Effect of short-term GnRH pulse therapy on pituitary-testicular function in adolescent male patients with congenital hypogonadotropic hypogonadism

doi:10.3969/j.issn.1674-8115.2023.01.005

Abstract

Abstract:

Objective ·To investigate the effect of short-term gonadotropin-releasing hormone (GnRH) pulse therapy on pituitary and testicular function in the adolescent male patients with congenital hypogonadotropic hypogonadism (CHH). Methods ·A retrospective study was conducted on 20 adolescent male patients with CHH who received GnRH pulse therapy from January 2016 to June 2021, and their clinical data were collected. They were treated with subcutaneous continuous pulsed administration of gonadorelin by the pump for 1 week (20 cases), of which 5 cases were treated for 3 months. The dose was 8?10 μg per pulse, and the pulse interval was 90 min. The levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone were measured before GnRH pulse therapy at 1 week, 1 month and 3 months after treatment. After 3 months of treatment, the testicular volume was measured. All 20 patients with CHH underwent whole exome sequencing. Results ·The age of 20 CHH patients was 14.35 (14.08, 15.31) years old. The clinical manifestations were infantile testis (20/20) and micropenis (20/20), followed by obesity (12/20), dysosmia (9/20), insulin resistance (4/20), cryptorchidism (4/20), and short stature (3/20). The patients' height was 161.79 (154.90, 173.25) cm, body mass index was 23.80 (20.51, 27.46) kg/m², and testicular volume was 0.91 (0.55, 1.25) mL. Inhibin B was 39.67 (11.29, 64.97) pg/mL; the base values of LH, FSH and testosterone before therapy were 0.20 (0.10, 0.30) IU/L, 0.87 (0.23, 0.89) IU/L, and 0.92 (0.38, 1.49) nmol/L, respectively. After 1 week of continuous GnRH pulse therapy, the base and peak values of LH and FSH and the peak value of testosterone in the 20 patients significantly increased (all P<0.05). In the 5 patients treated for 3 months, the base values and peak values of LH and FSH gradually increased with the prolongation of treatment time. After 3 months of treatment, the base values and peak values of LH and FSH, and the peak value of testosterone were significantly higher than those before treatment (all P<0.05), and the testicular volume was also significantly increased (P=0.004). Gene mutations were detected in only 14 of 20 patients, including fibroblast growth factor receptor 1 (FGFR1) mutations in 7 cases, anosmin 1 (ANOS1) mutations in 4 cases, prokineticin receptor 2 (PROKR2) mutations in 2 cases, and a prokineticin 2 (PROK2) mutation in 1 case. There was no significant difference of the effect of GnRH pulse therapy for 1 week on pituitary-testicular function between the patients with FGFR1 mutations and ANOS1 mutations. Conclusion ·The continuous GnRH pulse therapy for 1 week can make pituitary-testicular function respond in adolescent male CHH patients; the treatment for 3 months helps to induce the secondary sexual characteristics of puberty.

Key words: hypogonadotropic hypogonadism, gonadotropin-releasing hormone (GnRH), pulse therapy, adolescent

CLC Number:

R725.8

WANG Fei, GONG Yan, XU Liya, LIU Qingxu, LI Yan, GUO Sheng, LI Pin. Effect of short-term GnRH pulse therapy on pituitary-testicular function in adolescent male patients with congenital hypogonadotropic hypogonadism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(1): 36-43.

Figures/Tables 4

TrendMD

References 27

1	CANGIANO B, SWEE D S, QUINTON R, et al. Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease[J]. Hum Genet, 2021, 140(1): 77-111.
2	BIANCO S D C, KAISER U B. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism[J]. Nat Rev Endocrinol, 2009, 5(10): 569-576.
3	SWEE D S, QUINTON R. Current concepts surrounding neonatal hormone therapy for boys with congenital hypogonadotropic hypogonadism[J]. Expert Rev Endocrinol Metab, 2022, 17(1): 47-61.
4	HAO M, NIE M, YU B Q, et al. Gonadotropin treatment for male partial congenital hypogonadotropic hypogonadism in Chinese patients[J]. Asian J Androl, 2020, 22(4): 390-395.
5	GONG C X, LIU Y, QIN M, et al. Pulsatile GnRH is superior to hCG in therapeutic efficacy in adolescent boys with hypogonadotropic hypogonadodism[J]. J Clin Endocrinol Metab, 2015, 100(7): 2793-2799.
6	YOUNG J, XU C, PAPADAKIS G E, et al. Clinical management of congenital hypogonadotropic hypogonadism[J]. Endocr Rev, 2019, 40(2): 669-710.
7	孙首悦, 王卫庆, 蒋怡然, 等. 微量泵脉冲输注戈那瑞林治疗特发性低促性腺激素性性腺功能减退症[J]. 中华内分泌代谢杂志, 2011, 27(8): 654-658.
	SUN S Y, WANG W Q, JIANG Y R, et al. Treatment of idiopathic hypogonadotropic hypogonadism with pulse infusion of gonadorelin via micro pump[J]. Chinese Journal of Endocrinology and Metabolism, 2011, 27(8): 654-658.
8	GACH A, PINKIER I, SAŁACIŃSKA K, et al. Identification of gene variants in a cohort of hypogonadotropic hypogonadism: diagnostic utility of custom NGS panel and WES in unravelling genetic complexity of the disease[J]. Mol Cell Endocrinol, 2020, 517: 110968.
9	WANG Y, GONG C X, QIN M, et al. Clinical and genetic features of 64 young male paediatric patients with congenital hypogonadotropic hypogonadism[J]. Clin Endocrinol (Oxf), 2017, 87(6): 757-766.
10	MAIONE L, DWYER A A, FRANCOU B, et al. Genetics in endocrinology: genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing[J]. Eur J Endocrinol, 2018, 178(3): R55-R80.
11	AMATO L G L, MONTENEGRO L R, LERARIO A M, et al. New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism[J]. Eur J Endocrinol, 2019, 181(2): 103-119.
12	GACH A, PINKIER I, SZARRAS-CZAPNIK M, et al. Expanding the mutational spectrum of monogenic hypogonadotropic hypogonadism: novel mutations in ANOS1 and FGFR1 genes[J]. Reprod Biol Endocrinol, 2020, 18(1): 8.
13	LIU Q X, YIN X Q, LI P. Clinical, hormonal, and genetic characteristics of 25 Chinese patients with idiopathic hypogonadotropic hypogonadism[J]. BMC Endocr Disord, 2022, 22(1): 30.
14	FESTA A, UMANO G R, MIRAGLIA DEL GIUDICE E, et al. Genetic evaluation of patients with delayed puberty and congenital hypogonadotropic hypogonadism: is it worthy of consideration?[J]. Front Endocrinol (Lausanne), 2020, 11: 253.
15	KIM J H, SEO G H, KIM G H, et al. Targeted gene panel sequencing for molecular diagnosis of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism[J]. Exp Clin Endocrinol Diabetes, 2019, 127(8): 538-544.
16	WANG Y, QIN M, FAN L J, et al. Correlation analysis of genotypes and phenotypes in Chinese male pediatric patients with congenital hypogonadotropic hypogonadism[J]. Front Endocrinol (Lausanne), 2022, 13: 846801.
17	LI S Y, ZHAO Y L, NIE M, et al. Clinical characteristics and spermatogenesis in patients with congenital hypogonadotropic hypogonadism caused by FGFR1 mutations[J]. Int J Endocrinol, 2020, 2020: 8873532.
18	NEOCLEOUS V, FANIS P, TOUMBA M, et al. GnRH deficient patients with congenital hypogonadotropic hypogonadism: novel genetic findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A genes in a case series and review of the literature[J]. Front Endocrinol (Lausanne), 2020, 11: 626.
19	MOSBAH H, BOUVATTIER C, MAIONE L, et al. GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty[J]. Hum Reprod, 2020, 35(10): 2312-2322.
20	SEGAL T Y, MEHTA A, ANAZODO A, et al. Role of gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests in differentiating patients with hypogonadotropic hypogonadism from those with constitutional delay of growth and puberty[J]. J Clin Endocrinol Metab, 2009, 94(3): 780-785.
21	BINDER G, SCHWEIZER R, BLUMENSTOCK G, et al. Inhibin B plus LH vs GnRH agonist test for distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism in boys[J]. Clin Endocrinol (Oxf), 2015, 82(1): 100-105.
22	GAO Y T, DU Q, LIU L Y, et al. Serum inhibin B for differentiating between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty: a systematic review and meta-analysis[J]. Endocrine, 2021, 72(3): 633-643.
23	VARIMO T, MIETTINEN P J, KÄNSÄKOSKI J, et al. Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center[J]. Hum Reprod, 2017, 32(1): 147-153.
24	中华医学会内分泌学分会性腺学组. 特发性低促性腺激素性性腺功能减退症诊治专家共识[J]. 中华内科杂志, 2015, 54(8): 739-744.
	Division of Gonadal Disease, Chinese Society of Endocrinology. Expert consensus on the diagnosis and treatment of idiopathic hypogonadotropic hypogonadism[J]. Chinese Journal of Internal Medicine, 2015, 54(8): 739-744.
25	SHAH R, PATIL V, SARATHI V, et al. Prior testosterone replacement therapy may impact spermatogenic response to combined gonadotropin therapy in severe congenital hypogonadotropic hypogonadism[J]. Pituitary, 2021, 24(3): 326-333.
26	中华医学会儿科学分会内分泌遗传代谢学组. 性发育异常的儿科内分泌诊断与治疗共识[J]. 中华儿科杂志, 2019, 57(6): 410-418.
	The Subspecialty Group of Endocrinologic, Hereditary and Metabolic Diseases, the Society of Pediatrics, Chinese Medical Association. Consensus statement on the diagnosis and endocrine treatment of children with disorder of sex development[J]. Chinese Journal of Pediatrics, 2019, 57(6): 410-418.
27	LIU Y, REN X Y, PENG Y G, et al. Efficacy and safety of human chorionic gonadotropin combined with human menopausal gonadotropin and a gonadotropin-releasing hormone pump for male adolescents with congenital hypogonadotropic hypogonadism[J]. Chin Med J (Engl), 2021, 134(10): 1152-1159.

Gene	Inheritance	Variant	Amino acid	Type of variant	Pathogenicity	Source of variant
FGFR1	AD	c.1695_1696 insT	p.Lys566Ter	Heterozygous	P	De novo
FGFR1	AD	c.25G>A	p.Gly9Ser	Heterozygous	VUS	Mother
FGFR1	AD	c.761G>A	p.Arg254Gln	Heterozygous	LP	Father
FGFR1	AD	c.963dupA	p.Glu322Argfs*13	Heterozygous	P	De novo
FGFR1	AD	c.350A>G	p.Asn117Ser	Heterozygous	VUS	Mother
FGFR1	AD	c.580G>T	p.Gly194Cys	Heterozygous	VUS	De novo
FGFR1	AD	c.1981C>T	p.Arg661*	Heterozygous	P	De novo
ANOS1	XLR	c.1267C>T	p.Arg423*	Hemigygote	P	Mother
ANOS1	XLR	c.1897C＞T	p.Arg631Ter	Hemigygote	P	Mother
ANOS1	XLR	c.1525delA	p.Ser509Valfs*40	Hemigygote	P	De novo
ANOS1	XLR	c.463A>G	p.Asn155Asp	Hemigygote	VUS	De novo
PROKR2	AD	c.991G>A	p.Val331Met	Heterozygous	VUS	Mother
PROKR2	AD	c.533G>C	p.Trp178Ser	Heterozygous	VUS	De novo
PROK2	AD	c.223-4C>A	Unknown	Heterozygous	VUS	De novo

Gene	Inheritance	Variant	Amino acid	Type of variant	Pathogenicity	Source of variant
FGFR1	AD	c.1695_1696 insT	p.Lys566Ter	Heterozygous	P	De novo
FGFR1	AD	c.25G>A	p.Gly9Ser	Heterozygous	VUS	Mother
FGFR1	AD	c.761G>A	p.Arg254Gln	Heterozygous	LP	Father
FGFR1	AD	c.963dupA	p.Glu322Argfs*13	Heterozygous	P	De novo
FGFR1	AD	c.350A>G	p.Asn117Ser	Heterozygous	VUS	Mother
FGFR1	AD	c.580G>T	p.Gly194Cys	Heterozygous	VUS	De novo
FGFR1	AD	c.1981C>T	p.Arg661*	Heterozygous	P	De novo
ANOS1	XLR	c.1267C>T	p.Arg423*	Hemigygote	P	Mother
ANOS1	XLR	c.1897C＞T	p.Arg631Ter	Hemigygote	P	Mother
ANOS1	XLR	c.1525delA	p.Ser509Valfs*40	Hemigygote	P	De novo
ANOS1	XLR	c.463A>G	p.Asn155Asp	Hemigygote	VUS	De novo
PROKR2	AD	c.991G>A	p.Val331Met	Heterozygous	VUS	Mother
PROKR2	AD	c.533G>C	p.Trp178Ser	Heterozygous	VUS	De novo
PROK2	AD	c.223-4C>A	Unknown	Heterozygous	VUS	De novo

Index	Gene mutation		Statistical value	P value
Index	FGFR1 （n=7）	ANOS1 （n=4）	Statistical value	P value
Age/year	14.90 （14.33， 15.42）	14.75 （14.42， 15.39）	0.378	0.705
BMI/（kg·m^-2）	26.01 （22.89， 27.92）	22.66 （15.71， 29.78）	0.756	0.450
Height/cm	168.86 （162.80， 175.00）	152.10 （147.90， 155.70）	2.457	0.014
Cryptorchid/n	1	1	‒	‒
Dysosmia/n	2	2	‒	‒
Testicular volume/mL	1.12 （0.49， 2.00）	0.86 （0.43， 1.24）	0.213	0.831
INHB/（pg·mL^-1）	31.03 （10.08， 53.92）	41.09 （2.23， 79.84）	0.189	0.850
ΔLH base value/（IU·L^-1）^①	0.82 （0.35， 1.98）	0.71 （0.41， 2.09）	0.095	0.925
ΔLH peak value/（IU·L^-1）^①	1.12 （0.56， 2.85）	1.20 （0.59， 3.81）	0.189	0.850
ΔFSH base value/（IU·L^-1）^①	2.59 （1.79， 4.75）	2.16 （-0.06， 3.85）	1.323	0.186
ΔFSH peak value/（IU·L^-1）^①	2.66 （1.67， 5.72）	2.53 （-0.05， 5.10）	0.567	0.571
ΔTestosterone peak value/（nmol·L^-1）^①	1.41 （0.90， 2.16）	1.48 （0.78， 2.00）	0.095	0.927

Index	Gene mutation		Statistical value	P value
Index	FGFR1 （n=7）	ANOS1 （n=4）	Statistical value	P value
Age/year	14.90 （14.33， 15.42）	14.75 （14.42， 15.39）	0.378	0.705
BMI/（kg·m^-2）	26.01 （22.89， 27.92）	22.66 （15.71， 29.78）	0.756	0.450
Height/cm	168.86 （162.80， 175.00）	152.10 （147.90， 155.70）	2.457	0.014
Cryptorchid/n	1	1	‒	‒
Dysosmia/n	2	2	‒	‒
Testicular volume/mL	1.12 （0.49， 2.00）	0.86 （0.43， 1.24）	0.213	0.831
INHB/（pg·mL^-1）	31.03 （10.08， 53.92）	41.09 （2.23， 79.84）	0.189	0.850
ΔLH base value/（IU·L^-1）^①	0.82 （0.35， 1.98）	0.71 （0.41， 2.09）	0.095	0.925
ΔLH peak value/（IU·L^-1）^①	1.12 （0.56， 2.85）	1.20 （0.59， 3.81）	0.189	0.850
ΔFSH base value/（IU·L^-1）^①	2.59 （1.79， 4.75）	2.16 （-0.06， 3.85）	1.323	0.186
ΔFSH peak value/（IU·L^-1）^①	2.66 （1.67， 5.72）	2.53 （-0.05， 5.10）	0.567	0.571
ΔTestosterone peak value/（nmol·L^-1）^①	1.41 （0.90， 2.16）	1.48 （0.78， 2.00）	0.095	0.927

[1]	DONG Ting, YIN Xiaoqin, LI Yan, LI Pin. Effect of decreased 5⁃hydroxytryptamine synthesis during puberty development on the onset of puberty in female rats [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(3): 307-311.
[2]	Xuehong WANG, Xuzhuo CHEN, Yi MAO, Da SHEN, Shanyong ZHANG. Difference in recurrence rates after temporomandibular joint disc repositioning surgery with miniscrew anchor at different developmental stages in adolescents [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2022, 42(2): 173-177.
[3]	Nuo-shi QIAN, Wu HONG, Chun-bo LI. Progress of transcranial direct current stimulation in the treatment of children and adolescents psychiatric disorders [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(10): 1366-1370.
[4]	ZANG Shao-lian, YIN Xiao-qin, LÜ Yong-fen, XU Li-ya, GUO Sheng, LI Pin. Effects of silenced Ttf1 on genes expression of Kiss1 and GnRH in neuronal cells and arcuate nucleus of female rats [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(11): 1447-1453.
[5]	FENG Yong-hui, LI Hui, CHEN Meng-gui, CAI Xing-hua. Reliability and validity of Chinese version of Adolescent Reasons for Quitting Scale [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(11): 1509-1514.
[6]	LI Jia-hui1, HE Ya-ping1, XU Gang1, YU Jin-ming2, SHI Rong3, ZHU Jing-fen1,2. Influence of depression on current smoking and smoking intention among adolescents in Shanghai [J]. , 2019, 39(2): 182-.
[7]	SHI Fang-hui1, HE Ya-ping1, XU Gang1, ZHU Jing-fen1,2. Progress in research and application of new media in tobacco control among adolescents [J]. , 2019, 39(2): 213-.
[8]	RAN Min, WANG Hong, PENG Lin-li, HE Fang, YANG Jing-wei. Study on recent sedentary behaviors and influencing factors among children and adolescents in Chongqing area [J]. , 2018, 38(1): 95-.
[9]	JIANG Shu-tian, KUANG Yan-ping . Research progresses of the assisted reproductive techniques for hypogonadotropic hypogonadism patients [J]. , 2017, 37(1): 128-.
[10]	ZOU Zhen, ZHANG Jing, ZHENG Zhi-jie. Domestic and overseas research developments of obesity in children and adolescents [J]. , 2015, 35(4): 601-.
[11]	CAI Yong, QIAO Yun, ZHU Jing-fen, et al. Reliability and validity of questionnaire on tobacco control among adolescents in Shanghai [J]. , 2012, 32(7): 827-.
[12]	HUANG Feng-rong, HUANG Hong, ZHUANG Ming-hua, et al. Investigations on social psychology and sexual behavior of 52 male homosexual adolescents in Shanghai [J]. , 2010, 30(5): 581-.
[13]	YE Zhi-yi, FU Hong-liang, LI Jia-ning, et al. Analysis of ¹³¹I treatment for children and adolescents with differentiated thyroid carcinoma [J]. , 2010, 30(3): 264-.
[14]	SHEN Li-xiao, JIN Xing-ming, HUANG Hong. Investigations on status and requirement of knowledge of reproduction in pregnant adolescents with abortion [J]. , 2009, 29(7): 785-.
[15]	HUANG Feng-rong. Influential factors of human immunodeficiency virus infection in adolescents [J]. , 2009, 29(7): 798-.