Edition 75 - September 2019 / Subject Review

Subject Review – Ed. 75

Marco A. Rivarola y Alicia Belgorosky. Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina. 

For this issue of Endocrinología Pediátrica On Line, we have selected to comment on the following publication:

Horm Res Paediatr. 2019;91(2):93-103.
Hypogonadism in Children with a Previous History of Cancer: Endocrine Management and Follow-Up. van Santen HM1,2, van den Heuvel-Eibrink MM3, van de Wetering MD3, Wallace WH4.
1Department of Pediatric Endocrinology, Wilhelmina Children’s Hospital, UMCU, Utrecht, The Netherlands, 2Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands, 3Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. 4Department of Paediatric Haematology and Oncology, Royal Hospital for Sick Children, Edinburgh, United Kingdom.

Abstract
Hypogonadism after treatment for childhood cancer is a recognized complication and its cause may be subdivided into primary gonadal failure and central hypogonadism. Here, authors provide an overview of the risk factors for the development of hypogonadism, assessment and potential interventions and give a summary of the current recommendations for management and follow-up of hypogonadism in childhood cancer survivors.

Authors´ comments
Endocrine complications of treatment are seen in up to 50% of children cancer survivors (CCS). Gonadal dysfunction and infertility after cancer treatment is a major concern of CCS and their parents. For children surviving cancer an intact hypothalamic-pituitary gonadal axis is, first, needed for normal growth and pubertal development into adolescence. Secondly, having a normal timing of puberty is essential for participation in daily life with healthy peers. For this reason, it is of great importance that clinicians involved in childhood cancer follow up clinics are aware of the risk factors for hypogonadism, so that patients and parents are adequately counselled, and survivors of pubertal age are appropriately assessed. This will avoid delay in sex steroid replacement therapy and may subsequently prevent growth failure or psychological distress in teenagers. For this reason, clinical assessment of gonadal dysfunction should not be postponed to the long-term follow clinic (i.e., 5-year survival), but should start in children as they approach the normal age of pubertal onset, which is around 11 years in girls and around 12 years in boys in European countries. In the US and other countries, a downward trend is observed with regard to onset of puberty, implying assessment may be started earlier.
Primary gonadal insufficiency has been defined as ovarian insufficiency in females or androgen insufficiency in males in combination with elevated levels of pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH). Premature ovarian insufficiency (POI) is a clinical condition that develops under the age of 40 years and is characterized by the absence of menstrual cycles for ≥4 months and 2 sequential elevated FSH levels in the postmenopausal range. In males, primary gonadal failure is defined as decreased androgen concentrations in combination with elevated LH and FSH levels or failure to develop signs of puberty by age 14 or no change in pubertal stage for at least 6 months at the age at which progression would be expected in combination with elevated levels of LH and FSH. Central hypogonadism may arise because of damage to the hypothalamic-pituitary axis usually following radiation to a field that includes the hypothalamic-pituitary region or because of a tumor in the sellar or suprasellar region such as craniopharyngioma, germinoma, or low-grade glioma. In central hypogonadism, pulsatile release of FSH/LH from the anterior pituitary is absent or diminished leading to hypogonadism. In most cases, central hypogonadism is accompanied by deficiencies of other pituitary hormones, such as growth hormone (GH), thyroid stimulating hormone (TSH) and adrenocorticotrophic hormone (ACTH). In rare cases, primary gonadal insufficiency and central hypogonadism may coexist due to the combination of treatment with gonadotoxic chemotherapy and irradiation to the hypothalamic-pituitary region.

Primary gonadal Insufficiency
In children with cancer, the gonads may be damaged due to several reasons. First, the damage may be the consequence of the tumor itself, i.e. in children with ovarian tumors, gonadoblastoma, or testicular tumors. Secondly, gonadal insufficiency may be the consequence of treatment with cytotoxic drugs such as alkylating compounds. Thirdly, radiation exposure may damage the ovaries or the testes when these organs lie in the radiation field. Lastly, gonadal damage can occur after abdominal and pelvic surgery, due to compromise of vascular supply. In prepubertal treated children, gonadal damage may not become evident until there is a failure of pubertal development at an appropriate age. In pubertal/post pubertal children, gonadal insufficiency may be detected by an absent or reduced pubertal growth spurt, symptoms of estrogen or androgen insufficiency or as a consequence of screening LH and FSH concentrations. In young adults, changes in body composition, sexual activity and infertility may reveal hypogonadism. As the risk factors, assessment and interventions vary for males and females.

Premature Ovarian Insufficiency in CCS. Risk Factors
Overall, CCS have an estimated nonsurgical cumulative risk to develop POI by age 40 of approximately 8%. This may be the consequence of chemotherapy or radiation treatment. The human ovary is sensitive to cytotoxic agents, especially the alkylating agents, which are known to cause ovarian insufficiency. Commonly used alkylating and similar DNA inter strand cross-linking agents in pediatric oncology are the alkylating agents (busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine [nitrogen mustard], melphalan, thiotepa), the triazenes (procarbazine, dacarbazine, temozolomide), the nitrosoureas (carmustine [BCNU], lomustine [CCNU] and platinum agents [carboplatin, cisplatin]). In the literature, these are often all reported on as alkylating agents. For busulphan and melphalan, there is a high level of evidence for adverse effects on the ovary, but for other single agents such as for cyclophosphamide and procarbazine the level of evidence is much lower. For alkylating agents, there seems to be a dose-dependent effect to develop POI). Because in most studies patients are treated with combination therapy, it is difficult to determine the absolute risk of a single alkylating agent. For this purpose, in the Childhood Cancer Survivor Study, a method was developed to combine and compare cumulative dose of different alkylating agents for survivor outcomes, such as POI [Green DM et al., Pediatr Blood Cancer. 2014, 61:53–67]. This method uses the cyclophosphamide equivalent calculated dose (CED) which is calculated using an equivalent equation to account for cumulative effects of different therapeutic agents (procarbazine, ifosfamide, chlorambucil, cyclophosphamide, BCNU, CCNU, melphalan, Thio-TEPA, nitrogen mustard, busulfan), to quantify alkylating agent exposure and permit more direct comparison of different study results. Also, calculating the CED may help in counselling the patients and parents on the risk to develop POI to quantify alkylating agent exposure and permit more direct comparison of different study results. Radiation exposure is an acknowledged risk factor for damaging the ovarian tissue. The magnitude of the radiation effect is related to dose, fractionation and age at time of radiation exposure.
The key effects of cancer treatment on the ovary are infertility and estrogen. Next to estrogens, the ovary also produces androgens. Lack of androgen may lead to sexual dysfunction. Consequences of ovarian damage may therefore be infertility, decreased production of estrogen and androgens resulting in pubertal delay or failure, primary or secondary amenorrhea, osteoporosis, cardiovascular disorders, psychosocial problems and sexual health issues. For all these reasons, counselling those patients predicted to be at highest risk of POI remains important, and it should be done before treatment is started to allow patients the option of considering established fertility preservation options. Screening for POI in at risk survivors has been recommended by the International Guideline Harmonization Group (IGHG).

Assessment
Clinical assessment for POI in pre- and peripubertal survivors should be carried out by measuring height and calculating height velocity in conjunction with clinical examination of pubertal stage. As a rise in the concentration of serum FSH is a quite specific and sensitive tool to diagnose POI, determination of FSH level is the recommended screening tool in girls at risk for POI age 12 or up. For fertility counselling, determination of serum antiMüllerian hormone (AMH) levels and antral follicle count have been proposed. In the general population, determination of AMH levels is one of the best endocrine markers for age-dependent decline in ovarian reserve. However, the value of AMH in predicting early menopause in CCS remains uncertain and a very low AMH does not exclude spontaneous pregnancy in young CCS up to 25 years of age. For these reasons, AMH has currently not been recommended as a screening tool for POI  Of note, AMH levels seem to be influenced not only by treatment but also by the general disease state. Hence, prospective studies on full cohorts of childhood cancer patients are required to determine the value of AMH in children with cancer in daily clinical practice. In all female cancer survivors with elevated FSH levels, although the likelihood of previous treatment being the causative factor is high, a broad differential diagnosis of gonadal insufficiency should be considered, such as X linked genetic defects, Turner syndrome or auto-immune ovarian failure. For this reason, physical and laboratory examination should at least include evaluation of Turner stigmata such as short stature, webbed neck, low set ears, cardiac abnormalities and a peripheral blood karyotype.

Primary Gonadal Failure in Male CCS
For males, the key reproductive toxicities are either damage to spermatogenesis and/or steroidogenesis. Unlike in the female, where the two are intimately connected, they are distinct in the male, and spermatogenesis (supported by normal Sertoli cell function) can be impaired without manifest damage to steroidogenesis (Leydig cell function). However, although survival of the germ cells is crucial for future fertility, the somatic stem cells (Sertoli cells) are important for fertility, as they create the environment that is needed to support development and survival of the germ cells. As in females, the risk of treatment-related gonadotoxicity in males may cause emotional distress, with decreased testosterone concentrations leading to pubertal delay, or impaired spermatogenesis leading to reduced or lost fertility. Risk Factors The human testes comprise of testosterone-producing Leydig cells and spermatogonia supporting somatic Sertoli cells. Primary gonadal failure with androgen deficiency and impaired spermatogenesis may be the result of the tumor itself (testis tumor), or its treatment. Surgery, chemotherapy or radiation to the testes may all lead to testicular dysfunction due to direct damage to Leydig-, Sertoli- or the testicular germ cells. Indirect damage may also cause dysfunction of the Sertoli or Leydig cells, such as by vascular damage, damage by changes in hormone concentrations, growth factors or the structure of the seminiferous tubule structure that will indirectly mediate the effects of chemo-/radiotherapy on the germ cells. This also holds for interstitial effects on the Leydig cells leading to alterations in hormones or growth factors that may impact germ cells directly or indirectly (e.g., testosterone deficiency) through effects on other somatic cell populations. Studies on the effects of leukemia treatment on spermatogonial quantity and spermatogenic recovery in prepubertal boys showed that spermatogonial quantity after leukemia therapy involving alkylating agents results in long-term depletion of the spermatogonial pool in some long-term survivors, while survivors without alkylating agents remain within normative reference values for prepubertal boys. There is good published evidence for impaired spermatogenesis in males after treatment with busulphan, cyclophosphamide, chlormethine, ifosfamide, fludarabine/melphalan and procarbazine. Similar to the studies performed in females, as in most studies patients were treated with combination therapy, it remains difficult to determine the absolute risk of a single agent.
Radiotherapy to the testes, with a threshold of 12 Gy or more, or exposure to TBI, is associated with an increased risk for androgen deficiency. Consequences of androgen deficiency caused by testicular dysfunction in pre- and peripubertal boys may be pubertal delay or arrest, with increased levels of pituitary LH and FSH. In postpubertal boys and adolescent males, it may lead to osteopenia, decreased strength and muscle mass and impaired sexual function. Impaired spermatogenesis, due to damage to the testicular germ cells, may be caused by alkylating agents, testicular radiation or testicular surgery. It was shown that cyclophosphamide with an equivalent dose >5 g/m2 and radiation >2 Gy may induce impaired spermatogenesis. Impaired spermatogenesis may be reversible or permanent, depending on the combinations of treatment and on the cumulative dose of chemotherapy given. Infertility in male CCS may not only be the result of the direct toxic effect to the gonads, but may also be the result of a combination of factors such as impaired spermatogenesis, androgen insufficiency and sexual dysfunction. Each of these factors, in turn, can be the result of direct toxic effects of the given therapy or can be the consequence of psychosocial effects of having had cancer as a child. This must be taken into consideration when counselling is offered.

Assessment
Due to clinical uncertainty in making evidence-based recommendations, the International Guideline Harmonization Group (IGHG) formed a collaborative group for recommendations on who and how to screen for testicular insufficiency after treatment for childhood cancer. It was recommended that all survivors treated with one or more potentially gonadotoxic agents should be advised and counselled about the risk of impaired spermatogenesis and its implications for future fertility. Screening for primary gonadal failure in males should consist of an assessment of the history of the survivor, including sexual history (onset of puberty, libido, presence of erections, sexual activity), physical examination, including monitoring of height, BMI and Tanner stage, including testicular volume in pre- and peripubertal boys. Laboratory investigation should include an early morning determination of serum testosterone and LH/FSH levels from age 13 onwards.
As inhibin B is secreted by the Sertoli cells, it was evaluated for use in screening for gonadal damage in male CCS. One study showed inhibin B concentrations to be independently correlated with sperm concentration in males treated for childhood Hodgkin’s lymphoma with combination chemotherapy (adriamycin/epirubicin, bleomycin, vinblastine, dacarbazine) with or without MOPP (mechlorethamine, vincristin, prednisone, procarbazine) (r = 0.86; p < 0.001). In a study of 25 males, it was found that in prepubertal boys, inhibin B concentration, together with sensitive measurements of FSH concentration, was a potential marker of the gonadotoxic effects of chemotherapy, but not as good as the gold standard (semen analysis). Two other studies that investigated the diagnostic value of inhibin B concentrations and FSH concentrations for detecting azoospermia and oligospermia, showed that measurements of FSH, inhibin B concentrations and using the inhibin-FSH ratio all show fairly diagnostic value for detecting azoospermia. The accuracy of FSH as a predictor of azoospermia in adult survivors of childhood cancer remains controversial, with conflicting results in the published literature. In a recent study, the optimal FSH threshold was 10.4 IU/L with specificity 81% (95% CI, 76–86%) and sensitivity 83% (95% CI, 76–89%) for azoospermia. This study provides strong supporting evidence for the use of serum FSH as a surrogate biomarker for azoospermia in adult males who have been treated for childhood cancer. However, it is still strongly recommended that if survivors want assessment of their fertility, the gold standard is semen analysis and not determination of FSH or inhibin B concentration. Androgen deficiency may lead to pubertal delay or arrest and sexual impairment, and may be treated with testosterone replacement therapy. Awareness and screening for sexual impairment in postpubertal males at risk is important since sexual health has been shown to be important for overall health and quality of life. Next to CCS with androgen deficiency, awareness of sexual impairment is also important in males who have been treated with surgery or radiation involving the lower spinal cord, prostate, distal colon or rectum, due to disruption of the innervation required for erection and ejaculation. These CCS may be referred to the urology department for specific techniques to improve sexual function. Interventions.
There are several experimental and established techniques for preservation of male fertility. Sperm banking, which is established, should be offered to all postpubertal patients diagnosed with cancer, before exposure to potentially gonadotoxic agents. In postpubertal males, sperm may be banked by cryopreservation after masturbation, or if masturbation is not possible and there is a high risk of infertility, alternative techniques such as vibration, electro-ejaculation, and microsurgical epididymal sperm aspiration or testicular sperm cell extraction have been described.
In prepubertal males, preservation of male fertility is more challenging and remains experimental. Several research groups are exploring the possibility that cryopreservation of prepubertal testicular tissue with a view to subsequent spermatogonial stem cell transplantation may preserve future fertility. In some animal models, this has been successful; in humans, this must still be considered experimental. In case of exposure to radiation, in pre- and postpubertal males, the testes should be shielded against radiation when these are within the radiation field.

Central Hypogonadism
Central hypogonadism, or hypogonadotrophic hypogonadism, may occur after cranial radiation including the hypothalamic-pituitary axis (HPA) with > 22–30 Gy, due to tumors in the sellar or suprasellar region such as craniopharyngioma or germinoma, or following neurosurgery in the HP-region, such as in patients with low-grade glioma. The overall incidence of hypogonadotrophic hypogonadism in CCS was reported to be 6.3%. In a national Dutch cohort of 481 childhood brain tumor survivors age 12 years or older, 4.2% were found to have LH/FSH deficiency after a median onset of 4.5 years (range 0.2–9.5 years) after diagnosis of the primary brain tumor. In 748 children followed for a median period of 27.3 years (range, 10.8–47.7 years) after cranial irradiation, the prevalence of LH/FSH deficiency was found to be 10.8%, and was significantly associated with male sex and obesity. Central hypogonadism in males and females will lead to pubertal delay or arrest, as well as all the consequences of sex steroid deficiency as mentioned above. When there has been no exposure to gonadotoxic treatments such as alkylating chemotherapy or abdominal radiation, fertility is not expected to be impaired, but will require intervention with human chorionic gonadotropin (HCG) or FSH injections. This information is important to share with the survivor when counselling upon hypogonadism as the survivor may not be aware of the differences between hyper (primary) – and hypogonadotropic (central) hypogonadism.

Treatment of Gonadal Insufficiency (Primary and Central)
Females
For prepubertal girls that have survived their cancer, timing and dosing of estrogen substitution is essential to enable a normal pubertal development as well as a normal social development during the teenage years. This treatment should be guided by an experienced pediatric endocrinologist through monitoring Tanner stage in relation to age, growth velocity and skeletal maturation at regular basis. This may especially be challenging in girls who have been exposed to gonadotoxic agents in combination with cranial radiation or a tumor in the sellar region resulting in hypopituitarism. In this case, simultaneous GH deficiency and LH/FSH deficiency may be present, influencing growth velocity, bone maturation and interpretation of laboratory values such as insulin like growth factor-1, LH and FSH.
In postpubertal girls and women, replacement of sex steroids will positively influence bone health and cardiovascular status. For all females, replacement of estrogen may influence growth of the uterus, enabling possible future (donor) pregnancy. Concerns have been raised that sex steroid replacement therapy will increase the risk of breast cancer in CCS. In non-CCS women, estrogen replacement therapy has not been shown to increase the long-term breast cancer risk. Although the literature in CCS on this subject is very limited, the result of the Childhood Cancer Survivor Study was very reassuring, i.e. they reported that survivors with POI and treatment with estrogen replacement therapy have lower risk to develop breast cancer than the CCS without POI.
The timing and dosage or route of estrogen replacement in female CCS is the same as recommended for girls with Turner syndrome or other causes for POI. There is some evidence that transdermal versus oral replacement therapy in female CCS may be of advantage; however, this was considered insufficient to form a strong recommendation. Treatment with estrogen needs to be combined with progestin for endometrial cycling. In case of simultaneous GH deficiency, it may be chosen to first start GH replacement therapy before estrogen replacement therapy, to ensure an adequate pubertal growth velocity. These choices should be made individually and should be discussed with the teen-survivor, balancing the advantages of estrogen replacement and pubertal development versus delaying this and optimizing final height. To ensure optimal transition from pediatric to adult medicine, collaboration between the departments of pediatric and adult endocrine, fertility and obstetric medicine in childhood cancer and survivor centers is of utmost importance.

Males
Sex steroid replacement in males may be started from around age 13 years. In case of primary gonadal failure, the rise in FSH/LH or decline in serum testosterone concentrations may indicate that replacement should be started. In the case of hypogonadotrophic hypogonadism, the timing of testosterone substitution therapy is dependent on family history of pubertal development, the psychosocial development of the boy in combination with height and skeletal maturation. Testosterone may be administered orally, intramuscularly or topically. The goal of sex steroid replacement in males is to obtain adequate pubertal development in combination with optimization of final height, and accrual of bone mass. Alternatively, pubertal induction may be done using HCG. In this situation, aside from virilization, the testes will enlarge which may give the developing teenager more self-confidence and improve body satisfaction. Disadvantages of HCG versus testosterone replacement therapy are the manner of administration and the cost-effectiveness; HCG is given twice a week subcutaneously versus an intramuscular testosterone injection once every 3 weeks, and HCG is more expensive. These advantages and disadvantages should be discussed with the survivor by the pediatric endocrinologist. There seems to be no difference in effect of treatment with HCG versus testosterone replacement therapy on virilization (in case of sufficient testis function) or fertility outcome.

Pregnancy Outcomes in Cancer Survivors
Male and female childhood cancer survivors are at increased risk for infertility. In the Childhood Cancer Survivor Study, male survivors were shown to have a reduced chance of siring a pregnancy than siblings (hazard ratio [HR], 0.56; 95% CI), especially after exposure to more than 7.5 Gy radiotherapy to the testes and higher cumulative doses of alkylating chemotherapy. Female survivors also showed decreased fertility, with greatest risk for ever being pregnant for survivors after treatment with hypothalamic/pituitary radiation dose ≥30 Gy (RR, 0.61; 95% CI) or an ovarian/uterine radiation dose > 5 Gy (RR, 0.56 for 5–10 Gy; 95% CI). In women exposed to cranial and abdominal radiation, an increased spontaneous pregnancy loss rate has been reported (1.4- to 6.1-fold and 1.4- to 2.8-fold increase, respectively). Also, more preterm births have been reported in female CCS, which may be due to the condition of the uterus after radiation exposure or lack of sex steroids. A recent Scottish study has provided robust, population-based evidence for the effect of cancer and its treatment on subsequent pregnancy in women aged under 40 at the time of diagnosis. There was an overall reduction in the likelihood of pregnancy after diagnosis of 38% compared to the general population, with a comparable reduction in the incidence of first pregnancy after cancer [Anderson RA et al., The impact of cancer on subsequent chance of pregnancy: a population-based analysis. Hum Reprod. 2018 33:1281–90. ].
In a large Swedish cohort of CCS, it was found that the HR for having a first live birth was significantly lower than in healthy controls. In this cohort, adolescent men with cancer had lower HR for a first live birth than men surviving childhood cancer (HR 0.56 vs. 0.70). For women surviving childhood cancer, the opposite was found, with a lower HR than when compared to women diagnosed with cancer in adolescence (HR 0.47 vs. 0.89) [van Dorp W et al. Reproductive Function and Outcomes in Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Review. J Clin Oncol 2018 36:2169–80, Armuand G. et al, Reproductive Patterns Among Childhood and Adolescent Cancer Survivors in Sweden: A Population-Based Matched-Cohort Study. J Clin Oncol. 2017 35:1577–83.]. This study clearly showed that there are large differences in HR for first live birth between groups of cancer survivors with different diagnoses. In the survivors of CNS tumors, the lowest HR were found (HR 0.53 and 0.62, for males and females, respectively),
This may be explained by many factors, such as the combined chemotherapy, radiotherapy, and/or surgery, in combination with a higher risk for neurocognitive impairment. This is in turn associated with lower educational level, higher unemployment, less independent living, and a higher risk of never getting married. All these factors may influence the chance for pregnancy. As assisted reproductive treatment regimens continuously change and fertility options improve, future cohort studies will remain important for insight on gonadotoxicity of current treatment and future pregnancy outcomes in current childhood cancer cohorts.

Conclusions
Children with cancer may be at risk for gonadal insufficiency due to the tumor or its treatment. All children and their parents need to be informed about this important subject before cancer treatment is administered and, if necessary and possible, ways to preserve gonadal function or fertility should be offered. Children surviving cancer should be followed in specialized centers with a multidisciplinary team including a pediatric endocrinologist, pediatric oncologist, andrologist as well as fertility and obstetric medicine care experts. The role of the pediatric endocrinologist is to inform and counsel the patient and the parents about the consequences of gonadal insufficiency and to monitor growth velocity in relation to pubertal development. This will enable timely substitution of sex steroids, if necessary, to optimize linear growth, bone development, development of the uterus (in girls) and psychosocial development.


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