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

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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

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