By Robert W. Rebar, MD

Founding Chair Emeritus and Professor, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI

Dr. Rebar reports no financial relationships relevant to this field of study.

SYNOPSIS: A large Danish-based population cohort study documents that survivors of cancers arising in adolescence and young adulthood are at increased risk of subsequently developing a variety of endocrine disorders.

SOURCE: Jensen MV, Rugbjerg K, de Fine Licht S, et al. Endocrine late effects in survivors of cancer in adolescence and young adulthood: A Danish population-based cohort study. JAMA Netw Open 2018;1:e180349. doi:10.1001/jamanetworkopen.2018.0349

Because survivors of cancers in adolescence and young adulthood (defined as those in whom cancer was diagnosed between the ages of 15 and 39 years) are becoming increasingly common, it is important to know what risks these individuals will have in later life. Studies of the long-term sequelae of cancers have focused largely on those in childhood cancer survivors, despite evidence that cancers are seven-fold more frequent in adolescents and young adults.¹ More than 32,500 one-year cancer survivors aged 15 to 39 years at diagnosis and identified from the Danish Cancer Registry over a 30-plus-year period ending Dec. 31, 2010, were compared to more than 188,700 cancer-free comparators matched by year of birth and sex, randomly selected from the Danish Card Registration system. Follow-up was for a median of 10 years, with a range of 0 to 34 years. A total of 2,129 survivors (6.5%) had at least one hospital contact or an endocrine disease, while 1,232 (3.8%) would have been anticipated, yielding a statistically significant increased relative risk (RR) of 1.73 (95% confidence interval [CI], 1.65-1.81). The risk for any endocrine disease compared to the risk in the normal population was higher in male survivors (RR, 2.41; 95% CI, 2.23-2.61) than in female survivors (RR, 1.46; 95% CI, 1.38-1.55), according to the authors, due likely because of the lower background rate of endocrine disease in males. The younger the age at cancer diagnosis, the greater the RR, and the risk of new-onset endocrine disease generally decreased with time after cancer diagnosis. The highest RRs were seen for testicular hypofunction (RR, 75.12; 95% CI, 45.99-122.70), ovarian hypofunction (RR, 14.65; 95% CI, 8.29-25.86), and pituitary hypofunction (RR, 11.14; 95% CI, 8.09-15.34).

Disorders of the thyroid gland, testicular dysfunction, and diabetes were the principal reasons for hospital contacts. The highest RRs for any endocrine disease were found in survivors of leukemia (RR, 3.97; 95% CI, 3.10-5.09), Hodgkin’s lymphoma (RR, 3.06; 95% CI, 2.62-3.57), and brain cancer (RR, 3.03; 95% CI, 2.53-3.64). Survivors of Hodgkin’s lymphoma had a particularly high excess risk for hypothyroidism. Individuals diagnosed with cancer after 1990 had an increased RR of endocrine disease that was 48% higher compared to those diagnosed prior to that time, likely because of changes in treatment protocols and increased patient survival. The within-cohort analysis showed that sex modified the risk for endocrine disease, with female survivors at greater risk than male survivors.

COMMENTARY

Although this study was published several months ago, it only recently came to my attention, and I believe it has important implications for women’s healthcare providers. I have been intrigued by the relationship between cancer survivors and endocrine dysfunction since I first started seeing young women with premature ovarian failure early in my career.

As a fellow at the National Institutes of Health in the mid-1970s, I learned about young survivors of leukemia who developed hypothalamic-pituitary dysfunction or evidence of ovarian dysfunction, sometimes leading to permanent failure and sometimes reversible. The report of those patients was among the first suggesting that irradiation and chemotherapy (especially with alkylating agents) together affected endocrine function.²

That irradiation can affect ovarian function has been known since 1939 when Jacox³ noted that irradiation of the ovaries with 800 rads over three days usually was enough to induce ovarian failure. Permanent amenorrhea, with gonadotropin concentrations increased into the range found in postmenopausal women, occurs in slightly less than half of the women undergoing irradiation as partial treatment for Hodgkin’s disease and receiving 400 to 600 rads to the ovaries over four to six weeks. In others, only temporary hypergonadotropic amenorrhea results.^4,5

Regarding chemotherapeutic agents, the effects of cyclophosphamide on ovarian function have been studies most extensively, beginning several years ago.⁶ Reversible ovarian “failure” has been reported following administration of cyclophosphamide as well as other alkylating agents.^2,6 In general, for both chemotherapeutic agents and irradiation, the younger the woman, the less likely the ovarian endocrine dysfunction is to be permanent. This is logical because there obviously are more primary and primordial follicles in younger women compared to older women of reproductive age.

There has been a recent effort to publicize the need for clinicians caring for young women with treatable malignancies to consider preserving embryos, oocytes, or ovarian tissue (depending on the circumstances) prior to initiation of therapy with chemotherapeutic agents and/or abdominal irradiation so that future pregnancies are possible following “cure.”^7,8 Unfortunately, too few young women are apprised of these possibilities at present.

This article points out that those of us who see these patients need to be mindful of endocrine dysfunction that does not involve the ovary or the hypothalamic-pituitary unit, particularly thyroid dysfunction and diabetes. It behooves us to focus on more than just ovarian function in young women who are cancer survivors. That is the lesson from this article in a journal not commonly read by women’s health providers that should not be forgotten. Remember, too, that endocrine dysfunction can occur in young men who survive cancer, as well.

REFERENCES

1. Coccia PF, Altman J, Bhatia S, et al. Adolescent and young adult oncology. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2012;10:1112-1150.
2. Siris ES, Leventhal BG, Vaitukaitis JL. Effects of childhood leukemia and chemotherapy on puberty and reproductive function in girls. N Engl J Med 1976;294:1143-1146.
3. Jacox HW. Recovery following human ovarian irradiation. Radiology 1939;32:538-545.
4. Baker JW, Morgan RL, Peckham MJ, Smithers DW. Preservation of ovarian function in patients requiring radiotherapy for para-aortic and pelvic Hodgkin’s disease. Lancet 1972;1:1307-1308.
5. Ray GR, Trueblood HW, Enright LP, et al. Oophoropexy: A means of preserving ovarian function following pelvic mega-voltage radiotherapy for Hodgkin’s disease. Radiology 1970;96:175-180.
6. Koyama H, Wada T, Nishizawa Y, et al. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer 1977;39:1403-1409.
7. Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2018;36:1994-2001.
8. Practice Committee of the American Society for Reproductive Medicine. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: A committee opinion. Fertil Steril 2019;112:1022-1033.