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.
The ovary is the main female organ that produces critical endocrine steroid hormones such as estrogen and progesterone. These endocrine hormones regulate the development of female sexual characteristics such as timing of reproductive cycles, breast development, and staging the uterus for successful pregnancy.
The ovary is also responsible for the development of mature oocytes capable of fertilization. The number of oocytes present in the ovaries at birth does not increase and determines the female reproductive lifespan [
The oocyte is surrounded by pre-granulosa/granulosa cells, which together form the follicle as a functional unit in the ovary [
Cancer therapy is like a 2-sided coin. It often causes many side effects in other organs including the risk of loss of ovarian follicles, while it increases the survival rate in the cancer patients [
Currently, there are options available for saving the ovarian follicles in cancer patients, which is dependent on their status [
Proposed mechanism of loss of PFs | Proposed adjuvants | |
---|---|---|
Activation | Direct | AS101 [ |
Indirect | AMH [ | |
Apoptosis | Direct | GnRH agonists [ |
Indirect | S1P [ |
AMH, anti-Müllerian hormone; 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; G-CSF, granulocyte-colony stimulating factor.
Oocytes from dormant primordial to early secondary follicle highly express tumor protein p63, TAp63α, an oocyte-specific isoform of p63 [
Gonadotoxic therapies deplete PFs in the ovarian reserve. There are two prevailing theories regarding the effect of chemotherapeutic agents on the oocytes of dormant PFs (
Intensive research has been conducted in the past decade to better understand how best to protect the ovarian germ cells from gonadotoxic agents such as chemotherapeutic agents or environmental toxins. However, it is unclear how ovarian germ cells die from chemotherapeutic agent insults and which approaches provide the best protection of the germ cells. Thus, this review revisits the current literature with a view towards unveiling the cytotoxic consequences of chemotherapeutic agents on PFs.
Existing literature supports the idea that activation of the PI3K/AKT/mTOR signaling pathway stimulates dormant PFs to enter the pool of growing follicles [
A study conducted by Goldman et al. [
A recent
Jang et al. [
The indirect activation concept for loss of the ovarian reserve was recently highlighted by Kano et al. [
Gonadotropin-releasing hormone (GnRH) agonists/antagonists are clinically used as ovoprotectants/fertoprotectants [
Recent studies from our laboratory indicate that the chemotherapeutic agents directly destroy oocytes of dormant PFs and supports the inactivation concept. In support of the notion, cyclophosphamide treatment in three different mouse strains (C57BL/6J, CD-1 and BALB/cJ) did not promote any increase in the total number of primary and secondary follicles [
Oxidative stress affects reproductive health in females through the production of reactive oxygen species (ROS). Although ROS play an important role in signal transduction during folliculogenesis, oocyte maturation, and embryogenesis [
Understanding the exact mechanisms responsible for the disruption of the ovarian reserve induced by different classes of chemotherapeutic agents and environmental ovotoxins will allow for a rational approach to identify drug targets that protect oocytes and germ line integrity, select specific adjuvants and protect the ovarian reserve following cancer treatments (
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.