Current concepts surrounding neonatal hormone therapy for boys with congenital hypogonadotropic hypogonadism

Figures & data

Figure 1. Proposed approach to suspected absent minipuberty in male neonates and infants.

CHH, congenital hypogonadotropic hypogonadism; HH, hypogonadotropic hypogonadism ^a”Red flag” signs of GnRH/gonadotropin deficiency: cryptorchidism, micropenis; Presence of other anterior pituitary deficiencies and/or nonreproductive CHH-associated phenotype including cleft lip/palate, hearing impairment, syndactyly or other anomaly of digits. ^bSerum FSH, LH, Testosterone ± Inhibin B, anti-Müllerian hormone; Male minipuberty peaks between 1 and 4 months.

Figure 2. Combined gonadotropin therapy regimens and outcomes studied in male neonates and infants with congenital hypogonadotropic hypogonadism.

Table 1. Studies of gonadotropin therapy in non-cryptorchid CHH infants

Study, No. of non-cryptorchid/total CHH subjects	Gonadotropin treatment		Treatment Outcomes (vs pretreatment values)					Remarks
	Age at start/Duration of therapy	Dosing regimen	TV (mL)	PL (mm)	T (nmol/L)	IB (pg/mL)	AMH (pmol/L)
Continuous Subcutaneous Infusion
Bougnères et al. 2008 [70], n = 2/2	2–14 wk/17-28 wk	LH 50–56 IU/d FSH: 67–125 IU/d	2.10 (3.7–4.7x)	21–38 (2.6–4x)	Mean 4.8–7.6 (80–253x)	Mean 426–701 (4–140x)	Mean 608–826 (1.5–2x)	Demonstrated that the a) suppression of AMH secretion by LH-driven T from LCs, which occurs in CHH adults, is not observed in CHH infants. b) SCs of CHH infants are resistant to FSH, requiring levels up to 18-fold ULN to achieve normal IB and AMH.
Sarfati et al. 2015 [71], n = 1/1	1 mo/6 mo	LH 75 IU/d FSH 75 IU/d	2.3 (2x)	38 (2.5x)	-	-	-	Baseline TV enlarged on treatment and remained normal (0.8 ml) for 1 year after treatment ended.
Stoupa et al. 2017 [74], n = 1/5	5.5 mo/3 mo	LH 150 IU/d FSH 75 IU/d	-	45 (3x)	^aPeak ~3	^aPeak >800	^aPeak ~150-200	^aEstimated from the graph (Figure 1) as no absolute values are provided.
Subcutaneous Injection
Main et al. 2002 [69], n = 1/1	7.9 mo/5.8 mo	LH: 20 IU 2x/wk x7 wk, then 40 IU 2x/wk x7 wk FSH: 21.3 IU 2x/wk x23 wk	0.084 (2.7x)	24 (1.5x)	< lower limit	2x (absolute value NA)	-	Penile growth occurred despite undetectable T, with further growth (24 → 27 mm) following T suppositories, 1 mg/d for 6 wks.
Kohva et al. 2019 [77], n = 3/5	1.3–4.2 mo/3-4.5 mo	LH: nil FSH: 7.5–16.7 IU 2x/wk	Testes ascended	30–35 (1.3–2.2x)	-	^b77-186 (2.3–5.1x)	-	^bData are only available for two subjects. Subjects concurrently received IM T 25 mg 1x/mo x 3 mo. Testes ascended before FSH therapy in 1 subject, and only after FSH therapy, in the other 2 subjects.

CHH, congenital hypogonadotropic hypogonadism; LH, luteinizing hormone; FSH, follicle-stimulating hormone; TV, testicular volume; PL, penile length; IB, inhibin B; AMH, anti-Müllerian hormone; ULN, upper limit of normal; d, day; mo, month; wk, week; IM, intramuscular; T, testosterone; SC, Sertoli cell; LC, Leydig cell.

Table 2. Studies that described testicular descent as an outcome of gonadotropin treatment in CHH neonates/infants

Mode of gonadotropin delivery	Study, No. of cryptorchid/total CHH subjects	Dosing regimen	Total cumulative dose per patient	Testicular Descent (per total No. testes)			Remarks
				Complete	Partial	No
Continuous subcutaneous infusion	Lambert and Bougnères et al. 2016 [75], n = 8/8	LH 75 IU/d + FSH 75–150 IU/d x5-6.5 mo	LH: 7,000 IU FSH: 21,000 IU	13/16	3/16	0/16	n = 1 failed to achieve adequate rise in AMH and IB levels during treatment and required orchidopexy after both testes retracted 11 mo following their original complete descent.
	Stoupa et al. 2017 [74], n = 4/5	LH 150 IU/d + FSH 75 IU/d x3-5.5 mo	LH: mean 17,775 IU (13,500–21,375) FSH: mean 9,450 IU (6750–13,500)	3/5	0/5	2/5	U/L (n = 3) and B/L cryptorchidism (n = 1). LH infusion dose increased from 75 to 150 IU /24 hr at 2.5 mo in n = 1. The 2 nonresponders (both U/L cryptorchid) had low to moderate AMH and IB responses. In contrast, the subject with greatest biochemical response had the fastest descent occurring in 3 mo.
Subcutaneous injections	Kohva et al. 2019 [77], n = 3/5^a (see remarks)	FSH 7.5–16.7 IU 2–3 x/week (3.4–7.5 IU/kg/wk). IM T inj. (25 mg/mo x3 mo). No LH or hCG given	FSH mean 325.2 IU (199.2–601.2)	0/6	0/6	0/6	n = 3 had B/L cryptorchidism prior to FSH therapy^a. Ascent of testes occurred after FSH treatment (n = 2). All boys required B/L orchidopexy. Compared to other studies, FSH monotherapy without LH/hCG and significantly lower doses were used.
	Papadimitriou et al. 2019 [56], n = 10/10	LH 75 IU/d + FSH 150 IU/d x3 mo	LH: 6,750 IU FSH: 13,500 IU	20/20	0/20	0/20	Fixed doses used for all subjects. Testicular descent occurred in 30% after 1 mo, in 40% after 2 mo, and in 30% after 3 mo (100% cumulative). In n = 2 (septo-optic dysplasia and hypoplastic pituitary), one of 2 testes later retracted to the low inguinal region requiring orchidopexy. At 3–10 yrs follow-up, all testes remained intrascrotal, with slight regression in size (1.0 ml, ranged 0.5–2.0).

CHH, congenital hypogonadotropic hypogonadism; LH, luteinizing hormone; FSH, follicle-stimulating hormone; IB, inhibin B; AMH, anti-Müllerian hormone; d, day; mo, month; IM, intramuscular; T, testosterone; U/L, unilateral and B/L bilateral (cryptorchidism)

Table 3. Single-center experience with gonadotropin-induced testicular descent in CHH beyond infancy [84]

hMG priming?	Subject: Age (yrs)	Subcutaneous Gonadotrophin Therapy^a	Outcomes (compared to baseline)				Time to testicular descent (mo)		Remarks; longer term follow-up data (if any)
			TV (ml)		T (nmol/L)	IB (pg/mL)	R	L
			R	L
Yes	#1: 1.5	hMG 25 IU 3x/wk x2 mo, then hMG 25 IU 3x/wk + hCG 250 IU 2x/week	0.17 -> 0.53	0.12 -> 0.64	5.7 (40x)	240 (3x)	5	2	L descended after 2 mo hMG monotherapy
			US
Yes	#2: 10.4	hMG 150 IU 3x/wk x 4mo, then hMG 150 IU 3x/wk + hCG 500 IU 2x/wk	0.5 -> 0.71	0.2 -> 0.49	1.4 (5.8x)	152 (17.5x)	4	6	R descended after 4 mo hMG monotherapy
			US
Yes	#3: 14.7	hMG 150 IU 3x/wk x 2 mo, then hMG 150 IU 3x/wk + hCG 500 IU 2x/wk	1	1	2.8 (16.7x)	125 (2.4x)	4	4	After 18 mo CGT: TV: 6 ml (R) and 8 ml (L); T 16.6 nmol/L Peak sperm concentration: not examined
			PO, no baseline measurement
No	#4: 12	hMG 75 IU 3x/wk + hCG 1,000 IU 2x/wk	0.2 -> 0.3	0.3 -> 0.4	4.2 (3.4x)	-	8	6	After 60 mo CGT: TV: 5 ml *r) and 5 ml (L); T 18.06 nmol/L Peak sperm concentration: 18 x 10^6/mL
			US
No	#5: 25	hMG 75 IU 3x/wk + hCG 2000 IU 3x/wk	2	2	6.0 (2.3x)	-	4	4	After 28 mo CGT: TV: 8 ml (R) and 6 ml (L); T 17 nmol/L Peak sperm concentration: 32 x 10^6/mL
			PO, no baseline measurement
No	#6: 26	hMG 75 IU 3x/wk + hCG 2000 IU 3x/wk	1	4	4.6 (21.8x)	-	failed to descend after 42 mo	already in scrotum at baseline	After 32 mo of CGT: TV: 1 ml (R) and 12 ml (L); T 14.56 nmol/L Peak sperm concentration: 5 x 10^6/mL Pregnancy reported in partner
			PO, no baseline measurement

^aAge-based dosing: (a) <10 yrs: hMG 3 IU/kg/dose 3x/wk + hCG 250 IU 2x/wk and (b) ≥10 yrs: hMG 75–150 IU 3x/wk + hCG 500–1,000 IU 2x/wk (10–20 yrs) or 2,000 IU 3x/wk (>20 yrs); CHH, congenital hypogonadotropic hypogonadism; US: ultrasound; PO: Prader Orchidometer; R: right; L: Left; wk: week; mo: month; hCG: human chorionic gonadotropin; hMG: human menopausal gonadotropin; wk, week; mo, month; TV, testicular volume; CGT, combined gonadotropin treatment; T, testosterone

Bougnères P, François M, Pantalone L, et al. Effects of an early postnatal treatment of hypogonadotropic hypogonadism with a continuous subcutaneous infusion of recombinant follicle-stimulating hormone and luteinizing hormone. J Clin Endocrinol Metab. 2008 Jun;93(6):2202–2205.

 PubMed Web of Science ®Google Scholar

Sarfati J, Bouvattier C, Bry-Gauillard H, et al. Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life. Orphanet J Rare Dis. 2015 Jun 9;10:71.

 PubMed Web of Science ®Google Scholar

Stoupa A, Samara-Boustani D, Flechtner I, et al. Efficacy and safety of continuous subcutaneous infusion of recombinant human gonadotropins for congenital micropenis during early infancy. Horm Res Paediatr. 2017;87(2):103–110.

 PubMed Web of Science ®Google Scholar

Main KM, Schmidt IM, Toppari J, et al. Early postnatal treatment of hypogonadotropic hypogonadism with recombinant human FSH and LH. Eur J Endocrinol. 2002 Jan;146(1):75–79.

 PubMed Web of Science ®Google Scholar

Kohva E, Huopio H, Hietamäki J, et al. Treatment of gonadotropin deficiency during the first year of life: long-term observation and outcome in five boys. Hum Reprod. 2019 May 1;34(5):863–871.

 PubMed Web of Science ®Google Scholar

Lambert A-S, Bougneres P. Growth and descent of the testes in infants with hypogonadotropic hypogonadism receiving subcutaneous gonadotropin infusion. Int J Pediatr Endocrinol. 2016;2016:13.

 PubMedGoogle Scholar

Papadimitriou DT, Chrysis D, Nyktari G, et al. Replacement of male mini-puberty. J Endocr Soc. 2019 May 9;3(7):1275–1282.

 PubMed Web of Science ®Google Scholar

Dunkel L, Taskinen S, Hovatta O, et al. Germ cell apoptosis after treatment of cryptorchidism with human chorionic gonadotropin is associated with impaired reproductive function in the adult. J Clin Invest. 1997 Nov 1;100(9):2341–2346.

 PubMed Web of Science ®Google Scholar