Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies

Lambertini, Matteo; Ceppi, Marcello; Poggio, F.; Peccatori, Fedro Alessandro; Azim, Hatem A.; Ugolini, Donatella; Pronzato, P.; Loibl, Sibylle; Moore, Halle C. F.; Partridge, Ann H.; Bruzzi, Paolo; Mastro, Lucia Del

doi:10.1093/annonc/mdv374

Cited by 194 publications

(173 citation statements)

References 43 publications

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“…Despite limitations in study design and statistical power, the most recent randomized controlled trials suggest a protective ovarian effect in both HR+ and HR-patients and no signal for harm from a breast cancer recurrence standpoint 76,77 . A recent metaanalysis supports these findings 78 . The BCY2 panel therefore agreed this strategy can be discussed with patients interested in potentially preserving fertility and/or ovarian function.…”

Section: Gnrh Agonists and Ovarian Function Preservationmentioning

confidence: 82%

Second international consensus guidelines for breast cancer in young women (BCY2)

et al. 2016

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Section: Gnrh Agonists and Ovarian Function Preservationmentioning

confidence: 82%

Second international consensus guidelines for breast cancer in young women (BCY2)

et al. 2016

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“…[123][124][125][126][127][128][129][130][131] Some meta-analyses have shown that GnRH agonist may be beneficial for fertility preservation. [132][133][134] However, the impact of these meta-analyses are limited by flaws such as only examining women with breast cancer and only including trials that were not adequately powered and did not use blinding and/ or a placebo condition. 135,136 Further, results from earlier meta-analyses were inconsistent, with some showing a potential benefit of GnRH to preservation of ovarian function, [137][138][139] while other reviews have been unable to come to this conclusion.…”

Section: Options For Femalesmentioning

confidence: 99%

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

Coccia¹,

Pappo²,

Beaupin³

et al. 2018

J Natl Compr Canc Netw

261

194

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“…However, strategies to date have focused on GnRH inhibition, which has had limited success (33)(34)(35), likely because gonadotropins regulate only the late, irreversible stages of follicular maturation rather than the recruitment of primordial follicles (36). By directly inhibiting primordial follicle activation, we hypothesize that MIS could provide a unique method of contraception and a therapeutic option for oncofertility.…”

Section: Significancementioning

confidence: 99%

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

Kano

Sosulski

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

166

171

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The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman's reproductive lifespan, resulting in menopause. Müllerian inhibiting substance (MIS) (or anti-Müllerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS-treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were given carboplatin, doxorubicin, or cyclophosphamide and were cotreated with AAV9-MIS, recombinant MIS protein, or vehicle controls. We found significantly more primordial follicles in MIS-treated animals than in controls. Thus treatment with MIS may provide a method of contraception with the unique characteristic of blocking primordial follicle activation that could be exploited to prevent the primary ovarian insufficiency often associated with chemotherapy.M üllerian inhibiting substance (MIS), also known as antiMüllerian hormone (AMH), has long been appreciated for its role in sex differentiation and reproduction, and sensitive ELISAs measuring blood levels are used in fertility clinics around the world as a measure of ovarian reserve (1-6). MIS plays important roles in the development of the gonad and the differentiation of the urogenital ridge. In the male fetus, MIS produced by the developing testes causes regression of the Müllerian duct (7). In the female fetus, MIS may play a role in early follicle assembly in the gonad by primordial germ cells (not to be confused with primordial follicles), since mice overexpressing MIS are devoid of germ cells shortly after birth (8), and, similarly, ex vivo incubation of fetal ovaries with MIS results in the inhibition of follicle assembly (9). These data highlight a role of MIS during fetal development that is distinct from its regulatory role of folliculogenesis postnatally.In the adult, MIS is produced predominantly by the cumulus (less so by the mural) granulosa cells of secondary and early antral...

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Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies

Cited by 194 publications

References 43 publications

Second international consensus guidelines for breast cancer in young women (BCY2)

Second international consensus guidelines for breast cancer in young women (BCY2)

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

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