LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse.
Premature ovarian failure and female infertility are frequent side effects of anticancer therapies, owing to the extreme sensitivity of the ovarian reserve oocytes to the damaging effects of irradiation and chemotherapy on DNA. We report here a robust protective effect of luteinizing hormone (LH) on the primordial follicle pool of prepubertal ovaries against the cisplatin (Cs)-induced apoptosis. In vitro LH treatment of prepubertal ovarian fragments generated anti-apoptotic signals by a subset of ovarian somatic cells expressing LH receptor (LHR) through cAMP/PKA and Akt pathways. Such signals, reducing the oocyte level of pro-apoptotic TAp63 protein and favoring the repair of the Cs-damaged DNA in the oocytes, prevented their apoptosis. Noteworthy, in vivo administration to prepubertal female mice of a single dose of LH together with Cs inhibited the depletion of the primordial follicle reserve caused by the drug and preserved their fertility in reproductive age, preventing significant alteration in the number of pregnancy and of delivered pups. In conclusion, these findings establish a novel ovoprotective role for LH and further support the very attracting prospective to use physiological 'fertoprotective' approaches for preventing premature infertility and risks linked to precocious menopause in young patients who survived cancer after chemotherapy.
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Valerio
V
Rossi
Medical Affair Department Fertility TA, Merck-Serono SAS, Rome, Italy.
Monica
M
Lispi
Global Medical Affair, Merck KGaA, Darmstadt, Germany.
Salvatore
S
Longobardi
STA, Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
Maurizio
M
Mattei
UOC Oncologia Medica Senologica, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G. Pascale, Naples, Italy.
Francesca
F
Di Rella
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Antonietta
A
Salustri
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Massimo
M
De Felici
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Francesca G
FG
Klinger
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000633:toxicity*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011974:Receptors, LH / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D009025:Morpholines; D010750:Phosphoproteins; D011974:Receptors, LH; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D002945:Cisplatin; D000077191:Wortmannin
Reprod Biol Endocrinol. 2009 Apr 03;7:26
19341483
N Engl J Med. 2015 Mar 5;372(10):923-32
25738668
Fertil Steril. 2011 Mar 15;95(4):1440-5.e1-7
21316047
Endocrinology. 1997 Jun;138(6):2417-24
9165031
Dev Biol. 2002 Jun 15;246(2):441-54
12051828
PLoS One. 2012;7(10):e46682
23071612
Endocrinology. 2011 Nov;152(11):4377-85
21914782
Cell Death Differ. 2013 Aug;20(8):987-97
23598363
Mol Reprod Dev. 2008 Jan;75(1):105-14
17549700
Reproduction. 2013 Aug 12;146(4):R125-30
23801781
Sci Transl Med. 2013 May 15;5(185):185ra62
23677591
Dev Biol. 2006 Nov 1;299(1):1-11
16970938
Cancer Metastasis Rev. 2015 Dec;34(4):807-22
26589603
Biol Reprod. 2000 Jul;63(1):320-7
10859274
Blood. 2003 Dec 1;102(12):3954-62
12907433
Mech Dev. 2005 Sep;122(9):1043-55
15922574
Cell Death Differ. 2015 Jan;22(1):108-17
25168238
Reprod Biomed Online. 2014 Nov;29(5):612-20
25246113
Biol Reprod. 1996 Sep;55(3):663-70
8862785
Endocrinology. 1994 Nov;135(5):1845-53
7525255
Mol Reprod Dev. 2000 Aug;56(4):483-94
10911398
Nat Med. 2012 Aug;18(8):1172-4
22869180
J Reprod Fertil Suppl. 1989;38:3-8
2552109
Reprod Biol Endocrinol. 2003 Feb 06;1:11
12646064
Toxicol Appl Pharmacol. 2011 Jun 1;253(2):94-102
21439308
Mol Hum Reprod. 2006 Feb;12(2):61-9
16481408
Cell Cycle. 2012 Dec 15;11(24):4545-51
23165243
Biol Reprod. 1997 Sep;57(3):602-8
9282997
Biol Reprod. 1995 Feb;52(2):365-72
7711205
Mol Cell. 2012 Nov 9;48(3):343-52
23000175
Curr Opin Obstet Gynecol. 2003 Oct;15(5):359-70
14501238
Anticancer Res. 1998 Sep-Oct;18(5A):3187-92
9858882
Fertil Steril. 2007 Jan;87(1):172-7
17081530
Science. 2014 Jan 31;343(6170):533-6
24482479
Hum Reprod. 2011 Nov;26(11):3094-101
21865234
Hum Reprod. 1996 Aug;11(8):1620-6
8921104
Ann Oncol. 2015 Dec;26(12):2408-19
26347105
Nature. 2006 Nov 30;444(7119):624-8
17122775
PLoS One. 2015 Sep 01;10(9):e0137164
26325271
Cancer. 2007 Nov 15;110(10):2222-9
17932880
Reproduction. 2001 Jan;121(1):77-88
11226030
Mol Cell Endocrinol. 2012 Jul 6;358(1):18-26
22366471
Hum Reprod. 2015 Dec;30(12):2912-25
26466909
Endocrinology. 2006 May;147(5):2280-6
16439460
Biol Reprod. 2015 May;92(5):133
25810474
Arch Biochem Biophys. 2015 Jan 15;566:58-66
25524737
Mol Endocrinol. 2008 Apr;22(4):924-36
18187604
Hum Reprod. 2012 Jun;27(6):1801-10
22456922
Neuro Oncol. 2014 Oct;16(10):1313-23
24811392
J Gynecol Oncol. 2016 Mar;27(2):e22
26768785
Nat Med. 2009 Oct;15(10):1179-85
19783996
Reproduction. 2008 Jan;135(1):3-12
18159078
J Clin Endocrinol Metab. 1997 Nov;82(11):3748-51
9360535
Nat Med. 2009 Oct;15(10):1124-5
19812566
Biol Reprod. 2012 Mar 30;86(3):96
22190700
Oncologist. 2007 Sep;12(9):1044-54
17914074
Mol Cell. 2014 Jun 19;54(6):999-1011
24950377
Gynecol Endocrinol. 2015 Apr;31(4):272-7
25483005