The testes are the male reproductive organs. These oval glands are each approximately 2 inches long when fully mature. They are enclosed in a sac called the scrotum. Each testicle contains hundreds of densely coiled tubes (called seminiferous tubules) that contain spermatogonia—cells that produce sperm. The creation of sperm depends on the presence of adequate FSH (follicle-stimulating hormone) and healthy germ cells.

Leydig cells, found throughout the testicles, produce the hormone testosterone. Leydig cell function is prompted by LH (luteinizing hormone). These two cell lines—spermatogonia and Leydig cells—react very differently to treatment for cancer.

Organ damage

The testes can be damaged by radiation, chemotherapy, or surgery. The following information is about “primary failure,” when treatment affects the testes themselves.

Radiation: Spermatogonia

Spermatogonia are very sensitive to radiation. One hundred to 500 cGy of radiation to the testes can cause a temporary drop or stoppage of sperm production, and more than 600 cGy usually results in permanent sterility. When sperm production is permanently affected, reduced testicular size and softer testicles result. Survivors likely to have received these doses are:

• Boys treated for testicular leukemia.

• Recipients of stem cell transplants whose conditioning included radiation.

• Boys or teens with Hodgkin lymphoma treated with “inverted-Y” radiation.

• Boys or teens with soft tissue sarcomas in the thigh, groin, or abdomen.

If damage to sperm-producing cells occurs before puberty, the first clue that there is a problem occurs when the testes do not grow to a normal size during puberty. These boys develop secondary sexual characteristics (e.g., facial hair, deepening voice), but the testes remain small and soft. If the teen is rendered infertile by treatment after puberty, his testicles may become softer and smaller over time.

Radiation: Leydig Cells

Compared to spermatogonia, testosterone-producing Leydig cells are very resistant to radiation. Whereas male sperm production is affected quickly by small amounts of radiation, it takes approximately 2000 or more cGy to the testes before Leydig cells start to become damaged. The younger the patient, the more severe the effect of the radiation on the Leydig cells.

Cranial or craniospinal radiation, given to children with ALL or brain tumors (other than those near the pituitary), rarely causes damage to testosterone production.

Chemotherapy

Chemotherapy can be devastating to the production of sperm, although sperm production may resume months to years after chemotherapy ends. The drugs that most affect sperm are the alkylators:

• Mechlorethamine and procarbazine (contained in MOPP—mechlorethamine, vincristine, procarbazine, and prednisone)

• Cyclophosphamide (contained in COPP—cyclophosphamide, vincristine, procarbazine, and prednisone)

• Ifosfamide

• Chlorambucil

• Nitrosoureas

• Melphalan

The higher the doses of these drugs, the more damage may occur to the sperm-producing cells.

Chemotherapy used to treat boys with leukemia does not usually affect sperm production unless high doses of cyclophosphamide were given. Vinblastine, bleomycin, and etoposide used to treat other cancers can temporarily affect sperm production, but the majority of survivors, over time, recover the ability to produce sperm.

It was thought for many years that testosterone-producing Leydig cells were immune to damage from chemotherapy, but this has proven not to be the case. High doses (nine courses or more) of MOPP or COPP can cause irreversible damage to the Leydig cells. These high doses are generally only seen in survivors who relapsed and received large amounts of chemotherapy drugs.

Patients treated during adolescence can have low testosterone and high LH. There can also be a lowering of libido despite a normal testosterone level. This means that for a survivor who received and is experiencing any abnormalities in puberty or sexual functioning, a thorough evaluation may help determine the cause and identify solutions.

In this situation, an endocrinologist should talk with the young man about his testosterone level and how it affects his life. Replacement testosterone does not just govern sex drive; it affects energy, stamina, and secondary sexual characteristics, and it contributes to an overall sense of well-being. It is also important to psychological and sexual development. Many teens and men with low-functioning Leydig cells feel much better when taking supplemental testosterone.

The preceding information discussed primary failure—damage to the glands themselves. Spermatogonia and Leydig cell functioning can be affected by damage to the HPA as well; this is called “secondary failure.” A dose of 4500 cGy to the HPA in the brain can shut down both Leydig cells and sperm production. If there is nothing wrong with the testes but they have been shut down by the brain, they can be stimulated with hormones to produce sperm. It’s vital to determine whether a survivor has primary or secondary failure so he can get the best treatment.

Surgery can also affect sexual functioning in males. If a survivor had an abdominal lymph node dissection, side effects can include impotence or inability to ejaculate. For more information, see Chapter 14 . Surgery for a brain tumor involving the hypothalamus or pituitary also can disrupt the functioning of the testes.

Survivors may be concerned about the health of any children they father. The research is reassuring in this regard. The children of male survivors are just as healthy as those of the general population (the one exception are children born to a parent who carries the gene for an eye tumor called retinoblastoma). For more information, see Chapter 3 .

Signs and symptoms

Signs and symptoms of damage to the testes depend on age during treatment. If testosterone-producing Leydig cells are damaged before puberty, boys usually won’t go into puberty. If the Leydig cells are damaged after puberty, survivors may lose interest in sex and may become impotent.

If the sperm-producing cells are damaged before puberty, the testes won’t grow as large as they normally would have. Survivors will have testosterone, so will look like a normal male and can function sexually like a normal male, but the testes will be smaller and softer. If sperm-producing cells are damaged after puberty, sexual functioning will be unaffected, but the survivor may not produce sperm. Therefore, function is normal, but the survivor may be infertile.

Primary testicular failure. Signs and symptoms of primary testicular failure (i.e., damage directly to the testicles) include the following:

• Absence of or change in libido (sex drive) if Leydig cells are affected

• Low or absent sperm counts

• Increased breast size

Secondary testicular failure. Signs and symptoms of secondary testicular failure (damage to the HPA) include the following:

• Lack of secondary sex characteristics (e.g., facial and pubic hair) and decreased testicular size

• Decreased libido

• Impotence

• Low testosterone levels

Screening and detection

Survivors should receive a thorough annual evaluation if they received chemotherapy or radiation that might have damaged their testes. Also, any boy showing signs of puberty before age 9 or who has not begun puberty by age 14 needs to be examined by an endocrinologist. This examination may include the following:

• A thorough history, including height, weight, and age when puberty occurred in all members of the family. The history should rule out other causes of precocious or delayed puberty, including hypothyroidism, medications such as steroids for bodybuilding, illegal drug use, chronic disease, or malnutrition.

• A careful physical evaluation, including evaluation of facial hair, underarm hair, pubic hair, length of penis, and size of testes.

• Analysis of a semen sample and a discussion about ejaculations, erections, and libido.

• Growth plotted on a chart to evaluate growth progression.

• LH, FSH, and testosterone levels.

• Prolactin level if radiation was given to the HPA.

• Discussion about fertility and libido.

Recovery of sperm production sometimes occurs 10 or more years after treatment. These tests should be repeated yearly for men who have a low sperm count.

Medical management

Male survivors who do not produce sperm as a result of direct damage to the testes (called primary failure) must simply wait to see if sperm production recovers over time. They should have periodic sperm counts and evaluations of testosterone production, as testosterone replacement may improve a sense of well-being.

Even if teens have no sperm production after treatment ends, it can return. Healthcare providers should explain if new advancements in reproductive technology, such as intracytoplasmic sperm injection, might be an option for survivors who want to father a child. Survivors should not assume that they are infertile; they should use birth control unless they are trying to become a parent.

In addition, if the testes have been shut down by radiation or surgery to the brain, survivors may begin to produce sperm if they received LH and FSH supplementation.

Teens or adults with primary Leydig cell damage need replacement testosterone. A testosterone patch or injection into the muscle every 2 to 4 weeks are the most common methods of supplementation for males with low testosterone. The treatment begins at the time of normal puberty and starts with doses of 25 to 50 mg per month of testosterone enanthate (not methyltestosterone). Dosage is increased by 50 mg every 6 months until the survivor is receiving 200 to 300 mg per month. This treatment helps the development of the genitals. In addition, the growth of prepubertal boys with low testosterone levels may be enhanced by injections of growth hormone (if they are growth hormone deficient). Boys with Leydig cell damage should be treated by a pediatric endocrinologist with experience treating survivors of childhood cancer.

High-dose radiation (more than 5500 cGy) to the HPA can cause hyperprolactinemia. Treatment with bromocriptine can sometimes resolve the symptoms, which include decreased libido, impotence, and low testosterone.

Children or teens with pelvic tumors (e.g., rhabdomyosarcoma, Ewing sarcoma) who receive high doses of abdominal radiation may have nerve damage that affects sexual functioning. Even with hormone replacement, these survivors sometimes continue to have sexual problems. Working closely with a pediatric endocrinologist and urologist will help survivors achieve the best possible outcome given their treatment.

Medical management also includes counseling to help cope with the possibility of late effects on sexuality and fertility. For infertile males, counseling is helpful to explore other ways to become a parent (such as using donor sperm or adoption). Also, education about the difference between infertility (the inability to father a child biologically) and impotence (the inability to have or maintain erections) is tremendously important. The majority of male survivors of childhood cancer are able to have satisfying sexual relationships.