Damage to hypothalamus and pituitary gland

The hypothalamus and the pituitary gland are not normally damaged by chemotherapy. But abnormalities occur after radiation to the brain, face, or neck. The pituitary gland can tolerate higher doses of radiation. The hypothalamus is more delicate and can be affected by doses as low as 1800 to 2000 cGy, but each survivor is different. The amount of damage depends on total dose, method (proton; photon) used to deliver radiation, and age of the child when irradiated.

Growth hormone deficiency is the most common problem after radiation to the HPA. It is often not immediately obvious and tends to worsen over time. The survivors most affected by damage to the HPA are those who were treated for brain tumors. Almost all younger children treated with more than 3000 cGy to the brain experience growth disruptions.

Survivors whose growth is most likely to be affected are:

• Survivors of childhood brain tumors

• Surgery in the area near the HPA and high doses of radiation can both cause severe growth impairment

• Children exposed to radiation to the brain; the younger the age when irradiated, the more severe the effect on height

• Children who had spinal radiation (see Chapter 18, Muscles and Bones)

• Children who were treated with total body radiation prior to a hematopoietic stem cell transplant (this term includes bone marrow transplants). A single high dose of radiation causes more problems than radiation given in smaller doses. Children (especially girls) who enter puberty before age 8 (precocious puberty) are at the highest risk.

Short stature. An early linear growth spurt combined with sexual maturation can also result in short stature. Short stature occurs because the bones stop growing when sexual maturity is reached. When this happens at a young age, the child loses 2 or 3 years of additional growth.

Hormonal abnormalities. Children or adolescents who received high-dose radiation (more than 3000 cGy) to the area of the hypothalamus and pituitary often develop a variety of hormonal abnormalities. They are at risk for growth hormone deficiencies, early sexual development, deficiencies in production of LH, FSH, adrenocorticotrophic hormone (ACTH), and thyroid-stimulating hormone (TSH); and may produce too much prolactin. These problems may develop years after treatment, so these survivors need long-term endocrine follow-up.

Although this chapter describes each of these problems separately, survivors often have combinations of endocrine problems. There are numerous other problems from damage to the HPA that do not directly involve growth. These rare problems are listed below.

Rare problems that can occur from damage to HPA:

• Hyperprolactinemia (higher levels of prolactin in the blood) can occur in children who receive more than 3000 cGy to the HPA. In females, prolactin is involved in breast development when there is adequate estrogen, progesterone, and growth hormone. Adolescents or women with too much prolactin stop having periods. Men who produce too much prolactin may have a lower sexual drive.

• Panhypopituitary dysfunction is when the pituitary gland does not make one or more hormones or does not make enough. It is a complication in children with brain tumors who get much higher doses of radiation to the HPA and replacement hormones may be needed.

Signs and symptoms of damage to the HPA

Signs and symptoms of damage to the HPA can take many forms. Common late effects are decreased growth, early or late puberty, and low levels of LH and FSH hormones.

Decreased growth. Decreased growth is a common problem for all children and adolescents on therapy for cancer. Many children experience catch-up linear growth after their cancer treatment ends. A few survivors continue to have slowed growth long after therapy ends. The symptoms may vary among children but may include:

• Significant changes in the growth percentiles (e.g., a child who used to be in the 90th percentile who is now in the 50th percentile)

• Below normal sitting height

• Growth hormone deficiency (GHD), a rare condition in which the body does not make enough growth hormone (GH) that controls children’s growth

Early (precocious) puberty. Precocious puberty can occur in children who were treated with cranial radiation.

Signs and symptoms of precocious puberty are:

• Physical signs of puberty in girls (e.g., breast development, underarm hair, body odor) before the age of 8

• Physical signs of puberty in boys (e.g., testicular enlargement, development of the penis, underarm hair, facial hair) before the age of 9 years

• Growth hormone deficiency

FIGURE 10-2. Growth hormone deficiency (GHD) causes decreased or slow growth (©Alexʼs Lemonade Stand Foundation, 2025)

Late puberty. Puberty can also be delayed by treatment for childhood cancer. Normally, puberty begins by age 13 in girls and 14 in boys. However, if hormones produced by the pituitary (LH and FSH) are disrupted or decreased by treatment, girls and boys may not start puberty at the normal time.

Signs and symptoms of delayed puberty are:

• No signs of sexual maturation in girls (e.g., breast development, underarm hair, body odor) by age 13 years

• No signs of sexual maturation in boys, including underarm hair, deepening voice, and penial development by age 15 years

• Children who are shorter than their peers because they have not experienced a pubertal growth spurt.

Abnormal LH and FSH hormone levels. See Table 10-2 for signs of abnormal LH/FSH levels in both females and males.

Screening and detection of damage to the HPA

Growth failure. Any child or adolescent who had radiation to the brain should be carefully screened for growth failure. A healthcare provider should measure standing height and plot it on a growth chart (graph that indicates if a child is growing normally for age) every 6 months. Sitting heights should also be obtained for any survivor who had radiation to the spine (i.e., total body radiation, mantle, spinal). The heights should be analyzed in light of the child’s pre-cancer growth, current bone age (determined from a hand x-ray), stage of puberty, and height of parents.

Any child who, after treatment, is growing slowly (i.e., less than 2 inches a year) or is in the fifth percentile or below for height should have additional tests:

• Bone age (measures the maturation of bones in the hand)

• Thyroid function tests

• Somatomedin-C (IGF1) and IGFBP3 (blood tests that measure the amount of hormone available to support normal growth)

• Bloodwork to check on the functioning of other major organs. All children with growth concerns should be referred to a pediatric endocrinologist.

Puberty status. All children should be evaluated for puberty status after radiation to the HPA, regardless of age. Any child who appears to be entering precocious puberty should have a bone age (x-ray of the hand) and GnRH testing done. Most facilities also test growth hormones in any child who appears to be entering precocious puberty because the two problems—slowed growth and early puberty tend to occur together. Children entering precocious puberty should be referred to a pediatric endocrinologist with experience treating survivors of childhood cancer. If your follow-up facility does not have such a specialist, you can find list of pediatric endocrinologists across the US at website: https://pedsendo.org and Search: Patient resources, Find a pediatric endocrinologist.

Some adolescents do not begin puberty at the normal age and need comprehensive evaluation by a pediatric endocrinologist that includes bone age, LH and FSH levels, testosterone or estradiol (estrogen) levels, and thyroid function tests for those who had high levels of radiation (of at least 3000 cGy) to the HPA. Consult an endocrinologist for further testing needs.

Medical management of damage to HPA

Healthcare providers (specifically endocrinologists) should discuss the signs and symptoms of HPA damage with survivors at risk and their parents (or older survivors) and complete a thorough yearly evaluation.

The following are the current methods used by most survivorship clinics to treat HPA problems:

• GH deficiency. Replacement GH is given in a daily injection (shot).

• Low LH and FSH. Females who produce no LH or FSH are usually treated with estrogen and synthetic progesterone (progestin). Adolescents and women with partial deficiencies may require only monthly progestin therapy to cause a period. Males with low LH are given sustained-release testosterone (through an injection into the muscle every 2 to 4 weeks, a daily patch on the skin, or in a cream).

• Precocious puberty. The drug Lupron^® is given through a monthly or every three (3) month injection into the muscle to stop puberty until the time it should begin. Another medication, Supprelin is an implant placed just under the skin. Replacement GH and GHRH are given if the child also has low GH. Speak with your own health care provider about these options.

• Hyperprolactinemia (too much prolactin). This condition is treated with bromocriptine or a related medication.