My Master of Reproductive Medicine has finished up for the year, but I thought it would be nice to share one of my essays with you so you can see what I get up to behind the scenes as I study and work towards this big goal. As you may have read in my previous blog post, I’m doing the Master of RM to further my own education, but also to bridge the gap between allopathic and complementary medicine, for the benefit of patients. The essay below is from the subject Clinical Reproductive Endocrinology, and covers the endocrine effects experienced by female paediatric cancer survivors and how that impacts fertility. Enjoy.
Endocrine Effects of Paediatric Cancer Treatment in Females and the Impact on Fertility.
The 5 year survival rate of paediatric malignancies is currently above 80%, and as such there is a need to consider the prevalence and treatment of endocrine deficiencies in these children as they age.(1,2) Within 30 years of diagnosis, roughly 70% of survivors will experience a medical complication of their previous oncology treatment, with 40% to 50% of those complications being an endocrine disorder.(1,3) The endocrine deficiencies experienced by females post- childhood cancer treatment, include growth hormone deficiency, precocious puberty, hypogonadotropic hypogonadism, hyperprolactinaemia, thyroid dysfunction including hypothyroidism, hyperthyroidism and auto-immune thyroid disease, adrenocorticotropic hormone (ACTH) deficiency, acute ovarian failure, premature ovarian insufficiency, premature menopause, metabolic syndrome, and diabetes mellitus.(3,4) All of these endocrine deficiencies have a negative impact on female fertility, which may require pre-planning from time of diagnosis, through to management during each stage of life.
Some endocrine disorders can occur due to the malignancy itself, however the majority are due to the therapies used to treat the cancer.(4) According to the Childhood Cancer Survivor Study, more than 85% of survivors were treated with at least two modalities, and 44% were treated with a combination of radiation, chemotherapy, and surgery.(5) These treatments can cause damage to the hypothalamic-pituitary-gonadal axis which will affect fertility.(2) The risk of infertility usually relates to the type of treatment, it’s dosage, the area of the body treated, and the combination of therapies utilised.(2)
Growth hormone (GH) deficiency involves inadequate secretion of GH from the pituitary, and is the most common form of endocrine deficiency caused by cranial radiation treatments in paediatric cancer patients.(1,4) The relationship between the dose of radiation and the level of GH deficiency correlates closely, with higher radiation doses causing multiple pituitary deficiencies.(3,4,6) Additional endocrine deficiencies ultimately develop in 35% of patients with GH deficiency, which often includes ACTH, gonadotropin and TSH deficiency.(4) Once patients reach adulthood, it can be more challenging to recognise GH deficiency due to lack of data on their growth rate.(4)
In female fertility, GH is associated with follicular growth by increasing the sensitivity of the ovaries to stimulation by gonadotropins.(7) Studies have shown that low GH concentrations result in less fertile oocytes compared to normal concentrations of antral fluid GH.(7) Supplementation of GH during assisted reproductive technology can improve pregnancy rates in women who were previously poor responders.(7) In younger patients, GH deficiency can result in short stature and delayed puberty, with reports of sexual problems in adult female survivors being three times higher than the general population.(4)
Precocious puberty, which is the result of the hypothalamic-pituitary-gonadal axis being activated prematurely, is estimated to occur in 11.9% to 15.2% of paediatric cancer survivors.(1) Low radiation doses have been linked to precocious puberty, with additional risk factors being younger age and female gender.(6) Studies have shown overall good outcomes in terms of fertility, however some have suggested an increased incidence of polycystic ovary syndrome (PCOS), which is known to be linked to decreased fertility through oligo-anovulation and hyperandrogenism.(8,9)
When paediatric cancer is treated via irradiation of the hypothalamus or pituitary, it can cause hypogonadotropic hypogonadism (HH) and a reduction in the secretion of luteinising hormone (LH) and follicle stimulating hormone (FSH).(10) This then results in a reduction of circulating sex hormones, which can lead to infertility and delayed puberty.(2,11) According to previous studies, patients who receive more than 30 Gy of radiation treatment are less likely to experience a pregnancy.(3) The reduction in GnRH secretion experienced by HH patients results in amenorrhoea, which affects fertility through anovulation.(12) Due to the ability of HH to be treated successfully with hormone therapy, puberty and fertility can be restored.(13)
Tumours, surgery or radiation of the brain in the hypothalamic area can lead to hyperprolactinaemia, which interferes with the pulsatile secretion of gonadotropin releasing hormone (GnRH), as we have just explored in hypogonadotropic hypogonadism.(6) The diagnosis of hyperprolactinaemia may come about through the observation of clinical signs such as galactorrhea, menstrual irregularities, delayed puberty, hot flashes, reduced libido, infertility, and tests that show high prolactin levels.(4,6) The HH that results from the hyperprolactinaemia is what causes the infertility, therefore the goal of fertility treatment is to normalise prolactin levels to reverse the hypogonadism.(14) Mouse models of kisspeptin administration have shown to reduce hyperprolactinaemia and restore ovulation and fertility.(14)
Disorders of the thyroid are a frequent complication of childhood cancer treatment, and they can include thyroid stimulating hormone (TSH) deficiency, hypothyroidism, hyperthyroidism, and auto-immune thyroid disease.(1,3) The thyroid gland is more susceptible to radiation treatment in childhood than in adulthood, shown in the prevalence of thyroid disease in paediatric cancer survivors who were treated under 10 years of age.(11) Thyroid hormones impact the menstrual cycle directly through the ovaries, and indirectly through effects on hormones such as sex hormone binding globulin (SHBG), prolactin, and secretion of GnRH.(15) Normal thyroid levels are necessary for maturation of the follicle to achieve ovulation, showing the link between thyroid disorder and infertility.(15)
The prevalence of hypothyroidism in the general infertile female population is 2% to 4%, however in the paediatric cancer population, it can be as high as 23% from cranial radiation, and 7% – 31% in children treated with haemopoietic stem cell transplantation.(3,11,16) Due to the high risk of hypothyroidism, lifelong surveillance is important, especially considering hypothyroidism can occur as late as 25 years after the completion of cancer therapy.(3) Fertility effects of hypothyroidism occur due to anovulation, defects in the luteal phase, hormone imbalance, and hyperprolactinemia.(16) Treatment of hypothyroidism can improve conception rates by as much as 76.6%, and should be preferential to treatment of hyperprolactinemia because a reduction in thyrotropin releasing hormone will lead to less secretion of prolactin.(16)
Hyperthyroidism is less common than hypothyroidism in paediatric cancer survivors, and is most frequently associated with radiation of the neck in Hodgkin’s lymphoma.(3) Studies have found hyperthyroid women have a 65% incidence of menstrual irregularities compared to only 17% in healthy controls.(15) Hyperthyroidism can impact fertility through an increase in SHBG, altered metabolism of oestrogen, and an increase in conversion of oestrogen to androgens.(15)
Auto-immune thyroid diseases (AITD) such as Grave’s disease and Hashimoto’s thyroiditis have been seen in paediatric cancer survivors, presumably due to donor cell transfer such as haemopoietic stem cell transfer.(11) AITD is a frequent cause of hypothyroidism and hyperthyroidism, however not all cases evolve into clinical dysfunction.(15) Studies have shown a link between AITD and endometriosis and polycystic ovarian syndrome, which are both conditions that can adversely affect fertility.(15)
Adrenocorticotropic hormone (ACTH) deficiency, which is characterised by reduced secretion of cortisol, is rare in the general population, however the 4 year incidence in high dose radiation treatment of the hypothalamic-pituitary area in children is 38%.(1,3,4) Due to the rarity of this condition, the impacts on fertility are not definitively known, however cases have been documented where infertility and amenorrhoea were linked to ACTH deficiency.(17,18)
At the time of cancer diagnosis, some patients will choose to undergo fertility preservation treatments, such as oocyte collection, however this is not always possible due to financial or time constraints.(2) There is a significant risk of damage to future fertility through gonadal injury during cancer treatment, especially if multiple treatment therapies are combined or radiation is targeted directly over the ovaries.(2) Damage can be mitigated by ovarian transposition to an area away from the radiation target, which can reduce exposure to radiation by 50% to 90% and preserve ovarian function.(2,4)
Acute ovarian failure has an incidence of 6.3% in paediatric cancer survivors, and is defined as premature ovarian insufficiency (POI) within 5 years of treatment.(4) Radiation doses over 20 Gy cause permanent ovarian failure, and may also inhibit puberty in young girls.(2) Acute ovarian failure is more prevalent with increased age at time of treatment.(3)
Premature ovarian insufficiency (POI) often involves regular menstrual function, however sonographic and endocrine changes in this condition show that fertility is compromised.(19) Due to damage from cancer treatments, the fertility potential of patients with POI is reduced by roughly 10 years.(19) Low anti-mullerian hormone and low inhibin B levels can indicate loss of ovarian function in paediatric cancer survivors, as well as a low antral follicle count.(4,19) Ovarian function is directly linked to maturation of primordial follicles, therefore POI results in reduced ovarian function and may lead to infertility.(2)
Premature menopause, the cessation of menstruation before age 40, can occur from paediatric cancer treatments, and has a 10-fold increased prevalence compared to sibling controls.(2) Patients may experience menopausal symptoms such as vaginal dryness and hot flashes, which are due to premature loss of oestrogen.(3) Younger patients have a better chance of maintaining some ovarian function, resulting in puberty and menstruation, but studies have shown that reduced ovarian functioning is progressive and leads to premature menopause and infertility.(11) Of patients who are treated with haemopoietic stem cell transplantation, less than 3% become pregnant, with risk factors such as pregnancy loss, low birth weight and early delivery.(11)
Metabolic syndrome involves obesity, dyslipidaemia, hypertension and insulin resistance, and often occurs after paediatric cancer treatments.(4) Metabolic syndrome can interfere with hypothalamic-pituitary function and ovarian function, which results in infertility.20 Suppression of kisspeptin can also cause hypogonadism.(20) Obesity is commonly seen in the infertile population, and they often have decreased insulin sensitivity which can lead to PCOS.(20)
Metabolic syndrome can progress to type 2 diabetes mellitus in some paediatric cancer patients due to dysfunction in pancreatic insulin secretion from radiation treatment, with a 1.6 times higher incidence than sibling controls.(4) Diabetes has been linked to hypogonadotropic dysfunction, including low gonadotropins, reduced LH surges, and defective ovulation, all leading to reduced fertility.(20) The hyperglycaemia in diabetes also induces oxidative stress which can lead to foetal development being adversely affected.(20)
In conclusion, it can be seen that many endocrine deficiencies can occur after paediatric cancer, predominantly from the treatments themselves. Each of the previously mentioned endocrine deficiencies plays a role in reduction of fertility in female patients, mostly through impact on the hypothalamic-pituitary-gonadal axis. Counselling at the time of diagnosis and regular monitoring of paediatric cancer patients throughout their life can help to manage the endocrine deficiencies that occur due to treatment.
1. Sklar CA, Antal Z, Chemaitilly W, Cohen LE, Follin C, Meacham LR, Murad MH. Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2018;103(8):2761-84.
2. Hudson MM. Reproductive Outcomes for Survivors of Childhood Cancer. Obstetric Gynecology. 2010;116(5):1171-83.
3. Chemaitilly W, Sklar CA. Endocrine complications in long-term survivors of childhood cancers. Endocrine-Related Cancer. 2010;17:R141-R59.
4. Rose SR, Horne VE, Howell J, Lawson SA, Rutter MM, Trotman GE, Corathers SD. Late endocrine effects of childhood cancer. Nature Reviews Endocrinology. 2016;12:319-36.
5. Sklar C. Paying the Price for Cure-Treating Cancer Survivors with Growth Hormone. The Journal of Clinical Endocrinology & Metabolism. 2000;85(12):4441-3.
6. Nandagopal R, Laverdiere C, Mulrooney D, Hudson MM, Meacham L. Endocrine Late Effects of Childhood Cancer Therapy: A Report from the Children’s Oncology Group. Hormone Research. 2007;69:65-74.
7. Magon N, Agrawal S, Malik S, and Babu KM. Growth hormone in the management of female infertility. Indian Journal of Endocrinology and Metabolism. 2011;15(3):S246-S7.
8. Fuqua JS. Treatment and Outcomes of Precocious Puberty: An Update. The Journal of Clinical Endocrinology & Metabolism. 2013;98(6):2198-207.
9. Melo AS, Ferriani RA, Navarro PA. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics 2015;70(11):765-9.
10. Green DM, Kawashima T, Stovall M, Leisenring W, Sklar CA, Mertens AC, Donaldson SS, Byrne J, Robison LL. Fertility of Female Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. Journal of Clinical Oncology. 2009;27(16):2677-85.
11. Wei C, Albanese A. Endocrine Disorders in Childhood Cancer Survivors Treated with Haemopoietic Stem Cell Transplantation. Children. 2014;1(1):48-62.
12. Silveira LFG, Latronico AC. Approach to the Patient With Hypogonadotropic Hypogonadism. The Journal of Clinical Endocrinology & Metabolism. 2013;98(5):1781-8.
13. Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic Hypogonadism Revisited. Clinics. 2013;68(1):81-8.
14. Kaiser UB. Hyperprolactinemia and infertility: new insights. The Journal of Clinical Investigation. 2012;122(10):3467-8.
15. Poppe K, Velkeniers B, Glinoert D. Thyroid disease and female reproduction. Clinical Endocrinology. 2007;66:309-21.
16. Verma I, Sood R, Juneja S, Kaur S. Prevalence of hypothyroidism in infertile women and evaluation of response of treatment for hypothyroidism on infertility. International Journal of Applied Basic Medical Research. 2012;2(1):17-9.
17. Kacem FH, Charfi N, Mnif MF, Kamoun M, Akid F, Mnif F, Naceur BB, Rekik N, Mnif Z, Abid M. Isolated adrenocorticotropic hormone deficiency due to probable lymphcytic hypophysitis in a woman. Indian Journal of Endocrinology and Metabolism. 2013;17(1):S107-S10.
18. Atkin SL, Masson EA, White MC. Isolated adrenocorticotropin deficiency presenting as primary infertility. Journal of Endocrinological Investigation. 1995;18(6):456-9.
19. Larson EC, Muller J, Schmiegelow K, Rechnitzer C, Anderson AN. Reduced Ovarian Function in Long-Term Survivors of Radiation- and Chemotherapy- Treated Childhood Cancer. The Journal of Clinical Endocrinology & Metabolism. 2003;88(11):5307-14.
20. Awlaqi AA, Alkhayat K, Hammadeh ME. Metabolic Syndrome and Infertility in Women. International Journal of Women’s Health and Reproduction Sciences. 2016;4(3):89-95.