Endocrinologia

Endocrinologia della riproduzione nel feto, infanzia e adolescenza

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L’ipofisi anteriore e il lobo ipofisario intermedio si sviluppa  nel feto dalla parete anteriore della tasca di Rathke entro la quinta settimana, subito dopo che quest’ultima si è staccata dall’abbozzo faringeo.

La tasca di Rathke è un’invaginazione dell’apparato oro-faringeo in via di sviluppo, stomodeo, di derivazione ectodermica. 

Entro la 7a settimana dalla tasca di Rathke si sviluppa il peduncolo ipofisario. La formazione dei vasi portali ipofisari ipotalamici inizia tra la 12ª e la 17ª settimana (1).

In gravidanza l’ipotalamo fetale inizia la secrezione di Gn-RH dalla 6a settimana; dalla 10ª settimana di gestazione l’ipofisi fetale inizia la secrezione di FSH ed LH. Queste gonadotropine  si possono riscontrare nel sangue fetale in quantità dosabili a partire dalla 11-12a. Questa notevole secrezione di gonadotropine è riconducibile all’immaturità dell’ipotalamo fetale non ancora sensibile al feed-back negativo esercitato dagli steroidi sessuali circolanti, sia di origine placentare che fetale (1-4).  Prelievi ematici effettuati mediante cordocentesi a 17-24 settimane hanno permesso di rilevare che le gonadotropine sono molto più elevate nei feti di sesso femminile che in quelli di sesso maschile (LH, 48 ± 4 vs 6.3 ± 0,7 mUI/ml; FSH, 35 ± 2 vs 0,7 ± 0,1 mUI/ml) (2). In parallelo, sotto lo stimolo delle gonadotropine, androgeni ed estrogeni di origine placentare aumentano nel circolo fetale e stimolano crescita e maturazione delle gonadi.

Gli androgeni e gli estrogeni fetali sono derivati ​​principalmente dalla placenta. La placenta non ha attività del citocromo P450 (CYP17) e 17α-idrossilasi e 17,20-liasi. La placenta sintetizza l’estrogeno dai precursori ricevuti dalla corteccia surrenale fetale. La corteccia surrenale fetale manca dell’enzima 3β-idrossisteroide-deidrogenasi e non può, sintetizzare progesterone o 17α-idrossiprogesterone. Tuttavia, la corteccia surrenale fetale secerne il deidroepiandrosterone (DHEA) e il deidroepiandrosterone solfato (DHEAS) in risposta all’ACTH. Questi intermedi steroidogenici sono utilizzati nella biosintesi degli estrogeni placentari, bypassando CYP17. Gli estrogeni consentono la crescita e lo sviluppo del feto aumentando il flusso ematico uterino durante la gravidanza e inoltre a termine di gravidanza aumentano la contrattilità miometriale e l’insorgenza del travaglio. Nel maschio, le cellule di leydig producono testosterone in risposta alla gonadotropina corionica umana (hCG) e LH tra la 10a e la 20a settimana (39-52).

Con il progredire della gravidanza si osserva una graduale maturazione dei recettori ipotalamici e quindi si ha una inibizione della dismissione di Gn-RH dell’ipotalamo ad opera del feed-back negativo esercitato dagli steroidi. Infatti nella seconda metà della gravidanza si ha una progressiva riduzione dei livelli di FSH ed LH nei feti sia maschili che femminili (LH, 0,24 ± 0,05 vs ± 0,3 mUI/ml; FSH 0,45 ± 0.1 e 0.5 ±  0,1 mUI/ml) (3-5).

Nel feto ci sono aumenti esponenziali delle concentrazioni plasmatiche di cortisolo negli ultimi 10 giorni di gestazione preceduti da incremento di ACTH fetale (3).

Lo stress prenatale, la grave malnutrizione materna, l’insufficienza placentare e l’esposizione materna a glucocorticoidi esogeni   possono provocare nel feto alterazioni permanenti della funzionalità dell’asse ipotalamo-ipofisi-surrene (HPA). A tali alterazioni fetali dell’asse ipotalamo-ipofisi-surrene possono essere correlati diabete mellito, ipertensione arteriosa e dislipidemia ad insorgenza in età adulta  (4) specialmente nei feti di sesso femminile (5). La  terapia con glucocorticoidi a fine gravidanza per promuovere la maturazione polmonare fetale e prevenire la sindrome delle membrane ialine non sembra avere gravi complicazioni, a basse dosi, sull’asse HPA per la diminuita sensibilità recettoriale ipotalamica in questo periodo della gravidanza (6,7).  Tuttavia i glicocorticoidi sintetici, a differenza dei glucocorticoidi endogeni,

  • non sono metabolizzati dalla steroido-deidrogenasi placentare (11-β-HSD2) e  conseguentemente aumentano i mineralcorticoidi nel circolo fetale (8)
  • i glicocorticoidi sintetici possono legarsi oltre che ai recettori per i glicocorticoidi anche ai recettori neurosteroidei cerebrali (9)

I recettori glucocorticoidi (GR) e  mineralcorticoidi (MR) sono presenti nella corteccia cerebrale fetale e in tutte le regioni dell’ippocampo e giro dentato dal 40°  giorno di gestazione con un picco al 3° mese ed una costante diminuzione dal 2° trimestre fin quasi a termine di gravidanza per poi ripresentare un picco all’inizio del travaglio (10).

Per tali motivi, in Nord America, una conferenza di aggiornamento consenso National Institutes of Health raccomanda di limitare l’uso di dosi multiple e ripetute di betametasone e raccomandazioni analoghe sono state fatte in Europa (6-8).

Alla nascita si ha una caduta degli steroidi di origine placentare e materna (17-alfa-OH-P, DHEA, EE) e questo provoca nel neonato un aumento della concentrazione delle gonadotropine ipofisarie che inizia al termine della prima settimana di vita (11-14). Tale aumento delle GN si osserva nel maschio fino al 1° mese di nascita per poi decrescere rapidamente fino a raggiungere i valori pre-puberali. Nelle femmine, invece, la concentrazione di FSH e LH  aumenta fino al 4° anno di vita prima di decrescere ai valori pre-puberali. Il decremento delle gonadotropine è dovuto all’incremento della secrezione steroidea ad opera dell’asse ipotalamo-ipofisi-surrenale. 

Dopo la nascita, nel neonato le concentrazioni di FSH ed LH aumentano a causa del feed-back positivo esercitato dalla brusca caduta dei livelli steroidei di origine materna e placentare.  Nelle femmine l’aumento di Gn continua fino ai tre  mesi di vita, dopo di che cominciano a decrescere per raggiungere i valori prepuberali verso i 3-4 anni di vita.

Nel neonato di sesso maschile, invece, l’aumento è molto meno evidente, il massimo viene raggiunto intorno al primo mese di vita, dopo di che i valori decrescono per raggiungere i valori prepuberali intorno  al quarto mese (15-38).

Immagine correlata

Fanciullezza: è il periodo che va da 4 agli 8 anni di età, si hanno bassi livelli di gonadotropine e di steroidi sessuali in tutti e due i sessi.

Questi valori ridotti sono dovuti alla sensibilità dei centri ipotalamici al meccanismo di feed-back negativo esercitato dagli steroidi che in questo periodo è particolarmente evidente. E’ inoltre da tenere presente che in questa fase, come nella precedente, manca l’effetto di feed-back positivo esercitato dagli estrogeni, ed in particolare dall’estradiolo, sull’ipotalamo nella vita adulta. Durante questa fase si ha un graduale aumento dell’escrezione urinaria degli steroidi di origine gonadica, mentre dopo gli otto anni cominciano ad aumentare gli steroidi di origine surrenalica. 

Il 17-α-OH-P é un ormone steroideo, progestinico naturale, prodotto in gran parte dalle cellule della teca interna del follicolo in crescita e del corpo luteo e, in quantità minore, dalla corteccia surrenale. La concentrazione sierica di 17-α-OH-P decresce rapidamente dopo la nascita e, per entrambi i sessi ,rimane bassa e costanei durante l’infanzia (0.1-0.5 ng/ml) e aumenta progressivamente durante la pubertà, dove raggiunge i livelli dell’adulto di circa 10-15 ng/ml. Il 17-α-OH-P deriva dalla idrossilazione del progesterone e costituisce il precursore della serie degli androgeni C19 (androstenedione e testosterone). Il suo principale catabolita è il pregnandiolo escreto per via urinaria (12%) e nelle feci (10%). Il 17-α-OH-P non ha un ruolo fisiologico definito tranne che come precursore ma la sua secrezione rappresenta una importante indice dell’attività surrenalica.  Attualmente è sempre più oggetto di valutazione per lo studio dell’irsutismo e della PCOS(53-62)

 

Verso i 10 anni di età inizia nelle femmine lo sviluppo mammario (telarca)  fa seguito l’adrenarca (sviluppo dei peli pubici e ascellari): inizia a livello pubico e prosegue   a livello  ascellare; come per il telarca, Tanner distingue cinque fasi di adrenarca, da P1 a P5.  L’adrenarca è  dovuto alla secrezione surrenalica di DHEA ed all’inizio della secrezione di androstenedione da parte  delle cellule dello stroma ovarico.  La secrezione del DHEA aumenta prima della maturazione dell’asse ipotalamo-ipofisi-ovaio; il DHA compare in circolo prima delle gonadotropine mentre il testosterone compare quando inizia la secrezione dell’FSH e dell’LH. E’ probabile, quindi, che il DHEA giochi un ruolo importante sulla maturazione dell’asse ipotalamo-ipofisi-ovaio.

PUBERTA’: la pubertà segue l’adrenarca di circa due anni.  Il momento del passaggio dalla fanciullezza all’adolescenza e quindi l’inizio della pubertà, è dato da una riduzione della sensibilità dell’ipotalamo al feed-back negativo esercitato dagli steroidi sessuali sulla dismissione degli ormoni ipotalamo-ipofisari.

In una fase più avanzata dello sviluppo puberale si manifesta anche un meccanismo di feed-back positivo da parte degli estrogeni, specie dell’estradiolo, sulla secrezione gonadotropinica.  A tale meccanismo è dovuto il caratteristico picco gonadotropinico che compare a metà ciclo nella donna adulta. Alla modificazioni della risposta ipotalamica agli stimoli endocrini di natura gonadica, va aggiunto un processo di maturazione del sistema nervoso centrale, che interviene con un meccanismo non ancora conosciuto sull’asse ipotalamo-ipofisi-gonadico; si avrebbe l’aumento della secrezione di un fattore gonadotropinico-stimolante o la riduzione di un fattore gonadotropino-inibente. Da tutto ciò deriva un aumento dell’increzione del Gn-RH, cui segue un aumento della secrezione ipofisaria di FSH e LH, la maturazione follicolare e l’elevazione del tasso degli steroidi circolanti che porta alla comparsa dei caratteri sessuali secondari.

Pertanto mentre la fanciullezza è caratterizzata da bassi livelli di gonadotropine, l’adolescenza si accompagna a valori progressivamente crescenti delle gonadotropine e degli steroidi sessuali, sia ovarici che surrenalici.

Oltre alle variazioni quantitative degli ormoni ipotalamo-ipofisi-gonadici, si hanno anche variazioni qualitative delle loro cellule bersaglio, che diventano più sensibili agli stimoli ormonali.

L’inizio della pubertà é caratterizzato dalla comparsa di variazioni cicliche delle concentrazioni ormonali, che corrispondono alla maturazione del follicolo, all’ovulazione ed alla formazione del corpo luteo. Verso i 10 anni, oltre al lieve aumento dei valori basali di FSH ed LH, nonché dell’estradiolo, si cominciano ad osservare delle oscillazioni della concentrazione di LH: inizialmente si ha la comparsa di picchi notturni che scompaiono con la maturazione sessuale.

In quest’ultima fase, si manifesta completamente la secrezione pulsatile delle gonadotropine, tipica dell’età adulta. Tale modalità di secrezione è strettamente dipendente dalla concentrazione degli steroidi sessuali ed infatti la frequenza e l’ampiezza delle scariche pulsatili varia nelle diverse fasi del ciclo mestruale in rapporto alla concentrazione degli steroidi circolanti.

Oltre a queste variazioni che si osservano nel corso della giornata, nella prima pubertà si cominciano ad avere cicli mensili di increzione gonadotropinica (da 28 a 40 giorni), che determinano la maturazione e regressione dei follicoli ovarici, con conseguente incremento della produzione di steroidi.

Nella media pubertà alla caduta degli estrogeni, durante il ciclo, segue la prima mestruazione o “menarca”. La comparsa del menarca è secondaria non solo alle citate variazioni ormonali, ma anche al raggiungimento  di un peso” critico”. 

Normalmente nei primi due anni dopo il menarca, i cicli sono anovulatori nel 55-90%; tale frequenza scende a circa il 20% nei primi 5 anni.

La situazione ormonale tipica dell’età adulta, compare verso i 14-16 anni, epoca in cui in seguito alla maturazione del tratto ipotalamo-ipofisi-gonadico si ha l’instaurarsi del ciclo mestruale normale.

La pubertà è associata ad un cambiamento della responsività dell’ipofisi al Gn-RH.

E’ sufficientemente documentato che un’alterazione del metabolismo degli androgeni può produrre una pubertà ritardata e che una elevata concentrazione di testosterone inibisce l’asse ipotalamo-ipofisi-ovaio. Una iperreazione delle surrenali allo stress che nell’adolescenza è spesso secondario a problemi psicologici può determinare danni all’orologio biologico con anovularietà ed amenorrea.

La produzione di DHEA e DHEAS, cui segue un lieve aumento dell’androstenedione, inizia verso i 7 anni ed aumenta gradualmente.

L’increzione di testosterone comincia ad aumentare verso i 9-10 anni e raggiunge gradualmente i valori della donna adulta verso i 16 anni.

Gli androgeni, oltre a determinare l’adrenarca, coadiuvano con il GH ipofisario alla crescita staturale; assieme agli estrogeni stimolano l’accrescimento delle cartilagini di coniugazione, ma contemporaneamente sulla stessa cartilagine hanno un’azione maturativa, determinandone l’ossificazione e l’arresto della crescita.

Riassumendo, il quadro ormonale si modifica in primo luogo per la riduzione della sensibilità ipotalamica al feed-back negativo degli estrogeni con innesco dei meccanismi di controllo della pulsatilità ipotalamica della secrezione di LHRH.

L’ipofisi risponde all’LHRH prima con il rilascio del solo FSH, in seguito tende a prevalere la produzione dell’LH.  L’FSH comincia a stimolare i follicoli primordiali ed induce lo sviluppo dei recettori allo stesso FSH; in presenza degli estrogeni, inoltre, può indurre anche lo sviluppo dei recettori all’LH, coadiuvato da altri ormoni, quali prolattina, corticosteroidi surrenalici e, forse, GH.

Sotto lo stimolo gonadotropinico le ovaie iniziano la loro attività steroidogenetica, rilasciando inizialmente estrogeni, più tardivamente anche progesterone.

Con l’aumento degli estrogeni ed adeguata disponibilità di LHRH a livello ipotalamico, si ha lo sviluppo del feed-back positivo agli estrogeni, responsabile dell’ “LH surge” a metà ciclo.  Anche la prolattina subisce un lieve aumento rispetto ai livelli plasmatici infantili.

Un’ altra modifica riguarda la SHBG (Sex Hormon Binding Globulin), proteina che veicola principalmente estrogeni e testosterone. Durante la pubertà la sua concentrazione plasmatica si riduce lievemente, aumentando così la quota libera, e quindi attiva, di steroidi sessuali.

La sintesi androgenica della corteccia surrenalica sembra avere un ruolo determinante nella progressiva maturazione puberale.  Sembra che gli androgeni surrenalici siano attivatori dei centri ipotalamici dai quali parte l’impulso per l’inizio della pubertà.  Si dosano gli steroidi urinari sulla seconda minzione rapportando i valori ai livelli di creatininuria.

Valutazione dell’attività della 3-ß-deidrogenasi mediante il rapporto Androsterone + Etiocolanolone/DHEA.  Valutazione dell’attività della 21 idrossilasi mediante il rapporto THS + 5-Pregnantriolo/Pregnantriolo.  Valutazione dell’attività della 17-a-idrossilasi mediante il rapporto pregnatriolo/pregnandiolo.

Valutazione dell’attività della 17-20 desmolasi mediante il rapporto Androsterone + Etiocolanolone/Pregnantriolo.

Alcuni AA. (1) hanno dimostrato:

1)  un aumento significativo (p< 0.001) dell’attività della 17-20 desmolasi fra lo stadio T1 e T2 a conferma di uno shift enzimatico surrenalico in favore della produzione di androgeni.

2)  DHEA presente in quantità minima e rappresenta il 50-70% di tutti i 17-K-steroidi presenti nel plasma. Maggiormente rappresentati sono l’androsterone e l’etiocolanolone.

 La relazione fra altezza e menarca sembra essere notevole anche se non tale da definire un’altezza “critica”. In uno stadio immediatamente prepuberale notiamo un aumento significativo dell’altezza in concomitanza all’aumento sia degli androgeni che dei corticosteroidi. Così pure molta importanza sembra attribuirsi alla presenza di una massa grassa “critica” al di sotto della quale non scatta il “grilletto” della pubertà (2).

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  46. Mesiano S, Jaffe RB. Neuroendocrine-metabolic regulation of pregnancy. In: Strauss JF 3rd, Barbieri RL, editors. Reproductive Endocrinology. 5th ed. Philadelphia: WB Saunders; 2004. pp. 327–66.
  47. Diczfalusy E. Endocrine functions of the human fetoplacental unit. 1964. Am J Obstet Gynecol. 2005;193:2024.
  48. Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB. Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus. J Clin Endocrinol Metab. 1997;82:3509–12. 
  49. Couse JF, Korach KS. Estrogen receptor null mice: What have we learned and where will they lead us? Endocr Rev. 1999;20:358–417. 
  50. Garcia-Falgueras A, Pinos H, Collado P, Pasaro E, Fernandez R, Jordan CL, et al. The role of the androgen receptor in CNS masculinization. Brain Res. 2005;1035:13–23.
  51. Naftolin F, Brawer JR. The effect of estrogens on hypothalamic structure and function. Am J Obstet Gynecol. 1978;132:758–65. 
  52. Colciago A, Negri-Cesi P, Pravettoni A, Mornati O, Casati L, Celotti F. Prenatal Aroclor 1254 exposure and brain sexual differentiation: Effect on the expression of testosterone metabolizing enzymes and androgen receptors in the hypothalamus of male and female rats. Reprod Toxicol. 2006;22:738–45.
  53. Honour JW   17-Hydroxyprogesterone in children, adolescents and adults. Ann Clin Biochem. 2014 Jul;51(Pt 4):424-40.
  54. ughes IA, Winter JS: The application of a serum 17OH-progesterone radioimmunoassay to the diagnosis and management of congenital adrenal hyperplasia. J Pediatr 1976;88:766-773.
  55. Speiser PW, White PC: Congenital adrenal hyperplasia. N Engl J Med 2003;349:776-788.
  56. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC, Endocrine Society: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:4133-4160.
  57. Makela SK, Ellis G: Nonspecificity of a direct 17 alpha-hydroxyprogesterone radioimmunoassay kit when used with samples from neonates. Clin Chem 1988;34:2070-2075.
  58. Lee A, Ellis G: Serum 17 alpha-hydroxyprogesterone in infants and children as measured by a direct radioimmunoassay kit. Clin Biochem 1991;24:505-511.
  59. Ballerini MG, Chiesa A, Scaglia P, Gruñeiro-Papendieck L, Heinrich JJ, Ropelato MG: 17Alpha-hydroxyprogesterone and cortisol serum levels in neonates and young children: influence of age, gestational age, gender and methodological procedures. J Pediatr Endocrinol Metab 2010;23:121-132.
  60. Sippell WG, Dörr HG, Bidlingmaier F, Knorr D: Plasma levels of aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, cortisol, and cortisone during infancy and childhood. Pediatr Res 1980;14:39-46.
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    and 17-hydroxyprogesterone levels in congenital adrenal hyperplasia. J Clin Endocrinol Metab 1983;57:1150–1154.
  62. Sippell WG, Becker H, Versmold HT, Bidlingmaier F, Knorr D: Longitudinal studies of plasma aldosterone, corticosterone, deoxycorticosterone, progesterone, 17-hydroxyprogesterone, cortisol, and cortisone determined simultaneously in mother and child at birth and during the early neonatal period. I. Spontaneous delivery. J Clin Endocrinol Metab 1978;46:971–985.


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