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REVIEW ARTICLE
Year : 2020  |  Volume : 32  |  Issue : 4  |  Page : 153-156

Prostate cancer therapies and fertility: What do we really know?


1 2nd Department of Urology, Sismanogleio General Hospital, National and Kapodistrian University of Athens, Athens, Greece
2 2nd nd Deparment of Urology, Athens Medical School, National and Kapodistrian University of Athens, Sismanogleio General Hospital, Athens, Greece

Date of Submission05-Mar-2021
Date of Decision14-Mar-2021
Date of Acceptance24-Mar-2021
Date of Web Publication13-Aug-2021

Correspondence Address:
Panagiotis Mourmouris
2nd Department of Urology, Sismanogleio General Hospital, National and Kapodistrian University of Athens, 1st Sismanogleiou Str, Marousi 15125, Athens
Greece
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HUAJ.HUAJ_9_21

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  Abstract 


We reviewed the literature for articles in English in the Medline database from 1970 until today. The keywords used were “prostate cancer,” “fertility,” “radical prostatectomy,” “external beam radiotherapy,” “androgen deprivation therapy,” and “chemotherapy.” Only the studies with full paper were included in our review. The knowledge for this important issue is minimal and more minimal tends to be the consent of the patients. Prostate cancer does not seem to directly influence fertility, but all its therapies directly or indirectly seem to do so. In many of them, the impact may be reversible, but the mechanisms of this impact are still under consideration. Prostate cancer treatments, predominantly radiation, can cause long-term azoospermia; however, the data in the literature are sparse, mainly derived from small series, and based on these, no safe conclusions can be drawn.

Keywords: Androgen deprivation therapy, chemotherapy, infertility, prostate cancer, radical prostatectomy, radiotherapy


How to cite this article:
Mourmouris P, Tzelves L, Deverakis T, Lazarou L, Tsirkas K, Fotsali A, Roidi C, Varkarakis I. Prostate cancer therapies and fertility: What do we really know?. Hellenic Urology 2020;32:153-6

How to cite this URL:
Mourmouris P, Tzelves L, Deverakis T, Lazarou L, Tsirkas K, Fotsali A, Roidi C, Varkarakis I. Prostate cancer therapies and fertility: What do we really know?. Hellenic Urology [serial online] 2020 [cited 2021 Sep 24];32:153-6. Available from: http://www.hellenicurologyjournal.com/text.asp?2020/32/4/153/323813




  Introduction Top


According to the American Cancer Society, prostate cancer is the most popular cancer with rates up to 19% (except for skin cancer).[1] The rates of the first diagnosis of prostate cancer in the age group of 35–44 and 45–54 are 0.5% and 9.2%, respectively.[2] The above-mentioned statistic data in conjunction with the mean age of man childbirth (33 years) along with the fact that men tend to start thinking of having children even after 55 years (13.3%), transform the decision for prostate cancer management, in a significant one.[3] In this study, we are reviewing literature about the impact of prostate cancer and its therapy in men fertility, in an effort to increase the 8.7% of informed consent of the patients, according to a very recent study,[4] for fertility issues after prostate cancer therapy.


  Prostate Cancer and Infertility Top


The most important parameter when informing the patient is whether prostate cancer itself can affect spermatogenesis and, as a result, lead to infertility before starting any treatment. In contrast to testicular cancer, which is extensively reported in the literature, the data on prostate cancer are few and not well documented. A recent analysis of 409 men cryopreserving 717 sperm samples showed that just 6% of them suffered from prostate cancer. These patients with an average sperm count of 83.5 × 106 and an average combined motion rate of 50.2% did not have any sperm disorder in their majority.[5] The same results are reported in other relevant studies.[6],[7] Cancer can produce catastrophic physiological changes in the body, systematic disorders from mediated factors such as interleukins,[8] tumor necrosis factors, and other factors, as well as organic stress produced by the secretion of various hormonal factors. All the above results in decreased sperm quality ending to infertility.[9] However, it is important to emphasize that none of the above data have been specifically studied for prostate cancer. The above leads us to the conclusion that prostate cancer itself does not cause significant changes in sperm quality fact that must be included in the patient consent form before treatment.


  Radical Prostatectomy Top


The first and obvious mechanism, influencing the fertility of the patient undergoing radical prostatectomy, is anatomical. During radical prostatectomy, ligation of the seminal ducts, removal of the prostate and the seminal vesicles takes place, and erectile dysfunction occurs as a direct complication, which causes loss of ejaculation and inability to fertilize. However, the above does not directly affect spermatogenesis and the patient theoretically remains fertile and capable of fertilization by other means like in vitro fertilization. However, questions are raised by researchers on the possible effect of prostate removal on the patient's hormonal profile and on whether this effect can negatively affect spermatogenesis. Miller et al. studying 63 men who underwent open radical prostatectomy, concluded that postsurgery showed an increase in serum total and free testosterone, oestradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) while showing a decrease in dihydrotestosterone (DHT) (P < 0.0001).[10] The researchers conclude that the prostate probably participates in a negative biofeedback mechanism with the hypothalamic–pituitary axis through substances that remain to be demonstrated. Similarly, a more recent study has shown that a statistically significant reduction of LH by 53% and DHT by 13% was observed in a 55-man sample, while FSH increased by 21% and inhibin B was also changed.[11] The above studies, combined with even bigger,[12] suggest a correlation of the hypothalamic–pituitary axis with the prostate as the main mechanism of disorder of the hormone profile of patients after radical prostatectomy. In this case, considering the fact that the values of inhibin B and FSH are directly related to spermatogenesis,[13],[14] we conclude that radical prostatectomy itself may play a direct role in the infertility of patients.


  Radiation Therapy and Brachytherapy Top


Testicles are extremely sensitive to radiation, especially the cells of the genital cord. Doses above 4 Gy can cause permanent damage to these cells. Instead, hypogonadism due to Leydig cell damage requires higher doses of radiation (20 Gy). However, radiation therapy for prostate cancer causes a rather negligible destruction of the testicular tissue,[15] despite the fact that the latter receives a 3%–8% of the radiation dose.[16],[17],[18] Surprisingly, there are many reports in the literature on clinically significant hypogonadism that persists for at least 2 years after radiotherapy for prostate cancer,[19],[20],[21] while histological examination of testis samples taken for recurrent prostate cancer has revealed significant testicular atrophy.[22]

Apart from the dose of radiation, there are other factors that affect the quality of the sperm. These include direct or indirect radiation, number and duration of dosages, and personalized factors such as the response of the patient's tissue to radiation and age. Doses between 0.35 and 0.5 Gy result in reversible azoospermia which is reversed after 10–18 months. However, if the dose rises above 1.2 Gy, then the risk of nonreturn to normal levels is greater.[23],[24],[25] Clearly newer imaging and radiotherapy techniques can further reduce testicular radiation in an effort to maintain a patient's fertility.[26] Finally, it is important not to neglect, the potential effects of brachytherapy for prostate cancer on the fertility of patients. Very few data are available in the literature; however, they support that after this therapy, the dose that testicles absorb is clearly negligible (<0.2Gy). A mild and mainly transient oligoasthenospermia may be observed in patients, however the authors suggest waiting from 4 to 12 months for a childbearing attempt.[27],[28]


  Androgen Deprivation Therapy Top


Hormonal manipulations succeed in controlling prostate cancer by suppressing testicular testosterone, but it leads to both oligoasthenospermia, loss of libido, and erectile function of patients, leading to infertility. However, most authors are focusing on the study of the potential return of testosterone and spermatogenesis after discontinuation of hormonal manipulation. The quality of the data available in the literature is low because most of them are small case series. In one of these, authors, following 14 patients under androgen blockade, studied the hormonal profile of patients after discontinuation of hormonal manipulation. The conclusion of this study is that although the return of the hypothalamic–pituitary–testicular axis was different among patients, the trend was for prolonged maintenance of low testosterone levels even for more than 1 year after hormone disruption.[29] This low testosterone, following long-term administration of the Luteinizing hormone-releasing hormone (LHRH) agonist, may not stem from permanent suppression of the axis but from an irreversible destruction of Leydig cells.[30] In contrast, a study of animal models revealed a potential reversal of fertility after discontinuation of a short-term hormone therapy.[31]


  Chemotherapy Top


The incidence of chemotherapeutic agents in fertility has been extensively studied for the most widely used agents and for the treatment of the most common neoplasms. In this context, it has been found that alkylating agents such as cyclophosphamide and iphosphamide are at high risk for prolonged azoospermia, while agents such as vincristine and methotrexate are rather low-risk therapies for infertility.[32] However, there are no direct data on the potential for infertility after chemotherapy for prostate cancer, and this may be due to the fact that these patients may not be interested in becoming parents, so organize such a study would be difficult if not impossible. However, there is evidence from indirect studies using the chemotherapeutic agents that are also used in prostate cancer such the recent study by Chatzidarellis et al. who found a statistically significant reduction of inhibin B and FSH (P < 0.001 and P = 0.000, respectively) after taxane administration, which was maintained throughout the follow-up (6 months).[33] Authors conclude that the above changes in combination with the observed bilateral decrease in testicular size indicate a significant gonadal damage following the administration of chemotherapeutic agents such as docetaxel. The results of the above study, if combined with the results of studies demonstrating the direct correlation of inhibin B values with spermatogenesis,[33],[34] can lead to the indirect conclusion that chemotherapy for prostate cancer can cause infertility in patients receiving it.


  Conclusions Top


As the age of the first diagnosis of prostate cancer decreases, the need for clear answers and solutions for the possible infertility that the treatments potentially cause will increase. Both prostate cancer itself and its treatments, predominantly radiation, can cause long-term azoospermia; however, the data in the literature are sparse, mainly derived from small series, and based on these, no safe conclusions can be drawn.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Miller LR, Partin AW, Chan DW, Bruzek DJ, Dobs AS, Epstein JI, et al. Influence of radical prostatectomy on serum hormone levels. J Urol 1998;160:449-53.  Back to cited text no. 10
    
11.
Olsson M, Ekström L, Schulze J, Kjellman A, Akre O, Rane A, et al. Radical prostatectomy: Influence on serum and urinary androgen levels. Prostate 2010;70:200-5.  Back to cited text no. 11
    
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Bantis A, Zissimopoulos A, Athanasiadou P, Gonidi M, Agelonidou E, Strataki A, et al. Serum testosterone, dihydrotestosterone, luteinizing hormone and follicle-stimulating hormone versus prostate specific antigen in patients with localized prostate adenocarcinoma who underwent radical prostatectomy. Radioimmunoassays measurements. Hell J Nucl Med 2007;10:56-61.  Back to cited text no. 12
    
13.
Klingmüller D, Haidl G. Inhibin B in men with normal and disturbed spermatogenesis. Hum Reprod 1997;12:2376-8.  Back to cited text no. 13
    
14.
Andersson AM, Petersen J, Jorgensen N, Jensen TK, Skakkebaek NE. Serum inhibin B and follicle-stimulating hormone levels as tools in the evaluation of infertile men: Significance of adequate reference values from proven fertile men. J Clin Endocrinol Metab 2004;89:2873-9.  Back to cited text no. 14
    
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Zagars GK, Pollack A. Serum testosterone levels after external beam radiation for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1997;39:85-9.  Back to cited text no. 15
    
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Talcott JA, Rieker P, Clark JA, Propert KJ, Weeks JC, Beard CJ, et al. Patient-reported symptoms after primary therapy for early prostate cancer: Results of a prospective cohort study. J Clin Oncol 1998;16:275-83.  Back to cited text no. 20
    
21.
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22.
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23.
Meistrich ML, Vassilopoulou-Sellin R, Lipshultz LI. Adverse effects of treatment: Gonadal dysfunction. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 2560-74.  Back to cited text no. 23
    
24.
Colpi GM, Contalbi GF, Nerva F, Sagone P, Piediferro G. Testicular function following chemo-radiotherapy. Eur J Obstet Gynecol Reprod Biol 2004;113 Suppl 1:S2-6.  Back to cited text no. 24
    
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Howell SJ, Shalet SM. Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr. 2005:12-7.  Back to cited text no. 25
    
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Mydlo JH, Lebed B. Does brachytherapy of the prostate affect sperm quality and/or fertility in younger men? Scand J Urol Nephrol 2004;38:221-4.  Back to cited text no. 28
    
29.
Hall MC, Fritzsch RJ, Sagalowsky AI, Ahrens A, Petty B, Roehrborn CG. Prospective determination of the hormonal response after cessation of luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer. Urology 1999;53:898-902.  Back to cited text no. 29
    
30.
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31.
Kostanski JW, Jiang G, Dani BA, Murty SB, Qiu W, Schrier B, et al. Return to fertility after extended chemical castration with a GnRH antagonist. BMC Cancer 2001;1:18.  Back to cited text no. 31
    
32.
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33.
Chatzidarellis E, Makrilia N, Giza L, Georgiadis E, Alamara C, Syrigos KN. Effects of taxane-based chemotherapy on inhibin B and gonadotropins as biomarkers of spermatogenesis. Fertil Steril 2010;94:558-63.  Back to cited text no. 33
    
34.
Kumanov P, Nandipati K, Tomova A, Agarwal A. Inhibin B is a better marker of spermatogenesis than other hormones in the evaluation of male factor infertility. Fertil Steril 2006;86:332-8.  Back to cited text no. 34
    




 

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Abstract
Introduction
Prostate Cancer ...
Radical Prostate...
Radiation Therap...
Androgen Depriva...
Chemotherapy
Conclusions
References

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