Impact of cancer therapy on the reproductive axis.

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Abstract

Cancer therapy includes surgery, chemotherapy and irradiation. Depending on the diagnosis, the location of the neoplasm and the age of the patient, these treatment modalities may be given alone or in combination. All forms of cancer therapy can affect the hypothalamic-pituitary-gonadal axis. The long-term consequences for reproductive function depend on several aspects. The sex of the patient is important, since ovarian and testicular function differ significantly. Sex hormone production in the female is dependent on the presence of germ cells, whereas this is not the case in the male. The sensitivity of germ cells to cancer therapy also differs between the sexes. Moreover, the sensitivity of both the hypothalamic-pituitary axis and the gonads is highly age dependent. With regard to chemotherapy, the possible damage to the gonads is dependent on the total dose and type of agent given. According to current knowledge, the hypothalamic-pituitary axis is not affected by conventional doses of chemotherapy. Radiotherapy has by far the most damaging effect on the reproductive axis, having serious adverse effects on both the hypothalamic-pituitary area as well as on the gonads themselves. The harmful effect of irradiation depends on the total dose of irradiation, the radiation field, as well as the number and size of fractions given. The long-term consequences of recently introduced radiotherapeutic methods such as stereotactic irradiation are not yet known. The present review will focus on the late effects of cancer therapy in children and young adults with acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, brain tumour, Hodgkin's lymphoma or Wilms' tumour, including the adverse effects of bone marrow transplantation.

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Hypothalamic-pituitary dysfunction after radiation for brain tumors.

R Raubertas, Jeff D. Cann, G. Mick … (1993)

Patients with brain tumors who are treated with radiation frequently have growth hormone deficiency, but other neuroendocrine abnormalities are presumed to be uncommon. We studied endocrine function in 32 patients (age, 6 to 65 years) 2 to 13 years after they had received cranial radiotherapy for brain tumors. The doses of radiation to the hypothalamic-pituitary region ranged from 3960 to 7020 rad (39.6 to 70.2 Gy). Nine patients also received 1800 to 3960 rad (18.0 to 39.6 Gy) to the craniospinal axis. Serum concentrations of thyroid, gonadal, and pituitary hormones were measured at base line and after stimulation. Nine patients (28 percent) had symptoms of thyroid deficiency, and 20 patients (62 percent) had low serum total or free thyroxine or total triiodothyronine concentrations. Of the 23 patients treated only with cranial radiation, 15 (65 percent) had hypothalamic or pituitary hypothyroidism. Of the nine patients who also received spinal (and thus direct thyroid) radiation, three (33 percent) had evidence of primary thyroid injury. Seven of the 10 postpubertal, premenopausal women (70 percent) had oligomenorrhea, and 5 (50 percent) had low serum estradiol concentrations. Three of the 10 men (30 percent) had low serum testosterone concentrations. Overall, 14 of the 23 postpubertal patients (61 percent) had evidence of hypogonadism. Mild hyperprolactinemia was present in 50 percent of the patients. Responses to stimulation with corticotropin-releasing hormone and corticotropin were normal in all patients except one, who had panhypothalamic dysfunction. However, serum 11-deoxycortisol responses to the administration of metyrapone were low in 11 of the 31 patients (35 percent) tested. Three of the 32 patients, (9 percent) had no endocrine abnormalities, 9 (28 percent) had an abnormal result on tests of thyroid, gonadal, prolactin, or adrenal function, 8 (25 percent) had abnormalities in two axes, 8 (25 percent) in three axes, and 4 (12 percent) in all four axes. Cranial radiotherapy in children and adults with brain tumors frequently causes abnormal hypothalamic-pituitary function. The most frequent changes are hypothyroidism and gonadal dysfunction, although subtle abnormalities in adrenal function may also be present.

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Reproduction post-chemotherapy in young cancer patients.

Dror Meirow (2000)

High-dose chemotherapy and radiotherapy has increased long-term survival of young patients with cancer. Sometimes however, the price paid is ovarian failure and sterility. It is highly important to detect who are the patients at risk in order to verify when fertility preservation is indicated. With conventional chemotherapy, there is significant differences in ovarian failure rate according to patients age, disease for which patients are treated for, and the drugs used. Bone marrow transplantation in cancer patients almost invariably induced ovarian failure, irrespective of patient age, treatment protocol or administration of hormonal treatment. Moreover, normal reproductive parameters post-chemotherapy does not necessarily imply that the ovaries escaped damage; ovarian injury is not an all or none phenomenon--partial loss of primordial follicle reserve can result in premature menopause as a delayed reaction to treatment. This should be taken into account while consulting former cancer patients about future planed pregnancies. The direct mechanisms of chemotherapy induced ovarian failure are poorly understood. An in vitro study has demonstrated that in the human ovary chemotherapy acts primarily on primordial follicles through induction of apoptotic changes in pregranulosa cells which lead to follicle loss. Protecting fertility potential in females exposed to chemotherapy with IVF and embryo cryopreservation or cryopreservation of ovarian tissue is practiced. Ovarian tissue cryopreservation: A recent study has demonstrated that laparoscopic ovarian biopsy performed with the round biopter is a safe and efficient method for collecting ovarian tissue for cryopreservation in cancer patients. In order to avoid possible hazards of transferring malignant cells, genetic and immunohistochemical markers for detection of minimal residual cancer cells in ovarian tissue are currently used. However, the reproductive potential of this method is still questionable. IVF: IVF and embryocryopreservation is currently used in infertile patients, however, several obstacles prevent it's wide implementation in cancer patients such as the need for male partner and the time needed for ovarian stimulation. A highly important issue is the possible risk of performing IVF and embryo cryopreservation to preserve fertility in females already exposed to chemotherapy. An animal study has raised serious concerns regarding the consequences of chemotherapy on future pregnancies. High abortion and malformation rates related to the different stages of oocyte maturation at the time of exposure to chemotherapy were demonstrated. These results should be taken into account when considering the use of IVF and embryo cryopreservation following chemotherapy treatment in cancer patients.

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Gonadal function following chemotherapy for childhood Hodgkin's disease.

Diane Radford, S. Shalet, N Mackie (1996)

Gonadal function was assessed in 101 postpubertal subjects after chemotherapy for childhood Hodgkin's disease. All had received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisolone) chemotherapy alone, with no radiotherapy below the diaphragm. Gonadotropin levels were available in 46 (79.3%) male and 32 (74.4%) female subjects. The mean age at diagnosis in the male cohort was 12.2 years (range 8.2-15.3) and in the females 13.0 years (9.0-15.2). The males and the females were studied at a median of 6 years (range 2.5-11.1) and 4.3 years (range 1.9-11.5) from diagnosis, respectively. Forty-one (89.1%) male subjects had elevated follicle-stimulating hormone (FSH) levels, confirming severe germinal epithelial damage. Germinal epithelial damage was seen in subjects up to 10 years out of therapy. Subtle Leydig cell dysfunction was identified in 24.4% with raised luteinzing hormone (LH) levels. All subjects, however, progressed spontaneously through puberty. Seventeen (53%) women had raised gonadotropin levels, with variable estradiol levels. Of these, 10 subjects presented with symptomatic ovarian failure and 6 received hormone replacement therapy (HRT). Nine women had 11 successful pregnancies, two of whom had previously had symptoms of ovarian failure with one requiring HRT. A much higher prevalence of ovarian failure has been observed, than has previously been considered in the prepubertal and pubertal female following combination chemotherapy. These conclusions have important implications for future counseling, management, and research in this population.