Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone

E Kohva, T Varimo, H Huopio, S Tenhola, R Voutilainen, J Toppari, P J Miettinen, K Vaaralahti, J Viinamäki, J T Backman, M Hero, T Raivio, E Kohva, T Varimo, H Huopio, S Tenhola, R Voutilainen, J Toppari, P J Miettinen, K Vaaralahti, J Viinamäki, J T Backman, M Hero, T Raivio

Abstract

Study question: Does treatment of constitutional delay of growth and puberty (CDGP) in boys with aromatase inhibitor letrozole (Lz) or conventional low-dose testosterone (T) have differing effects on developing seminiferous epithelium?

Summary answer: Anti-Müllerian hormone (AMH) declined similarly in both treatment groups, and the two Sertoli cell-derived markers (AMH and inhibin B (iB)) exhibited differing responses to changes in gonadotrophin milieu.

What is known already: Boys with CDGP may benefit from puberty-inducing medication. Peroral Lz activates gonadotrophin secretion, whereas intramuscular low-dose T may transiently suppress gonadotrophins and iB.

Study design, size, duration: Sera of 28 boys with CDGP who participated in a randomised, controlled, open-label trial at four paediatric centres in Finland between August 2013 and January 2017 were analysed. The patients were randomly assigned to receive either Lz (2.5 mg/day) (n = 15) or T (1 mg/kg/month) (n = 13) for 6 months.

Participants/materials, setting, methods: The 28 patients were at least 14 years of age, showed first signs of puberty, wanted medical attention for CDGP and were evaluated at 0, 3, 6 and 12 months of visits. AMH levels were measured with an electrochemiluminescence immunoassay and Lz levels with liquid chromatography coupled with tandem mass spectrometry.

Main results and the role of chance: AMH levels decreased in both treatment groups during the 12-month follow-up (P < 0.0001). Between 0 and 3 months, the changes in gonadotrophin levels (increase in the Lz group, decrease in the T group) correlated strongly with the changes in levels of iB (FSH vs iB, r = 0.55, P = 0.002; LH vs iB, r = 0.72, P < 0.0001), but not with the changes in AMH (P = NS). At 12 months, AMH levels did not differ between the groups (P = NS). Serum Lz levels (range, 124-1262 nmol/L) were largely explained by the Lz dose per weight (at 3 months r = 0.62, P = 0.01; at 6 months r = 0.52, P = 0.05). Lz levels did not associate with changes in indices of hypothalamic-pituitary-gonadal axis activity or Sertoli cell markers (in all, P = NS).

Limitations, reasons for caution: The original trial was not blinded for practical reasons and included a limited number of participants.

Wider implications of the findings: In early puberty, treatment-induced gonadotrophin stimulus was unable to counteract the androgen-mediated decrease in AMH, while changes in iB levels were associated with changes in gonadotrophin levels. AMH decreased similarly in both groups during the treatment, reassuring safety of developing seminiferous epithelium in both treatment approaches. Since a fixed dose of Lz induced variable serum Lz levels with a desired puberty-promoting effect in all boys, more research is needed to aim at a minimal efficient dose per weight.

Study funding/competing interest(s): This study was supported by the Academy of Finland, the Foundation for Pediatric Research, the Emil Aaltonen Foundation, Sigrid Juselius Foundation and Helsinki University Hospital Research Funds. The authors have nothing to disclose.

Trial registration number: NCT01797718.

Keywords: anti-Müllerian hormone; constitutional delay of growth and puberty; inhibin B; letrozole; testosterone.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Figures

Figure 1
Figure 1
AMH in the two treatment groups. Serum AMH levels during 6 months of letrozole [Lz] (in red) or testosterone [T] (in blue) treatment and 6 months of follow-up in 28 boys with constitutional delay of growth and puberty (CDGP). The error bars indicate ± SD. Mo, months; AMH, anti-Müllerian hormone.
Figure 2
Figure 2
Individual AMH levels in CDGP boys during 6-month treatment. Boys treated with testosterone [T] in blue (n = 13) and letrozole [Lz] in red (n = 15).
Figure 3
Figure 3
Correlation between gonadotrophins and Sertoli cell–secreted peptides. Correlations between changes in FSH and LH and changes in AMH (in blue) and inhibin B (in red) from baseline to 3-month-measurements in 28 boys with CDGP treated either with testosterone or letrozole.
Figure 4
Figure 4
Relationship between letrozole (Lz) dose and serum Lz concentration. Correlations in serum Lz concentrations against Lz doses per weight in 15 boys with constitutional delay of growth and puberty at 3 (r = 0.62, P = 0.01) and 6 months (r = 0.52, P = 0.05) of Lz treatment (2.5 mg/day). Solid line marks linear regression line and dotted lines 95% confidence intervals.

References

    1. Aksglaede L, Olesen IA, Carlsen E, Petersen JH, Juul A, Jørgensen N. Serum concentration of anti-Müllerian hormone is not associated with semen quality. Andrology 2018;6:286–292.
    1. Albuquerque EVA, Scalco RC, Jorge AAL. MANAGEMENT OF ENDOCRINE DISEASE: diagnostic and therapeutic approach of tall stature. Eur J Endocrinol 2017;176:R339–R353.
    1. Andersson AM, Müller J, Skakkebaek NE. Different roles of prepubertal and postpubertal germ cells and Sertoli cells in the regulation of serum inhibin B levels. J Clin Endocrinol Metab 1998;83:4451–4458.
    1. Benyi E, Kieler H, Linder M, Ritzén M, Carlstedt-Duke J, Tuvemo T, Westphal O, Sävendahl L. Risks of malignant and non-malignant tumours in tall women treated with high-dose oestrogen during adolescence. Horm Res Paediatr 2014;82:89–96.
    1. Borrie AE, Rose RV, Choi Y-H, Perera FE, Read N, Sexton T, Lock M, Vandenberg TA, Hahn K, Dinniwell R et al. . Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer. Breast Cancer Res Treat 2018;172:371–379.
    1. Chemes HE, Rey RA, Nistal M, Regadera J, Musse M, González-Peramato P, Serrano A. Physiological androgen insensitivity of the fetal, neonatal, and early infantile testis is explained by the ontogeny of the androgen receptor expression in Sertoli cells. J Clin Endocrinol Metab 2008;93:4408–4412.
    1. Cortes D, Müller J, Skakkebaek NE. Proliferation of Sertoli cells during development of the human testis assessed by stereological methods. Int J Androl 1987;10:589–596.
    1. Crowne EC, Wallace WH, Moore C, Mitchell R, Robertson WH, Holly JM, Shalet SM. Effect of low dose oxandrolone and testosterone treatment on the pituitary-testicular and GH axes in boys with constitutional delay of growth and puberty. Clin Endocrinol (Oxf) 1997;46:209–216.
    1. Desta Z, Kreutz Y, Nguyen AT, Li L, Skaar T, Kamdem LK, Henry NL, Hayes DF, Storniolo AM, Stearns V et al. . Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. Clin Pharmacol Ther 2011;90:693–700.
    1. Grinspon RP, Andreone L, Bedecarrás P, Ropelato MG, Rey RA, Campo SM, Bergadá I. Male central precocious puberty: serum profile of anti-Müllerian hormone and inhibin B before, during, and after treatment with GnRH analogue. Int J Endocrinol 2013;2013: 823064.
    1. Grinspon RP, Urrutia M, Rey RA. Male central hypogonadism in paediatrics—the relevance of follicle-stimulating hormone and Sertoli cell markers. Eur Endocrinol 2018;14:67–71.
    1. Hannema SE, Sävendahl L. The evaluation and management of tall stature. Horm Res Paediatr 2016;85:347–352.
    1. Hendriks AEJ, Drop SLS, Laven JSE, Boot AM. Fertility of tall girls treated with high-dose estrogen, a dose-response relationship. J Clin Endocrinol Metab 2012;97:3107–3114.
    1. Hero M, Norjavaara E, Dunkel L. Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. J Clin Endocrinol Metab 2005;90:6396–6402.
    1. Hero M, Tommiska J, Vaaralahti K, Laitinen E-M, Sipilä I, Puhakka L, Dunkel L, Raivio T. Circulating antimüllerian hormone levels in boys decline during early puberty and correlate with inhibin B. Fertil Steril 2012;97:1242–1247.
    1. Jensen TK, Finne KF, Skakkebæk NE, Andersson A-M, Olesen IA, Joensen UN, Bang AK, Nordkap L, Priskorn L, Krause M et al. . Self-reported onset of puberty and subsequent semen quality and reproductive hormones in healthy young men. Hum Reprod 2016;31:1886–1894.
    1. Johnson L, Zane RS, Petty CS, Neaves WB. Quantification of the human Sertoli cell population: its distribution, relation to germ cell numbers, and age-related decline. Biol Reprod 1984;31:785–795.
    1. Jørgensen N, Liu F, Andersson A-M, Vierula M, Irvine DS, Auger J, Brazil CK, Drobnis EZ, Jensen TK, Jouannet P et al. . Serum inhibin-b in fertile men is strongly correlated with low but not high sperm counts: a coordinated study of 1,797 European and US men. Fertil Steril 2010;94:2128–2134.
    1. Kohva E, Huopio H, Hero M, Miettinen PJ, Vaaralahti K, Sidoroff V, Toppari J, Raivio T. Recombinant human FSH treatment outcomes in five boys with severe congenital hypogonadotropic hypogonadism. J Endocr Soc 2018;2:1345–1356.
    1. Leschek EW, Flor AC, Bryant JC, Jones JV, Barnes KM, Cutler GB. Effect of antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog on adult height in familial male precocious puberty. J Pediatr 2017;190:229–235.
    1. Lukas-Croisier C, Lasala C, Nicaud J, Bedecarrás P, Kumar TR, Dutertre M, Matzuk MM, Picard J-Y, Josso N, Rey R. Follicle-stimulating hormone increases testicular anti-Mullerian hormone (AMH) production through Sertoli cell proliferation and a nonclassical cyclic adenosine 5′-monophosphate-mediated activation of the AMH gene. Mol Endocrinol 2003;17:550–561.
    1. Mauras N, Bell J, Snow BG, Winslow KL. Sperm analysis in growth hormone-deficient adolescents previously treated with an aromatase inhibitor: comparison with normal controls. Fertil Steril 2005;84:239–242.
    1. Mauras N, Gonzalez de Pijem L, Hsiang HY, Desrosiers P, Rapaport R, Schwartz ID, Klein KO, Singh RJ, Miyamoto A, Bishop K. Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. J Clin Endocrinol Metab 2008;93:823–831.
    1. Mauras N, Ross JL, Gagliardi P, Yu YM, Hossain J, Permuy J, Damaso L, Merinbaum D, Singh RJ, Gaete X et al. . Randomized trial of aromatase inhibitors, growth hormone, or combination in pubertal boys with idiopathic, short stature. J Clin Endocrinol Metab 2016;101:4984–4993.
    1. Orth JM, Gunsalus GL, Lamperti AA. Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development. Endocrinology 1988;122:787–794.
    1. Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med 2012;366:443–453.
    1. Rey R. Endocrine, paracrine and cellular regulation of postnatal anti-müllerian hormone secretion by Sertoli cells. Trends Endocrinol Metab 1998;9:271–276.
    1. Rosenfeld RG, Northcraft GB, Hintz RL. A prospective, randomized study of testosterone treatment of constitutional delay of growth and development in male adolescents. Pediatrics 1982;69:681–687.
    1. Sansone A, Kliesch S, Isidori AM, Schlatt S. AMH and INSL3 in testicular and extragonadal pathophysiology: what do we know? Andrology 2019;7:131–138.
    1. Sharpe RM, McKinnell C, Kivlin C, Fisher JS. Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction 2003;125:769–784.
    1. Soliman AT, Khadir MM, Asfour M. Testosterone treatment in adolescent boys with constitutional delay of growth and development. Metab Clin Exp 1995;44:1013–1015.
    1. Tanii H, Shitara Y, Horie T. Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women. Eur J Clin Pharmacol 2011;67:1017–1025.
    1. Varimo T, Huopio H, Kariola L, Tenhola S, Voutilainen R, Toppari J, Toiviainen-Salo S, Hämäläinen E, Pulkkinen M-A, Lääperi M et al. . Letrozole versus testosterone for promotion of endogenous puberty in boys with constitutional delay of growth and puberty: a randomised controlled phase 3 trial. Lancet Child Adolesc Health 2019;3:109–120.
    1. Venn A, Bruinsma F, Werther G, Pyett P, Baird D, Jones P, Rayner J, Lumley J. Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility. Lancet 2004;364:1513–1518.
    1. Wickman S, Sipilä I, Ankarberg-Lindgren C, Norjavaara E, Dunkel L. A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial. Lancet 2001;357:1743–1748.
    1. Wit JM, Hero M, Nunez SB. Aromatase inhibitors in pediatrics. Nat Rev Endocrinol 2011;8:135–147.
    1. Young J, Chanson P, Salenave S, Noël M, Brailly S, O’Flaherty M, Schaison G, Rey R. Testicular anti-mullerian hormone secretion is stimulated by recombinant human FSH in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2005;90:724–728.
    1. Young J, Rey R, Couzinet B, Chanson P, Josso N, Schaison G. Antimüllerian hormone in patients with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1999;84:2696–2699.
    1. Young J, Rey R, Schaison G, Chanson P. Hypogonadotropic hypogonadism as a model of post-natal testicular anti-Müllerian hormone secretion in humans. Mol Cell Endocrinol 2003;211:51–54.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj