EFFECT OF CANCER TREATMENT ON FEMALE
REPRODUCTIVE SYSTEM
Although cancer incidence rates in women less than 50 years old continue to increase during recent years, mortality rates are dramatically decreasing due to the modern advanced in treatment. Increasing number of survivors is now confronted with the long-term consequence of exposure to these treatments. Cancer therapy can have a profound impact on ovarian function: loss of fertility is one of the most devastating consequences of radio- or cytotoxic therapy, especially for young patients who, having overcome their disease, have expectation of a normal reproductive life (11).
Acute ovarian failure can occur during or after completation of chemotherapy or irradiation and may be transient or permanent so the consequences in pediatric population are particularly challenging. At a time when cancer survival is the first priority, questions regarding future reproductive ability and childbearing are difficult issue for physicians, patients and parents. Nevertheless, having foreknowledge of potential treatment-related ovarian failure will allow the physician to better counsel the patient and her family
regarding the importance and timing of fertility preservation given an estimated window of fertility (12).
2.1 NORMAL OVARIAN DEVELOPMENT AND FOLLICULAR DEPLETION
Current normal understandings of human ovarian reserve presume that the ovary establishes several million non-growing follicles (NGFs) during the second half of intrauterine life, which is followed by a decline to the menopause when approximately 1000 remain at an average of 50-51. In particular, by the inset of puberty, 400.000 follicles remain, which mature under the influence of hormones secreted within the hypothalamic-pituitary-ovarian axis. The secretion of gonadotrophin-releasing hormone (GnRH) from the hypothalamus stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. With each cycle, multiple follicles are selected to enter in the growing pool and begin to mature; an elevation in FSH results in one of these follicles becoming the dominant follicle that is selected for ovulation while the remaining follicles undergo atresia. The dominant follicle produces estradiol, which triggers an LH surge mid-cycle and results in the ovulation. This process—and additional atresia and apoptosis of unselected follicles—determine a decline in the number of ovarian primordial follicles during lifespan until menopause (13).
In a recent study, the first model of human ovarian reserve from conception to menopause has been described (fig 2.1). This model allows us to estimate the number of NGFs present in the ovary at any given age, and it suggests that 81% of the variance in NGF population is due to age alone. Further analysis demonstrated that 95% of NGF
population variation is due to age alone for ages up to 25. The remaining 5% is due to factors other than age e.g. smoking, body mass index, parity and stress (14).
The natural depletion of the finite number of follicles present in an individual female’s ovaries can be accelerated by cancer treatment.
FIG.2.1THE BEST MODEL FOR THE ESTABLISHMENT OF THE NGF POPULATION AFTER CONCEPTION, AND THE SUBSEQUENT DECLINE UNTIL AGE AT MENOPAUSE IS DESCRIBED BY AN ADC MODEL WITH PARAMETERS A =5.56(95%CI5.38–5.74), B =25.6(95%CI24.9–26.4), C =52.7(95%CI51.1–54.2), D = 0.074(95%CI0.062–0.085), AND E =24.5(95%CI20.4–28.6). MODEL HAS CORRELATION COEFFICIENT R2=0.81, FIT STANDARD ERROR =0.46 AND F-VALUE =364.THE FIGURE SHOWS THE DATASET (N =325), THE MODEL, THE 95% PREDICTION LIMITS OF THE MODEL, AND THE 95% CONFIDENCE INTERVAL FOR THE MODEL.
2.2 CLINICAL DETENCTION OF OVARIAN DMAGE INDUCED BY ANTI-CANCER THERAPY
Many studies use amenorrhea as a surrogate for ovarian failure, with biochemical confirmation that is elevated follicle stimulating hormone (FSH) concentration. However, these two parameters only detect the endpoint of the decline of ovarian function. It would be useful to have a biochemical or biophysical marker of the number of follicle in the ovary to allow detection of lesser degrees of damage and earlier changes during the progress to ovarian failure. This allows a more refined assessment of chemotherapeutic agents’ effects on the ovary and, from a clinical point of view, it allows to individualized therapeutic approach (15).
Follicle stimulating hormone (FSH) is the most widely used marker of incipient ovarian failure, but it has low sensitivity and inter-cycle variability.
Inhibin B is a product of the granulosa cells of growing follicles and shows a fair prediction of oocyte recovery following superovulation. It is produced by the granulosa cells of large and small antral follicles and its concentration declines only late in reproductive life so its value as a marker of loss of ovarian reserve is limited.
Anti-Müllerian hormone (AMH) is produced by the granulosa cells of smaller growing follicles (16). AMH secretion begins only at the start of follicle development and declines abruptly in the early antral stages. It is not a product of the dominant follicles and only to a limited extent of FSH-recruited follicles. Its serum concentration declines with age and shows much less variation across and between menstrual cycles than FSH or Inhibin B. Thus, AMH is the best currently available marker of the number of small growing follicles in the ovary.
Data are increasingly available on AMH’s utility to detect chemotherapy –induced loss of ovarian reserve in survivors of childhood and adult cancer (17) and limited data from prospective studies illustrate its ability to reflect acute gonatoxicity (18).
Ultrasound can also be used to assess the ovarian reserve. Antral follicle count and, to a lesser extent, ovarian volume have been explored as a markers of ovarian damage during chemotherapy. In a prospective study of women undergoing chemotherapy for breast cancer, both AFC and ovarian volume decreased during treatment (19).
2.3 CHEMOTHERAPY AND INFERTILITY
The impact of cancer treatment on reproductive potential depends on patient’s age at the time of treatment, the particular chemotherapeutic agents used, the duration of treatment, the total cumulative dose administered, and, likely, patient-specific factors, as similar regimens can have very different effects on women of the same age. The effect of age is presumably related to the smaller number of follicles in the ovaries of older patients at the time of treatment such that acute ovarian failure may be more likely to occur in older women and premature menopause in younger women or adolescents.
The ovary is susceptible to chemotherapy-induced damage, particularly following treatment with alkylating agents such as cyclophosphamide (20). Ovarian damage is drug and dose-dependent and it’s related to age at the time of treatment, with progressively smaller doses required to produce ovarian failure with increasing age. The effect of chemotherapy on the ovary is not an “all or nothing” phenomenon and the number of surviving primordial follicles following exposure to chemotherapy correlates inversely with
Histological studies of human ovaries have shown chemotherapy to cause ovarian atrophy and global loss of primordial follicles (21).
The mechanism involved in the loss of primordial follicles in response to anti-cancer therapy is not well understood. A few human and animal studies have demonstrated that chemotherapy induces damage to ovarian pre-granulosa cells and that apoptosis occurs during oocyte and follicle loss. In addition, injury blood vessels and focal fibrosis of the ovarian cortex are further patterns of ovarian damage caused by chemotherapy (22).
As dividing/proliferating cells are chemoterapeutic agents’ target, granulosa cells of growing follicles are the most chemotherapy sensitive cells in the ovary. This may be the reason of AMH serum levels decline during chemotherapy and the cessation of menstrual bleeding for a few months after therapy due to loss of growing larger follicles. Study in animals show that the loss of inhibitory influence of small growing follicle on initiation of primordial follicle growth will result in increased activation of the resting pool of primordial follicles which will be further destroyed by chemotherapy (23).
Assessing the contribution of individual chemotherapeutic agents on ovarian damage is difficult, as almost all drugs are given as part of multimodality regimen.
Cyclophosphamide and procarbazine are particularly toxic to the ovary and therefore present a relatively high risk to maintenance of fertility after treatment. Anthracyclines, such as doxorubicin and the platinum agents cisplatin and carboplatin, also confer a high risk of gonadotoxicity, although usually less than that of alkylating agents. Recent research in humans suggests that the mechanism of ovarian injury by doxorubicin also involves microvascular and stromal damage (13).
common therapy for Hodgkin lymphoma and caused amenorrhea in up to 80% of females and acute ovarian failure in 39–46% of young adults (24).
The BEACOPP regimen (bleomycin/ etoposide/ adriamycin/ cyclophosphamide/ oncovin/ procarbazine/ prednisone), results in amenorrhea in approximately 20% of women overall, but this rises to 67% in women treated with 8 cycles of dose-escalated BEACOPP (13). Regimens that limit the use of alkylating agents, such as ABVD (adriamycin, bleomycin, vinbkastine, dacarbazine) result in significantly less gonadotoxicity especially in women under 25 years old.
CMF (cyclophosphamide, methotrexate, 5- fl uorouracil), once used in the treatment of breast cancer, is found to be associated with rates of amenorrhea ranging from 21% to 71% in women under 40 years of age and 40–100% of women older than 40 years of age . Newer regimens such as AC (doxorubicin, cyclophosphamide) are associated with a significantly lower rate of amenorrhea (55%), whereas the addition of taxane is associated with a significantly higher rate of amenorrhea (64%) (13).
The high dose of cyclophosphamide that is often used as conditioning for hematopoietic stem cell transplant (HSCT)—in conjunction with other chemotherapy agents or total body irradiation (TBI)—carries a high risk for ovarian failure (25).
Little informations are available on newer chemotherapy agents and targeted therapies, and it is therefore important that this be a future research focus within the field of oncofertility.
irradiation, and the extent of the damage is related to the radiation dose, fractionation schedule and age at the time of treatment (26).
The uterus is at significant risk of following abdominal, pelvic or TBI in a dose and age-dependent manner (27).
Ionizing radiations cause the accumulation of DNA damage of cancer cells causing their death; even if cells of normal tissues have mechanisms for gene repair, they may also be affected by the radiation treatment. Tissue damage caused by ionizing radiation can be somatic, relating to the individual, or germinal, when they occur in its offspring. The somatic damage may be stochastic or non-stochastic: the first one consists in random alterations not related to the dose (solid tumours, leukaemia); the latter one is represented by not random alterations dose related such as infertility, dermatitis, cataracts, acute radiation syndrome. The germinal damage consists of stochastic gene mutations or chromosomal aberrations. Radiosensitivity degree is not the same for all kind of tissue: germinal tissue is one of the most radiosensitive and infertility can be non-stochastic effects of radiation treatment. Infertility can, also, occur either as a result of primary hypogonadism due to a direct damage on the gonads, both of secondary hypogonadism due to irradiation of the pituitary and hypothalamic regions, which results in a deficit in the secretion of gonadotrophin-releasing hormone (GnRH) with direct impact on gonadal function.
Irradiation of the ovaries in doses as low as 1–2 Gray in girls and 4–6 Gy in adults can have a permanent negative effect on the ovaries by causing the depletion of half the number of existing oocytes (the LD50) (28). As with chemotherapy exposure, the risk is
sensitive to radiation-induced ovarian damage. Doses ranging between 5 and 20 Gy are sufficient to cause permanent gonadal dysfunction, regardless of age of the patient, dose of 30 Gy premature menopause is certain in 60% of women aged less than 26 years (29), while over 40 years doses of 5/6 are enough to cause permanent damage.
High-dose cranial irradiation, in the dose range of 35–40 Gy or greater, can cause hypogonadism through effects on the hypothalamus and pituitary (30). Impaired fertility achieved trough this mechanism differs from direct irradiation of the ovaries: it appears to be related to absence of inhibitors influences on the hypothalamus, which results in the increase of the frequency and intensity of the pulsatile secretion of GnRH from the hypothalamus itself.
Uterine function may be impaired following radiation doses of 14-30 Gy as a consequence of disruption to uterine vasculature and musculature elasticity (31).
