
AUC_(LH)	0.77	0.74–0.79	–	0.002^b	<0.001	<0.001
AUC_(FSH)	0.73	0.70–0.75	0.002	–	0.021	<0.001
AUC_(LH/FSH)	0.68	0.65–0.71	<0.001	0.021	–	<0.001
AUC_(E2)	0.61	0.59–0.64	<0.001	<0.001	<0.001	–

AUC, area under curve, –, Data is not available. ^ap-Values of AUC comparisons between each AUC of basal hormone. ^bp-values of AUC_(LH) vs. AUC_(FSH).

Table 4:

Sensitivity and specificity of deferent basal hormone levels for predicting positive results on GnRH stimulation test.

Hormone	Cutoff, AUC	Cutoff	True+	False+	False−	True−	Sensitivity, %	Specificity, %	Youden’s index^a	PPV, %	NPV, %
LH	0.73	0.35 IU/L	270	149	112	357	63.96	76.35	0.40	100.00	37.32
	0.86	0.61 IU/L	282	368	51	505	43.47	90.37	0.34
	0.89	0.78 IU/L	258	494	29	555	34.23	95.10	0.30
	0.99	2.72 IU/L	59	1018	0	612	5.45	100.00	0.05
FSH	0.73	3.03 IU/L	274	179	117	339	57.99	76.69	0.35	100.00	37.30
	0.87	4.22 IU/L	267	455	55	496	34.75	90.03	0.25
	0.93	5.24 IU/L	204	671	29	553	22.99	95.10	0.18
	0.998	8.12 IU/L	38	1062	0	612	3.43	100.00	0.03
LH/FSH	0.65	0.11	–	–	–	–	63.00	65.70	0.29	97.50	36.91
	0.93	0.28	–	–	–	–	23.46	90.07	13.53
	0.97	0.44	–	–	–	–	10.28	95.03	5.31
	–	12.00	–	–	–	–	0.00	100.00	0.00
E2	0.66	18.00 pg/mL	168	206	61	166	44.51	72.59	0.18	100.00	37.20
	0.78	23.00 pg/mL	164	351	53	223	31.46	80.54	0.12
	0.90	39.00 pg/mL	148	824	27	556	14.95	95.26	0.10
	0.99	288.00 pg/mL	2	1135	0	611	0.18	100.00	0.02

^aThe maximum value of Youden’s J index. –, data is not available; NPV, negative predictive value; PPV, positive predictive value.

Discussion

Our study showed that the basal LH level was useful for predicting gonadal axis activation. Activation of the gonadal axis is important for diagnosing CPP, which can accelerate bone maturation, result in impaired adult height and early menstruation, and can greatly affect the patient’s psychological health [12]. Previous studies have shown that early menstruation is related to adverse health outcomes in later life [13], [14], [15]. Therefore, timely diagnosis and appropriate treatment can help to improve the prognosis of these patients. Diagnosing CPP is difficult and should include clinical manifestations and correct and timely assessment of activation of the HPG axis. However, clinically diagnosing activation of the HPG axis by a simple examination and clinical data is challenging. Currently, the biochemical criteria for diagnostic confirmation of gonadal axis activation are primarily based on the LH response during a standard GnRH stimulation test. A stimulated LH value ≥5 IU/L and/or a stimulated peak LH/FSH ratio >0.6 are considered pubertal responses during GnRH testing [2], [16], [17]. Pubertal LH secretion is characterized by high levels of peak LH secretion, which leads to higher levels of sex hormones in pubertal compared with prepubertal subjects. This eventually leads to the appearance of pubertal physical signs and accelerated growth [18]. With the development of newer and more sensitive immunoassays that measure serum gonadotropins, measurement of basal gonadotropins is hypothesized to allow discrimination between activated and inactivated values in HPG axis maturity.

In our single-center study, we investigated 1750 girls with early breast development. We found that basal LH values that were obtained during the GnRH stimulation test were significantly correlated with stimulated LH values. Additionally, LH values were useful as a screening test for predicting a positive response during the GnRH test. The highest Youden’s J index (0.40) was used to determine the appropriate cutoff LH value for diagnosing activation of the HPG axis. The basal LH cutoff point was 0.35 IU/L, with a sensitivity of 63.96% and specificity of 76.35%. When the basal LH value was 2.72 IU/L, the specificity reached 100%, although sensitivity decreased to 5.45%, which is higher than the value reported by Houk et al. [19]. They evaluated basal LH levels for discriminating activation of the HPG axis using two different chemiluminescent third-generation immunoassays (Wallac DELFIA and Architect) in 55 girls. Using the Architect assay, the LH cutoff point was 0.83 U/L, with a sensitivity of 93% and a specificity of 100%. Using the Delphi assay, the LH cutoff point was 1.05 U/L, with a sensitivity of 100% and a specificity of 100%. However, in the current study the basal LH cutoff level for evaluating activation of the HPG axis is different from previous studies. Pasternak et al. [20] measured basal serum LH and FSH levels using a chemiluminescent immunometric assay. They showed that low basal serum LH levels (≤0.1 IU/L) were sufficient for ruling out a positive response in the GnRH test in 94.7% of 38 prepubertal girls, with a sensitivity of 64%. Additionally, Suh et al. [21] reported cutoff values of basal LH (0.22 IU/L) that were measured using the sequential two-step immunoenzymatic assay (Access hLH, FSH Reagent Pack; Beckman Coulter, Inc., Brea, CA, USA). They detected a positive response of the GnRH stimulation test with 87.8% sensitivity and 20.9% specificity in 540 girls with clinical signs. They also demonstrated that basal FSH levels, basal E2 levels, and the basal LH/FSH ratio did not have predictive values for the diagnosis of CPP [21]. Mogensen et al. [22] showed that basal LH levels were superior in predicting the maximal LH level during GnRH testing compared with FSH, E2, and inhibin B levels. In another study, a total of 803 girls were included, and serum LH and FSH levels were measured using the immunoradiometric assay [23]. Based on the ROC curve, the optimal cutoff point for the basal LH level that was related to a pubertal response was 1.1 IU/L, which was associated with a sensitivity of 69.1% and specificity of 50.5%. Because of these different results among studies, clinicians must first determine the local cutoff before GnRH stimulation in patients with precocious puberty when applying this method.

In the present study, the AUC for LH was greater than that for FSH, the LH/FSH ratio, and E2. This finding indicated that basal LH levels were superior to FSH, the LH/FSH ratio, and E2 levels for determining activation of the HPG axis. Moreover, some researchers believe that determination of the LH/FSH ratio is helpful for improving the diagnostic accuracy of CPP [24]. However, FSH levels overlap between prepubertal and pubertal girls, which can affect the LH/FSH ratio and limit its application in evaluating activation of the gonadal axis. Our study showed that, when the cutoff value of basal LH levels was 0.35 IU/L, the sensitivity and specificity were 63.96% and 76.35%, respectively, which were relatively low. A basal LH value that reached 2.72 IU/L showed a specificity of 100%, but sensitivity decreased to 5.45%. These data indicated that increased basal LH levels were associated with a positive response to the GnRH test. Therefore, physicians should pay attention to basal LH testing in patients with early breast development. However, the appropriate cutoff value depends on sensitive measurement of basal gonadotropins and clinical manifestations. Therefore, conducting further GnRH stimulation tests might be necessary. Notably, evaluation of HPG axis activation based on LH cutoff values is not consistent between research centers. This could be due to hormone testing methods, apparatus, and GnRH stimulation test methods.

In conclusion, measurement of basal LH levels could be better than FSH levels, the LH/FSH ratio, and E2 levels for initial evaluation of HPG axis activation with clinically suspected early puberty. Increased basal LH values are a significant predictor of a positive response during the GnRH stimulation test for assessing activation of the HPG axis.

Corresponding authors: Xiaodong Huang, MD, Department of Endocrinology, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Shanghai 200127, P.R. China, Phone: +86-21-38626161-86035; and Shijian Liu, PhD, Department of Clinical Epidemiology and Biostatistics, Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Shanghai 200127, P.R. China, Phone: +86-21-38625637

Acknowledgments

We thank Ellen Knapp from Liwenbianji (www.liwenbianji.cn) for linguistic assistance during preparation of this manuscript.

Author contributions: H.X., L.S., and S.Y. designed the study; D.Y., L.J., Y.Y., Y P., and L.H. performed the study; D.Y. and L.S. drafted the manuscript and performed statistical analyses; L.S. and H. X. contributed to interpretation of the results and critically reviewed the manuscript; H.X. had primary responsibility for final content. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This research was supported by the Shanghai Municipal Science and Technology Commission (Grant No. 12411950402), The Project of Shanghai Children’s Health Service Capacity Construction (GDEK201708), National Human Genetic Resources Sharing Service Platform (2005DKA21300), Science and Technology Development Program of Pudong Shanghai New District (PKJ2017-Y01), and Science Innovation Funding of Shanghai Jiaotong University School of Medicine (Z2016-02).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Received: 2017-3-30

Accepted: 2017-12-22

Published Online: 2018-2-21

Published in Print: 2018-3-28

Articles in the same Issue

https://doi.org/10.1515/jpem-2017-0124

Keywords for this article

diagnosis; gonadotropin-releasing hormone stimulation test; hypothalamic–pituitary–gonadal axis; precocious puberty; sex hormones