Endocrinologia

Senescenza ovarica precoce (POF, Premature Ovarian Failure)

Hits: 2257

  Definizione: il termine menopausa deriva dal greco “μήν μηνός” (mese) e “παὒσις” (cessazione) e indica appunto la fine del ciclo mestruale e dell’età fertile della donna. Dall’epoca dei Greci e dei Romani le donne vanno in menopausa all’età di 51 anni circa.  La menopausa precoce è la cessazione delle mestruazioni, con il suo corredo sintomatologico ed endocrino-metabolico,  prima dei 40 anni di età (1).  Fuller Albright et al. nel 1942 per primi riportarono il caso di una giovane donna affetta da tale sindrome. Escluse le cause chirurgiche, la menopausa precoce è dovuta a un esaurimento ovarico precoce (POF, Premature Ovarian Failure) con cui si identifica. Alla pubertà le ovaie possiedono circa 400.000 follicoli sufficienti per 400 ovulazioni cioè per 40 anni circa di vita fertile.  Indipendentemente dall’etiologia, la POF si evidenzia con amenorrea secondaria, sintomatologia vasomotoria da deprivazione estrogenica, elevati livelli di FSH ed LH e depressione dei livelli sierici di estradiolo, β-Inibina e AMH in correlazione con la diminuzione e arresto della funzionalità follicolare. Nelle fasi iniziali è presente una residua funzionalità ovarica con episodiche ovulazioni e mestruazioni anche in presenza delle citate anormalità endocrine (2,3).

Frequenza:

Interessa circa l’1-4% della popolazione mondiale (3-4).

Etiologia:
1. Idiopatica: le cause non sono identificabili nonostante ricerche mirate; comprende la quasi totalità dei casi (42).
2. Difetti genetici del cromosoma X: (S. Turner 45,X e turneriane, S. X fragile) con conseguente perdita dell’enzima 17-α-idrossilasi, enzima che converte il testosterone in estradiolo e l’androstenedione in estrone (43).

3. patologia ovarica autoimmune che causa distruzione del patrimonio follicolare ovarico (46-48) e può essere distinta in:
• Auto-anticorpi anti-ovaio (53)
• Auto-anticorpi verso i recettori ovarici delle gonadotropine
Sindrome polighiandolare autoimmune

4. Patologia ovarica iatrogena:
• chemioterapia: gli ovociti sono molto sensibili all’azione dei chemioterapici. Ogni mese di chemioterapia comporta una riduzione di 18 mesi di vita fertile.
• terapia radiante pelvica o “total body”
• terapia chirurgica: resezione cuneiforme eccessiva, cistectomia con eccessiva asportazione del parenchima ovarico, ovariectomia.
• virus della parotite epidemica: l’infiammazione delle gonadi se cronicizza provoca ne provoca la perdita della funzionalità.

5. Difetti enzimatici:
Galattosemia: l’incapacità di metabolizzare il galattosio è responsabile dell’insorgenza della POF presente nell’81% delle pazienti affette da galattosemia (49, 50).

. Deficit di aromatasi (52)
 6.Talassemia major ed emocromatosi conseguente a scarso utilizzo del ferro da deficit di sintesi dell’eme o da eccessivo accumulo di ferro dopo trasfusioni. L’emocromatosi è molto più frequente negli uomini che nelle donne, ma in menopausa la differenza fra i due sessi si annulla per la cessazione delle mestruazioni, gravidanze e allattamenti. L’accumulo di ferro a livello gonadico induce disfunzionalità ovarica (come anche per tiroide, pancreas, fegato, cuore e cervello) e quindi ipogonadismo.
 7. Post-abortiva: Flamigni riporta tre casi di ovaio resistente, insorti dopo aborto spontaneo e regrediti spontaneamente e che hanno avuto gravidanze spontanee e mette in guardia dal fare prognosi negative senza prima avere effettuato una biopsia ovarica.
 8. Stress psico-fisici
 9. Varianti del gene della α-inibina (4)
 10. TBC dell’apparato genitale: l’infiammazione delle gonadi se cronicizzata è responsabile della perdita di funzionalità delle gonadi.
11) Prolungata terapia con Gn-RH
12. COH ripetute per metodica PMA
13. Anomalie strutturali delle gonadotropine (44-45)

14. FSH-r (recettori del FSH): Il genotipo del recettore dell’FSH svolge un ruolo importante nel determinare la risposta ovarica ad una stimolazione con l’ormone FSH. Sono stati finora evidenziati 2 anomalie strutturali dei recettori del FSH: i polimorfismi Asn680Ser e Thr307Ala. si tratta di polimorfismi a singolo nucleotide localizzati a livello dell’esone 10 del gene FSHR (45).  

– il polimorfismo Asn680Ser, determinato da una variazione nucleotidica A→G in posizione 2039, che produce una variazione aminoacidica da Asn a Ser in posizione 680;

Polimorfismo Thr307Ala, determinato da una variazione nucleotidica A→G in posizione 919, che produce una variazione aminoacidica da Thr ad Ala in posizione 307.

I suddetti polimorfismi sono tra loro in cosiddetto linkage disequilibrium, cioè a Ser680 è associata anche 307Ala, rendendo molto frequenti due combinazioni alleliche delle quattro possibili: Thr307”“Asn680 e Ala307”“Ser680.

Diversi studi hanno associato la variante Ser680 ad una ridotta risposta alla stimolazione ovarica a seguito di somministrazione di FSH, dovuta ad una parziale resistenza del recettore all’ormone (39). Quindi le pazienti che presentano la variante Ser680 richiedono un dosaggio maggiore di FSH ricombinante per produrre una crescita follicolare ottimale ed un’adeguata concentrazione sierica di Estradiolo. Infatti, il numero medio di fiale di FSH somministrate per ottenere una stimolazione efficace è risultato più alto nelle pazienti di genotipo Ser/Ser che nelle pazienti Asn/Ser o Asn/Asn. La variante Ser680, influenzerebbe anche i livelli sierici di Estradiolo, ridotti nelle pazienti Ser/Ser, per cui le pazienti con genotipo Asn/Asn, ottenendo dei valori di estradiolo più elevati, potrebbero presentare un rischio maggiore di OHSS, sebbene questa ipotesi è tuttora controversa. Alcuni autori hanno inoltre riscontrato una maggiore frequenza dell’allele Asn680 in forme gravi di OHSS, suggerendo che il polimorfismo Asn680Ser possa rappresentare un marker predittivo sulla gravità dei sintomi in casi di OHSS, in quanto i soggetti Asn680 sarebbero più suscettibili a forme gravi di OHSS.

Inoltre, nelle pazienti con ciclo mestruale normale e genotipo Ser/Ser, sono stati riscontrati valori basali di FSH significativamente più alti che nei genotipi Asn/Ser e Asn/Asn. Ciò viene spiegato con il fatto che la variante Ser/Ser del recettore dell’FSH è meno sensibile all’azione dell’FSH, e che i maggiori livelli basali di FSH costituiscono una naturale compensazione dell’organismo per determinare una normale crescita follicolare.

L’analisi del genotipo del recettore dell’FSH permette di modulare in maniera individuale la somministrazione di FSH e quindi di aumentare l’efficacia e la sicurezza della terapia. Infatti, le pazienti con un genotipo “low-responder” devono essere stimolate utilizzando un dosaggio di FSH 1.5 volte maggiore rispetto al gruppo con genotipo “high-responder”. Probabilmente questo dosaggio potrebbe essere eccessivo per il gruppo “high-responder”, e viceversa, il dosaggio ideale per questo gruppo potrebbe non risultare efficace per il gruppo “low-responder”.

 15. Fumo: le donne fumatrici sono a rischio di menopusa precoce. Sono alcune sostanze chimiche, i cosiddetti idrocarburi aromatici policiclici (PAHs) principalmente contenuti nel fumo di sigarette, che, dopo essersi legate a un particolare recettore (Ahr), attivano un gene (Bax) in grado di arrecare disturbi alla gametogenesi (39).
16. Inquinamento ambientale: emissioni di fossil fuel, alcuni tipi di scarichi industriali e solventi contenenti 2-bromopropane possono provocare menopausa precoce non per mancanza di follicoli ma per alterazione della loro funzionalità o per alterazione dei siti recettoriali ovarici per le gonadotropine.

17. Alcoolismo, Disordini alimentari, BMI <20 e BMI >35: il consumo di alcool danneggia il fegato e conseguentemente diminuisce la secrezione di SHBG  con aumento dei livelli sierici di androgeni liberi. 

18. Bassa statura

Sintomatologia:

Amenorrea secondaria
Metrorragie e menometrorragie
Sindrome pre-mestruale
Disturbi vasomotori
Osteoporosi e artrosi (5)
Tachiaritmie
Insonnia
Depressione
Secchezza cutanea e delle mucose
Secchezza vaginale
Diminuzione della libido e alopecia (6-8)

Astenia, perdita di tono muscolare, perdita di concentrazione e di memoria a causa della diminuzione dei livelli sierici di DHEA
Aumentato rischio di patologia cardiaca, tiroidite di Hashimoto, m. di Addison e malattie autoimmuni: tiroiditi autoimmuni, Sindrome polighiandolare di I e II tipo, ipoparatiroidismo, artrite reumatoide, diabete IDDM, anemia perniciosa, porpora trombocitopenica idiopatica, vitiligine, lupus sistemico eritematoso, M.  di Addison).
Disfunzioni vescicali
Diabete mellito tipo II
Ipoparatiroidismo
Artrite reumatoide
Anemia perniciosa
Vitiligine
Lupus sistemico eritematoso (SLE)

Diagnostica:

  • AMH (Anti Mϋllerian Hormone) glicoproteina secreta dai follicoli primari e dai piccoli follicoli pre-antrali (<2 mm). Mostra una correlazione inversa a quella dell’FSH. I suoi valori sierici nelle donne in età fertile hanno valori costanti fra un ciclo e l’altro e  indipendenti dal giorno del ciclo. L’AMH presenta un decremento lineare con l’avanzare dell’età. Il suo decremento è più precoce ed affidabile come POF-marker rispetto a tutti i markers appresso descritti  (9). Valori sierici di AMH <1 ng/ml sono da riferire a ridotta riserva ovarica (29-32) e valori <0.5 ng/ml indicano una riduzione del 90% circa della riserva ovarica (33).
  • β-inibina:  glicoproteina prodotta dai follicoli pre-antrali, diminuisce in menopausa.. Valori normali oscillano fra 50 e 150 pg/ml. Il suo ruolo è quello di esercitare un feed-back negativo sulla produzione di FSH. Mostra, come l’AMH, una correlazione inversa a quella dell’FSH (9). Concentrazioni basali (3° giorno) sieriche <45 pg/ml corrispondono ad un   Pregnancy Rate del 28%; mentre concentrazioni  >45 pg/ml fanno prevedere un PR del 95%. Attualmente la sua significatività come test di screening per la diagnosi di POF è messa in dubbio dall’evidente variabilità dimostrata da un ciclo all’altro e quindi alla beta inibina è preferito l’AMH (10,11).
  • FSH: in 3a giornata, v.n. 2-6 mUI/ml. Aumenta in caso di POF. La secrezione di FSH è inibita dalla beta inibina e dall’estradiolo. Valori sierici in terza giornata >10 mUI/ml (v.n. 2-6 mUI/ml) indicano una senescenza ovarica precoce (25).  Come per la beta inibina, una delle principali limitazioni nell’impiego routinario del dosaggio di FSH basale ai fini della valutazione della riserva ovarica è però  costituita dalla sua estrema variabilità  spesso tra un ciclo e l’altro in quanto la secrezione di tale ormone da parte dell’ipofisi può essere  influenzata da vari fattori (26-28)
  • E2:  diminuisce in caso di POF. Valori sierici <30 pg/ml indicano una scarsa riserva ovarica; valori sierici di E2 <20 pg/ml indicano un totale esaurimento dell’attività follicolare ed una produzione di estradiolo in modo residuale; valori di E2 >50 pg/ml indicano la presenza di attività follicolare.
  • SHBG (Sex Hormone Binding Globuline): diminuisce in caso di POF. E’ sintetizzata a livello epatico, nella donna fertile i valori sierici normali sono 40-120 nmol/l. La sua sintesi è inibita da diete ipercaloriche ed iperlipidiche, ipotiroidismo, alti livelli di insulina, IGF-1 e androgeni ed invece stimolata da tiroxina, ipertiroidismo, Growth Hormone, estrogeni ed epatopatie. In pazienti In menopausa e POF diminuiscono nettamente al di sotto di 20 nmol/l. Una diminuzione significativa dell’SHBG comporta un aumento significativo dell’attività androgenica periferica (acne, virilismo, PCOS) ed una diminuzione dell’attività ovarica.
  • DHEA:  ormone prodotto dal surrene. Presenta valori sierici di   3-8 ng/ml  e  diminuisce in caso di POF. Valori sierici <3 ng/ml indicano uno stato di insufficienza ovarica
  • Testosterone totale, free T (12)
  • Clomifene Challenge test: dosaggio dei valori sierici  di FSH al 3° giorno del ciclo; somministrazione di 100 mg di clomifene dal 5° al 9° giorno del ciclo; dosaggio FSH al 10° giorno. Il clomifene stimola la produzione di FSH chee la crescita multifollicolare, la secrezione di estradiolo e l’aumento della beta inibina; nelle donne fertili l’innalzamento della beta inibina provoca riabbassamento dei livelli sierici di FSH mentre nelle donne con ridotta riserva ovarica si ha un innalzamento della secrezione di FSH a cui però non segue una buona stimolazione ovarica, una buona secrezione di beta inibina e quindi i livelli di FSH restano alti (34-36).  
  • Conta dei follicoli antrali: conta dei piccoli follicoli (2-10 mm) dotati di liquido follicolare effettuata con sonda endovaginale al 3-5° giorno del ciclo. La presenza di un ridotto numero di follicoli antrali (tra 3 e 10 in totale nelle due ovaie) sarebbe, secondo alcuni studi, associata ad una scarsa risposta ovarica alla stimolazione ed ad una bassa probabilità di gravidanza (37). Al riguardo uno studio di Holte e coll. (38) ha evidenziato una correlazione lineare tra il numero di follicoli antrali e le percentuali di gravidanza ottenute in pazienti  sottoposte a fecondazione in vitro con percentuali comprese tra 0 e 15% nelle pazienti con una conta dei follicoli antrali compresa tra 0 e 5, pari al 16-25% nelle pazienti con conta tra 6 e 11, pari al 26-35% nelle  pazienti con conta tra 12 e 23 e maggiore del 35% nelle pazienti con conta totale dei follicoli antrali >23.
  • Volume ovarico: l’eccessiva variabilità dei risultati in rapporto ai diversi operatori, nonché la scarsa specificità rilevata nel complesso, sembrerebbero indicare uno scarso peso di tale marker nella valutazione della riserva ovarica. L’ovaio appare “shriveled”, “avvizzito”, “accartocciato”.

 

POF e FERTILITA’: la possibilità di gravidanza spontanea in tale stato è <10%. E’ possibile una ripresa sporadica spontanea dei cicli ovulatori senza alcuna terapia. Con maggiori probabilità si può avere una  ripresa transitoria di ovulazione e cicli ovulatori dopo sospensione della terapia sostitutiva estrogenica o estro-progestinica. E’ possibile indurre ovulazione (19%) mediante l’impiego di una sequenza estrogeni/HMG. Il numero di recettori ovarici per le  gonadotropine  condiziona ovviamente la risposta ovarica.  Il numero  dei  recettori per l’FSH è incrementato dagli estrogeni  mentre  il numero dei recettori per l’LH è incrementato dall’FSH. Terapia sostitutiva estrogenica transdermica iniziando con 50 mcg fino a livelli di LH prossimo allo 0; Stimolazione con HMG 150 UI al dì aumentando dopo 5 gg se necessario, ma continuando l’estrogeno-terapia fino a ovulazione perché i livelli delle gonadotropine tendono a risalire immediatamente dopo la sospensione  dell’estrogeno-terapia. Check e al.  (Fert.  Steril. maggio 1990) hanno ottenuto 8 gravidanze/100 pazienti sempre dopo innalzamento del livello sierico di E2, anche se i livelli delle gonadotropine erano alti, 68 ovulazioni/361 (16%) cicli di terapia (40).  In caso di  insuccesso somministrare progestinico 10 mg per 10 gg in modo da provocare il flusso mestruale.  Rinunciare in caso di anovulazione dopo 6 cicli di terapia. Se la soppressione veniva effettuata con analoghi  analoghi non si avevano gravidanze. Non si sono notate differenze relativamente al fattore età. La  supplementazione va effettuata con progesterone micronizzato os/vaginale o intramuscolare. Alto è il tasso di abortività probabilmente dovuto all’azione sull’endometrio degli alti livelli di estrogeni somministrati nella la fase di soppressione  oppure per LDP nonostante  la supplementazione con Progesterone. I migliori risultati si ottengono quando c’é un rialzo spontaneo dell’E2 endogeno perché significa che l’ovaio inizia a maturare autonomamente e l’HMG contribuisce alla maturazione (13,14).

Terapia:
 

  1. Pillola contraccettiva: Nelle forme iniziali si possono somministrare estro-progestinici combinati presenti nella pillola contraccettiva. Proteggono da gravidanze indesiderate, attenuano la sintomatologia da deprivazione estrogenica e inducono flussi mestruali ritmici.
  2. HRT combinata sequenziale non continua in dosi superiori a quelle per le donne in climaterio ordinario: se non ci sono controindicazione come l’ipertensione arteriosa, il diabete mellito, trombofilia ereditaria, flebiti, varicosità degli arti inferiori , epatopatie e nelle fumatrici con età >35 anni. La via transdermica è da preferire perché bypassa il circolo epatico.  Progesterone dal 15-18° al 24° giorno del ciclo: per modulare i casi di meno metrorragia.
  3. DHEA (DHEA cpr 25 mg Puritans Pride, Prastera cpr, Prasterone cpr, Fidelin cpr, Fluasterone cpr) a bassi dosaggi (25 mg x 3 volte al dì fino a 100 mg nelle donne obese per almeno 2 mesi e fino a β-HCG positivo): può indurre ovulazioni spontanee, gravidanze e combatte l’astenia, l’ipotonia muscolare, la diminuzione della libido e migliora il tono dell’umore (13-19). Il meccanismo d’azione sembra estrinsecarsi attraverso un aumento del free insulin-like growth factor I e un decremento delle HDL (20). La supplementazione con DHA riduce il tasso di aborti probabilmente mediante riduzione delle aneuploidie soprattutto nelle pazienti con età >35 anni (21). Il DHA sembra efficace per migliorare l’outcome ovulatorio e gravidico in tutte le pazienti sottoposte a tecniche PMA per infertilità (15).
  4. Cortisonici: Nelle forme autoimmuni la terapia immunosoppressiva corticosteroidea é di scarso ausilio ai fini del ripristino della fertilità (41, 51).
  5. FIV/ICSI + ET con ovodonazione: in caso di fallimento della COH
  6. Crioconservazione del tessuto ovarico: può essere utilizzato nelle giovani donne a rischio di POF.
  7. Testosterone: a piccole dosi per le stesse indicazioni della somministrazione di DHA e solo in caso che non si desiderano gravidanze.
  8. SSRI (Selective Serotonin Reuptake Inhibitors): farmaci antidepressivi utilizzati per la terapia dell’ansia, depressione ed alcuni casi di insonnia. Agiscono inibendo il reuptake della serotonina (detta anche 5-idrossi-triptamina, 5-HT) nelle cellule pre-sinaptiche e quindi aumentando la quantità di serotonina disponibile per i recettori post-sinaptici.Inibiscono anche il reuptake della dopamina e della nor-epinefrina. Tra i più noti farmaci in commercio ricordiamo la fluoxetina (Prozac©), la paroxetina (Daparox©).
  9. Attività fisica aerobica: 30 minuti/die di alta attività aerobica e esercizi di allungamento muscolare  aumenta i livelli sierici di HDL colesterolo, aumenta il livello di beta endorfine e previene e riduce l’obesità.
  10. Controllo del peso (BMI 20-24), attività fisica aerobica, moderazione nel consumo di alcool e caffè, dieta bilanciata da 1.500-1700 KCal circa ricca di fibre e frutta fresca, privilegiando il consumo di pesce azzurro per la quota proteica.
  11. Gn-RH-a: in caso di chemioterapia per preservare la funzionalità ovarica (54). Si somministra i.m. l’analogo del Gn-RH 3.75 mg in forma depot (Decapeptyl® depot fl 365 mg, Enantone® 365 mg fl) ogni 28 giorni iniziando una settimana prima della chemioterapia e durante tutta la chemioterapia.   L’incidenza della menopausa precoce nel gruppo triptorelina era del 8.9% vs. 25.9% del gruppo non trattato con analoghi.
Queste  pagine fanno parte del sito www.fertilitycenter.it  in internet da marzo 2011. I testi, le tabelle, i disegni e le immagini pubblicati in queste pagine sono coperte da copyright ma a disposizione di tutti per copia e riproduzione purchè venga citata la fonte con Link al sito www.fertilitycenter.it.

References:

  1. Beck-Peccoz P, Persani L (2006). “Premature ovarian failure”. Orphanet J Rare Dis 1: 9. doi:10.1186/1750-1172-1-9.
  2. Buckler HM J Clin Endocrinol Metabol 72:116-124, 1991.
  3. Speroff L, Fritz MA (2005). Clinical Gynecologic Endocrinology and Infertility (7th ed.). Philadelphia PA: Lippincott Williams & Wilkins.
  4. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol., 1986; 67: 604-6
  5. Prakash, G. J.; Ravi Kanth, V. V.; Shelling, A. N.; Rozati, R.; Sujatha, M. (2010). “Mutational analysis of inhibin alpha gene revealed three novel variations in Indian women with premature ovarian failure”. Fertility and Sterility 94 (1): 90. doi:10.1016/j.fertnstert.2009.02.014. PMID 19324345
  6. Graziottin A.: “Sexuality, aging and chronic diseases: iatrogenic premature menopause in cancer survivors“. Schneider H.P.G (Ed.), Menopause: state of the art, Parthenon Publishing, London, pag. 408-415, 2003
  7. Dennerstein L. Koochaki P.E. Barton I. Graziottin A.: “Hypoactive sexual desire disorder in menopausal women: a survey of western european women“. The Journal of Sexual Medicine 2006; 3: 212-222
  8. Graziottin A. Leiblum S.R.: “Biological and Psychosocial Pathophysiology of Female Sexual Dysfunction During the Menopausal Transition“. The Journal of Sexual Medicine 2005; 2 (suppl. 3): 133-145
  9. Burger H.G. Hale G.E. Dennerstein L. Robertson: “Cycle and hormone changes during perimenopause: the key role of ovarian fu
  10. McIlveen M, Skull JD, Ledger WL. Evaluation of the utility of multiple endocrine and ultrasound measures of ovarian reserve in the prediction of cycle cancellation in a high-risk IVF population. Hum Reprod 2007;22:778-85.
  11. Muttukrishna S, McGarrigle H, Wakim R, Khadum I, Ranieri DM, Serhal P. Antral follicle count, anti-mullerian hormone and inhibin B: predictors of ovarian response in assisted  reproductive technology? Bjog 2005;112:1384-90nction“. Menopause, 2008 Jul-Aug; 15 (4 Pt 1): 603-12
  12. 11) De-Hua Cheng, Yue-Qiu Tan, Yu-Fen Di, Lu-Yun Li, Guang-Xiu Lu: “Crypt Y chromosome fragment resulting from an X;Y translocation in a patient with premature ovarian failure” Fertil Steril 2009; 92,2: 826-828
  13. Lumenfeld Z, Halachmi S, Peretz BA, et al. (April 1993). “Premature ovarian failure—the prognostic application of autoimmunity on conception after ovulation induction”. Fertil. Steril. 59 (4): 750–5. PMID 8458491.
  14. Blumenfeld Z (September 2007). “Pregnancies in patients with POF gonadotropin stimulation and pretreatment with ethinyl estradiol”. Fertil. Steril. 88 (3): 763; author reply 763. doi:10.1016/j.fertnstert.2007.07.001. PMID 17681336. http://linkinghub.elsevier.com/retrieve/pii/S0015-0282(07)01458-6.
  15. Gleicher N, Weghofer A, Barad DH (2010). “Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS)”. Reprod. Biol. Endocrinol. 8: 140. doi:10.1186/1477-7827-8-140. PMC 2992540. PMID 21067609. http://www.rbej.com/content/8//140.
  16. “DHEA: Treatment for Women with POA and POF”
  17. Casson PR, Linday MS, Pisarska MD, Carson SA, Buster JE: “Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod 2000, 15:2129-2132.
  18. Barad DH, Gleicher N: “Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril 2005,84:756.e1-3.
  19. Barad D, Gleicher N: “Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod 2006, 21:2845-2949.
  20. Barad D, Brill H, Gleicher N: Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. J Assist Reprod Genet 2007, 24:629-634.
  21. Casson PR, Santoro N, Elkind-Hirsch K, Carson SA, Hornsby PJ, Abraham G, Buster JE: “Postmenopausal dehyroepiandrosterone administration increases free insulin-like growth factor I and decreases high-density lipoprotein: a six-month trial”. Fertil Steril 1998, 70:107-110.
  22. N. Gleicher, E. Ryan3, A. Weghofer, S. Blanco-Mejia and D H Barad : “Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study”. Reproductive Biology and Endocrinology 2009, 7:108
  23. Jadoul, P.; Dolmans, M. -M; Donnez, J. (2010). “Fertility preservation in girls during childhood: is it feasible, efficient and safe and to whom should it be proposed?”. Human Reproduction Update 16 (6): 617. doi:10.1093/humupd/dmq010. PMID 20462941.edit
  24. Jan W. van der Steeg, Pieternel Steures, Marinus J. C. Eijkemans, J. Dik F. Habbema, Peter G. A. Hompes, Frank J. Broekmans, Peter X. J. M. Bouckaert, Patrick M. M. Bossuyt, Fulco van der Veen, and Ben W. J. Mol, on behalf of the Collaborative Effort for Clinical Evaluation in Reproductive Medicine (CECERM) Study Group: “Predictive Value and Clinical Impact of Basal Follicle- Stimulating Hormone in Subfertile, Ovulatory Women”.  (J Clin Endocrinol Metab 92: 2163–2168, 2007)
  25. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB.: “A systematic review of tests predicting ovarian reserve and IVF outcome”. Hum Reprod Update 2006;12:685-718.
  26. Bancsi LF, Broekmans FJ, Mol BW, Habbema JD, te Velde ER.: “Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become  pregnant after in vitro fertilization: a meta-analysis”. Fertil Steril 2003;79:1091-100.
  27. Jain T, Soules MR, Collins JA.: “Comparison of basal follicle-stimulating hormone versus the clomiphene citrate challenge test for ovarian reserve screening”. Fertil Steril 2004;82:180-5
  28. Muttukrishna S, McGarrigle H, Wakim R, Khadum I, Ranieri DM, Serhal P.: ” Antral follicle count, anti-mullerian hormone and inhibin B: predictors of ovarian response in assisted  reproductive technology?”.  Bjog 2005;112:1384-90.
  29. Ebner T, Sommergruber M, Moser M, Shebl O, Schreier-Lechner E, Tews G.: “Basal level of anti-Mullerian hormone is associated with oocyte quality in stimulated cycles”. Hum Reprod 2006;21:2022-6.
  30. Min Hye Choi, Ji Hee Yoo, Hye Ok Kim, Sun Hwa Cha, Chan Woo Park, Kwang Moon Yang, In Ok Song, Mi Kyoung Koong, Inn Soo Kang.: “Serum anti-Müllerian hormone levels as a predictor of the ovarian response and IVF outcomes”.  Clin Exp Reprod Med 2011;38(3):153-158
  31. Blazar AS, Lambert-Messerlian G, Hackett R, et al.:”Use of in-cycle antimüllerian hormone levels to predict cycle outcome”. Am J Obstet Gynecol, 2011;205:223.
  32. Gnoth C, Shuring AN, Frid K, Tigger J.: “Relevance of AMH measurement in a routine IVF program”. Hum Reprod, 2008;23:1359–65.
  33. Hannoun A, Abu Musa A, Awwad J, Kaspar H, Khalil A. Clomiphene citrate challenge test: cycle to cycle variability of cycle day 10 follicle stimulating hormone level. Clin Exp Obstet Gynecol 1998;25:155-6.
  34. Hendriks DJ, Broekmans FJ, Bancsi LF, de Jong FH, Looman CW, Te Velde ER. Repeated clomiphene citrate challenge testing in the prediction of outcome in IVF: a comparison with basal markers for ovarian reserve. Hum Reprod 2005;20:163-9.
  35. Hendriks DJ, Mol BW, Bancsi LF, te Velde ER, Broekmans FJ. The clomiphene citrate challenge test for the prediction of poor ovarian response and nonpregnancy in patients undergoing in vitro fertilization: a systematic review. Fertil Steril 2006;86:807-18
  36. Hendriks DJ, Mol BW, Bancsi LF, Te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal follicle-stimulating hormone level. Fertil Steril 2005;83:291-301. 54.
  37. Jan holte, Thomas Brodin, Lars Berglund, Nermin Hadziosmanovic, Matts Olovsson, Torbjorn Bergh. Antral follicle counts are strongly associated with live-birth rates after assisted reproduction, with superior treatment outcome in women with polycystic ovaries. Fertil Steril, 2011; 96: 594-9
  38. Sun L, Tan L, Yang F, Luo Y, Li X, Deng HW, Dvornyk V: “Meta-analysis suggests that smoking is associated with an increased risk of early natural menopause”.  Menopause. 2011 Sep 19. [Epub ahead of print]
  39. Aittomaki K, Herva R,Stenmann UH, Juntunen K, Ylostalo P, Hovatta O et al. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J Clin Endocrinol Metab, 1996; 81: 3722-6
  40. Check JH, Nowroozi K, Chase JS, Nazari A, Shapse D, Vaze M. Ovulation induction and pregnancies in 100 consecutive women with hypergonadotropic amenorrhea. Fertil Steril., 1990; 53: 811-6
  41. Corenblum B, Rowe T, Taylor PJ. High-dose, short-term glucocorticoids for the treatment of infertility resulting from premature ovarian failure. Fertil Steril., 1993; 59: 988-91
  42. Conway GS, Kaltsas G, Patel A, Davies MC, Jacobs HS. Characterization of idiopathic premature ovarian failure. Fertil Steril, 1996; 65: 337-41
  43. Devi AS, Metzger DA, Luciano AA, Benn PA. 45,X/46,XX mosaicism in patients with idiopathic premature ovarian failure. Fertil Steril., 1998; 70 (1): 89-93
  44. Goldenberg RL, Grodin RL, Rodbard D, Ross GT. Gonadotropins in women with amenorrhea. Am J Obstet Gynecol., 1973; 116: 1003-9
  45. Huhtaniemi IT, Aittomaki K. Mutations of follicle-stimulating hormone and its receptor; effects on gonadal function. Eur J Endocrinol., 1998; 138: 473-481
  46. Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr Rev, 1997; 18: 107-34
  47. La Barbera Ar, Miller MM, Ober C, Rebar RW. Autoimmune etiology in premature ovarian failure. Am J Reprod Immunol., 1988; 16: 115-22
  48. Sedmak DD, Hart WR, Tubbs RR. Autoimmune oophoritis: a histopathologic study of involved ovaries with immunologic characterization of the mononuclear cell infiltrate. Int J Gynecol Pathol, 1987; 6: 73-81
  49. HL, Driscoll SG, Porensky RS, Wender DF. Ovarian Failure in galactosemia. N Engl J Med., 1984; 310-50
  50. Waggoner DD, Buist NRM, Donnel GN. Long-term prognosis in galactosemia: results of a survey of 350 cases. J Inherit Metab Dis., 1990; 13: 802-18.
  51. Van Kasteren YM, Braat DDM, Hemrika DJ, Lambalk CB, Rekers-Mombarg LTM, Von Blomberg BME, Rekers-Mombarg LTM, Von Blomberg BME, Schoemaker JS. Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with premature ovarian failure: a randomized, placebo-controlled trial. Fertil Steril., 1999; 71: 90-95
  52. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab, 1995; 80: 3689-98
  53. Wheatcroft MJ, Toogood AA, Li TC, Cooke ID, Weetman AP. Detection of antibodies to ovarian antigens in women with premature ovarian failure. Clin Exp Immunol., 1994; 96: 122-8
  54. L Del Mastro, L Boni, A Michelotti, et al.. “Effect of the Gonadotropin-Releasing Hormone Analogue Triptorelin on the Occurrence of Chemotherapy-Induced Early Menopause in Premenopausal Women With Breast CancerA Randomized TrialFREE”. JAMA. 2011; 306 (3) :269-276. doi: 10.1001/jama.2011.991.


171 Comments

  1. Thank you for sharing, I would often to this site to read the information.

  2. Thank you for the information you posted in this article. It was really useful to me.

  3. An article or, thank you for giving me more information

  4. I just like the valuable infoгmation you supply
    on your articles. I will booκmark your ωeblog and takе а look at again here
    regulaгly. I’m moԁerately sure I’ll be told manу new stuff prοpeг here!
    Best of luck for the following!

  5. Hello! This is kind of off topic but I need some guidance from an established blog.
    Is it difficult to set up your own blog? I’m not very techincal but I can figure things out pretty quick.
    I’m thinking about setting up my own but I’m not sure where to begin.
    Do you have any ideas or suggestions? Many thanks

  6. Fastidious answer back in return of this issue with firm arguments and describing the
    whole thing concerning that.

  7. Lots of of quests and items await you at the show, together with very rare heroes that everyone desires, after all.

  8. Today, I went to the beachfront with my children. I found a sea shell and gave it to my 4 year old daughter and said “You can hear the ocean if you put this to your ear.” She placed the shell to her ear and screamed.

    There was a hermit crab inside and it pinched her ear.
    She never wants to go back! LoL I know this is completely
    off topic but I had to tell someone!

  9. Wow, this piece of writing is good, my younger
    sister is analyzing these things, thus I am going to tell her.

  10. Hi, I do believe this is a great site. I stumbledupon it
    😉 I may revisit yet again since i have book-marked it.
    Money and freedom is the greatest way to change, may you be rich
    and continue to help other people.

  11. With Sound Forge ready, click on its “Record” button while
    playing the audio file simultaneously on any audio player.
    Would you like to see Cara Delevingne play a prominent role in ‘Darker’.
    And with this exclusive and unique mark, Wellendoff promised to bring high quality
    and exquisite crafted jewelry for customers.

  12. I read this post completely regarding the difference
    of most recent and earlier technologies, it’s amazing article.

  13. I every time emailed this blog post page to all my friends, for the
    reason that if like to read it then my friends will too.

  14. I have been browsing on-line greater than 3 hours lately, yet I never discovered any interesting article like yours.
    It’s lovely price sufficient for me. In my view, if all webmasters and bloggers made good content material
    as you probably did, the internet will probably be a lot
    more useful than ever before.

  15. You’ve made some really good points there. I looked on the net for
    additional information about the issue and found most people will go along with your views on this site.

  16. I know this if off topic but I’m looking into starting my own blog and was wondering what all is required to get set up?
    I’m assuming having a blog like yours would cost a pretty penny?
    I’m not very internet savvy so I’m not 100% sure.
    Any tips or advice would be greatly appreciated. Cheers

  17. Excellent blog you have here.. It’s hard to find good quality writing like yours nowadays.
    I truly appreciate individuals like you!
    Take care!!

  18. xxx

    Hello, for all time i used to check blog posts here
    in the early hours in the daylight, as i enjoy to learn more
    and more.

  19. That is very interesting, You are an excessively skilled blogger.

    I’ve joined your rss feed and stay up for in quest game of war fire age gold
    extra of your magnificent post. Additionally, I’ve shared your web site in my social networks

  20. I think this is among the most important information for me.
    And i’m glad reading your article. But want to remark on some general things, The website style is ideal, the articles is really great : D.
    Good job, cheers

  21. WOW just what I was looking for. Came here by searching for anatomia

  22. It’s going to be finish of mine day, but before ending I am reading this impressive paragraph to increase my know-how.

  23. Excellent post. I used to be checking continuously this blog and I
    am impressed! Extremely helpful info specifically the final part 🙂 I
    maintain such info much. I used to be seeking this certain information for
    a long time. Thanks and good luck.

  24. Wow, wonderful blog format! How long have you ever been blogging for?
    you made blogging look easy. The whole look of your web site is magnificent,
    let alone the content material!

  25. Heya i’m for the first time here. I came across this board and I find It
    really useful & it helped me out a lot. I am hoping to give something again and aid others like you aided me.

  26. This design is incredible! You definitely know how to keep a reader entertained.
    Between your wit and your videos, I was almost moved to start my own blog (well,
    almost…HaHa!) Excellent job. I really enjoyed what you had to
    say, and more than that, how you presented it. Too cool!

  27. I don’t know if it’s just me or if everyone else experiencing problems with your
    blog. It appears like some of the written text in your posts are running off the screen. Can somebody else please
    provide feedback and let me know if this is happening to them as well?
    This might be a issue with my web browser because I’ve had
    this happen previously. Thanks

  28. Wow that was unusual. I just wrote an extremely long comment but after I clicked submit
    my comment didn’t appear. Grrrr… well I’m not
    writing all that over again. Anyway, just wanted to
    say fantastic blog!

  29. hello!,I like your writing so much! proportion we be in contact more approximately your article on AOL?
    I need an expert in this space to resolve my problem. May be that is you!
    Looking forward to look you.

  30. I love looking through a post that will make people think.
    Also, many thanks for permitting me to comment!

  31. Hello There. I found your blog using msn. This is a very well written article.
    I will make sure to bookmark it and come back to read more of your
    useful information. Thanks for the post. I’ll certainly comeback.

  32. You need to be a part of a contest for one of the
    finest sites on the internet. I am going to recommend this site!

  33. Howdy I am so thrilled I found your blog page, I really found you by mistake,
    while I was browsing on Askjeeve for something else, Nonetheless I
    am here now and would just like to say many thanks for a marvelous post and a all round
    enjoyable blog (I also love the theme/design), I don’t have time to look
    over it all at the moment but I have bookmarked it and also added your RSS feeds, so when I have time I will be back to read
    more, Please do keep up the superb job.

  34. It’s not my first time to visit this website, i am browsing this
    site dailly and get nice data from here every day.

  35. Write more, thats all I have to say. Literally, it seems as though you relied on the video to make your point.
    You obviously know what youre talking about,
    why waste your intelligence on just posting videos to your weblog when you could be giving us
    something enlightening to read?

  36. Very good info. Lucky me I recently found your
    site by chance (stumbleupon). I’ve saved as a favorite for later!

  37. Hi there mates, its enormous piece of writing concerning
    teachingand completely defined, keep it up all the time.

  38. Hello my family member! I wish to say that this article is awesome, nice written and include almost all
    important infos. I would like to see extra posts like this .

  39. Thɑnks foг sharing yoսr thoսghts. I trly apprеciate youг efforts and I will
    Ƅe waitіng for yoսr next ost thanks once аgain.

  40. Hey! I’m at work surfing around your blog from my new apple
    iphone! Just wanted to say I love reading through your blog and look forward to all your posts!
    Carry on the outstanding work!

  41. If you are going for best contents like I do, only pay a quick visit this web site all the time
    because it presents feature contents, thanks

  42. Ahaa, its pleasant dialogue regarding this paragraph here at this weblog, I
    have read all that, so now me also commenting here.

  43. I think this is among the most important info for me.

    And i’m glad reading your article. But should remark on few general things, The site style is perfect, the articles is
    really nice : D. Good job, cheers

  44. Wow! In the end I got a website from where I be capable of truly obtain helpful
    data concerning my study and knowledge.

  45. Hey! Do you use Twitter? I’d like to follow you if that would be okay.

    I’m definitely enjoying your blog and look forward to new posts.

  46. Heya i am for the first time here. I came across this board and I find It
    really useful & it helped me out much. I hope to give something back and
    help others like you helped me.

  47. Thanks on your marvelous posting! I seriously enjoyed reading it, you are
    a great author.I will always bookmark your blog and will come back down the road.

    I want to encourage you to definitely continue your great
    writing, have a nice holiday weekend!

  48. Hello there! Do you use Twitter? I’d like to follow you if that would be ok.
    I’m definitely enjoying your blog and look forward to new posts.

  49. Good replies in return of this query with genuine arguments and describing everything concerning that.

  50. Amazing! Its in fact awesome article, I have got much clear idea about from this paragraph.

  51. I am sure this paragraph has touched all the internet visitors, its
    really really pleasant post on building up new webpage.

  52. Wow that was unusual. I just wrote an very long comment but after
    I clicked submit my comment didn’t show up. Grrrr…
    well I’m not writing all that over again. Anyway, just wanted
    to say wonderful blog!

  53. Hi! I know this is sort of off-topic however I had to ask.
    Does managing a well-established blog such as yours take a large amount of work?
    I am completely new to blogging but I do write in my diary everyday.
    I’d like to start a blog so I can easily share my experience and thoughts online.
    Please let me know if you have any kind of recommendations or tips for new aspiring bloggers.
    Thankyou!

  54. Do you mind if I quote a few of your articles as long as I provide credit and sources back to your website?
    My website is in the exact same area of interest as yours and my users would definitely benefit from a lot of the information you provide here.
    Please let me know if this ok with you. Thank you!

  55. I am in fact delighted to glance at this website
    posts which contains lots of valuable information, thanks for
    providing these information.

  56. As the admin of this web site is working, no doubt very shortly it
    will be famous, due to its quality contents.

  57. If some one wants to be updated with newest technologies then he must
    be pay a visit this website and be up to date everyday.

  58. Thank you for the good writeup. It in fact was a amusement account it.
    Look advanced to more added agreeable from you! However, how could we communicate?

  59. Ahaa, its nice discussion about this paragraph here at this weblog, I have read all that, so at this time me also commenting here.

  60. Hey there! Do you know if they make any plugins to safeguard against hackers?
    I’m kinda paranoid about losing everything I’ve worked hard on.
    Any suggestions?

  61. Great post! We are linking to this particularly great content on our site.
    Keep up the great writing.

  62. Vraiment sympa ce site rendez vous defiscalisation, je trouve votre
    approche vraiment intéressante, Bravo pour la rédaction. je partage le lien de suite Pauline

  63. I read this article completely regarding the resemblance of most recent and earlier technologies, it’s awesome article.

  64. This is a great tip especially to those new to the blogosphere.

    Simple but very precise info… Many thanks for sharing this one.

    A must read post!

  65. Hi are using WordPress for your blog platform?
    I’m new to the blog world but I’m trying to get started and create my own.
    Do you need any html coding knowledge to make your own blog?
    Any help would be greatly appreciated!

  66. I all the time used to study piece of writing in news papers but now as I am a user of internet thus from now I
    am using net for posts, thanks to web.

  67. Hello there! I simply want to give you a big thumbs up
    for your excellent info you’ve got right here
    on this post. I am returning to your website for more soon.

  68. Good day! I could have sworn I’ve been to this website before but after reading through some of the
    post I realized it’s new to me. Anyways, I’m definitely happy I found it
    and I’ll be book-marking and checking back often!

  69. I read this article fully concerning the difference of newest
    and preceding technologies, it’s awesome article.

  70. I know this website offers quality dependent content and additional stuff, is
    there any other web site which provides these kinds of
    things in quality?

  71. Everyone loves it when folks come together and share ideas.
    Great site, continue the good work!

  72. Wonderful blog! I found it while browsing on Yahoo News. Do you have any tips on how to get
    listed in Yahoo News? I’ve been trying for a while but I never seem to get
    there! Thanks

  73. Just want to say your article is as astounding. The clarity
    on your post is simply excellent and that i can think you are an expert on this subject.
    Well with your permission let me to snatch your RSS feed to keep up to date with
    approaching post. Thanks a million and please carry on the
    enjoyable work.

  74. Amazing blog! Do you have any hints for aspiring writers?
    I’m hoping to start my own blog soon but I’m a little lost on everything.
    Would you advise starting with a free platform like WordPress or go for a paid option? There are so many choices out
    there that I’m totally overwhelmed .. Any tips?
    Appreciate it!

  75. Thanks a lot for sharing this with all of us you really recognise what you are talking
    approximately! Bookmarked. Kindly also consult with my website =).
    We may have a link exchange agreement between us

  76. Whoa! This blog looks just like my old one!
    It’s on a completely different subject but it has pretty much the same layout and design. Great choice of colors!

  77. It’s great that you are getting ideas from this paragraph
    as well as from our dialogue made at this time.

  78. May I simply say what a comfort to find a person that actually understands what
    they are talking about on the net. You certainly realize how to bring a problem to light and make it important.

    A lot more people should look at this and understand this side of your story.

    I can’t believe you’re not more popular since you certainly have the gift.

  79. Hello, Neat post. There is a problem along with your site in internet
    explorer, might check this? IE still is the market chief and
    a large portion of people will omit your magnificent writing because of this problem.

  80. For the reason that the admin of this site is working,
    no hesitation very shortly it will be well-known, due to its feature contents.

  81. Greetings from Los angeles! I’m bored at work so I decided to check out your blog on my iphone during lunch break.
    I enjoy the information you present here and can’t wait to take a look when I get home.
    I’m amazed at how fast your blog loaded on my cell phone ..
    I’m not even using WIFI, just 3G .. Anyways, great site!

  82. – Design robuste.

  83. Hey very nice web site!! Man .. Excellent .. Superb ..
    I will bookmark your website and take the feeds also?
    I am glad to seek out a lot of useful info here in the
    post, we’d like develop more strategies on this regard,
    thanks for sharing. . . . . .

  84. If you are going for most excellent contents like me, simply visit this website every day as it offers feature
    contents, thanks

  85. It’s an amazing piece of writing designed for all the online visitors; they will take benefit from it I am sure.

  86. I am not sure the place you are getting your information, but good topic.

    I needs to spend a while studying more or working out more.

    Thank you for excellent info I was searching for this information for my mission.

  87. It’s very simple to find out any matter on net as compared to textbooks, as I found
    this piece of writing at this web page.

  88. It is truly a great and useful piece of information. I
    am satisfied that you simply shared this useful information with us.
    Please stay us up to date like this. Thanks for
    sharing.

  89. This is my first time go to see at here and i am really impressed to read everthing
    at single place.

  90. This website certainly has all the information and facts I needed concerning this
    subject and didn’t know who to ask.

  91. I am truly happy to glance at this website posts which contains plenty of helpful information, thanks for
    providing such statistics.

  92. Definitely believe that which you stated. Your favorite reason seemed to be on the internet the
    simplest thing to be aware of. I say to you, I definitely get annoyed while people consider worries
    that they plainly don’t know about. You managed to hit the nail upon the top and also defined out the whole thing without having side effect , people
    could take a signal. Will likely be back to get more. Thanks

  93. I got this web page from my pal who informed me concerning this website and at the moment this time I am browsing this web site and reading very informative posts here.

  94. Very nice post. I just stumbled upon your weblog and
    wanted to say that I have really enjoyed surfing around your
    blog posts. After all I’ll be subscribing to your
    feed and I hope you write again very soon!

  95. Magnificent goods from you, man. I have understand your stuff previous to and you are just extremely excellent.
    I really like what you have acquired here, certainly like
    what you’re stating and the way in which you say it.
    You make it entertaining and you still take care of
    to keep it smart. I can not wait to read much more from you.
    This is really a great website.

  96. I am curious to find out what blog system you happen to be utilizing?
    I’m having some small security problems
    with my latest blog and I would like to find something more
    secure. Do you have any recommendations?

  97. It’s an remarkable post in favor oof all the web viewers;
    they will get benefit ffrom it I am sure.

  98. This design is incredible! You certainly know how to keep a reader entertained.
    Between your wit and your videos, I was almost moved to start my own blog (well, almost…HaHa!) Fantastic job.
    I really enjoyed what you had to say, and more than that, how
    you presented it. Too cool!

  99. I was pretty pleased to find this web site. I need to to thank you for your time just
    for this wonderful read!! I definitely savored every bit of it and i also have you book-marked to look at new stuff on your website.

  100. That is really interesting, You’re an excessively skilled blogger.
    I’ve joined your rss feed and stay up for seeking extra of your magnificent
    post. Additionally, I’ve shared your site in my
    social networks

  101. What also must be mentioned are the unimaginable features that make this FIFA 15 cheats tool undetectable and protected to work with.

  102. Wow, incredible weblog structure! How long have you been running a blog for?
    you made running a blog look easy. The entire glance of your website is
    great, let alone the content material!

  103. Hi there mates, good article and fastidious arguments commented at this
    place, I am truly enjoying by these.

  104. It’s impressive that you are getting ideas from this article as well
    as from our argument made at this time.

  105. Pretty! This has been an incredibly wonderful post. Thanks for supplying these details.

  106. I’m impressed, I must say. Rarely do I encounter a blog that’s both equally
    educative and engaging, and let me tell you, you have
    hit the nail on the head. The issue is something which too few folks are speaking
    intelligently about. I am very happy that I found this in my search
    for something concerning this.

  107. Ahaa, its good dialogue regarding this article at this
    place at this webpage, I have read all that, so at this time
    me also commenting at this place.

  108. Finally, another very popular stock simulator is Fantasy Stock Market.
    The math involved to adequately predict the price movement is far more difficult than the
    average person can handle. But that is a dangerous route to follow,
    as you will end up chasing your own tail with no clear indication of when to
    enter and exit a trade.

  109. Its not my first time to pay a quick visit this web
    site, i am browsing this web page dailly
    and take pleasant facts from here daily.

  110. That is a really good tip particularly to those new to
    the blogosphere. Brief but very accurate information… Many thanks for sharing this one.
    A must read post!

  111. In my opinion, what makes Hay Day so good is that the team who made it took a step back.

  112. Your means of describing the whole thing in this article is really
    nice, all be capable of without difficulty understand
    it, Thanks a lot.

  113. Hey very nice blog!

  114. Oh my goodness! Incredible article dude! Thank you so much, However I am experiencing troubles with your RSS.
    I don’t understand the reason why I cannot subscribe to it.
    Is there anyone else getting identical RSS issues? Anyone who knows
    the answer can you kindly respond? Thanks!!

  115. Very good site you have here but I was wanting to know
    if you knew of any discussion boards that cover the same topics discussed in this article?

    I’d really love to be a part of online community where I can get opinions from other knowledgeable individuals that share the same interest.
    If you have any suggestions, please let me know.

    Thanks!

  116. This is my first time pay a quick visit at here and i am really pleassant to read all
    at single place.

  117. Hi all, here every one is sharing such familiarity, therefore it’s nice to read this web site,
    and I used to visit this blog daily.

  118. bookmarked!!, I like your blog!

  119. It is not my first time to visit this web site, i am visiting this site dailly and obtain fastidious facts from here all
    the time.

  120. I know this if off topic but I’m looking into
    starting my own blog and was wondering what
    all is required to get setup? I’m assuming having a blog like yours would cost a pretty penny?
    I’m not very web smart so I’m not 100% certain. Any recommendations or advice would
    be greatly appreciated. Many thanks

  121. As it was already explained, a building inspection covers different parts
    of the property and systems. Price charged by leading commercial pest control is
    best in the industry. Centered around London and Hertfordshire are some of the top major pest control
    specialists.

  122. My brother recommended I would possibly like this blog.
    He was entirely right. This put up actually made my
    day. You can not consider simply how so much time I had spent for this
    info! Thanks!

  123. Admiring the persistence you put into your blog
    and detailed information you offer. It’s good to come across a
    blog every once in a while that isn’t the same outdated rehashed material.
    Wonderful read! I’ve saved your site and I’m adding your RSS feeds to
    my Google account.

  124. It’s genuinely very difficult in this busy life to listen news on Television, therefore I just use
    web for that reason, and get the latest information.

  125. Hi, yes this piece of writing is genuinely pleasant and I have learned lot of things from it concerning blogging.
    thanks.

  126. I was suggested this blog by my cousin. I am not sure whether this post is written by him as nobody else know such detailed about my problem.

    You are wonderful! Thanks!

  127. Your style is unique in comparison to other folks I have read stuff from.
    Thank you for posting when you have the opportunity, Guess I
    will just bookmark this site.

  128. Spot on with this write-up, I really feel this web site needs a lot more attention.
    I’ll probably be back again to see more, thanks for the advice!

  129. Hey just wanted to give you a quick heads up. The
    text in your article seem to be running off the screen in Ie.
    I’m not sure if this is a formatting issue or something to do with internet browser compatibility but I thought I’d post to let you know.
    The layout look great though! Hope you get the problem resolved soon. Many thanks

  130. You could definitely see your expertise in the article you write.
    The world hopes for more passionate writers like
    you who aren’t afraid to say how they believe. At all times go after your
    heart.

  131. I’m really inspired together with your writing skills as smartly as with
    the structure on your weblog. Is this a paid subject or did
    you customize it your self? Anyway stay up the nice quality writing, it’s rare to see a great
    blog like this one these days..

  132. I have read so many articles or reviews on the topic of the
    blogger lovers however this piece of writing
    is actually a pleasant paragraph, keep it up.

  133. Hi there! I could have sworn I’ve been to this website before but after browsing through
    many of the articles I realized it’s new to me.
    Nonetheless, I’m definitely happy I found it and I’ll
    be book-marking it and checking back frequently!

  134. I visited many blogs except the audio quality for audio songs
    present at this web page is truly fabulous.

  135. Quality content is the important to interest the people to pay a quick visit the web site, that’s what this website is providing.

  136. Hello! Would you mind if I share your blog with my zynga group?
    There’s a lot of folks that I think would really enjoy your
    content. Please let me know. Cheers

  137. This website was… how do you say it? Relevant!!

    Finally I’ve found something which helped me.
    Many thanks!

  138. Great delivery. Great arguments. Keep up the amazing effort.

  139. It’s great that you are getting thoughts from this post as well as from our discussion made at this time.

  140. Attractive component of content. I just stumbled upon your web site and in accession capital to claim that I get actually enjoyed account your weblog
    posts. Anyway I’ll be subscribing for your augment or even I success you get entry to consistently fast.

  141. Wow, this article is nice, my younger sister is analyzing such things, therefore I am
    going to inform her.

  142. After looking over a number of the blog posts on your web page, I honestly appreciate your way of blogging.
    I book-marked it to my bookmark website list and will be checking back in the near future.
    Please visit my website as well and let me know what you think.

  143. I am regular reader, how are you everybody? This post posted at this website is truly pleasant.

  144. I love reading sites such as this! Causes educated as well as me to experience a comfortable
    enjoyable feeling! Thank you so much!

  145. Pretty nice post. I simply stjmbled upon your blog and wanted to say that Ihave really loved browsing your weblog posts.
    After all I’ll be subscribing to your rss feed and I am hoping you write once more very soon!

  146. Its not my first time to pay a quick visit this website,
    i am browsing this web site dailly and take good data from
    here all the time.

  147. I absolutely love your blog and find nearly all
    of your post’s to be exactly what I’m looking for. Does one offer guest
    writers to write content for yourself? I wouldn’t mind composing
    a post or elaborating on most of the subjects you write related to here.
    Again, awesome weblog!

  148. I’m truly enjoying the design and layout of your blog.
    It’s a very easy on the eyes which makes it
    much more enjoyable for me to come here and visit more often. Did you hire
    out a developer to create your theme? Great work!

  149. What’s up, all is going nicely here and ofcourse every one is sharing information,
    that’s truly fine, keep up writing.

  150. I absolutely love your blog and finmd the majority of your post’s too be exactly
    I’m looking for. Does one offer guest writers to write content availablle for you?
    I wouldn’t mind creating a post or elaborating on mostt of the subjects youu write concerning here.

    Again, awesome blog!

  151. Everyone loves what you guys tend to be up too.
    This sort of clever work and coverage! Keep up the excellent works guys I’ve incorporated
    you guys to my personal blogroll.

  152. It’s an amazing piece of writing designed for all the web visitors; they will take benefit from it I am sure.

  153. Hi, I do believe this is an excellent blog. I stumbledupon it
    😉 I may come back once again since i have saved as a favorite it.
    Money and freedom is the best way to change, may you be rich and continue to guide
    others.

  154. I do consider all of the concepts you have introduced
    to your post. They’re really convincing and can definitely work.
    Still, the posts are very brief for beginners. May you please
    prolong them a little from subsequent time? Thanks
    for the post.

  155. Asking questions are truly good thing if you are not understanding anything fully, however this piece of writing offers
    nice understanding even.

  156. [url=http://flagyl-online-buy.net/]Metronidazole 500 Mg[/url] Priligy Dapoxetine http://lasix-buy-online.net/

  157. Fantastic post but I was wondering if you could write a litte more on this subject?

    I’d be very thankful if you could elaborate a little bit more.

    Kudos!

  158. Great article. I’m experiencing a few of these issues as well..

  159. Thanks to my father who shared with me concerning this
    webpage, this website is really awesome.

  160. Thanks for finally writing about > Senescenza ovarica precoce (POF,
    Premature Ovarian Failure) | FertilityCenter < Loved it!

  161. Very nice post. I simply stumbled upon your blog and wished to say that I have really loved browsing your weblog posts.
    In any case I will be subscribing in your feed and I am hoping you write once more soon!

  162. Its such as you read my mind! You seem to
    understand a lot approximately this, such as you wrote the book in it or something.
    I think that you simply can do with some percent to pressure the message house a little bit, however other than that, this is great blog.

    A great read. I’ll certainly be back.

  163. These are in fact fantastic ideas in on
    the topic of blogging. You have touched some pleasant
    factors here. Any way keep up wrinting.

  164. Interesting articles on information like this is a great find. It’s like finding a treasure. I appreciate how you express your many points and share in your views. Thank you.

  165. wow, awesome blog article.Really looking forward to read more. Awesome.

  166. This is very interesting, You’re an excessively professional blogger. I have joined your feed and look ahead to looking for more of your fantastic post. Also, I have shared your web site in my social networks

  167. Wow, that’s what I was looking for, what a information! present here at this blog, thanks admin of this website.

  168. I do agree with all the ideas you have offered for your post.
    They are really convincing and will definitely work. Still, the posts are very short for newbies.
    May you please extend them a little from subsequent
    time? Thanks for the post.

  169. Good day! I know this is kinda off topic but I was wondering which blog
    platform are you using for this website? I’m getting fed up of WordPress because I’ve
    had issues with hackers and I’m looking at options for another platform. I would be awesome if you could point me in the direction of a good platform.

  170. Emilio Cavuoto

    Interessante e completo.
    Grazie

  171. This web site definitely has all of the info I needed concerning
    this subject and didn’t know who to ask.

Lascia un commento

Il tuo indirizzo email non sarà pubblicato. I campi obbligatori sono contrassegnati *

Captcha loading...