Gonadal Toxicity Following Malignancy Treatment

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In addition to Hodgkin and non-Hodgkin's lymphoma, acute lymphocytic leukemia and acute myeloid leukemia are among the most common neoplastic disorders during the reproductive years.10 As the mortality rate decreases and the survival rate increases, the consequences of cancer treatment vis-a-vis impaired fertility are more frequently encountered.


Chemotherapeutic agents enter testis via blood vessel plexus in the interstitial region. Although the Sertoli cells usually maintain a protective barrier between the blood and the testicular germ cells, many chemothera-peutic drugs can severely interrupt the integrity of this barrier.

Germ cells that do actively differentiate are more susceptible to cytotoxic injury, resulting in necrosis, whereas testicular somatic cells are affected only in function. As a result, cytotoxic therapy can deplete germ cells to the point where the seminiferous tubules contain only Sertoli cells. The depletion occurs in a time-dependant manner because late-stage germ cells (spermatocytes onward) are relatively more resistant. However, studies in rodents revealed that these late-stage cells are susceptible to mutagenesis, and any mutations in their DNA can be passed on to the next generation.11 Surviving stem cells can remain in the testis, but will fail to differentiate into mature spermatozoa for several years after cytotoxic abuse. The eventual recovery of sperm production depends on the survival of the spermatogonial stem cells, as well as on their ability to differentiate.12

The effects of cancer therapy on testicular architecture vary with the patient's age and pubertal status. It was initially thought that the testicles of pre- and peri-pubertal males were less vulnerable to toxic effects induced by treatment. However, it is now clear that these patients experience as much testicular structure damage following chemo/radiotherapy as adults.13

Hormonal imbalances

The loss of germ cells exerts secondary effects on the hypothalamic-pituitary-gonadal axis. Germinal apla-sia reduces the size of the testes. Consequently, testic-ular blood flow decreases, thus reducing the testosterone levels in the circulation.14 Because testosterone is a negative regulator of luteinizing hormone (LH), which is secreted by the pituitary, and LH is the primary stimulator of testosterone synthesis by the Leydig cells, LH increases to maintain constant serum testosterone levels. In addition, inhibin secretion by the Sertoli cells declines and, as inhibin limits follicle-stimulating hormone (FSH) secretion by the pituitary, serum FSH levels tend to rise.


Histological sections of ovaries exposed to cytotoxic drugs show a spectrum of changes, ranging from reduced number of follicles to no follicles and fibrosis.15 The exact incidence of premature ovarian failure (POF) after chemotherapy is difficult to establish because there are many contributing factors. Depending on the type of chemotherapy regimen used, the incidence of amenorrhea ranges from 0% to 100%.16 Cytotoxic drugs may impair follicular maturation and/or deplete primordial follicles.1517 Temporary amenorrhea occurs when cytotoxic drugs destroy maturing follicles, whereas permanent amenorrhea or POF occurs when all primordial follicles are destroyed. The close structural and functional relationship between the oocyte and the hormone secreting-granulosa cells makes it difficult to identify an exact target for cytotoxic drugs. The destruction of one leads to the demise of the other.

Hormonal imbalances

Unlike male germ cells, female germ cells proliferate only during prenatal life; after birth, these progressively decrease in number due to apoptosis, and ovulation. Germ cells inside the female gonad do not proliferate, whereas the somatic cells do. Radiation and chemotherapy induce oocytes to undergo apoptosis, which reduces the number of germ cells,18 resulting in estrogen insufficiency. Therefore, when follicles are destroyed by cytotoxic therapy, the frequency of menses decreases and amenorrhea commonly occurs. Irreversible ovarian failure and menopause occur if the number of follicles falls below that is required for menstrual cyclicity.

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