Hormonal control of spermatogenesis in men: Therapeutic aspects in hypogonadotropic hypogonadism

Hormonal control of spermatogenesis in men: Therapeutic aspects in hypogonadotropic hypogonadism

+Model ANDO-622; No. of Pages 3 ARTICLE IN PRESS Disponible en ligne sur ScienceDirect www.sciencedirect.com Annales d’Endocrinologie xxx (2014) xxx...

260KB Sizes 0 Downloads 17 Views

+Model ANDO-622; No. of Pages 3

ARTICLE IN PRESS Disponible en ligne sur

ScienceDirect www.sciencedirect.com Annales d’Endocrinologie xxx (2014) xxx–xxx

Journées Klotz 2014

Hormonal control of spermatogenesis in men: Therapeutic aspects in hypogonadotropic hypogonadism Contrôle hormonal de la spermatogenèse : approches thérapeutiques des hypogonadismes hypogonadotropes Nelly Pitteloud ∗ , Andrew Dwyer Endocrine, diabetes, & metabolism service, centre hospitalier universitaire Vaudois, rue du Bugnon-46, 1011 Lausanne, Switzerland

Abstract During the first two trimesters of intrauterine life, fetal sex steroid production is driven by maternal human chorionic gonadotropin (hCG). The HPG axis is activated around the third trimester and remains active for the first 6-months of neonatal life. This so-called mini-puberty is a developmental window that has profound effects on future potential for fertility. In early puberty, GnRH secretion is reactivated first at night and then night and day. Pulsatile GnRH stimulates both LH and FSH, which induce maturation of the seminiferous tubules and Leydig cells. Congenital hypogonadotropic hypogonadism (CHH) results from GnRH deficiency. Men with CHH lack the mini-pubertal and pubertal periods of Sertoli Cell proliferation and thus present with prepubertal testes (< 4 mL) and low inhibin serum levels – reflecting diminished SC numbers. To induce full maturation of the testes, GnRH-deficient patients can be treated with either pulsatile GnRH, hCG or combined gonadotropin therapy (FSH + hCG). Fertility outcomes with each of these regimens are highly variable. Recently, a randomized, open label treatment study (n = 13) addressed the question of whether a sequential treatment with FSH alone prior to LH and FSH (via GnRH pump) could enhance fertility outcomes. All men receiving the sequential treatment developed sperm in the ejaculate, whereas 2/6 men in the other group remained azoospermic. A large, multicenter clinical trial is needed to definitively prove the optimal treatment approach for severe CHH. © 2014 Published by Elsevier Masson SAS. Keywords: Spermatogenesis; Hypogonadotropic hypogonadism; Mini-puberty; FSH sequential treatment

Résumé Au cours des deux premiers trimestres de la vie intrautérine, la production fœtale de stéroides sexuels est contrôlée par l’hormone chorionique gonadotrophique maternelle humaine (hCG). L’axe gonadotrope est activé au cours du 3e trimestre et demeure actif pendant les 6 premiers mois de la vie néonatale. life. Cette « mini-puberté » est une fenêtre de développement qui a de profonds effets sur le futur potentiel de fertilité. S’installe ensuite une période de quiescence. Puis, au début de la puberté, la sécrétion de GnRH est réactivée, d’abord la nuit, puis la nuit et le jour. La pulsatilité de la GnRH stimule à la fois la LH et la FSH, ce qui induit une maturation des tubes séminifères et des cellules de Leydig. L’hypogonadisme hypogonadotrope congénital (CHH) résulte d’un déficit en GnRH. Les hommes atteints d’un CHH n’ont ni mini-puberté ni prolifération pubertaire des cellules de Sertoli et se présentent donc avec de petits testicules prépubertaires (< 4 mL) et des concentrations d’inhibine sérique basses – reflet du nombre faible de cellules de Sertoli. Afin d’induire une maturation complète des testicules, les patients déficients en GnRH peuvent être traités par de la GnRH pulsatile, de l’hCG ou une combinaison de gonadotrophines (FSH + hCG). Le pronostic de la fertilité avec chacune de ces options thérapeutiques est très variable. Récemment, une étude randomisée, ouverte incluant 13 patients a tenté de répondre à la question de savoir si un

DOIs of original articles: http://dx.doi.org/10.1016/j.ando.2014.03.007, http://dx.doi.org/10.1016/j.ando.2014.04.010, http://dx.doi.org/10.1016/j.ando.2014.03. 004, http://dx.doi.org/10.1016/j.ando.2014.04.006, http://dx.doi.org/10.1016/j.ando.2014.04.011, http://dx.doi.org/10.1016/j.ando.2014.03.008, http://dx.doi.org/ 10.1016/j.ando.2014.03.010, http://dx.doi.org/10.1016/j.ando.2014.04.004, http://dx.doi.org/10.1016/j.ando.2014.03.001, http://dx.doi.org/10.1016/j.ando.2014.03. 003, http://dx.doi.org/10.1016/j.ando.2014.03.009, http://dx.doi.org/10.1016/j.ando.2014.03.011, http://dx.doi.org/10.1016/j.ando.2014.04.001, http://dx.doi.org/ 10.1016/j.ando.2014.04.003, http://dx.doi.org/10.1016/j.ando.2014.04.005, http://dx.doi.org/10.1016/j.ando.2014.03.002, http://dx.doi.org/10.1016/j.ando. 2014.03.005 ∗ Corresponding author. E-mail address: [email protected] (N. Pitteloud). http://dx.doi.org/10.1016/j.ando.2014.04.002 0003-4266/© 2014 Published by Elsevier Masson SAS.

Please cite this article in press as: Pitteloud N, Dwyer A. Hormonal control of spermatogenesis in men: Therapeutic aspects in hypogonadotropic hypogonadism. Ann Endocrinol (Paris) (2014), http://dx.doi.org/10.1016/j.ando.2014.04.002

+Model ANDO-622; No. of Pages 3 2

ARTICLE IN PRESS N. Pitteloud, A. Dwyer / Annales d’Endocrinologie xxx (2014) xxx–xxx

traitement séquentiel avec la FSH seule avant la LH et la FSH (via une pompe à GnRH) pouvait améliorer le pronostic de la fertilité. Tous les hommes ayant rec¸u un traitement séquentiel avaient des spermatozoïdes dans leur éjaculat, tandis que 2 hommes sur 6 demeuraient azoospermiques dans l’autre groupe. Un essai clinique multicentrique plus large serait nécessaire afin de confirmer l’efficacité de cette approche thérapeutique dans les CHH sévères. © 2014 Publié par Elsevier Masson SAS. Mots clés : Spermatogenèse ; Hypogonadisme hypogonadotrope ; Minipuberté ; Traitement séquentiel par la FSH

Elucidating the endocrine mechanisms underlying human testicular development and spermatogenesis has been challenging. Species differences have precluded direct extrapolations from model organisms and the dynamic hypothalamicpituitary-gonadal (HPG) axis in humans contributes additional difficulties. Even so, it is known that hormonal regulation of the developing gonad changes from fetal life through puberty. During the first two trimesters of intrauterine life, fetal sex steroid production is driven by maternal human chorionic gonadotropin (hCG). The HPG axis is activated around the third trimester and remains active for the first 6-months of neonatal life. This so-called mini-puberty is a developmental window that has profound effects on future potential for fertility [1]. This neonatal production of LH and FSH impacts both compartments of the testes. Increased LH levels induce the interstitial Leydig cells to produce testosterone and FSH induces proliferation of immature Sertoli cells (SCs) within seminiferous tubules (cords) resulting in secretion of inhibin B (IB) and antiMüllerian hormone (AMH) [2]. This brief period of activation of the HPG axis in the male ends at approximately 6-months of age. Subsequently, in the absence of gonadotropin-releasing hormone (GnRH) secretion, serum gonadotropin levels fall and boys enter an apparent neuroendocrine quiescence of childhood marked by low frequency and low amplitude GnRH pulses leading to low serum gonadotropin levels. In early puberty, GnRH secretion is reactivated first at night and then night and day. Pulsatile GnRH stimulates both LH and FSH, which induce maturation of the seminiferous tubules and Leydig cells. This leads to increased testosterone production from the mature Leydig cells. In contrast to the mini-puberty, the androgen receptors are now expressed on SCs [3]. Thus, intra-testicular testosterone can act on SCs in concert with FSH resulting in the first wave of spermatogenesis, ending SC proliferation [4]. Because each SC can only support a finite number of germ cells, achieving a full complement of SCs is critical for spermatogenic capacity and fertility [5]. Congenital hypogonadotropic hypogonadism (CHH) results from GnRH deficiency. Men with CHH lack the minipubertal and pubertal periods of SC proliferation and thus present with prepubertal testes (< 4 mL) [6] and low IB serum levels – reflecting diminished SC numbers as is evident histologically [7–9]. To induce full maturation of the testes, GnRH-deficient patients can be treated with either pulsatile GnRH (stimulating the release of endogenous LH and FSH) [10], hCG [11], or combined gonadotropin therapy (FSH + hCG) [12]. Fertility outcomes with each of these regimens are highly variable with poorer responses in patients with signs indicating

absent mini-puberty (prepubertal testes, cryptorchidism, and/or low serum IB levels) [6]. Better responses are noted for those men with partial pubertal development. While it seems plausible that fertility potential could be maximized by recreating the initial rise in FSH during early puberty (i.e. administering FSH alone), the optimal regimen for such severe cases remains unclear. Recently, we published the results of a randomized, open label treatment study (n = 13) addressing the question of whether a sequential treatment with FSH alone prior to LH and FSH (via GnRH pump) could enhance fertility outcomes [13]. Notably, among these men with prepubertal testes and no cryptorchidism, testicular volume (TV) doubled after 4-months of recombinant FSH treatment due to SC proliferation as evidenced by histology and a significant increase in serum IB. Additionally, histology revealed not only proliferative changes but also cytoskeletal changes suggesting a much broader role for FSH in gonadal development. Thus, there appears to be a prepubertal window when FSH can induce SC and germ cell proliferation in immature testes, which terminates after exposure to androgen production from the Leydig cells. All men receiving the sequential treatment (7/7) developed sperm in the ejaculate, whereas 2/6 men in the other group remained azoospermic. Due to a limited sample size, despite trends, the FSH pre-treatment (followed by GnRH) was not statistically superior to GnRH-only treatment in either TV, maximal sperm count or time to sperm in the ejaculate. Of clinical relevance, we found that the IB did not increase further after 2 months of pre-treatment suggesting that it may be reasonable to shorten pre-treatment to 8-weeks of FSH to maximize and prime the SC compartment prior to androgen-induced maturation by GnRH or hCG. This confirms a prior study of prepubertal men with gonadotropin deficiency (of diverse etiologies) also pre-treated with variable rFSH regimens before adding hCG [14]. Of the four CHH men included in this study, all but one (who had a history of cryptorchidism), developed sperm in the ejaculate. Therefore while these data are highly promising, a large, multicenter clinical trial is needed to definitively prove the optimal treatment approach for severe CHH. However, given the rarity of such patients a collaboration of a higher order is needed to achieve this. Further, key studies examining gonadotropin therapy during mini-puberty are promising [15]. Such novel approaches not only will enhance our understanding of normal development but may be avenues to maximize treatment outcomes for patients later in life as well as to ameliorate some of the dramatic psychosocial and psychosexual impact that CHH

Please cite this article in press as: Pitteloud N, Dwyer A. Hormonal control of spermatogenesis in men: Therapeutic aspects in hypogonadotropic hypogonadism. Ann Endocrinol (Paris) (2014), http://dx.doi.org/10.1016/j.ando.2014.04.002

+Model ANDO-622; No. of Pages 3

ARTICLE IN PRESS N. Pitteloud, A. Dwyer / Annales d’Endocrinologie xxx (2014) xxx–xxx

has on patients. Lastly, with the flood of data emerging from next-generation sequencing technologies, subsequent discoveries may provide additional clues such as molecular signatures to identify the optimal treatment strategies for patients seeking to develop fertility. Disclosure of interest The authors have not supplied their declaration of conflict of interest. References [1] Grumbach MM. A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metabol 2005;90(5):3122–7. [2] Grinspon RP, Rey RA. Anti-mullerian hormone and sertoli cell function in paediatric male hypogonadism. Horm Res Paediatr 2010;73(2): 81–92. [3] Regadera J, et al. Androgen receptor expression in sertoli cells as a function of seminiferous tubule maturation in the human cryptorchid testis. J Clin Endocrinol Metab 2001;86(1):413–21. [4] Andersson AM, Muller 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 Metabol 1998;83(12):4451–8. [5] 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(3):787–94.

3

[6] Pitteloud N, et al. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metabol 2002;87(9):4128–36. [7] Kumar PA, et al. Testis morphology in patients with idiopathic hypogonadotropic hypogonadism. Hum Reprod 2006;21(4):1033–40. [8] Young J, et al. Testicular anti-mullerian hormone secretion is stimulated by recombinant human FSH in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metabol 2005;90(2):724–8. [9] Bougneres P, 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 Metabol 2008;93(6):2202–5. [10] Hoffman AR, Crowley Jr WF. Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med 1982;307(20):1237–41. [11] Finkel DM, Phillips JL, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med 1985;313(11):651–5. [12] Bouloux PM, et al. Induction of spermatogenesis by recombinant folliclestimulating hormone (puregon) in hypogonadotropic azoospermic men who failed to respond to human chorionic gonadotropin alone. J Androl 2003;24(4):604–11. [13] Dwyer AA, et al. Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metabol 2013;98(11):E1790–5. [14] Raivio T, Wikstrom AM, Dunkel L. Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome. Eur J Endocrinol 2007;156(1):105–11. [15] Bouvattier C, et al. Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism. Nat Rev Endocrinol 2012;8(3):172–82.

Please cite this article in press as: Pitteloud N, Dwyer A. Hormonal control of spermatogenesis in men: Therapeutic aspects in hypogonadotropic hypogonadism. Ann Endocrinol (Paris) (2014), http://dx.doi.org/10.1016/j.ando.2014.04.002