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Endocrine and Fertility Effects in Male Cancer Survivors: Changes related to androgen-deprivation therapy and other treatments require timely intervention.

Thaler-DeMers, Debra BSN, RN, OCN, PRN-C

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Debra Thaler-DeMers is a staff nurse and chemotherapy and biotherapy instructor at Stanford University Hospital and Clinics, Peterson Cancer Treatment Center, San Jose, CA. Contact author: The author of this article has no significant ties, financial or otherwise, to any company that might have an interest in the publication of this educational activity.

Men who survive cancer treatment face many long-term consequences that often are neglected at the time of diagnosis and during initial treatment, when both the health care team and the patient are focusing on survival. Each type of cancer treatment has a unique adverse-effect profile; many of these adverse effects concern sexual function.

Men who have cancers arising from the lower gastrointestinal tract (small and large bowel, rectum, and anus) and the genitourinary system (kidney, bladder, ureters, urethra, penis, prostate, and testes) are especially at risk for alterations in sexual function, including erectile and reproductive dysfunction. They also are at increased risk for problems such as urine or bowel leakage, incontinence, and fistula formation. 1–6 Retroperitoneal lymph node dissection, a surgical staging procedure often used for gastrointestinal and genitourinary cancers, increases the risk of sexual and reproductive dysfunction. 7

Chemotherapy and radiotherapy, especially that which targets the gonads or the hypothalamus and pituitary gland, are well-known causes of endocrine disturbances and infertility. 8 External beam radiotherapy for prostate cancer causes a decline in erectile function, but the change occurs much later in the lives of survivors than does erectile dysfunction after prostatectomy. 9 Cranial irradiation may result in hypogonadism, hypothyroidism, growth hormone deficiency, cardiovascular problems, and infertility. 10 Androgen-deprivation therapy, also known as medical or surgical castration, is a form of hormonal manipulation commonly used in the management of prostate cancer and can lead to myriad changes, which are discussed below. 11, 12

Often, neither health care professionals nor patients raise issues of long-term sexual function and fertility before treatment begins, except in the case of cancers involving the sexual organs. For some men, infertility is associated with decreased virility, and it may affect sexual self-image as well as self-esteem. 13 The interdisciplinary care team should address these issues, emphasizing the availability of treatment options for the adverse sexual effects of treatment.

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Androgen-deprivation therapy can be accomplished by surgically removing the testosterone-producing testes. Medical castration is accomplished by administration of gonadotropin-releasing hormone agonists such as leuprolide (Lupron and others) or goserelin (Zoladex). The goal of hormonal manipulation is to achieve “castration” testosterone plasma levels of less than 0.5 ng/mL.

There is little in the nursing literature on the endocrine changes caused by androgen-deprivation therapy and the implications for cancer survivors. The medical literature indicates that the acute adverse effects of androgen-deprivation therapy include hot flashes, fatigue, impotence, loss of libido, cognitive changes, and depression. 14 Longer term androgen-deprivation therapy also may be associated with sexual dysfunction, changes in cognitive function, and depression and may result in anemia, loss of lean muscle mass, weight gain, osteoporosis, risk of bone fracture, loss of body hair, and risk of secondary malignancy. 14–18 Some of these effects can be mitigated through the use of intermittent rather than continuous androgen-deprivation therapy, as well as by medications to alleviate hot flashes and gynecomastia (breast enlargement) and to minimize osteoporosis and the risk of bone fractures. 19

Quality-of-life surveys reflect vastly different perceptions between health care professionals and cancer survivors with respect to endocrine changes. 20, 21 Nurses tend to focus quality-of-life research on such matters as the ability to live a normal life, happiness and satisfaction, and physical and mental capabilities. 22 Survivors have identified other key characteristics of quality of life in the cancer experience, including changing perceptions of what is important, a loving connection with a special person, and learning to tolerate feeling alienated from a societal norm. 21 To improve the quality of life for survivors, both nursing education and survivor education programs must be developed.

Currently, the nursing literature fails to cite interventions to assist survivors in dealing with treatment-related endocrine changes. Research should focus on interventions that will improve survivors’ quality of life without diminishing the effectiveness of androgen-deprivation therapy. Alternatives such as the use of estradiol or intermittent androgen-deprivation therapy schedules have shown promising results. 19 Phosphodiesterase type 5 inhibitors such as sildenafil (Viagra) are often prescribed to address the diminished libido and erectile dysfunction common among men treated with androgen-deprivation therapy, but the medications have not been evaluated for use in this population. 23

Men treated with androgen-deprivation therapy are at high risk for decreased bone mineral density and subsequent increased risks for osteopenia, osteoporosis, and skeletal fractures. 24, 25 Studies have demonstrated the value of bisphosphonates in cancer survivors with osteoporosis and those with androgen-dependent prostate cancer and skeletal metastases. 26–28 Nonmedical therapies also may be beneficial. For example, implementation of individual and community-based fall prevention programs can decrease the risk of falls and subsequent fractures. 29, 30 Interventions to reduce falls generally include assessment and modification of home hazards and exercises for muscle strengthening and balance training. 29–31

The relationship between androgen-deprivation therapy and depression requires study. Depression is a normal aspect of the adjustment to a diagnosis of cancer, but cancer survivors should be monitored periodically for major depression and the risk for suicide. Nurses and all health care team members should be trained in screening survivors for suicidal ideation. This skill should be developed in the nursing curriculum and consistently reinforced.

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Studies of the reproductive implications of cancer treatment do not include baseline fertility data obtained before diagnosis. Therefore, it is not known whether the quality of sperm (count and motility) harvested from cancer patients before treatment is poor because of the disease process itself. Time constraints at the time of diagnosis make it difficult to obtain multiple sperm samples for cryopreservation with the recommended 48 to 72 hours between sample collections.

The effect of chemotherapy and radiation on male fertility seems to involve both destruction of stem cell spermatogonia (stem cells that give rise to spermatocytes) and arrest of spermatogenesis (the process in which immature spermatogonia become spermatocytes and then transform into spermatozoa). 32 Factors affecting fertility include drugs, dosages, age at treatment, duration of treatment, and type of malignancy. Table 1 (page 67) lists chemotherapeutic agents that have been implicated in male infertility and the types of cancer for which they are used. It should be noted that long-term effects on fertility have not been studied for newer therapies such as imatinib (Gleevec) and gefitinib (Iressa), which target specific molecules involved in the development and progression of cancer cells, and for biologic agents such as interferons, inter-leukins, and monoclonal antibodies.

Table 1
Table 1
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The effect of cancer treatment on sperm counts may be temporary or permanent. Some men with azoospermia (the absence of living sperm in semen) immediately after cancer treatment eventually recover sperm counts sufficient to conceive children without assisted reproductive techniques. 33 Recovery of spermatogenesis may also occur in some cases after bone marrow transplant. 34

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Genetic alterations.

The risk of genetic damage caused by chemotherapy or radiation is controversial. Chromosomal abnormalities have been observed in survivors during and immediately after treatment. 35, 36 This could result in miscarriages, still-births, or birth defects in the offspring of survivors. 37 However, studies comparing the offspring of survivors with the offspring of survivors’ siblings have demonstrated no increased risk of birth defects among the children of survivors. 35

Because of the uncertainty about treatment-related chromosomal damage, men should wait at least six months after the end of cancer treatment before attempting to harvest sperm for assisted reproduction. Given the possibility that genetic deformities may not manifest in the first generation (an issue that has not yet been raised in the literature), continued monitoring of the offspring of cancer survivors for several generations will be necessary to resolve the question of whether treatment of cancer increases the risk of malignancy or genetically transmitted abnormalities. 38

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Assisted reproduction options.

Intracytoplasmic sperm injection (ICSI), combined with in vitro fertilization (IVF), has made it possible for survivors with low sperm counts or poor sperm motility to father children after cancer treatment. With ICSI, a single spermatozoon is injected directly into the oocyte. One reason this option is not widely used is that many practicing oncologists, including those who offer sperm banking, are unaware of the latest advances in reproductive technology. 33, 39–41 Costs are another barrier. Many insurance companies do not cover the cost of harvesting or storing sperm or testicular tissue. The cost for the initial consultation, blood tests, and harvesting of ejaculated sperm is several hundred dollars. Annual storage fees for cryopreserved sperm or tissue can range from $300 to $600. Patients generally do not have time before treatment of cancer begins, nor do they have the physical and emotional resources required to compare the costs and benefits of different sperm or tissue banks. IVF costs for one cycle range from $10,000 to $15,000 for medications, testing, procedures, and cryopreservation of viable embryos. In at least seven states, the costs of IVF must be covered by health insurance. 33

Some techniques are currently available for survivors who are not able to ejaculate but wish to father children, and other techniques are in development (see Table 2, at right).

Table 2
Table 2
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Legal and ethical concerns.

Preservation of fertility in cancer survivors raises legal and ethical issues. The legal ownership of cryopreserved tissue must be determined. If the donor dies, would this tissue be destroyed, available for use by a surviving spouse or other relative, donated for use by other infertile couples (survivors or not), or donated for medical research?

Genetic counseling should be made available to survivors contemplating parenthood. Their offspring should be monitored for potential genetic anomalies, and this monitoring may be necessary for several generations.

If cancer survivors remain infertile after exhausting their options for assisted reproduction, adoption remains a possibility. Laws have not dealt with whether cancer survivors must be required to disclose their cancer history when seeking to adopt a child. Nor has the legal system determined whether adoption agencies, private or public, are prohibited from discrimination against cancer survivors as potential parents based solely on their cancer history. These issues need to be adequately addressed.

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In an ideal situation, nurses would be able to meet with patients at least a week before the start of cancer treatment. Routine explanation of treatment options and symptom management would include options for sperm and tissue banking. Written information that is easy to understand, culturally sensitive, and available in the patient’s native language would be provided and also explained in detail. A case manager would be available to assist with any insurance or financial issues.

Orientation programs for new graduates and continuing education for oncology nurses must include current information on preservation of fertility for cancer survivors. This information should be part of the core competency for oncology nursing practice.

Priorities for medical and nursing research include the following:

* the mechanism of treatment-related infertility

* methods to improve the techniques for harvesting and preserving gonadal tissue

* potential chemoprotective agents for gonadal tissue

* connection between androgen-deprivation therapy and depression

* ways to minimize effects of androgen-deprivation therapy

Long-term follow-up of survivors, with coordinated data collection, is essential. Nursing research should focus on physiologic changes associated with treatment and the implications of late and long-term effects of treatment on the quality of life of cancer survivors.

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What to Ask Male Cancer Survivors

* Are you seeing an oncology professional at least once a year to get checked for recurrence, new symptoms, and long-term effects from your illness and treatment?

* Have you had changes in your sexual relationships or ability to have sex since you got cancer? (Many cancer survivors experience such changes.)

* Are you interested in information about having children some day, or about the effect that your cancer treatment may have on your children?

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© 2006 Lippincott Williams & Wilkins, Inc.