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CASE-BASED LEARNING

The impact of cancer treatment on reproductive health in young women

implication is that a population of patients is emerging that have chronic reproductive morbidity consequent to their cancer treatment. Modalities of cancer treatment employed alone, or as is often the case in combination, are potentially damaging to both males and females gonads, and can irreversibly alter various organ systems and impact future quality of life. Endocrine and fertility problems resulting in reproductive dysfunction are a major concern in this patient group and contribute to major psychological disorders. An increasing number of patients are referred for reproductive counselling whilst planning or delivery of cancer treatment or, as often the case, after treatment is completed. Gynaecologist and Gynaecological Oncologists are not necessarily prepared to provide the kind of care this group of patients demand. In this review we highlight common reproductive problems encountered in survivors of childhood, adolescents and young adult cancers and expound the various strategies to optimize their care.

Tukur A Jido Margaret E Cruickshank

Abstract The diagnosis of cancer can precipitate a re-evaluation of life at all ages. In children, adolescents and young adults, a cancer diagnosis and its treatment poses specific challenges that can affect all aspects of reproductive health resulting in considerable physical, psychological and psychosexual burden. Improved survival means that this cohort of patients is expanding and with an improving life span, the resulting morbidity is also extended. The demands of this group of patients are often not fully integrated in the operational functions of the health service with considerable variation in care. This review discusses the common reproductive morbidities amongst survivors of childhood, adolescent and young adult cancer whilst planning, delivering and following cancer treatment. This includes the current issues on the assessment of ovarian reserve and preservation of fertility.

Case 1: premature menopause A 21-year-old woman presents to her GP with secondary amenorrhoea, hot flushes and night sweats. She has been in remission for 5 years having undergone chemotherapy and radiotherapy for Hodgkin’s lymphoma. She has seen the gynaecology team who have explained that she is experiencing symptoms of a premature menopause and they recommended cyclical hormone replacement therapy (HRT). On further questioning she admits that she does not take the HRT as it makes her feel ‘like an old woman’. Premature menopause is a condition characterized by amenorrhoea, hypoestrogenism and elevated levels of gonadotropins in a woman younger than 40 years. The majority of cases are spontaneous but it is often commonly associated with radical pelvic radiotherapy and exposure to chemotherapy, particularly high doses of alkylating agents (for example cyclophosamides used in the treatment of lymphoma). Both reproductive and endocrine functions of the ovary are affected with resultant loss of fertility, psychosexual dysfunction and long term bone and cardiovascular consequences. Premature menopause following cancer therapy is a result of destruction of primordial follicles by anticancer agents. At birth the female infant has about 2 million primordial follicles in the ovary. This rapidly regresses through atresia such that at puberty the count is down to about 600,000. Subsequent progressive depletion with each ovulation results in menopause when the count is down to about one thousand, usually at the age 52 years. Factors such as surgery, cytotoxic chemotherapy, irradiation, genetic, hereditary and immunological are known to accelerate follicular atresia. Similarly these factors may have debilitating effect on spermatogenesis in the young male. A host of these factors are associated with cancer treatment. Premature menopause may represent the end of spectrum of ovarian failure. In the occult form, women present with unexplained loss of fertility with normal levels of gonadotropins in contrast to biochemical ovarian insufficiency commonly described in patients with unexplained infertility and elevated levels of follicle stimulating hormone (FSH). Both categories may

Keywords chemotherapy; cryopreservation; fertility; oncofertility; ovarian reserve; radiotherapy

Introduction Young cancer survivors face specific challenges in their physical, psychological and reproductive lives. A cancer diagnosis and its treatment in childhood and adolescence impact negatively on almost all body systems, the ability to complete education, continue or secure an employment and fulfil reproductive wishes. Unsurprisingly there is an associated increase in psychosocial and psychological problems amongst young women who survive cancer. There are a number of different types of cancers which arise in childhood, adolescence and young adults. About one in 650 children develop cancer in the first 15 years of life. In the USA, 72,200 adolescents and young adults, defined as those aged 15e39 years were diagnosed with cancer in 2006. Advances in surveillance and treatment of cancers have impacted positively on survival such that long term survival is expected in 80% of children and adolescents diagnosed with cancer. The

Tukur A Jido MBBS DRH FWACS MRCOG is a Specialist Trainee in Obstetrics and Gynaecology at Aberdeen Royal Infirmary, Aberdeen, UK. Conflicts of interest: none declared. Margaret E Cruickshank MB ChB FRCOG MD is a Senior Lecturer in Gynaecology at the Division of Medical Education, Suttie Centre, Aberdeen, UK. Conflicts of interest: none declared.

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maintain some measure of menstrual function. Whereas in overt ovarian failure, elevated basal levels of FSH are seen in patients with oligomenorrhoea or amenorrhoea and loss of reproductive function. Complete depletion of primordial follicles results in irreversible infertility, amenorrhoea and markedly elevated FSH (>30 mmol/L). It is pertinent to note that the progress in this continuum is unpredictable but it can be accelerated by cancer therapy. Where ovarian failure precedes puberty, other physiological processes like growth may also be affected. The diagnostic work up includes a urinary pregnancy test, thyroid function test, autoantibody testing and in those with primary amenorrhoea, karyotyping may elicit concomitant genetic predisposition that is hitherto unsuspected. Long term, annual dual energy X-ray absorptiometry (DEXA) scans to measure bone density are advised. The tests for ovarian reserve will be considered later and ovarian biopsy is not indicated. HRT is required to alleviate immediate symptoms of hypooestrogenism, maintain bone health and improve long term cardiovascular health. Administered in a cyclical combine form, this treatment gives the psychological reassurance of mimicking the normal menstruation and may be helpful in some young women. Nonetheless, the more common concern amongst these patients is reluctance to continue with therapy owing to its age related psychological impact. The choice of HRT should be individualized and in these young patients the advantages of oral cyclical combine preparation is already highlighted. Oestrogen patches obviate the need to remember oral therapy on a regular basis and may offer a minimum total dose of steroids. If menstrual-like bleeding is not considered important, oral continuous combined preparation may be appropriate. Attempts to overcome the psychological impact of using HRT in young women by substituting it with the combine oral pill, must be considered carefully in the context of the differential doses of steroid hormones in the two preparations and some endocrinologists caution against such practice. When the patient still has a uterus, oestrogen treatment needs to be combined with progesterone to protect the endometrium. Formulations available include medroxyprogesterone acetate 10 mg daily for 10e12 days or micronized progesterone 200 mg daily for 10e12 days. The Mirena intrauterine system may also be used to provide progesterone protection. Patients with premature menopause have lower levels of testosterone, but only 13% have levels below the normal reference ranges. Androgen replacement therapy is only offered in selected patient groups: those with persistent fatigue, low libido and poor well being despite adequate HRT in the absence of depression and thyroid disease. Methyl testosterone 1.25e2.5 mg per day or parenteral testosterone esters 50 mg every 6 weeks are in common use as well as subcutaneous slow release preparations every 6 months. The concept of premature menopause is challenging to even the most resolute young woman. Long term follow up in a multidisciplinary setting provide the women with optimal support to cope with a difficult clinical condition. Dietary supplementation with calcium, response to HRT, fertility support and advice as well as psychosexual counselling needs to be specifically raised and regularly appraised during follow up. Spontaneous return to fertility may occur in patients with

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premature menopause so effective contraception is advised to prevent unplanned pregnancy.

Case 2: primary infertility A 26-year-old woman is seen in the fertility clinic with 18-month history of primary infertility. Her partner has a child from previous relationship. She is menstruating regularly and is in good health. She had pelvic irradiation for treatment of a Wilm’s tumour at the age of 5 years. Her baseline early follicular phase FSH is 11 IU/L and LH is 7 IU/L. The gonadotoxic effect of cancer related treatment particularly radiotherapy and chemotherapy is well established. The degree of damage depends on the age at treatment, type of treatment, dose intensity in the case of radiotherapy and duration of treatment. The British childhood cancer survivor study reports the rapid depletion of primordial follicles attributed to chemotherapy with the survivors being up to thirteen times as likely to experience premature menopause as age matched controls. In these women, regular menstruation is maintained yet high levels of FSH suggest diminished levels of ovarian reserve.

Measurement of ovarian reserve The functional capacity of the ovary reflected by the number and quality of oocytes is known as ovarian reserve. A wide range of tests exist all aimed at predicting the fertility potential or possibilities either prior to or after cancer treatment. Tests carried out before treatment helps to select patients eligible for fertility preserving procedures in those deemed to have diminished reserve. Post-treatment testing apart from providing fertility prognosis may help in deciding the prospect of spontaneous fertility or whether fertility preserving measures when used before treatment should be used to achieve conception. These tests share as an end point fertility potential, whereas fecundity should ideally be measured when you consider that some treatments compromises the ability of the uterus to nurture a pregnancy to term. However a fecundity test has still to be developed. Available tests of ovarian reserve are broadly categorized into static and dynamic tests. Static tests assess biochemical and ultrasound parameters of ovarian reserve at a given point in time. Dynamic tests assess the ovarian response to exogenous stimulation and involve measurement of hormones before and after the stimulation. The evidence base for these various tests varies in clinical practice. Ovarian antral follicle count (AFC) in combination with antimullarian hormone (AMH) is the most common static tests. AMH is produced by granulosa cells in developing follicles. With natural ageing, AMH levels rises at around age 37 when the woman’s follicular count is in the region of 25 000. In regularly menstruating women, AMH inversely correlates with the number of antral follicles in the ovary and is the endocrine factor which best predicts transition to menopause in the next 4 years. The mean antral follicular count in regularly menstruating women with no fertility concerns is high and lower counts are associated with high levels of AMH and diminished fertility potential. The number of antral follicles correlates best with the ovarian age. The role of AFC and AMH combined is well established in clinical practice as a measure of the number of primordial follicles

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independent of the patient’s age and are a proxy to ovarian age and functional reserve. The use of AMH and AFC as a measure of ovarian reserve has been effectively integrated in oncofertility practice. A high correlation between AMH and AFC is reported in post-treatment patients. Levels of both of which are significantly lower than in non-cancer treatment exposed cohorts. Indeed evidence exists in longitudinal studies that shows marked decrease in both AFC and AMH following cancer therapy. These tests are in the core of static measures of ovarian reserve with a robust evidence base. Other measures include ovarian volume, baseline day 1e5 FSH, oestradiol, and inhibin B; but the evidence for these is tenuous. Dynamic tests in clinical practice are clomiphene citrate challenge test (CCCT), GnRH agonist stimulation test (GAST) and exogenous FSH ovarian reserve test (EFORT). First described in 1987 by Navot et al., CCCT involves administration of 100 mg of clomiphene citrate from day 5e9 of the cycle and measurement of FSH levels on days 3 and 10. Abnormally high levels of FSH, defined as levels >10 U/L correlates well with poor pregnancy rates and cycle cancellation in IVF patients. A recent metanalysis of 5 studies concluded that the post test prediction of no pregnancy for CCCT at cut-off FSH >10 U/L is 0.81 (95% CI 0.71e0.92). GnRH agonist stimulation test, described by Padilla et al. in 1990, elicits a dose response curve rather than a normal or abnormal result given with other measures. This test measures the pituitary production of FSH and LH to stimulate follicular development in the ovary as an indicator of follicular reserve. In exogenous FSH ovarian reserve test (EFORT) recombinant FSH is used to induce follicular growth in the ovary. This method was first reported by Fanchin et al. in 1994; basal oestradiol and FSH are compared with post injection levels to assess the ovarian reserve. Maheshwari et al. in a recent systematic review were unable to arrive at conclusion on the predictive ability of GAST (eight studies) or EFORT (seven studies). The baseline investigations for this patient include FSH, LH, prolactin, day 21 progesterone, AMH and oestradiol. She needs a pelvic ultrasound scan to check the antral follicular count, exclude major uterine abnormalities like uterine fibroids and hycosy (Hystero Contrast Salpingogram) to check for tubal patency. Her partner needs semen analysis. Options of treatment will be considered with patient and her partner based on the result of these tests.

methods like in-vitro egg maturation. These will be examined with the emphasis on their present applicability in current oncofertility practice and the evidence base for their effectiveness where available. As a general principle, the method depends on the age of the patient, state of puberty, type of cancer, ovarian reserve prior to therapy and the type, duration and frequency of treatment. Embryo cryopreservation is the standard method in clinical practice. Embryo freezing, subsequent thawing and in-vitro fertilization (IVF) is a routine procedure in fertility clinics with well established effectiveness. Patients are hyperstimulated prior to their cancer treatment, to produce oocytes. These are collected, fertilized in-vitro or by intracytoplasmic sperm injection (ICSI) and the resulting embryo cryofrozen (slow freezing or vitrification) and stored for future use. It presupposes that the patient is in a stable relationship, or prepared to accept donor sperm from either an identified or anonymous donor. While this is potentially applicable to this patient, she and the partner need to carefully consider the long term implication of any embryo resulting given the early stage of their relationship. Other potential constraints here include ethical, legal, cultural and religious considerations. Furthermore, this may be appropriate for the post-pubertal girl but its applicability in younger patients is limited by the immaturity of the gamete. Her oncologist may be wary of the time delay to arrange and conduct these procedures and the potential impact on delivery of patient care and outcome of treatment. The effect of the medications used on the biological behaviour of different tumours is not exhaustively enunciated and may be a source of reservation for some. Oocyte cryopreservation presently considered experimental remain a potential option for this patient, those who are not in a stable relationship, those whose male partners withhold consent for creating embryo, those who themselves decline the option of creating embryo or women in relationship yet seek to maintain reproductive independence. The procedure involves hormone stimulation of the ovaries prior to treatment to produce multiple ova. These are collected and frozen for future use. The evidence base in terms of its effectiveness for subsequent utilization to produce embryo is less robust, its potential nonetheless make it an option in these category of patients. Most fertility services will require local ethical board approval to provide this method of treatment but this should not be a deterrent in the context of the oncology patient. Some fertility clinics have achieved comparable pregnancy rates with frozen as fresh eggs in invitro fertilization. Beside issues of consent, egg freezing is only applicable in those patients who can delay cancer treatment to allow for ovarian stimulation and egg collection (typically 2e5 weeks) and tumour types in which hormones can be used. In the others, as in prepubertal girls, ovarian tissue or whole ovary cryopreservation is an alternative. Ovarian or ovarian tissue cryopreservation is an alternative for women in whom hormonal stimulation is contraindicated or cancer treatment cannot be delayed owing to the stage of the disease or cancer type. Ovarian cortical strips are taken for cryopreservation or in instances the whole ovary has been cryopreserved. This can be subsequently transplanted back to the patient autotransplantation or if the risk of transplanting

Case 3: preservation of female fertility A 28-year-old woman was referred to the fertility clinic following a recent diagnosis of FIGO stage 2A cervical cancer. She is nulliparous and has just started a new relationship. She is keen to have a family sometime in the future. Her cancer specialist has recommended chemoradiation. She wishes to explore her future options for motherhood. Infertility following cancer treatment is a recognized quality of live issue in survivors and effort should be made to help young cancer patients retain their fertility. The search for strategies for fertility preservation is ever expanding with an array of options coming into clinical practice from laboratory research. These range from the well established methods like in-vitro fertilization and embryo freezing to developmental

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cancer cells back is a concern, eggs are isolated matured invitro and fertilized and the resulting embryo transferred in standard manner or to a surrogate mother as appropriate. There is sufficient evidence for restoration of hormonal and fertility functions with autotransplantation of cryopreserved ovarian tissue. However the evidence base for in-vitro follicular maturation is rather tenuous and the method is limited to a research setting. Recently Oktay et al. reported consecutive spontaneous viable pregnancies after heterotropic ovarian tissue transplantation. Surgical methods like ovarian shielding and/or transposition to limit the effect of irradiation have been employed with varying outcome as data is sparse. This could be performed laparoscopically to place the ovaries above the level of the pelvic brim and irradiated field in this case. In rare cases of genetic cancers, preimplantation genetic diagnosis has been employed to limit the risk of transmitting oncogenic gametes. These techniques are successfully used to screen for cancer predisposing syndromes like BRCA gene for breast and ovarian cancer, von Recklinghausen’s disease and adenomatous polyposis colon the precursor of Lynch II syndrome. Patients seeking to use oncofertility services for preservation of their fertility require extensive counselling. This is best offered in specialized centres. Areas of focus should include the limited success rate of ART within non-cancer and in cancer populations, side effect of the cancer treatment including potential effect on developing fetus and impact on the capacity of the uterus to nurture a pregnancy to term in the case of radiotherapy and surgical methods like radical trachelectomy. Rare congenital defects known to be associated with birth resulting from these technologies like Angelman syndrome and maternal hypomethylation should be covered.

the procedure. Plante et al. reported 106 pregnancies in 58 women following vaginal radical trachelectomy. First and second trimester miscarriges were 20% and 3% respectively. Of the 77 pregnancies that reach the 3rd trimester only 58 reached term. Exposure of the uterine tissue to high dose irradiation compromises endometrial receptability and myometrial distensibility and increases the risk of miscarriage and preterm delivery. The preterm delivery rate is 14% and 9% of all live born babies are of low birth weight. Doppler studies suggest reduction in blood flow, a factor that may be important in the pathophysiology of small for gestational age and intrauterine growth retardation often seen in exposed patients. Reports on the pregnancy outcome in the British childhood cancer survivors survey found a 3-fold increased risk of preterm labour (OR 3.2, 95% CI, 2.1e4.7), 2-fold increased in low birth weight (OR 1.4, 95% CI 1.0e1.9) and small increase in miscarriage. Overall live birth rates were two-third of expected and were lowest in those who had brain and abdominal irradiation. Concerns among pregnant cancer survivors on the effect of treatment on risk of genetic disorders, congenital malformation and secondary cancers in the off spring appear low except in the off springs born to survivors with germline cancer predisposing mutation. Irradiation exposure related miscarriage in female cancer survivors almost always occur after 12 weeks’ gestation, data for miscarriage before 12 weeks is inconsistent. Patients should be counselled on the risk of miscarriage, preterm labour and low birth weight. Pelvic ultrasound to assess the size of the uterus, endometrial thickness and structural defects of the uterus should be carried out in this case. Doppler studies may be used to assess uterine blood flow. Endometrial biopsy and studies of endometrial function can be undertaken but functional distensibility of the uterus is difficult to assess. Pregnancy in cancer survivors with such reproductive outcome should be managed as high risk in a consultant led care. Early dating and mid trimester anomaly scans may reassure the patient. A

Case 4: pregnancy outcome A 28-year-old woman presents to the early pregnancy assessment unit with silent miscarriage, diagnosed at her antenatal dating scan. This is her second pregnancy with the same partner; her first pregnancy ended in spontaneous miscarriage at 6 weeks gestation. She gave a history of bone marrow transplantation with fractionated radiotherapy for acute lymphocytic leukaemia in her teens. She wishes to discuss the implication of this for her future pregnancies. The long term effects of cancer therapy on reproductive function are less well understood. Clear cause effect relationship between in utero exposure of the fetus to irradiation and adverse outcomes including secondary childhood cancers is well established. Similarly previous irradiation of the pelvis is associated with increased risk of miscarriage, preterm labour and small for gestational age. In the British childhood cancer survivor survey, live birth rate was 72.9%, miscarriage rate was 14.8%, termination of pregnancy 11.8% and still birth rate of 0.6% in patient exposed to abdominal radiotherapy. Adverse effects attributable to chemotherapy are less well elucidated. The risk of preterm delivery following large loop excision of the transformation zone for cervical intraepithelial neoplasia is about twice the background population risk. Following radical trachelectomy where all the cervix along with paracervical tissue is removed, insertion of a cervical cerclage is a part of

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FURTHER READING Cameron IT, O’Shea FC, Rolland JM, Hughes EG, de Kretser DM, Healy DL. Uccult ovarian failure: a syndrome of infertility, regular menses and elevated follicle stimulating hormone concentrations. J Clin Endocrin Metab 1988; 67: 1190e4. Collins IM, Fay L, Kennedy MJ. Strategies for fertility preservation after chemotherapy: awareness among Irish cancer specialists. Ir Med J 2011; 104: 6e9. De Bruin ML, Van Dulmen-den Broader E, Van den Berg MH, Lambalk CB. Fertility in female cancer survivors. Endocr Dev 2009; 15: 135e58. Duncan FE, Jozefik JK, Kim AM, Hirsfeld-Cytron J, Woodruff TK. The Gynaecologist has a unique role in providing oncofertility care to young cancer patients. Obstet Gynaecol 2011; 6: 24e34. Faddy MJ, Gosden RG, Gougeon A, et al. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992; 7: 1342e6.

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Green DM, Sklar CA, Boice JD, et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: result from the childhood cancer survivor study. J Clin Oncol 2009; 27: 2374e81. Hudson MM. Reproductive outcomes for survivors of childhood cancer. Obstet Gynaecol 2010; 116: 1171e83. Maheshwari A, Gibreel A, Bhattacharya S, Johmson NP. Dynamic tests of ovarian reserve: a systematic review of diagnostic accuracy. Reprod Biomed Online 2009; 18: 717e34. NCI. A Snapshot of adolescent and young adult cancers. 2009. Available on: www.cancer.gov/aboutnci/servingpeople/aya-snapshot.pdf. Plante M, Gregoire J, Renaud MC, Roy M. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. Gynaecol Oncol 2011; 121: 290e4. Reulen RC, Zeegers MP, Wallace WHB, et al. Pregnancy outcomes in adult survivors of childhood cancer: the British childhood cancer study. Can Epid Biomark 2009; 18: 2239e47. Redriguez-Wallberg KA, Oktay K. Recent advances in oocyte and ovarian tissue maturation and transplantation. Best Pract Res Clin Obstet Gynaecol 2012; Jan 31 (e pub ahead of print).

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The gonadotoxic effect of cancer related treatment particularly radiotherapy and chemotherapy is well established Women should be referred for reproductive counselling whilst treatment for cancer is being planned The use of AMH and AFC as a measure of ovarian reserve has been effectively integrated in oncofertility practice Cryopreservation of sperm and embryos are established methods of preserving fertility before cancer treatment Oocyte cryopreservation is presently still experimental Abdominal and pelvic radiotherapy is associated with increased risk of miscarriage, preterm labour and small for gestational age Survivors of pelvic radiotherapy should be counselled in the risks in pregnancy. Predictive tests and interventions are limited but early dating and mid trimester anomaly scans may reassuring

Ă“ 2012 Elsevier Ltd. All rights reserved.


impact of cancer treatment on repro