Growth Hormone and Endometrial Receptivity

MINI REVIEW published: 24 Sep embe 2019 doi: 10.3389/ endo.2019.00653 F on ie s in Endoc inology | www. on ie sin.o g 1Sep embe 2019 | Volume 10 | A icle 653 Edi ed by: John Lui Yo ich, Pi e Medical Cen e , Aus alia Re iewed by: Biagio Cangiano, Uni e si y o Milan, I aly Nalini Mahajan, Independen Resea che , India *Co espondence: Signe Al mäe signeal mae@ug .es Special y sec ion: This a icle was submi ed o Rep oduc ion, a sec ion o he jou nal F on ie s in Endoc inology Recei ed: 09 July 2019 Accep ed: 09 Sep embe 2019 Published: 24 Sep embe 2019 Ci a ion: Al mäe S and Aghajano a L (2019) G ow h Ho mone and Endome ial Recep i i y. F on . Endoc inol. 10:653. doi: 10.3389/ endo.2019.00653 G ow h Ho mone and Endome ial Recep i i y Signe Al mäe1,2,3*and Lusine Aghajano a4 1Depa men o Biochemis y and Molecula Biology, Facul y o Sciences, Uni e si y o G anada, G anada, Spain, 2Compe ence Cen e on Heal h Technologies, Ta u, Es onia, 3Ins i u o de In es igación Biosani a ia ibs.GRANADA, G anada, Spain, 4Di ision o Rep oduc i e Endoc inology and In e ili y, Depa men o Obs e ics and Gynecology, S an o d School o Medicine, Sunny ale, CA, Uni ed S a es Adminis a ion o g ow h ho mone (GH) du ing o a ian s imula ion has shown bene icial e ec s on in i o e iliza ion (IVF) ou comes. I is gene ally belie ed ha his imp o emen is due o he s imula ing e ec o GH on oocy e quali y. Howe e , s udies a e eme ging ha show possible posi i e e ec o GH adminis a ion on endome ial ecep i i y, hus sugges ing an addi ional po en ial bene i a he le el o he u e us, especially among women wi h ecu en implan a ion ailu e, hin endome ium, and olde no mal esponde s. This e iew summa izes ecen da a on GH co- ea men e ec s on endome ium and endome ial ecep i i y among in e ile women unde going IVF, and p oposes possible mechanisms o GH ac ions in he endome ium. Keywo ds: endome ium, endome ial ecep i i y, g ow h ho mone, in e ili y, in i o e iliza ion, ansc ip ome INTRODUCTION Recep i e endome ium is an absolu e p e equisi e o a success ul emb yo implan a ion, being de ined by a limi ed ime- ame when he endome ium is a o able o emb yo adhesion and he subsequen a achmen and in asion p ocesses (1). Endome ial ecep i i y is a complex p ocess ha is o ches a ed by he syne gis ic ac ions o main ep oduc i e ho mones es ogen and p oges e one, as well as plead o o he endoc ine, pa ac ine and au oc ine ac o s (2,3). Impai ed endome ial ecep i i y is hough o be one o he majo easons o emb yo implan a ion ailu e (4). In assis ed ep oduc i e echnologies (ART), whe e he good quali y emb yos a e ans e ed as a s anda d o ca e, implan a ion ailu e emains an unsol ed obs acle (5,6). Rega dless o he ad ances in assis ed ep oduc ion, pa icula ly ega ding he mo e e ec i e means o emb yo selec ion and c yop ese a ion, many pa ien s epea edly ail he ea men p ocedu e. Wha we a e acing oday is ha implan a ion ailu e in ART is common, and we lack he e idence-based he apeu ic solu ions o ea ing i . As a esul , clinicians o en eel obliged o o e ea men s ha a e la gely empi ical, based on some biologic a ionale bu wi h li le clinical e idence o suppo hei use (7,8). The ea men ailu e is equally us a ing o bo h pa ien s and hei p o ide s, which e en mo e emphasizes he u gen need o no el e ec i e ea men o p e en ye ano he ailu e. The ole o g ow h ho mone (GH) in emale ep oduc ion has gained enewed in e es and has become a hea ed opic o e he las decade. The local GH p oduc ion in he ep oduc i e issues hemsel es exe an impo an au oc ine/in ac ine e ec s on hose issues, in addi ion o he pi ui a y p oduc ion o GH (9). Mo eo e , local insulin g ow h ac o 1 (IGF-1) p oduc ion (known downs eam media o o GH) has been shown o be con olled by gonado opins and es adiol as well (10). E idence eme ging om clinical p ac ice sugges s ha GH adminis a ion du ing o a ian s imula ion may imp o e oocy e quali y [highe numbe o oocy es collec ed, highe e iliza ion Al mäe and Aghajano a GH and he Endome ium a e, and highe numbe o emb yos eaching he ans e s age (11–15)], inc ease p egnancy a e (16–24), implan a ion a e (16, 20–23,25,26), and li e bi h a e (12,16,19,20,23,25,27). The accumula ing bene icial e ec s o GH on assis ed ep oduc ion ou comes do no exclude he possibili y ha his e ec is due, a leas in pa , o an ac ion o GH on endome ial ecep i i y. GROWTH HORMONE IN THE ENDOMETRIUM GH is a pep ide ho mone sec e ed by he an e io pi ui a y gland, ha ing impo an ole in cell g ow h and me abolism h oughou he body. GH oge he wi h i s ecep o , GHR, and ela ed g ow h ac o s including IGF-1, is exp essed in he endome ium o a s and human (28–31). The s udy by Sb acia e al. ob ained biopsies om women in p oli e a i e and sec e o y phases, as well as i s imes e decidua ( om elec i e p egnancy e mina ions) (28). They showed ha he e was no GH exp ession in p oli e a i e glandula epi helium, bu GH immuno eac i i y appea ed in he mid-lu eal sec e o y phase (no subdi ision wi hin sec e o y phase was done) and inc eased in he decidua om he i s imes e abo ions, wi h simila exp ession in he decidual samples om he e m p egnancies, sugges ing a ole in emb yo implan a ion p ocess. In e es ingly, no s omal exp ession o GH was obse ed in any sample (28). Mo eo e , he au ho s analyzed GH exp ession in he endome ium om women wi h “lu eal phase de ec ,” de ined by low p oges e one le els <8 ng/mL and delayed endome ial ma u a ion, and saw signi ican ly lowe exp ession o GH (28). This da a sugges ed close ela ionship be ween GH exp ession in endome ium and p oges e one le el/ unc ion. Fu he , a ecen s udy on human endome ial cell line indica ed ha GH may ac in a di ec o IGF-1-media ed manne on human endome ial cells o p omo e p oli e a ion and ascula iza ion and up- egula ion o ecep i i y- ela ed genes such as ascula endo helial g ow h ac o (VEGF) and in eg in be a 3 (ITGB3) (21). VEGF is an impo an playe in angiogenesis (32), and i has been shown o ac in an au oc ine manne on endome ial epi helial cell adhesion as a key egula o in he implan a ion p ocess (33). ITGB3 is a well-known bioma ke o ecep i i y (34), and down- egula ion o his bioma ke (phenomenon de ec ed in women wi h unexplained in e ili y, endome iosis, and lu eal phase de iciency) has been ela ed o lowe p egnancy a es (35,36). Apa om he e ec s o ci cula ing GH and locally p oduced GH on endome ium, he e is a p oposed indi ec e ec o o a ian GH on endome ial unc ion, namely i s in ol emen in he unc ion and main enance o he co pus lu eum (37, 38). While he majo i y o he da a come om a ious animal models, hey a e ne e heless signi ican . Lu eal unc ion and i s main enance a e i al o he es ablishmen o p egnancy and i s iabili y due o he p oduc ion o p oges e one by he co pus lu eum— he main “keepe ” o he no mal ea ly p egnancy. Hence, he s imula o y e ec o GH on o a ian s e oidogenic cell unc ion may play a majo ole in endome ial unc ion and dys unc ion ia i s e ec on o a y (see Figu e 1 o he p oposed mechanisms o GH ac ion on endome ium). CLINICAL USE OF GH AND EFFECT ON THE ENDOMETRIUM Ini ial epo s on he use o GH in clinical p ac ice come om cases o hypogonado opic hypogonadism o panhypopi ui a ism (46). Subsequen ly, he use o GH has been expanded on di e en pa ien popula ion, such as women wi h poo o a ian ese e, poo esponde s, o wi h poo oocy e quali y due o ad anced ma e nal age (25,47,48). In gene al, GH adminis a ion in he in e ili y clinic se ing has ocused on GH e ec s on oocy e, and he e ec on endome ium has been la gely o e looked. Subsequen ly, he a en ion has been u ned on o he endome ium, and in e es ing obse a ions ha e been made sugges ing posi i e e ec o g ow h ho mone ea men on endome ial hickness and implan a ion po en ial (see Table 1 o he s udies). A case epo o a pa ien wi h panhypopi ui a ism demons a ed imp o ed endome ial hickness and success ul implan a ion and p egnancy a e adding g ow h ho mone o he ea men p o ocol ollowing mul iple ailed in i o e iliza ion (IVF)/emb yo ans e cycles (55). Al e na i ely, a s udy on 20 pa ien s wi h documen ed GH de iciency epo ed imp o ed emb yo quali y, bu no imp o emen in endome ial hickness, when supplemen ed wi h GH in IVF cycle (15) (Table 1). Below we will discuss he a ailable li e a u e on he use o GH in a ious clinical IVF se ings. In e ile Pa ien s Wi h Recu en Implan a ion Failu e This is a g oup o pa ien s ha ail o achie e p egnancy in esh o ozen emb yo ans e cycles despi e app op ia e endome ial de elopmen ( hickness and pa e n) and good quali y emb yo ans e ed. Pa ien s wi h ecu en implan a ion ailu e (RIF), ha ing unde gone h ee o mo e emb yo ans e cycles a e IVF ea men wi hou a clinical p egnancy, a e among he mos di icul pa ien s o ea , wi h no p o en s anda d ea men . Impai ed endome ial ma u a ion is sugges ed as a common cause o RIF (56–58), making i a a ge pa ien g oup who could po en ially bene i om GH co-adminis a ion du ing IVF p ocedu e. Chen e al. s udy on 42 RIF pa ien s unde going IVF ea men ound ha GH ea men h oughou he s imula ion inc eased he endome ial hickness and consequen p egnancy and li e bi h a es among young pa ien s <35 yea s old supplemen ed wi h GH when compa ed o no GH RIF g oup (19). Pa ien s in bo h g oups had simila peak es adiol le els and simila numbe o oocy es e ie ed (19). While i is unclea i he di e ence in endome ial hickness o 11.61 ±2.9 s. 9.7 ±1.46 mm be ween s udy and con ol g oups, espec i ely was c ucial in achie ing highe p egnancy a es in he s udy g oup, he obse a ion is ne e heless impo an . This has been epo ed again in he second s udy, a andomized clinical ial including 70 RIF pa ien s in oocy e dona ion p og am (as an ideal model o assessing GH e ec on pa ien ’s endome ium wi hou F on ie s in Endoc inology | www. on ie sin.o g 2Sep embe 2019 | Volume 10 | A icle 653 Al mäe and Aghajano a GH and he Endome ium FIGURE 1 | Possible mechanisms o GH e ec s on o a ian and endome ial unc ion (A) and on endome ial cells (B). Numbe s in he igu e indica e s udies whe e he in o ma ion is p esen ed in de ail: 1 (39); 2 (40,41); 3 (42); 4 (23); 5 (21); 6 (43); 7 (44); 8 (45). con ounding ac o s o o a ian age and esponse) (20). In ha s udy pa ien s, who we e ea ed wi h GH h oughou medica ed ozen emb yo ans e cycle demons a ed signi ican ly hicke endome ium, 9.3 ±1.5 mm s. 8.6 ±1.0 mm, espec i ely, and highe p egnancy and li e bi h a es compa ed wi h RIF pa ien s in he placebo g oup (20) (Table 1). These a e he i s wo s udies assessing GH e ec s on endome ium in RIF pa ien s, and, al hough he indings a e p omising, clea ly mo e s udies on la ge pa ien popula ion, as well as andomized clinical ials (RCTs), a e needed o any clinically meaning ul conclusions. I is well-accep ed ha endome ial hickness does no necessa ily mean ha he endome ium is ecep i e, ye i is conside ed as a measu e o endome ial ma u i y, and op imal g ow h o he endome ium (>7 mm) is equi ed o a success ul emb yo implan a ion (59–61). F on ie s in Endoc inology | www. on ie sin.o g 3Sep embe 2019 | Volume 10 | A icle 653 Al mäe and Aghajano a GH and he Endome ium TABLE 1 | S udies assessing he e ec o g ow h ho mone (GH) co- ea men in in i o e iliza ion ( esh ea men cycles and ozen emb yo ans e cycles) on endome ium. S udy RCT S udy g oup; E hnici y GH/con ol (mean age) Inclusion c i e ia Exclusion c i e ia In e en ion P ima y ou come E ec on endome ial hickness (mm) GH Con ol p- alue FRESH EMBRYO TRANSFER CYCLE Rajesh e al. (15) No In e ile women wi h GH de iciency; Chinese 20/20* (32.9 y) *same women cycle be o e wi hou GH se ed as con ols GH de iciency based on clonidine es ; p e ious IVF cycle wi hou GH; became p egnan wi h GH ea ed cycle Panhypopi ui a ism; GH de icien pa ien s wi h p e ious cycle ea ed a o he hospi al 12 IU GH e e y 3 d day, s a ing om GnRH s imula ion day un il hCG adminis a ion Imp o ed emb yo quali y; highe e iliza ion a e a ICSI 11.4 ±1.9 10.3 ±1.5 0.108 E ekha e al. (49) Yes Poo esponde s; I anian 40/42 (36.0 ±4.6 y/36.2 ±3.7 y) p e ious ailed IVF-ET cycles wi h ≤3 oocy es, and ≤3 emb yos ob ained; and/o E2 le els ≤500 pg/mL on hCG day BMI ≥30, FSH >15 IU/L, endoc ine o me abolic diso de s, and PCOS, se e e endome iosis and azoospe mia GnRH an agonis p o ocol; + ea men g oup 4 IU/d GH om day 21 om p e ious cycle un il hCG igge ing Highe numbe o e ie ed oocy es and ob ained emb yos, while no e ec on implan a ion and p egnancy a es 8.5 ±1.0 8.1 ±0.9 0.158a Bayoumi e al. (50) Yes Poo esponde s; Egyp ian 72/73 (34.9 ±4.9 y/34.8 ±5.6 y) ESHRE consensus c i e ia 2011 o poo esponde s FSH >20 IU/l; p e ious o a ian su ge y; in e ili y o he han poo o a ian esponse; endoc ine diso de ; male ac o in e ili y GnRH agonis (mic o la e) p o ocol; + ea men g oup 7.5 IU/d GH om day 6 o hMG s imula ion un il day o hCG igge ing Highe numbe o ma u e oocy es and emb yos ob ained, while no e ec on implan a ion and p egnancy a es 11.9 ±1.6 11.7 ±1.7 0.590a Dakhly e al. (51) Yes Poo esponde s; Egyp ian 74/74/68/71* (36.4 ±5.8 y/38.1 ±5.0 y/36.8 ±6.3 y/36.4 ±5.8 y) *Compa ison o 4 di e en GH p o ocols, no con ol g oup ESHRE consensus c i e ia 2011 o poo esponde s >45 y; FSH >20 IU/l; p e ious o a ian su ge y; o he causes o in e ili y (o he han poo esponde ); male ac o o in e ili y G 1: GnRH long p o ocol; G 2: GnRH sho p o ocol; G 3: GnRH an agonis p o ocol; G 4: GnRH mini la e p o ocol. In all g oups 7.5 IU/d GH om day 6 o hMG s imula ion un il day o hCG igge ing The long/GH (G 1) p o ocol was supe io ega ding he numbe o oocy es e ie ed and e ilized. No signi ican di e ences in p egnancy a es 11.5 ±1.6 (G 1); 11.4 ±1.6 (G 2) 12.1 ±1.4 (G 3); 11.1 ±1.8 (G 4) NA 0.003a (G 3 s. G 4) Bassiouny e al. (13) Yes Poo esponde s; Egyp ian 68/73 (35.8 ±5.6 y/35.5 ±6.0 y) ESHRE consensus c i e ia 2011 o poo esponde s FSH >20 IU/l; p e ious o a ian su ge y; in e ili y o he han poo o a ian esponse GnRH an agonis p o ocol; + ea men g oup 7.5 IU/d GH om day 6 o hMG s imula ion un il day o hCG igge ing Highe numbe o ma u e oocy es and emb yos ob ained, while no e ec on p egnancy a es 12.1 ±1.3 11.6 ±1.6 0.029a (Con inued) F on ie s in Endoc inology | www. on ie sin.o g 4Sep embe 2019 | Volume 10 | A icle 653 Al mäe and Aghajano a GH and he Endome ium TABLE 1 | Con inued S udy RCT S udy g oup; E hnici y GH/con ol (mean age) Inclusion c i e ia Exclusion c i e ia In e en ion P ima y ou come E ec on endome ial hickness (mm) GH Con ol p- alue Du e al. (16) No No mal esponde s; Chinese 556/558 (32.8 ±4.3 y/31.6 ±4.4 y) (*olde women ≥35 y: 278/265; **younge women <35 y: 278/293) 20-45 y; allopian ube mal unc ion o male s e ili y; no mal ho mone le els; no mal u e ine ca i y; egula mens ual cycles, BMI <25 Recu en spon aneous abo ion; se e e pel ic adhesions o hyd osalpinx; ce eb o ascula , li e o kidney disease; endoc ine diseases; PCOS; endome iosis; u e ine leiomyoma; adenomyosis Long GnRH agonis p o ocol; + ea men g oup 4.5 IU/d GH o 5 days s a ing om day o FSH adminis a ion Highe implan a ion and clinical p egnancy a es 12.2 ±4.7 *12.0 ±2.2 **12.5 ±7.0 11.8 ±4.8 *11.6 ±2.5 **12.0 ±6.8 0.18b *0.038b **0.50 b Choe e al. (52) Yes In e ile women wi h diminished o a ian ese e; Ko ean 62/65 (39.8 ±3.6 y/39.4 ±4.1 y) ≥40 y o any o he ac o o poo o a ian esponse; ≤3 oocy es wi h con en ional s imula ion p o ocol; an al ollicle coun <5–7 o AMH <0.5–1.1 ng/ml; no mal u e us; egula mens ual cycle Gene ic cause o in e ili y; BMI >30; abno mal u e ine bleeding; o a ian umo ; b eas cance ; hyd osalpinx; con aindica ion o GH ea men GnRH an agonis p o ocol; + ea men g oup sus ained- elease GH (20 mg) 3×be o e and du ing COS (mid-lu eal, la e lu eal, cycle day 2) Highe numbe o ma u e oocy es ob ained, while no e ec on p egnancy a es 8.8 ±2.2 9.1 ±1.9 0.24a Dakhly e al. (53) Yes Poo esponde s; Egyp ian 120/120 (36.4 ±4.4 y/36.2 ±4.5 y) ESHRE consensus c i e ia 2011 o poo esponde s >45 y; FSH >20 IU/l; p e ious o a ian su ge y; o he causes o in e ili y (o he han poo esponde ); male ac o o in e ili y GnRH long p o ocol; + ea men g oup 7.5 IU/d GH om day 21 o p e ious cycle un il day o hCG igge ing Highe numbe o oocy es and emb yos ob ained, while no e ec on implan a ion and p egnancy a es 11.8 ±1.3 11.3 ±1.2 <0.001a Chen e al. (19) No Recu en implan a ion ailu e (RIF) pa ien s; Chinese 22/20 (33.9 ±2.9 y/34.0 ±3.4 y) No mal ho mone le els; no use o syn he ic ho mones >3 mon hs p io o en y P io endome ial esec ion o endome ial polyps; an iphospholipid synd ome; in ec ious disease; hype hy oidism; hype p olac inemia; ch omosomal abno mali ies; halassemia; male ac o s GnRH; + ea men g oup 4 IU/d GH h ough s imula ion un il he day o hCG adminis a ion Highe clinical p egnancy and li e bi h a es 11.6 ±2.9 9.7 ±1.5 0.009a Liu e al. (24) No No mal esponde s; Chinese 781/781 (31.3 ± 3.6 y/31.3 ±3.3 y) No mal o a ian esponse; age 20–40 y; poo quali y emb yos in p e ious IVF/ICSI; epe i i e esh o ozen ET wi hou p egnancy Poo o high o a ian esponse; adju an he apy as DHEA, CoQ10; se ious and uns able diseases (ca dio ascula , ce eb o ascula diseases); ecu en spon aneous abo ion; male ac o in e ili y GH ea men g oup 2 IU/4 IU GH daily since day 2 o p e ious cycle (6 weeks GH p e ea men ) o day 2 om o a ian s imula ion un il hCG igge (2 weeks GH p e ea men ) Inc eased p egnancy a e 12.0 ±2.2 11.6 ±2.8 0.036a (Con inued) F on ie s in Endoc inology | www. on ie sin.o g 5Sep embe 2019 | Volume 10 | A icle 653 Al mäe and Aghajano a GH and he Endome ium TABLE 1 | Con inued S udy RCT S udy g oup; E hnici y GH/con ol (mean age) Inclusion c i e ia Exclusion c i e ia In e en ion P ima y ou come E ec on endome ial hickness (mm) GH Con ol p- alue FROZEN EMBRYO TRANSFER/OOCYTE DONATION PROTOCOL Wu e al. (43) NA Pa ien s wi h hin endome ium; Chinese 32/30 (NA) NA NA HRT; + ea men g oup subcu aneous injec ions o GH Imp o ed endome ial blood low and inc eased endome ial hickness 8.8 ±1.3 7.1 ±1.9 <0.05 Yu e al. (54) No Pa ien s wi h pe sis en hin endome ium; Chinese 5/5* (32.2 ±5.5 y) *same women se ed as con ols be o e en e ing GH ea men Regula mens ual cycle; use o a i icial cycle; endome ium ≥7 mm; no abno mali ies wi h hys e oscopy; <40 y; pel ic ubal o male ac o in e ili y NA HRT; +GH ea men wi h 4–5 in au e ine GH pe usions o 6 IU GH dilu ed wi h 0.5 ml 0.9% saline on 9 h o 12 h day o he cycle (bed es 15 min) Imp o ed endome ial hickness and ecep i i y 8.0 ±0.6 5.8 ±0.7 <0.05b Xue-Mei e al. (23) No In e ile women unde going FET; Chinese 77 G 1/ 77 G 2/ 76 con ols (cycles; n=240 women) (30.3 ±4.1 y/31.3 ±5.0 y/30.7 ±4.3 y) ≤38 y; i i ied emb yos no olde han 2 y; ≥2 emb yos ozen Congeni al o acqui ed u e ine mal o ma ion; endome ial polyps; submucosal ib oids; in au e ine adhesion; se e e endome iosis o adenomyosis; diabe es melli us; abno mal blood clo ing HRT wi h o al es adiol ale a e om cycle day 3. + ea men g oup 1 (G 1): 4 IU/d GH injec ions om cycle day 8 un il p og injec ion; + ea men g oup 2 (G 2): 4 IU/d GH injec ions om cycle day 3 un il p og injec ion Highe implan a ion, clinical p egnancy and li e bi h a es 9.2 ±0.9 (G 1); 9.6 ±1.0 (G 2) 9.2 ±0.8 <0.001b Al mäe e al. (20) Yes RIF pa ien s wi h esh dona ed oocy es; Spanish 35/70 (42.2 ±4.5 y/42.4 ±3.7 y/43.8 ±2.5 y) (35 GH RIF; Con ol G 1 35 nonGH RIF; Con ol G 2 35 pos con ols unde going 1s oocy e dona ion) RIF (≥2 implan a ion ailu es); 30–51 y NA GnRH agonis +o al es adiol; + ea men g oup daily injec ions o 1 mg GH (∼3 IU) o 10 days o p oli e a i e phase induced by exogenous o al es adiol. 1–2 days la e aginal P ea men was s a ed Highe implan a ion, p egnancy and li e bi h a es 9.3 ±1.5 8.6 ±1.0 (G 1 non-GH); 9.4 ±1.7 (G 2 pos con ol) 0.046b Yang e al. (22) No Pa ien s wi h hin endome ium; Chinese 184/61 (cycles; n=225 women) (33.7 ±3.6 y/33.7 ±3.4 y) <40 y; ecei ing 2 blas ocys s; endome ial hickness <8 mm on p og adminis a ion day. All pa ien s wi h hys e oscopy o adhesions be o e FET U e ine mal o ma ions; se e e endome iosis o adenomyosis; umo ; diabe es melli us; immune abno mali ies GnRH agonis +es adiol ale a e om day 2–3 o cycle+ aginal es adiol a e mens ua ion + p og o 5 days; + ea men g oup 4.5 IU GH e e y al e na e day subcu aneously injec ed om day o p og adminis a ion un il ET Highe clinical p egnancy and implan a ion a es 6.6 ±2.9 6.7 ±0.7 0.24c (Con inued) F on ie s in Endoc inology | www. on ie sin.o g 6Sep embe 2019 | Volume 10 | A icle 653 Al mäe and Aghajano a GH and he Endome ium TABLE 1 | Con inued S udy RCT S udy g oup; E hnici y GH/con ol (mean age) Inclusion c i e ia Exclusion c i e ia In e en ion P ima y ou come E ec on endome ial hickness (mm) GH Con ol p- alue Cui e al. (21) Yes Pa ien s wi h hin endome ium; Chinese 40/53 (29.8 ±3.0 y/29.7 ±3.6 y) Endome ium ≤7 mm; <40 y; no mal o a ian ese e; esh ET canceled due o hin endome ium; ≥2 D3 emb yos ozen U e ine anomaly; in au e ine adhesion; endome ial polyp; adenomyosis; malignancy O al es adiol ale a e om day 3 o cycle un il day 18 + i ginal es adiol on days 15–18 o cycle. + ea men g oup 5 IU/d GH subcu aneous injec ions cycle days 15–18 Highe implan a ion and clinical p egnancy a es 7.9 ±0.7 6.3 ±0.9 <0.001b aDay o hCG adminis a ion. bDay o ET. cDay o p oges e one adminis a ion. AMH, an i-Mülle ian ho mone; BMI, body mass index (kg/m2); COS, con olled o a ian s imula ion; ET, emb yo ans e ; FET, ozen emb yo ans e ; GH, g ow h ho mone; HRT, ho mone eplacemen he apy; GnRH, gonado opin- eleasing ho mone; hCG, human cho ionic gonado opin; hMG, human menopausal gonado opin; ICSI, in acy oplasmic spe m injec ion; IU, in e na ional uni ; NA, no applicable; PCOS, polycys ic o a ian synd ome; Pos, posi i e; P og, p oges e one; RIF, ecu en implan a ion ailu e; RCT, andomized clinical ial. Bold ex highligh s he GH g oup o signi ican di e ence om con ol g oup. Thin Endome ium In e ile women wi h hin endome ium ep esen ano he po en ial pa ien popula ion ha could bene i om he GH adminis a ion. All s udies on GH co- ea men du ing ea men o in e ile women wi h hin endome ium we e conduc ed in ozen emb yo ans e (FET) cycles, whe e GH was adminis e ed du ing he endome ial p epa a ion o FET (21,22,43,54) (Table 1). The la ges s udy by Yang e al. was conduc ed on 225 in e ile women, and did no de ec any signi ican GH e ec on endome ial hickness, while epo ing signi ican ly highe clinical p egnancy and implan a ion a es (22). They assessed GH e ec on endome ial hickness on he day o p oges e one adminis a ion, which could explain he di e ence in hei esul s om he es o he s udies. The o he h ee s udies all no ed signi ican imp o emen in endome ial hickness on he day o emb yo ans e among pa ien s wi h hin endome ium a e adminis e ing GH h oughou he FET cycle (21,43,54), and signi ican ly highe implan a ion and clinical p egnancy a es (21). Wu e al. s udy also de ec ed imp o ed endome ial blood low in he GH-adminis e ed pa ien g oup (43), simila o la e indings by Xue-Mei e al. s udy (23), who showed inc eased VEGF exp ession and imp o ed pe usion o he u e ine a e ies in he g oup o in e ile women ea ed wi h GH. In line wi h abo e, Cui e al. s udy de ec ed VEGF up- egula ion oge he wi h ITGB3 and IGF-1 in endome ial cells when exposed o GH (21). The s a e o high blood low esis ance and VEGF down- egula ion wi h inadequa e epi helial g ow h and ascula iza ion ha e been desc ibed as pa hophysiologic cha ac e is ics o hin endome ium (62), and subendome ial blood low on he day o emb yo ans e is ela ed o he implan a ion and p egnancy a e in IVF (63). Cui e al. concluded ha up- egula ed VEGF in hei s udy se ing, in he GH g oup, pa ly esul ed in he inc ease o subendome ial blood low and he eby imp o ed endome ial ecep i i y (21). Ne e heless, he exac mechanisms o GH ac ions on he endome ium and endome ial ecep i i y in gene al a e o be un a eled in u u e s udies. Also new s udies wi h la ge s udy g oups and well-designed RCTs a e equi ed in o de o cla i y whe he in e ile women wi h hin endome ium bene i om he GH ea men . Poo Responde s Women wi h poo o a ian esponse in ART is ano he pa ien g oup whe e GH co- ea men in s imula ion p o ocols ha e been s udied. All hese s udies (see Table 1) ha e been RCTs, howe e wi h limi ed sample sizes, and all ha e epo ed bene icial e ec o GH adminis a ion on he numbe and quali y o oocy es and on he numbe o emb yos ob ained. Rema kably, while some imp o emen o endome ial hickness has been no ed, hose s udies ailed o show any bene icial e ec on clinical p egnancy and li e bi h a es (13,49–53). Based on hese indings, one could conclude ha GH co- ea men in poo esponde s wi h no mal endome ium does no seem o ha e any signi ican impac on endome ial ecep i i y and hence p egnancy a es. Ne e heless, we should be cau ious in d awing p elimina y and po en ially w ong conclusions in his ype o s udies wi hou aking in o ca e ul conside a ion all po en ial con ounde s, including quali y and numbe o emb yos ans e ed, clea age F on ie s in Endoc inology | www. on ie sin.o g 7Sep embe 2019 | Volume 10 | A icle 653 Al mäe and Aghajano a GH and he Endome ium s. blas ocys s age emb yos and e en ype o lu eal suppo p o ided in esh and/o ozen emb yo ans e cycles (64). In addi ion, he o al p oduc i i y a e om a single oocy e e ie al is highes when mo e and be e quali y emb yos a e ob ained, which can be exac ly he case wi h GH-supplemen ed cycles in poo esponde s, esul ing in highe cumula i e p egnancy a es a he han pe cycle success in his g oup o pa ien s. Clea ly, ca e ully designed la ge s udies wi h ans e s o single good quali y emb yo ( esh and ozen) a e wa an ed, albei qui e challenging o pe o m, in o de o cla i y whe he endome ial ecep i i y in in e ile women wi h poo esponse in ART would bene i om GH adminis a ion. No mal Responde s Thus a , he la ges g oup o in e ile pa ien s in ol ed in s udies on GH adminis a ion du ing IVF has been he no mal esponde s (Table 1). The i s s udy was pe o med on 240 in e ile women unde going FET, whe e wo di e en GH supplemen a ion p o ocols we e compa ed—GH adminis a ion h oughou he FET, and a single GH injec ion on day 8 o es ogen ea men (23). No ably, signi ican endome ial hickness imp o emen oge he wi h highe emb yo implan a ion, clinical p egnancy, and li e bi h a es we e de ec ed among women wi h longe GH adminis a ion (23). The au ho s also no ed ha he longe GH addi ion o he ea men p o ocol inc eased he le els o es adiol, IGF-1, and VEGF se um le els, and imp o ed pe usion o he u e ine endome ial a cua e a e y (23). The pulsa ili y index, esis ance index, and peak sys olic eloci y/end dias olic eloci y o he u e ine a cua e a e ies ep esen he esis ance o blood low om he poin o measu emen downs eam; inc eased impedance o hese a e ies migh co ela e wi h poo endome ial ecep i i y and clinical ou comes (65). The nex s udies analyzed 1,114 (16) and 1,562 (24) in e ile women, espec i ely unde going o a ian s imula ion o IVF wi h GH co-adminis a ion h oughou he s imula ion, and a posi i e GH e ec on endome ial hickness in addi ion o he highe clinical p egnancy a es was de ec ed in s udy compa ed o con ol g oups. GH e ec on endome ial hickness was signi ican ly inc eased among olde in e ile women o ≥35 yea s old compa ed o <35 yea s old, while bo h g oups exhibi ed highe implan a ion and clinical p egnancy a es, mos likely a ibu ed o he highe numbe o high quali y emb yos ob ained in GH- ea ed g oups (16). In humans, changes in GH sec e ion could be age- ela ed, as pos -adolescence he sec e ion o GH dec eases wi h age, which is why GH hyposec e ion is obse ed in olde pa ien s (66). GH insu iciency can dis up o a ian unc ion and lead o ep oduc i e di icul ies (66). As men ioned abo e, in Du e al. s udy (16), GH- ea ed olde women (≥35 yea s old) had implan a ion and clinical p egnancy a es mo e han wo imes highe han hose obse ed du ing IVF cycles wi hou GH. This esul sugges ed ha adding GH migh be bene icial o olde pa ien s. To conclude, esea ch on he e ec s o GH co- ea men in ART among no mal esponde s has been pe o med on su icien ly powe ed s udies in e ms o he sample size, ne e heless as all hese s udies we e no andomized con olled ials, u he well-designed esea ch is needed o objec i ely assess he GH e ec on ART ou comes in (young) women wi h no mal o a ian ese e and no mal esponse o o a ian s imula ion. Fu u e Pe spec i es Fu he s udies a e wa an ed in o de o de e mine he op imal dose, ime, and du a ion o GH adminis a ion and o in es iga e he long- e m sa e y o GH o pa ien s and hei o sp ing. The dosage and ea men du a ion o GH di e ed among conduc ed s udies (see Table 1). Because o he limi ed expe ience wi h he GH co- ea men p o ocols, he e is a lack o e idence o suppo he supe io i y o one o e he o he . In all he p o ocols used (see Table 1), GH was adminis e ed ia subcu aneous injec ions, excep o one s udy whe e GH in au e ine pe usion in 5 pa ien s wi h non- esponsi e hin endome ium was success ully used (54). Ano he c ucial pa is o de ine he app op ia e pa ien popula ion ha would uly bene i om GH ea men o imp o ing hei u e ine lining quali y in e ms o hickness and/o ecep i i y. GH seems o p omo e endome ial g ow h, and i s use could be conside ed in women whose endome ium does no g ow and/o ma u e su icien ly wi h s anda d ea men p o ocols. In addi ion, he cu en e iew concludes ha e en no mal esponde s could po en ially bene i om he GH adminis a ion in IVF p og ams, howe e , he imp o ed p egnancy a es in some o he s udies u ilizing esh IVF cycles could no be sepa a ed om imp o ed emb yo quali y. While endome ial hickness and pa e n upon GH adminis a ion has been eco ded and epo ed, e alua ion o endome ial ecep i i y is no as simple. Fu u e s udies need o ocus on he molecula le el in o de o e alua e he endome ial ansc ip ome/p o eome/sec e ome (67), wi h emphasis on ecep i i y ma ke s o unde s and and cla i y he possible mechanisms o GH on endome ial ecep i i y. An ideal se ing would be o design an RCT wi h GH-supplemen ed mock cycles s. con ol, du ing which endome ial ecep i i y could be s udied on molecula le el in de ail ( ansc ip omics and/o use o comme cially a ailable endome ial ecep i i y es s; epigenomics and/o p o eomics analyses). The mock cycle could be ollowed by a “ ue” FET cycle o enable e alua ion and co ela ion o p egnancy a es. To sum up, undoub edly mo e esea ch on la ge coho s wi h ca e ully designed s udies [as highligh ed in a ecen commen (64)] is needed o iden i y he pa ien g oup in whom he addi ion o GH o he ea men p o ocol in IVF p og ams will be mos aluable. Sample size and objec i ely designed s udies ( andomized clinical ials) is a delica e opic in ART as s ic double- blind, placebo-con olled, RCTs a e di icul o accomplish (68). I is ex emely ha d o pe o m ully blinded RCTs in IVF because o he pa ien ec ui men issues, whe e aging women p e e no o pa icipa e in he placebo g oup ha equi es commi men o se e al mon hs o hei ep oduc i e li espan and which ul ima ely may no help hem achie e p egnancy (68). Unde s andingly, pa ien s end o op o any addi ional ea men , cos pe mi ing, ha would po en ially help hem o become p egnan . As a esul , he s udies o GH ea men e ec s F on ie s in Endoc inology | www. on ie sin.o g 8Sep embe 2019 | Volume 10 | A icle 653 Al mäe and Aghajano a GH and he Endome ium on IVF ou comes a e a he limi ed on i s sample size and/o a e e ospec i e o obse a ional in na u e; none heless, hey p o ide impo an da a conce ning he apeu ic in e en ions in IVF and open up u u e possibili ies o imp o ing in e ili y ea men p o ocols. CONCLUSIONS The cu en e iew summa izes he ecen da a on GH co- ea men e ec s on endome ial pa ame e s in assis ed ep oduc ion and p oposes possible mechanisms o GH ac ions in he endome ium. S udies a e indica ing ha co- ea men wi h GH could imp o e he endome ial hickness, and possibly ecep i i y among in e ile women. This e ec migh occu h ough inc easing endome ial blood pe usion and he exp ession o genes and p o eins ela ed o endome ial ecep i i y such as VEGF and ITGB3 oge he wi h IGF-1, howe e he exac mechanisms in he endome ium emain o be cla i ied. Whe he GH adminis a ion du ing IVF is use ul and which pa ien g oups could bene i om i needs u he in es iga ion, bu he p elimina y da a sugges ha women su e ing RIF, pa ien s wi h hin endome ium and olde no mo- esponde s could bene i om GH ea men when unde going ART. S ill, ca e ully designed and su icien ly powe ed coho s udies, RCTs, a e equi ed in he ield in o de o es ablish he mos sui able he apeu ic egimen o hese pa ien s and o cla i y he con usion a isen om a ious s udies ha ha e shown ei he inconsis en o con lic ing indings, used small pa ien coho s and/o ha e been poo ly designed wi h no blinding o placebo con ols. AUTHOR CONTRIBUTIONS SA and LA equally con ibu ed o he e iew idea and manusc ip w i ing. FUNDING This s udy was suppo ed by he Uni e si y o G anada Plan P opio de In es igación 2016–Excellence ac ions: Uni o Excellence on Exe cise and Heal h (UCEES)–and Plan P opio de In es igación 2018–P og ama Con a os-Puen e, and he Jun a de Andalucía, Conseje ía de Conocimien o, In es igación y Uni e sidades, Eu opean Regional De elopmen Funds ( e . SOMM17/6107/UGR); and he Spanish Minis y o Economy, Indus y and Compe i i eness (MINECO), and Eu opean Regional De elopmen Fund (FEDER): g an s RYC-2016-21199 and ENDORE SAF2017-87526. ACKNOWLEDGMENTS We hank D . Albe o Sola-Ley a o his help in he igu e p epa a ion. REFERENCES 1. Wilcox AJ, Bai d DD, Weinbe g CR. Time o implan a ion o he concep us and loss o p egnancy. N Engl J Med. (1999) 340:1796–9. doi: 10.1056/NEJM199906103402304 2. Ca son DD, Lagow E, Tha hiah A, Al-Shami R, Fa ach-Ca son MC, Ve non M, e al. 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