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Hypogonadism and fertility issues following primary treatment for testicular cancer
Urologic Oncology: Seminars and Original Investigations ] (2015) ∎∎∎–∎∎∎
Review article
Hypogonadism and fertility issues following primary treatment for testicular cancer Jan Oldenburg, M.D., Ph.D.* Health Sciences, Høgskolen i Buskerud og Vestfold, Kongsberg, Norway Received 28 October 2014; received in revised form 14 December 2014; accepted 18 January 2015
Abstract Background: The majority of testicular cancer (TC) patients are cured and expected to live for decades after treatment, such that knowledge about hypogonadism and fertility issues is particularly important for the group of testicular cancer survivors (TCSs). Hypogonadism and fertility issues are related to treatment intensity. Testicular endocrine dysfunction comprises. Methods: In order to give an overview about hypogonadism in testicular cancer survivors (TCSs) the literature was reviewed. Testicular dysfunction was defined as inadequate spermatogenesis, as reflected by increased levels of Follicle Stimulating Hormone (FSH) and reduced fertility and/with or without insufficient testosterone (T) production with or without compensatory increased Luteinizing Hormone (LH) levels. Findings: Hypogonadism may lead to reduced sexual functioning and well-being, fertility problems, muscle weakness, loss of energy, and depression. Furthermore, hypogonadism also increases the risk of osteoporosis and is associated with the metabolic syndrome and cardiovascular disease (CVD). The hypothesized "Testicular Dysgenesis Syndrome" comprising low sperm counts, hypospadias, cryptorchidism, and finally TC, probably contributes to hypogonadism independent of applied TC treatment. Recently, an increased risk of accelerated hormonal ageing has been reported in TCSs in the very long term, i.e. 20 years after TC treatment. r 2015 Elsevier Inc. All rights reserved.
Keywords: Hypogonadism; Testosterone; Infertility; Testicular cancer; Subfertility; Cryopreservation; Accelerated ageing
1. Introduction Most patients with testicular cancer (TC) are cured and expected to live for decades after treatment [1]. Therefore, knowledge about long-term toxicities and long-term outcomes of hypogonadism and infertility or subfertility are particularly important for the group of testicular cancer survivors (TCSs) [2]. Hypogonadism and fertility issues are related to treatment intensity [3–5]. Testicular endocrine dysfunction, also called hypoandrogenism, comprises insufficient testosterone (T) production or compensatory increased luteinizing hormone (LH) levels. Inadequate spermatogenesis is measured by sperm counts, and as reflected by increased levels of follicle-stimulating hormone (FSH) and reduced fertility, which sometimes is the reason why some young males who contact the health care system *
Corresponding author. Tel.:þ472-293-4000. E-mail address: [email protected] http://dx.doi.org/10.1016/j.urolonc.2015.01.014 1078-1439/r 2015 Elsevier Inc. All rights reserved.
for fertilization assistance, may ultimately receive the diagnosis of TC during the diagnostic work-up [6]. The incidence of TC among men has with abnormal results on semen analysis has been calculated to be 20 times higher than in the normal population [7]. This association is in concordance with the “testicular dysgenesis syndrome” (TDS), which has been hypothesized by Skakkebaek et al. [8], comprising low sperm counts, hypospadias, cryptorchidism, and finally TC. This group of researchers work in Denmark, a country where nearly 1% of men are diagnosed with TC, almost 1% of men have penile abnormalities at birth, and 440% of men have poor semen quality [9]. In addition to epidemiological evidence, histopathologic findings support the concept of TDS, which is thought to be related to fetal development complications [8]. Interestingly, maternal smoking during pregnancy has a stronger effect on spermatogenesis than a man’s own smoking, also indicating that TDS symptoms that arise in adulthood may be already caused during fetal life [10].
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The group of Skakkebaek and Rajpert-De Meyts raised also concerns that not only TC incidence may have increased considerably during the recent years but also other components of the TDS, which may not be registered that reliably, such that TC may serve as a “whistleblower” of reproductive health problems [11]. Male hypogonadism is defined as a clinical syndrome that results from failure to produce physiological concentrations of T, normal amounts of sperm, or both [12], and may lead to reduced sexual functioning and well-being, fertility problems, muscle weakness, loss of energy, and depression [4,13,14]. Furthermore, hypogonadism also increases the risk of osteoporosis and is associated with the metabolic syndrome and cardiovascular disease [15–17]. In this article, an overview about fertility issues and hypogonadism has been provided, with a special focus on long-term hormonal ageing. 2. Physiology The testicles have 2 major functions: generation of sperm cells and T (endocrine function). Hypothalamus-derived gonadotropin-releasing hormone are stimulated with oscillating levels production of LH and FSH in the anterior pituitary gland and their release to the blood stream. Sperm cells (spermatozoa) are continuously produced by the testicular germinal epithelium, and the process from maturation of spermatogonias to mature sperm cells takes approximately 70 days. New cycles of spermatogenesis are initiated at regular time intervals (every 2–3 wk) before the previous ones are completed. FSH and T stimulate the Sertoli cells to provide hormonal and nutritional support for the spermatogenesis [18]. Regulated by FSH and spermatogenic status, Sertoli cells secrete Inhibin B, which limits FSH secretion through a negative feedback mechanism [19]. In adults, serum levels of Inhibin B correlate with total sperm count and testicular volume. Hence, both FSH and Inhibin B are useful markers of spermatogenesis. Spermatogenesis is usually evaluated by semen analyses, but in some cases, a testicular biopsy may be required. T production is the principal testicular endocrine function and is prone to an age-related decrease [20]. T is mostly bound to circulating plasma proteins; 40% to 50% loosely bound to albumin and 50% to 60% tightly to sexual hormone–binding globuline, with only 1% to 2% representing free T. The latter and the albumin-bound T fraction form the effective pool determining the biological activity of T. As the amount of sexual hormone–binding globuline increases by age, the free serum T decreases in a more pronounced manner than the total T concentration [21]. 3. Endocrine hypogonadism T production is believed to be reduced already before TC diagnosis owing to the TDS [8]. TC treatment further affects
the T production by the Leydig cells. Usually, the first sign of primary or testicular hypogonadism is an elevation of LH level to stimulate the Leydig cells. Firstly, when this stimulus is not sufficient, T levels start to decline. However, clinical symptoms such as loss of libido, anemia, fatigue, osteoporosis, and metabolic syndrome may, occur already when T production is compensated by increased LH. Alterations because of TDS might be subtle as Bandak et al. [22] found no significant differences in LH and T levels between controls and human choriogonadotropin negative–patients with unilateral stage I TC before orchiectomy. However, at 1 year after orchiectomy, a significant increase in LH level was observed. Elevated LH levels indicate critical Leydig cell capacity, as demonstrated by subsequently declining T level, rendering LH measurements clinically meaningful. On the long term, several aspects contribute to hypogonadism and its deterioration over time in TCSs: the status of having only 1 testicle, TDS, TC treatment after orchiectomy, and finally ageing. In unilaterally orchiectomized long-term survivors of testicular cancer TCSs, the prevalence of primary hypogonadism, as defined by LH levels 412 IU/l and/or testosterone o8 nmol/l, increases with treatment intensity [3]. After an observation time of median 11 years after treatment, TCSs had a 3.7-fold increased odds ratio (OR) for hypogonadism than age-matched males without TC did. Among TCSs, age greater than 45 years corresponded to a 1.4-fold increase in OR for hypogonadism. The corresponding ORs for TC treatment were 1.8 for surgery only, 3.6 for radiotherapy (RT), and 4.4 and 7.0 for cisplatin-based chemotherapy (CT) with cumulative cisplatin doses less than and greater than 850 mg, respectively. Systemic CT does obviously affect testicular function, despite the so-called blood-testis barrier. This barrier refers to an intratubular nutritional germ cell compartment formed by the Sertoli cells. Blood vessels at that site are permeable such that cytostatic substances reach the intratubular cells, i. e., Leydig and Sertoli cells and spermatogonia. Consequently, sperm production is reduced after CT. However, as late-stage germ cells are less sensitive to cytotoxic treatment than early-stage germ cells are, it may take weeks until an effect on spermatogenesis is observable by sperm counts. Recovery of spermatogenesis relies on the ability of spermatogonial stem cells to survive drug toxicity and to retain the potential to differentiate to spermatocytes.
4. Accelerated hormonal ageing An important question pertains to the further development of hypogonadism in long-term TCSs, which had been addressed by Sprauten et al. [5] in their publication “Longitudinal Serum Testosterone, Luteinizing Hormone, and Follicle-Stimulating Hormone Levels in a PopulationBased Sample of Long-Term Testicular Cancer Survivors”.
J. Oldenburg / Urologic Oncology: Seminars and Original Investigations ] (2015) 1–6
The methods of this study have to be explained in some depth to be able to grasp the findings. In all, 307 TCSs treated from 1980 to 1994 participated in this study. Blood samples had been drawn at 3 time points: after orchiectomy but before further treatment, median 11 years after treatment at Survey I (SI; 1998– 2002), and median 19 years after treatment Survey II (SII; 2007–2008). The levels of T, LH, and FSH were categorized according to quartiles and reference range (2.5 and 97.5 percentiles) of 599 controls for each decadal age group [20]. TCSs were categorized according to treatment: surgery, RT, or CT. The prevalence of hypogonadism did
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increase considerably from 10 years to 20 years after treatment. However, the declining T levels accompanied by rising LH and FSH levels represent a normal age-related phenomenon. To assess hypothetical accelerated hormonal ageing of TCSs over 20 years and more, the hormone levels were related to those of healthy controls in the form of percentiles such as those used in pediatrics (Fig. 1). The risk of lower T and higher LH and FSH levels was significantly increased for TCSs at both 1 and 2 decades after RT or CT. At SII (20 y after treatment), the OR for lower T after RT and CT was 3.3 (95% CI: 2.3–4.7) and 5.2 (95% CI: 3.5–7.9), respectively. The ORs for increased LH
Fig. 1. (A) Testosterone, (B) luteinizing hormone, and (C) follicle-stimulating hormone categories over time, adjusted for decadal age according to treatment group at the following time points: baseline (BL), Survey I (SI), and Survey II (SII). BL ¼ baseline, IQR ¼ interquartile range, SI ¼ Survey I (1 decade after treatment), SII ¼ Survey II (2 decades after treatment). T, LH, and FSH levels categorized according to reference levels and quartiles from controls for each decadal age group. The 25–75 percentile is depicted as interquartile range (IQR). (Reproduced with permission from Sprauten et al. [5].)
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and FSH levels were 4.4 (95% CI: 3.1–6.5) and 18.9 (95% CI: 11.0–32.6), respectively, for RT and 3.6 (95% CI: 2.4– 5.3) and 14.2 (95% CI; 8.3–24.4), respectively, for CT. These high and increasing ORs imply an accelerated hormonal ageing of TCSs. Those who are not familiar with the concept of ordinal logistic regression analysis and resulting ORs, may find the following explanation of Fig. 1 helpful to appraise this information. Lanes (A), (B), and (C) show T, LH, and FSH categories after surgery (left), RT (middle), and CT (right). The left column depicts the allocation of controls according to the percentiles, with the gray area presenting the interquartile range, i.e., 25th to 75th percentiles. Of note, percentiles were used for each decadal age group such that the physiological decline in sex hormones is adjusted for. The next 3 columns depict the hormone level categorization of TCSs at 3 time points (baseline, i.e., after orchiectomy but before potential subsequent treatment, SI—survey I at median 11 y after completion of TC treatment, and SII— survey II at median 19 y after completion of TC treatment). T levels are shown in lane (A) and the gray interquartile range area is at all time points lower than in the controls (with the upper bond below 60th percentile instead of 75th percentile) demonstrating lower androgen levels. At 10 years after CT, T levels are considerably lower than at baseline. These levels decline dramatically during the next decade, and more than 60% of TCSs have T values corresponding to the lowest quartile of age-matched controls at 2 decades after CT. The LH levels, lane (B), display a corresponding increase from SI to SII after surgery, RT,
Fig. 2. Odds ratios for increasing levels of sperm counts according to treatment group. Odds ratios for increasing levels of sperm counts according to treatment group (overall P ¼ 0.003 compared with surgery group: P o 0.001 (cis 4850 mg), and p ¼ 0.04 (cis o 850 mg), and p ¼ 0.37 (RT). Bars indicate 95% confidence intervals. In the proportional odds logistic regression model, sperm counts were grouped into 5 categories (azoospermia, few visible sperm to 1 million per ml, 1.1–9.9, 10–14.9, and 4 15 millions per ml). The model was adjusted for age at follow-up, follow-up time, and self-reported cryptorchidism (all nonsignificant). cis ¼ cisplatin. (Reproduced with permission of the publisher [25].)
and CT, indicating accelerated hormonal ageing in TCSs. FSH levels, lane (C), at baseline are already considerably higher in TCSs than in the age-matched controls. This observation is truly independent of treatment, and further declining spermatogenesis is reflected by steadily increasing FSH levels. At 2 decades after CT, more than 60% of TCSs have FSH levels greater than the 97.5th percentile. Comparison of the hormone level categories between TCSs and healthy men (controls) reveals significantly lower T and significantly higher LH and FSH levels already at baseline, defined as time after orchiectomy but prior to potential subsequent treatment (Fig. 1). In a survey at 10 years (SI), these differences are more pronounced and more so at 20 years after treatment (SII). The cumulative platinum dose was significantly associated with a risk of higher LH levels at both surveys and higher FSH level at SI. At SII (20 y after treatment), half the TCSs had at least 1 of 3 sex hormone levels outside the reference range, e.g., less than 2.5 percentile or greater than 97.5 percentile of controls.
5. Fertility issues The aforementioned increased FSH level indicates reduced fertility in patients with TC. The association between decreased male fertility and TC is well documented [23], and approximately half of the patients diagnosed with TC have reduced spermatogenesis after orchiectomy before additional treatment [24]. Furthermore, biopsies have revealed that 24% of patients with unilateral TC probably have irreversibly impaired spermatogenesis in the contralateral testicle [23]. This observation supports the concept of a “testicular dysgenesis syndrome” (TDS) [8]. In addition to TDSrelated reduced spermatogenesis, TCSs have usually only 1 testicle and thus approximately only half the number of spermatogonia. In addition, TC is usually diagnosed in the age between 20 and 40 years, during which phase most men establish their families and the ability to father children in the future is an important issue for most patients newly diagnosed with TC [4]. The diagnosis of a malignancy and the associated uncertainty about prognosis may delay family planning for a relevant period of time. Moreover, patients with TC who wish to father children are usually advised to wait at least 1 year after discontinuation of CT to minimize the risk of miscarriages due to damaged sperm cells. TC treatment affects the sperm counts, as demonstrated by Brydoy et al. [25]. In the same cohort of Norwegian TCSs treated between 1980 and 1994, serum levels of FSH, inhibin B, and sperm counts (millions per ml) were assessed at a median of 11 years after treatment, with paternity reported by a questionnaire. As many as 44% had oligospermia, defined as o15 millions per ml (29%) or azoospermia (15%). In TCSs treated with CT, sperm counts and inhibin B level were significantly lower and FSH level
J. Oldenburg / Urologic Oncology: Seminars and Original Investigations ] (2015) 1–6
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of cryopreserved semen. This rate was highest in the surveillance group (92%) and lowest in TCSs who received more than 850 mg cisplatin (48%) (Fig. 2). The median time from diagnosis to birth of a child was 6.6 years after treatment overall, but it varied according to treatment. Assisted reproductive technologies were used by 22% of the couples who attempted conception after treatment. Dry ejaculation, treatment group, pretreatment fatherhood, and marital status were statistically significant independent predictors for posttreatment fatherhood, with dry ejaculation being the most important negative factor [4]. 6. Conclusions
Fig. 3. Actuarial posttreatment fatherhood rates for testicular cancer survivors attempting conception by natural means according to treatment groups. cis ¼ cisplatin; RPLND ¼ retroperitoneal lymph node dissection; RT ¼ radiotherapy. Vertical bars indicate 95% CIs. (Reproduced with permission from Brydoy et al. [4].)
higher, as compared with those who underwent surgery only. All parameters were significantly more abnormal following high cumulative doses of CT, exceeding 850 mg as compared with lower cumulative doses of 850 mg or less. Of note, these parameters differed significantly between those who had fathered a child posttreatment and those with unsuccessful fatherhood attempts. The effect of TC treatment on sperm counts is shown in Fig. 3, where the surgery group served as a reference. RT reduced the sperm counts with an OR of 0.76, whereas CT corresponded to ORs of 0.54 and 0.18 for cumulative cisplatin doses less than and greater than 850 mg, respectively [25]. Lampe et al. [26] assessed sperm counts before and after CT in 170 patients with TC. Most had a sufficient recovery of sperm concentration such that the majority of patients who had normospermic counts before CT achieved this status again. It should be noted that 45% of the azoospermic patients regained oligospermic or normospermic counts after treatment. Importantly, sperm recovery may take time, often up to 5 years and sometimes more than 8 years. Important predictors for achieving sperm concentration of at least 1 million per ml were normal spermatogenesis before CT and application of 4 or less vs. more cycles of CT among others, whereas age less than or greater than 30 years was not associated with this recovery. Brydoy et al. [4] performed a population-based study on the conception rates of 554 TCSs who wished to father children after TC treatment. TCSs were grouped into 5 categories according their prior TC management: active surveillance, retroperitoneal lymph node dissection only, RT, cisplatin-based CT (o850 cumulative cisplatin), and cisplatin-based CT (4850 cumulative cisplatin). The overall actuarial posttreatment paternity rate 15 years after treatment was 71% without the use
Some men may suffer from gonadal dysfunction before diagnosis of TC. TC treatment affects all assessed aspects of hypogonadism and fertility. Sperm production seems to achieve preCT parameters in most patients. Patients wishing to become parents should be offered cryopreservation of their germ cells before initiation of TC treatment, including orchiectomy. References [1] Oldenburg J, Fossa SD, Nuver J, Heidenreich A, Schmoll HJ, Bokemeyer C, et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl 6):vi125–32. [2] Haugnes HS, Bosl GJ, Boer H, Gietema JA, Brydoy M, Oldenburg J, et al. Long-term and late effects of germ cell testicular cancer treatment and implications for follow-up. J Clin Oncol 2012;30:3752–63. [3] Nord C, Bjoro T, Ellingsen D, Mykletun A, Dahl O, Klepp O, et al. Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. Eur Urol 2003;44:322–8. [4] Brydoy M, Fossa SD, Klepp O, Bremnes RM, Wist EA, WentzelLarsen T, et al. Paternity following treatment for testicular cancer. J Natl Cancer Inst 2005;97:1580–8. [5] Sprauten M, Brydoy M, Haugnes HS, Cvancarova M, Bjoro T, Bjerner J, et al. Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 2014;32:571–8. [6] Jacobsen R, Bostofte E, Engholm G, Hansen J, Olsen JH, Skakkebaek NE, et al. Risk of testicular cancer in men with abnormal semen characteristics: cohort study. Br Med J 2000;321:789–92. [7] Raman JD, Nobert CF, Goldstein M. Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol 2005;174:1819–22. [8] Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16:972–8. [9] Andersen AG, Jensen TK, Carlsen E, Jorgensen N, Andersson AM, Krarup T, et al. High frequency of sub-optimal semen quality in an unselected population of young men. Hum Reprod 2000;15:366–72. [10] Juul A, Almstrup K, Andersson AM, Jensen TK, Jorgensen N, Main KM, et al. Possible fetal determinants of male infertility. Nat Rev Endocrinol 2014;10:553–62. [11] Skakkebaek NE, Rajpert-De ME, Jorgensen N, Main KM, Leffers H, Andersson AM, et al. Testicular cancer trends as ‘whistle blowers’ of testicular developmental problems in populations. Int J Androl 2007;30:198–204. [12] Basaria S. Male hypogonadism. Lancet 2014;383:1250–63.
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[13] Eberhard J, Stahl O, Cohn-Cedermark G, Cavallin-Stahl E, Giwercman Y, Rylander L, et al. Sexual function in men treated for testicular cancer. J Sex Med 2009;6:1979–89. [14] Dahl AA, Bremnes R, Dahl O, Klepp O, Wist E, Fossa SD. Is the sexual function compromised in long-term testicular cancer survivors? Eur Urol 2007;52:1438–47. [15] Haugnes HS, Aass N, Fossa SD, Dahl O, Klepp O, Wist EA, et al. Components of the metabolic syndrome in long-term survivors of testicular cancer. Ann Oncol 2007;18:241–8. [16] Haugnes HS, Wethal T, Aass N, Dahl O, Klepp O, Langberg CW, et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol 2010;28:4649–57. [17] Nuver J, Smit AJ, Wolffenbuttel BHR, Sluiter WJ, Hoekstra HJ, Sleifer DT, et al. The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol 2005;23:3718–25. [18] Dohle GR, Smit M, Weber RF. Androgens and male fertility. World J Urol 2003;21:341–5. [19] Meachem SJ, Nieschlag E, Simoni M. Inhibin B in male reproduction: pathophysiology and clinical relevance. Eur J Endocrinol 2001;145:561–71.
[20] Bjerner J, Biernat D, Fossa SD, Bjoro T. Reference intervals for serum testosterone, SHBG, LH and FSH in males from the NORIP project. Scand J Clin Lab Invest 2009;69:873–9. [21] Perheentupa A, Huhtaniemi I. Aging of the human ovary and testis. Mol Cell Endocrinol 2009;299:2–13. [22] Bandak M, Aksglaede L, Juul A, Rorth M, Daugaard G. The pituitary-Leydig cell axis before and after orchiectomy in patients with stage I testicular cancer. Eur J Cancer 2011;47: 2585–91. [23] Berthelsen JG. Testicular cancer and fertility. Int J Androl 1987;10:371–80. [24] Fossa SD, Abyholm T, Aakvaag A. Spermatogenesis and hormonal status after orchiectomy for cancer and before supplementary treatment. Eur Urol 1984;10:173–7. [25] Brydoy M, Fossa SD, Klepp O, Bremnes RM, Wist EA, Bjoro T, et al. Sperm counts and endocrinological markers of spermatogenesis in long-term survivors of testicular cancer. Br J Cancer 2012;107:1833–9. [26] Lampe H, Horwich A, Norman A, Nicholls J, Dearnaley DP. Fertility after chemotherapy for testicular germ cell cancers. J Clin Oncol 1997;15:239–45.
Review article
Hypogonadism and fertility issues following primary treatment for testicular cancer Jan Oldenburg, M.D., Ph.D.* Health Sciences, Høgskolen i Buskerud og Vestfold, Kongsberg, Norway Received 28 October 2014; received in revised form 14 December 2014; accepted 18 January 2015
Abstract Background: The majority of testicular cancer (TC) patients are cured and expected to live for decades after treatment, such that knowledge about hypogonadism and fertility issues is particularly important for the group of testicular cancer survivors (TCSs). Hypogonadism and fertility issues are related to treatment intensity. Testicular endocrine dysfunction comprises. Methods: In order to give an overview about hypogonadism in testicular cancer survivors (TCSs) the literature was reviewed. Testicular dysfunction was defined as inadequate spermatogenesis, as reflected by increased levels of Follicle Stimulating Hormone (FSH) and reduced fertility and/with or without insufficient testosterone (T) production with or without compensatory increased Luteinizing Hormone (LH) levels. Findings: Hypogonadism may lead to reduced sexual functioning and well-being, fertility problems, muscle weakness, loss of energy, and depression. Furthermore, hypogonadism also increases the risk of osteoporosis and is associated with the metabolic syndrome and cardiovascular disease (CVD). The hypothesized "Testicular Dysgenesis Syndrome" comprising low sperm counts, hypospadias, cryptorchidism, and finally TC, probably contributes to hypogonadism independent of applied TC treatment. Recently, an increased risk of accelerated hormonal ageing has been reported in TCSs in the very long term, i.e. 20 years after TC treatment. r 2015 Elsevier Inc. All rights reserved.
Keywords: Hypogonadism; Testosterone; Infertility; Testicular cancer; Subfertility; Cryopreservation; Accelerated ageing
1. Introduction Most patients with testicular cancer (TC) are cured and expected to live for decades after treatment [1]. Therefore, knowledge about long-term toxicities and long-term outcomes of hypogonadism and infertility or subfertility are particularly important for the group of testicular cancer survivors (TCSs) [2]. Hypogonadism and fertility issues are related to treatment intensity [3–5]. Testicular endocrine dysfunction, also called hypoandrogenism, comprises insufficient testosterone (T) production or compensatory increased luteinizing hormone (LH) levels. Inadequate spermatogenesis is measured by sperm counts, and as reflected by increased levels of follicle-stimulating hormone (FSH) and reduced fertility, which sometimes is the reason why some young males who contact the health care system *
Corresponding author. Tel.:þ472-293-4000. E-mail address: [email protected] http://dx.doi.org/10.1016/j.urolonc.2015.01.014 1078-1439/r 2015 Elsevier Inc. All rights reserved.
for fertilization assistance, may ultimately receive the diagnosis of TC during the diagnostic work-up [6]. The incidence of TC among men has with abnormal results on semen analysis has been calculated to be 20 times higher than in the normal population [7]. This association is in concordance with the “testicular dysgenesis syndrome” (TDS), which has been hypothesized by Skakkebaek et al. [8], comprising low sperm counts, hypospadias, cryptorchidism, and finally TC. This group of researchers work in Denmark, a country where nearly 1% of men are diagnosed with TC, almost 1% of men have penile abnormalities at birth, and 440% of men have poor semen quality [9]. In addition to epidemiological evidence, histopathologic findings support the concept of TDS, which is thought to be related to fetal development complications [8]. Interestingly, maternal smoking during pregnancy has a stronger effect on spermatogenesis than a man’s own smoking, also indicating that TDS symptoms that arise in adulthood may be already caused during fetal life [10].
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The group of Skakkebaek and Rajpert-De Meyts raised also concerns that not only TC incidence may have increased considerably during the recent years but also other components of the TDS, which may not be registered that reliably, such that TC may serve as a “whistleblower” of reproductive health problems [11]. Male hypogonadism is defined as a clinical syndrome that results from failure to produce physiological concentrations of T, normal amounts of sperm, or both [12], and may lead to reduced sexual functioning and well-being, fertility problems, muscle weakness, loss of energy, and depression [4,13,14]. Furthermore, hypogonadism also increases the risk of osteoporosis and is associated with the metabolic syndrome and cardiovascular disease [15–17]. In this article, an overview about fertility issues and hypogonadism has been provided, with a special focus on long-term hormonal ageing. 2. Physiology The testicles have 2 major functions: generation of sperm cells and T (endocrine function). Hypothalamus-derived gonadotropin-releasing hormone are stimulated with oscillating levels production of LH and FSH in the anterior pituitary gland and their release to the blood stream. Sperm cells (spermatozoa) are continuously produced by the testicular germinal epithelium, and the process from maturation of spermatogonias to mature sperm cells takes approximately 70 days. New cycles of spermatogenesis are initiated at regular time intervals (every 2–3 wk) before the previous ones are completed. FSH and T stimulate the Sertoli cells to provide hormonal and nutritional support for the spermatogenesis [18]. Regulated by FSH and spermatogenic status, Sertoli cells secrete Inhibin B, which limits FSH secretion through a negative feedback mechanism [19]. In adults, serum levels of Inhibin B correlate with total sperm count and testicular volume. Hence, both FSH and Inhibin B are useful markers of spermatogenesis. Spermatogenesis is usually evaluated by semen analyses, but in some cases, a testicular biopsy may be required. T production is the principal testicular endocrine function and is prone to an age-related decrease [20]. T is mostly bound to circulating plasma proteins; 40% to 50% loosely bound to albumin and 50% to 60% tightly to sexual hormone–binding globuline, with only 1% to 2% representing free T. The latter and the albumin-bound T fraction form the effective pool determining the biological activity of T. As the amount of sexual hormone–binding globuline increases by age, the free serum T decreases in a more pronounced manner than the total T concentration [21]. 3. Endocrine hypogonadism T production is believed to be reduced already before TC diagnosis owing to the TDS [8]. TC treatment further affects
the T production by the Leydig cells. Usually, the first sign of primary or testicular hypogonadism is an elevation of LH level to stimulate the Leydig cells. Firstly, when this stimulus is not sufficient, T levels start to decline. However, clinical symptoms such as loss of libido, anemia, fatigue, osteoporosis, and metabolic syndrome may, occur already when T production is compensated by increased LH. Alterations because of TDS might be subtle as Bandak et al. [22] found no significant differences in LH and T levels between controls and human choriogonadotropin negative–patients with unilateral stage I TC before orchiectomy. However, at 1 year after orchiectomy, a significant increase in LH level was observed. Elevated LH levels indicate critical Leydig cell capacity, as demonstrated by subsequently declining T level, rendering LH measurements clinically meaningful. On the long term, several aspects contribute to hypogonadism and its deterioration over time in TCSs: the status of having only 1 testicle, TDS, TC treatment after orchiectomy, and finally ageing. In unilaterally orchiectomized long-term survivors of testicular cancer TCSs, the prevalence of primary hypogonadism, as defined by LH levels 412 IU/l and/or testosterone o8 nmol/l, increases with treatment intensity [3]. After an observation time of median 11 years after treatment, TCSs had a 3.7-fold increased odds ratio (OR) for hypogonadism than age-matched males without TC did. Among TCSs, age greater than 45 years corresponded to a 1.4-fold increase in OR for hypogonadism. The corresponding ORs for TC treatment were 1.8 for surgery only, 3.6 for radiotherapy (RT), and 4.4 and 7.0 for cisplatin-based chemotherapy (CT) with cumulative cisplatin doses less than and greater than 850 mg, respectively. Systemic CT does obviously affect testicular function, despite the so-called blood-testis barrier. This barrier refers to an intratubular nutritional germ cell compartment formed by the Sertoli cells. Blood vessels at that site are permeable such that cytostatic substances reach the intratubular cells, i. e., Leydig and Sertoli cells and spermatogonia. Consequently, sperm production is reduced after CT. However, as late-stage germ cells are less sensitive to cytotoxic treatment than early-stage germ cells are, it may take weeks until an effect on spermatogenesis is observable by sperm counts. Recovery of spermatogenesis relies on the ability of spermatogonial stem cells to survive drug toxicity and to retain the potential to differentiate to spermatocytes.
4. Accelerated hormonal ageing An important question pertains to the further development of hypogonadism in long-term TCSs, which had been addressed by Sprauten et al. [5] in their publication “Longitudinal Serum Testosterone, Luteinizing Hormone, and Follicle-Stimulating Hormone Levels in a PopulationBased Sample of Long-Term Testicular Cancer Survivors”.
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The methods of this study have to be explained in some depth to be able to grasp the findings. In all, 307 TCSs treated from 1980 to 1994 participated in this study. Blood samples had been drawn at 3 time points: after orchiectomy but before further treatment, median 11 years after treatment at Survey I (SI; 1998– 2002), and median 19 years after treatment Survey II (SII; 2007–2008). The levels of T, LH, and FSH were categorized according to quartiles and reference range (2.5 and 97.5 percentiles) of 599 controls for each decadal age group [20]. TCSs were categorized according to treatment: surgery, RT, or CT. The prevalence of hypogonadism did
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increase considerably from 10 years to 20 years after treatment. However, the declining T levels accompanied by rising LH and FSH levels represent a normal age-related phenomenon. To assess hypothetical accelerated hormonal ageing of TCSs over 20 years and more, the hormone levels were related to those of healthy controls in the form of percentiles such as those used in pediatrics (Fig. 1). The risk of lower T and higher LH and FSH levels was significantly increased for TCSs at both 1 and 2 decades after RT or CT. At SII (20 y after treatment), the OR for lower T after RT and CT was 3.3 (95% CI: 2.3–4.7) and 5.2 (95% CI: 3.5–7.9), respectively. The ORs for increased LH
Fig. 1. (A) Testosterone, (B) luteinizing hormone, and (C) follicle-stimulating hormone categories over time, adjusted for decadal age according to treatment group at the following time points: baseline (BL), Survey I (SI), and Survey II (SII). BL ¼ baseline, IQR ¼ interquartile range, SI ¼ Survey I (1 decade after treatment), SII ¼ Survey II (2 decades after treatment). T, LH, and FSH levels categorized according to reference levels and quartiles from controls for each decadal age group. The 25–75 percentile is depicted as interquartile range (IQR). (Reproduced with permission from Sprauten et al. [5].)
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and FSH levels were 4.4 (95% CI: 3.1–6.5) and 18.9 (95% CI: 11.0–32.6), respectively, for RT and 3.6 (95% CI: 2.4– 5.3) and 14.2 (95% CI; 8.3–24.4), respectively, for CT. These high and increasing ORs imply an accelerated hormonal ageing of TCSs. Those who are not familiar with the concept of ordinal logistic regression analysis and resulting ORs, may find the following explanation of Fig. 1 helpful to appraise this information. Lanes (A), (B), and (C) show T, LH, and FSH categories after surgery (left), RT (middle), and CT (right). The left column depicts the allocation of controls according to the percentiles, with the gray area presenting the interquartile range, i.e., 25th to 75th percentiles. Of note, percentiles were used for each decadal age group such that the physiological decline in sex hormones is adjusted for. The next 3 columns depict the hormone level categorization of TCSs at 3 time points (baseline, i.e., after orchiectomy but before potential subsequent treatment, SI—survey I at median 11 y after completion of TC treatment, and SII— survey II at median 19 y after completion of TC treatment). T levels are shown in lane (A) and the gray interquartile range area is at all time points lower than in the controls (with the upper bond below 60th percentile instead of 75th percentile) demonstrating lower androgen levels. At 10 years after CT, T levels are considerably lower than at baseline. These levels decline dramatically during the next decade, and more than 60% of TCSs have T values corresponding to the lowest quartile of age-matched controls at 2 decades after CT. The LH levels, lane (B), display a corresponding increase from SI to SII after surgery, RT,
Fig. 2. Odds ratios for increasing levels of sperm counts according to treatment group. Odds ratios for increasing levels of sperm counts according to treatment group (overall P ¼ 0.003 compared with surgery group: P o 0.001 (cis 4850 mg), and p ¼ 0.04 (cis o 850 mg), and p ¼ 0.37 (RT). Bars indicate 95% confidence intervals. In the proportional odds logistic regression model, sperm counts were grouped into 5 categories (azoospermia, few visible sperm to 1 million per ml, 1.1–9.9, 10–14.9, and 4 15 millions per ml). The model was adjusted for age at follow-up, follow-up time, and self-reported cryptorchidism (all nonsignificant). cis ¼ cisplatin. (Reproduced with permission of the publisher [25].)
and CT, indicating accelerated hormonal ageing in TCSs. FSH levels, lane (C), at baseline are already considerably higher in TCSs than in the age-matched controls. This observation is truly independent of treatment, and further declining spermatogenesis is reflected by steadily increasing FSH levels. At 2 decades after CT, more than 60% of TCSs have FSH levels greater than the 97.5th percentile. Comparison of the hormone level categories between TCSs and healthy men (controls) reveals significantly lower T and significantly higher LH and FSH levels already at baseline, defined as time after orchiectomy but prior to potential subsequent treatment (Fig. 1). In a survey at 10 years (SI), these differences are more pronounced and more so at 20 years after treatment (SII). The cumulative platinum dose was significantly associated with a risk of higher LH levels at both surveys and higher FSH level at SI. At SII (20 y after treatment), half the TCSs had at least 1 of 3 sex hormone levels outside the reference range, e.g., less than 2.5 percentile or greater than 97.5 percentile of controls.
5. Fertility issues The aforementioned increased FSH level indicates reduced fertility in patients with TC. The association between decreased male fertility and TC is well documented [23], and approximately half of the patients diagnosed with TC have reduced spermatogenesis after orchiectomy before additional treatment [24]. Furthermore, biopsies have revealed that 24% of patients with unilateral TC probably have irreversibly impaired spermatogenesis in the contralateral testicle [23]. This observation supports the concept of a “testicular dysgenesis syndrome” (TDS) [8]. In addition to TDSrelated reduced spermatogenesis, TCSs have usually only 1 testicle and thus approximately only half the number of spermatogonia. In addition, TC is usually diagnosed in the age between 20 and 40 years, during which phase most men establish their families and the ability to father children in the future is an important issue for most patients newly diagnosed with TC [4]. The diagnosis of a malignancy and the associated uncertainty about prognosis may delay family planning for a relevant period of time. Moreover, patients with TC who wish to father children are usually advised to wait at least 1 year after discontinuation of CT to minimize the risk of miscarriages due to damaged sperm cells. TC treatment affects the sperm counts, as demonstrated by Brydoy et al. [25]. In the same cohort of Norwegian TCSs treated between 1980 and 1994, serum levels of FSH, inhibin B, and sperm counts (millions per ml) were assessed at a median of 11 years after treatment, with paternity reported by a questionnaire. As many as 44% had oligospermia, defined as o15 millions per ml (29%) or azoospermia (15%). In TCSs treated with CT, sperm counts and inhibin B level were significantly lower and FSH level
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of cryopreserved semen. This rate was highest in the surveillance group (92%) and lowest in TCSs who received more than 850 mg cisplatin (48%) (Fig. 2). The median time from diagnosis to birth of a child was 6.6 years after treatment overall, but it varied according to treatment. Assisted reproductive technologies were used by 22% of the couples who attempted conception after treatment. Dry ejaculation, treatment group, pretreatment fatherhood, and marital status were statistically significant independent predictors for posttreatment fatherhood, with dry ejaculation being the most important negative factor [4]. 6. Conclusions
Fig. 3. Actuarial posttreatment fatherhood rates for testicular cancer survivors attempting conception by natural means according to treatment groups. cis ¼ cisplatin; RPLND ¼ retroperitoneal lymph node dissection; RT ¼ radiotherapy. Vertical bars indicate 95% CIs. (Reproduced with permission from Brydoy et al. [4].)
higher, as compared with those who underwent surgery only. All parameters were significantly more abnormal following high cumulative doses of CT, exceeding 850 mg as compared with lower cumulative doses of 850 mg or less. Of note, these parameters differed significantly between those who had fathered a child posttreatment and those with unsuccessful fatherhood attempts. The effect of TC treatment on sperm counts is shown in Fig. 3, where the surgery group served as a reference. RT reduced the sperm counts with an OR of 0.76, whereas CT corresponded to ORs of 0.54 and 0.18 for cumulative cisplatin doses less than and greater than 850 mg, respectively [25]. Lampe et al. [26] assessed sperm counts before and after CT in 170 patients with TC. Most had a sufficient recovery of sperm concentration such that the majority of patients who had normospermic counts before CT achieved this status again. It should be noted that 45% of the azoospermic patients regained oligospermic or normospermic counts after treatment. Importantly, sperm recovery may take time, often up to 5 years and sometimes more than 8 years. Important predictors for achieving sperm concentration of at least 1 million per ml were normal spermatogenesis before CT and application of 4 or less vs. more cycles of CT among others, whereas age less than or greater than 30 years was not associated with this recovery. Brydoy et al. [4] performed a population-based study on the conception rates of 554 TCSs who wished to father children after TC treatment. TCSs were grouped into 5 categories according their prior TC management: active surveillance, retroperitoneal lymph node dissection only, RT, cisplatin-based CT (o850 cumulative cisplatin), and cisplatin-based CT (4850 cumulative cisplatin). The overall actuarial posttreatment paternity rate 15 years after treatment was 71% without the use
Some men may suffer from gonadal dysfunction before diagnosis of TC. TC treatment affects all assessed aspects of hypogonadism and fertility. Sperm production seems to achieve preCT parameters in most patients. Patients wishing to become parents should be offered cryopreservation of their germ cells before initiation of TC treatment, including orchiectomy. References [1] Oldenburg J, Fossa SD, Nuver J, Heidenreich A, Schmoll HJ, Bokemeyer C, et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl 6):vi125–32. [2] Haugnes HS, Bosl GJ, Boer H, Gietema JA, Brydoy M, Oldenburg J, et al. Long-term and late effects of germ cell testicular cancer treatment and implications for follow-up. J Clin Oncol 2012;30:3752–63. [3] Nord C, Bjoro T, Ellingsen D, Mykletun A, Dahl O, Klepp O, et al. Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. Eur Urol 2003;44:322–8. [4] Brydoy M, Fossa SD, Klepp O, Bremnes RM, Wist EA, WentzelLarsen T, et al. Paternity following treatment for testicular cancer. J Natl Cancer Inst 2005;97:1580–8. [5] Sprauten M, Brydoy M, Haugnes HS, Cvancarova M, Bjoro T, Bjerner J, et al. Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 2014;32:571–8. [6] Jacobsen R, Bostofte E, Engholm G, Hansen J, Olsen JH, Skakkebaek NE, et al. Risk of testicular cancer in men with abnormal semen characteristics: cohort study. Br Med J 2000;321:789–92. [7] Raman JD, Nobert CF, Goldstein M. Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol 2005;174:1819–22. [8] Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16:972–8. [9] Andersen AG, Jensen TK, Carlsen E, Jorgensen N, Andersson AM, Krarup T, et al. High frequency of sub-optimal semen quality in an unselected population of young men. Hum Reprod 2000;15:366–72. [10] Juul A, Almstrup K, Andersson AM, Jensen TK, Jorgensen N, Main KM, et al. Possible fetal determinants of male infertility. Nat Rev Endocrinol 2014;10:553–62. [11] Skakkebaek NE, Rajpert-De ME, Jorgensen N, Main KM, Leffers H, Andersson AM, et al. Testicular cancer trends as ‘whistle blowers’ of testicular developmental problems in populations. Int J Androl 2007;30:198–204. [12] Basaria S. Male hypogonadism. Lancet 2014;383:1250–63.
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[20] Bjerner J, Biernat D, Fossa SD, Bjoro T. Reference intervals for serum testosterone, SHBG, LH and FSH in males from the NORIP project. Scand J Clin Lab Invest 2009;69:873–9. [21] Perheentupa A, Huhtaniemi I. Aging of the human ovary and testis. Mol Cell Endocrinol 2009;299:2–13. [22] Bandak M, Aksglaede L, Juul A, Rorth M, Daugaard G. The pituitary-Leydig cell axis before and after orchiectomy in patients with stage I testicular cancer. Eur J Cancer 2011;47: 2585–91. [23] Berthelsen JG. Testicular cancer and fertility. Int J Androl 1987;10:371–80. [24] Fossa SD, Abyholm T, Aakvaag A. Spermatogenesis and hormonal status after orchiectomy for cancer and before supplementary treatment. Eur Urol 1984;10:173–7. [25] Brydoy M, Fossa SD, Klepp O, Bremnes RM, Wist EA, Bjoro T, et al. Sperm counts and endocrinological markers of spermatogenesis in long-term survivors of testicular cancer. Br J Cancer 2012;107:1833–9. [26] Lampe H, Horwich A, Norman A, Nicholls J, Dearnaley DP. Fertility after chemotherapy for testicular germ cell cancers. J Clin Oncol 1997;15:239–45.