Obstet Gynecol Sci.  2019 Nov;62(6):382-390. 10.5468/ogs.2019.62.6.382.

Consequences of chemotherapeutic agents on primordial follicles and future clinical applications

• Kim SY
• Cho GJ
• Davis JS

• KMID: 2462115
• DOI: http://doi.org/10.5468/ogs.2019.62.6.382

Abstract

The ovarian reserve is necessary for female fertility and endocrine health. Commonly used cancer therapies diminish the ovarian reserve, thus, resulting in primary ovarian insufficiency, which clinically presents as infertility and endocrine dysfunction. Prepubertal children who have undergone cancer therapies often experience delayed puberty or cannot initiate puberty and require endocrine support to maintain a normal life. Thus, developing an effective intervention to prevent loss of the ovarian reserve is an unmet need for these cancer patients. The selection of adjuvant therapies to protect the ovarian reserve against cancer therapies underlies the mechanism of loss of primordial follicles (PFs). Several theories have been proposed to explain the loss of PFs. The "burn out" theory postulates that chemotherapeutic agents activate dormant PFs through an activation pathway. Another theory posits that chemotherapeutic agents destroy PFs through an "apoptotic pathway" due to high sensitivity to DNA damage. However, the mechanisms causing loss of the ovarian reserve remains largely speculative. Here, we review current literature in this area and consider the mechanisms of how gonadotoxic therapies deplete PFs in the ovarian reserve.

Keyword

Ovarian follicle; Primary ovarian insufficiency; Fertility; Fertility preservation

MeSH Terms

Adolescent
Child
DNA Damage
Female
Fertility
Fertility Preservation
Humans
Infertility
Ovarian Follicle
Ovarian Reserve
Primary Ovarian Insufficiency
Puberty
Puberty, Delayed

Figure

• 

  Fig. 1 Mechanism of primordial follicle (PF) loss by chemotherapeutics and ovotoxicity along with proposed fertoprotective agents to maintain the ovarian reserve. PFs consist of oocytes and squamous pregranulosa cells, while growing follicles are surrounded by cuboidal granulosa cells in the ovary. Fertoprotective agents have been proposed against the cytotoxic consequences of chemotherapeutic agents or ovotoxicity on PFs. G-CSF, granulocyte-colony stimulating factor; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; ATM, ataxia-telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related; CHEK2, checkpoint kinase 2; CK1, casein kinase 1; S1P, sphingosine-1-phosphate; C1P, ceramide-1-phosphate; AMH, anti-Müllerian hormone.

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