Testicular Growth and Spermatogenesis: New Goals for Pubertal Hormone Replacement in Boys With Hypogonadotropic Hypogonadism?

A Multicentre Prospective Study of hCH/rFSH Treatment Outcomes During Adolescence

Julia Rohayem; Berthold P. Hauffa; Margaret Zacharin; Sabine Kliesch; Michael Zitzmann

Clin Endocrinol. 2017;86(1):75-87.

Conclusions

The availability of hCG and rFSH for replacement of gonadotropins provides an alternative option for endocrinologists to safely induce puberty in boys with hypogonadotropic hypogonadism, leading to normal linear growth and virilization, testicular enlargement and early induction of spermatogenesis. This method is effective and reassuring for affected individuals and is likely to reduce the expense, duration and anxiety of late fertility induction. Favourable outcomes during adolescence appear not to be compromised by short-term prior testosterone substitution. Clinical parameters, reflecting the onset and severity of GnRH and/or gonadotropin deficiency, may serve as tools to predict response to treatment.

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Acknowledgements
We thank the technical staff: Reinhild Sandhowe, Sabine Borchert for hormone analyses, Robin and Felix Rohayem for technical assistance, Prof. Eberhard Nieschlag for scientific advice and editing of the manuscript as well as Dr. Con Mallidis and Susan Nieschlag M.A. for language editing. The members of the "German Adolescent Hypogonadotropic Hypogonadism Study Group" are Achim Wüsthof, Hamburg, Bettina Tittel, Dresden, Michel Morlot, Hannover, Walburga Vorhoff, Düsseldorf, Elke Müller-Rossberg, Esslingen, Verena Wagner, Rostock, Katja Konrad, Essen, Kirsten Salzgeber, Ulm, Susanne Fricke-Otto, Krefeld, Joachim Wölfle, Bonn, Peter Willig, Hamburg, Beate Karges, Aachen, Erwin Lankes, Berlin, Michael Droste, Oldenburg, Annette Richter-Unruh, Dortmund/Münster, Klaus-Peter Liesenkötter, Berlin, Angela Hübner, Dresden, Stefanie Zichner, Dortmund, Maik Welzel, Kiel, Desiree Dunstheimer, Augsburg, Ulrike Poletajew, Karlsruhe, Sabine Heger, Hannover, Elke Hammer, Hamburg, Rudolf Oevering, Oldenburg, Silke Schmidt, Heidelberg, Eberhard Nieschlag, Münster.

Grants
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Table 1. Baseline and outcome measurements on hCG/rFSH therapy in previously prepubertal (A) and T-virilized (B) adolescents with HH
Cause of HH n:A/B	Baseline inhibin B (pg/ml)		Baseline AMH (ng/ml)		Baseline BTV (ml) Prader orchiometer/ultrasound		Cryptorchidism (% of cohort)		Inhibin B max. (pg/ml)		AMH min.(ng/ml)		Final BTV Prader orchio./ultrasound (ml)		Final sperm conc. (mill/ml)		Final total sperm count (mill)
Cause of HH n:A/B	A	B	A	B	A	B	A	B	A	B	A	B	A	B	A	B	A	B
Kallmann syndromen:11/9	20 ± 8	18 ± 18	21 ± 13	18 ± 12	3·5 ± 1·4/1·5 ± 0·6	4·2 ± 3·3/2·1 ± 0·6	82	56	112 ± 66	87 ± 52	3·7 ± 2·7	2·8 ± 3·2	30 ± 8/16 ± 8	31 ± 13/16 ± 5	37 ± 36	21 ± 52	19 ± 22	26 ± 43
CHH absent pubertyn:10/8	31 ± 19	28 ± 22	21 ± 14	26 ± 17	3·5 ± 1·7/1·9 ± 1·0	4·6 ± 2·4/2·2 ± 1·5	33	29	198 ± 145	266 ± 128	6·0 ± 5·7	5·1 ± 2·5	39 ± 18/26 ± 15	36 ± 16/24 ± 8	37 ± 48	24 ± 28	39 ± 57	68 ± 70
CHH pubertal arrestn:2/0	120 ± 13	–	10 ± 2	–	20 ± 6/14·0 ± 2·8	–	0	–	219 ± 52	–	5·0 ± 0	–	42 ± 12/31 ± 6	–	8·8 ± 9	–	19 ± 27	–
MPHD congenitaln:5/3	14 ± 1	31 ± 33	11 ± 5	13 ± 6	2·5 ± 2·0/0·9 ± 0·5	6·0 ± 5·0/2·6 ± 1·1	25	33	126	133 ± 173	3·7 ± 2·2	2·2 ± 2·9	23 ± 7/11 ± 6	26 ± 23/24 ± 16	19·3 ± 20	4·2	51 ± 16	59
MPHD after tumourn:4/6	94 ± 102	33 ± 29	32 ± 14	22 ± 11	5·5 ± 4·4/4·9 ± 6·2	6·3 ± 4·0/3·4 ± 2·8	0	0	270 ± 156	177 ± 35	8·7 ± 10·9	3·9 ± 1·5	60 ± 28/36 ± 11	24 ± 21/19 ± 9	180 ± 222	12 ± 12	261 ± 303	18 ± 12
CHARGE syndromen:2/0	48 ± 31	–	42 ± 47	–	4,0 ± 2·8/1·4 ± 0,9	–	100	–	49·7	–	1·85	–	36 ± 19 11	–	8·9 ± 11	–	2·8 ± 4	–
All patientsn:34/26*	39 ± 45	27 ± 23	31 ± 32	20 ± 13	4·6 ± 4·7/2·7 ± 3·8	5·0 ± 3·4/2·5 ± 1·6	45	32	177 ± 118	122 ± 73	5·8 ± 4·3	3·7 ± 2·7	35 ± 15 21 ± 12	32 ± 16/19 ± 8	40 ± 73	19 ± 38	60 ± 160	42 ± 55
P -value(A/B)	P = 0·02		P = 0·24, n.s		_		P = 0·89; n.sP = 0·48; n.s		P = 0·14, n.s.		P = 0·80, n.s.		P = 0·95, n.s.		P = 0·07, n.s.		P = 0·43, n.s.

*Semen was available for analysis in 23 group A and 19 group B patients.

Table 2. Outcomes of previous studies on gonadotropin replacement in adolescents with hypogonadotropic hypogonadism and outcomes of this study
Studies	Number of adolescent HH patients	Age (years)	Gonadotropin preparations and sequence of applications	Duration of replacement (months)	Adult T levels reached (%)	Mean±SD median (range) final single TV (ml) reached	Spermatogenesis achieved	Sperm concentration achieved (mill/ml) median (range) mean±SD	Time to sperm plateau (months)
Liu L et al. (1988)⁶	3 (subset of cohort)	16–17	hCG/HMG	n.a.	100	9 ± 1	n.a. total cohort: 80%	<5	n.a.
Schopohlet al. (1993)⁷	9 (subset of cohort)	18–24	hCG/MHM	20 ± 2	100	n.a. (8–30)	n.a. total cohort: 47%	n.a. (2–26)	20 ± 2
Barrio et al. (1999)⁸	14 IHH: 7 panhypopit: 7	13–21	hCG+rFSH	31	100	IHH: 10 ± 4 panhypopit: 15 ± 5	7/8 (87%) IHH: 4/5 panhypo: 3/3	n.a. (1·5–80)	n.a.
Raivio et al. (2007)⁹	14	10–18	rFSH→ rFSH+hCG	rFSH: 2–34 hCG+FSH: n.a	100	6 (2–37)	6/7 (86%)	8·5 (2·9–92)	n.a.
Sinsi et al. (2008)¹⁰	10 (subset of cohort)	11–25	hCG→ hCG+rFSH	hCG/rFSH: 12 (–24)	100	10 (7–15)	n.a. total cohort: 81%	29 (2·6–96)	n.a.
Zacharinet al. (2012)¹¹	7 (subset of the cohort)	16–22	hCG→ hCG+rFSH	hCG/rFSH: 9	100	12 ± 7 10 (5–27)	7/7 (100%)	1·2 (0·2–15) 4·6 ± 6	n.a.
This study	60 A:34 B:26	14–22	A: hCG→ hCG+rFSH B: Testo→ hCG→ hCG+rFSH	A: hCG: 31 ± 6 hCG/FSH: 25 ± 9 B: hCG: 30 ± 7 hCG/FSH: 25 ± 9	A: 100 B: 100	A: 17 ± 3; 15 (8–40) B: 16 ± 3 17·5 (2–30)	A: 21/23 (91%) B: 18/19 (95%)	A: 17 (0·2–337) 40 ± 73 B: 3·5 (0·1–158) 19 ± 38	A: 31 ± 6 B: 30 ± 7