1,2; Karim El Balouly
1; Vladimír Sobotka
1,2; Marta Šnajderová
3; Božena Kalvachová
4; Michael Urban
Authors place of work:
Univerzita Karlova v raze, 3. lékařská fakulta, Urologická klinika
1; Fakultní nemocnice Královské Vinohrady, Urologická klinika
2; Univerzita Karlova v raze, 2. lékařská fakulta, Pediatrická klinika
3; Endokrinologický ústav, Praha
Published in the journal:
Čas. Lék. čes. 2012; 151: 392-396
Background: The aim of the study was to evaluate prostate transrectal ultrasonography findings in men with congenital hypogonadism treated by long term testosterone replacement therapy.
Methods: We have gradually included 31 men with congenital hypogonadism in period of 2001-2011. The average follow-up was 7.3 years (2 months - 10.8 years). We have used Sustanon® 250 i.m. every 3 weeks or Nebido® i.m. every 3 months for continual testosterone replacement therapy. We performed to all patients the transrectal ultrasonography of prostate and seminal vesicles by biplanar rectal probe every 6 months.
Results: During the transrectal ultrasonography we observed in 22 (71.0 %) patients changes in prostatic tissue. In case of 12 patients were diagnosed asymptomatic prostatic cysts, in 9 patients prostatolithiasis and in 5 patients changes in echogenity of prostatic tissue. In 2 patients was found simultaneous occurrence of prostatic cyst and prostolithiasis, in further 2 patients simultaneous occurrence of hyperechogenic prostatic lesion and prostatolithiasis. The above described findings were diagnosed in 5 patients in the treatment lasting from 3 to 5 years, for the other 17 men with hormone replacement therapy longer than 5 years.
Conclusions: The study presents long term results of complex treatment in patients with disorders of sexual development, onset and progress of puberty. The long term treatment of these patients in interdisciplinary cooperation of endocrinologist and andrologist may significantly contribute to clarify an impact of testosterone replacement therapy on prostate development.
The article is intended to be published in the journal Časopis lékařů českých and has not been or will not be published elsewhere. The co-authors agree with the text of sent communication and publishing in this journal. The authors declare that they have no competing interests.
Male hypogonadism is a relatively common disorder in clinical practice. Significant effects on the fertility, sexual function, general health and well-being are well known (1-2).
Male hypogonadism has manifold etiology. Testicular disorders of different origin are the primary cause of (hypergonadotropic) hypogonadism. The functional disorders of the hypothalamus and pituitary gland cause the secondary (hypogonadotropic) hypogonadism. Male hypogonadism can also occur due to disorder at the level of androgen receptor, metabolism of androgens, severe systemic disease, certain medications and drugs or physiological aging.
The clinical symptoms of hypogonadism depend upon the stage of sexual development in which gonadal failure occurs. Boys with childhood and adolescence hypogonadism both hypogonadotropic and hypergonadotropic have absent or incomplete spontaneous pubertal development.
In boys with primary hypogonadism it is recommended to start hormonal induction of puberty by low dose of androgen at the appropriate age of 13-14 years (12 years of bone age), at age usual for puberty onset (3-4). A main and safe principle in testosterone replacement therapy is to mimic the normal pubertal development and to achieve normal concentrations of testosterone and its active metabolites (5-8). Patients with hypogonadotrophic hypogonadism may be initially given temporary human chorionic gonadotropin, which helps increase the volume of the testes (5). However, more common in adolescents with hypo- and hypergonadotrophic hypogonadism is to administer drugs with testosterone (oral or more often in injection form) since the early induction of puberty.
Aims of androgen replacement treatment in adolescent males with hypogonadism could be summarized as follows: to induce sex-specific secondary sexual characteristics, and then maintain them in adulthood, to optimize pubertal growth spurt and body proportions, to reach male adequate muscle and fat mass development, optimal bone mineral mass accrual, to determine adequate penile and internal genitalia growth, to reduce cardiovascular risk (metabolic factors), to induce sex-specific psychosocial and psychosexual maturation, assure normal social/sexual life and well-being in adolescence and adulthood (8).
The development of male prostate in androgen replacement therapy, which begins in adolescence, has not been yet studied in detail. The aim of our study was to observe the development of prostate in long term treatment by testosterone replacement therapy in young men with congenital hyper- and hypogonadotropic hypogonadism.
We have gradually included 31 adolescents with congenital hypogonadism in period of 2001-2011. Table 1 shows patient baseline characteristics before treatment. The patients underwent initial complex andrologic and endocrinologic evaluation, hypogonadotropic hypogonadism was detected by standardized GnRH test. After induction of puberty by gradually increasing dose of androgen (Undestor p.o. or Sustanon inj. according to the scheme recommended for induction of puberty, according to 5) we have used testosterone esters (250 mg intramuscularly every 3 weeks, Sustanon, Organon; since 2005 we used in all patients depot testosterone at a dose of 1000 mg intramuscularly every 3 months, Nebido, Bayer Shering Pharma) in long term replacement therapy.
Patients signed informed consent approved by the Ethical Committee of the 3rd Faculty of Medicine, Charles University in Prague.
Transrectal ultrasonography of prostate
Transrectal ultrasonography of prostate and seminal vesicles was performed by 7.5 MHz rectal probe (BK Medical, Harley, Denmark) with two crystals in transversal and sagittal planes in all patients every 6 months. Examinations were provided in supine position on the left side. In sonography, we evaluated the volume of prostate, tissue echogenity, presence of pathological deviations and the development of individual zones of the prostate.
Peripheral venous blood was drawn after an overnight fasting between 7-8 a.m. at the day of ultrasonographic examination and centrifugated at 2000 rpm for 20 minutes. Serums were stored at -70 °C until analyzed. Serum total testosterone was determined by radioimmunoassay kit, follicle stimulating hormone and luteinizing hormone were measured by radioimmunometric kits by Immunotech (Beckman Coulter Czech division, Marseille, France). Serum total prostate specific antigen (PSA) levels were measured with the use of the radioimmunoanalytical kit (Abbott, Chicago, USA).
Descriptive statistics was employed to assess demographic and clinical variables in all subjects. Statistical analysis was performed by nonparametric Mann-Whitney test, a p value <0.05 was considered to indicate significance with a use of Statistica 8.0 (Statsoft, Tulse, USA). This paper’s contents were developed with regard to current recommendations on reporting of observational studies (9).
The average follow-up was 7.3 years (2 months - 10.8 years). The average age in a group of patients with primary, resp. secondary hypogonadism throughout the period was 20.1 ± 6.2, resp. 21.5 ± 7.0 years.
The average serum concentration of total testosterone throughout the period was in patients with primary, resp. secondary hypogonadism 14.0 ± 5.1, resp. 15.9 ± 6.6 nmol/l, serum concentration of PSA 0.5 ± 0.2, resp. 0.5 ± 0.2 ng/ml and the prostate volume 14.0 ± 2.7, resp. 11.9 ± 5.3 ml. The average levels of total testosterone, PSA and prostate volume throughout the period presents graphs 1-3. We have not observed statistically significant differences in observed parameters in both groups throughout the period.
Before initiation of testosterone replacement therapy, all patients had normal findings of transrectal ultrasonography of prostate and seminal vesicles (Figure 1) and negative finding of digital rectal examination of the prostate.
Fig. 1. Transrectal ultrasonography of prostate with normal finding in 18 years old man with congenital hypogonadism before testosterone replacement therapy, transversal (a) and sagittal (b) planes
Ultrasonographic findings are summarized in Table 2. In 9 (29.0 %) patients we have not seen changes in prostatic tissue during treatment at ultrasonographic examinations. In 22 (71.0 %) patients we observed changes in prostatic tissue during treatment with transrectal ultrasonography. In 12 patients the prostatic cyst (Figure 2), in 9 patients prostatolithiasis (Figure 3) and in 5 patients hyperechogenic prostatic lesion (hyperechogenic areas) of prostatic tissue (Figure 4) were diagnosed. In 2 patients we found simultaneous occurrence of prostatic cyst and prostatolithiasis, in another 2 patients simultaneous occurrence of hyperechogenic areas in the prostatic tissue and prostatolithiasis. All patients had a negative finding of digital rectal examination.
In the first three years of treatment we have not seen in patients pathological deviations at transrectal ultrasonography. The above described findings were diagnosed in 5 patients in the treatment lasting from 3 to 5 years, for the other 17 men with hormone replacement therapy longer than 5 years.
To the best of our knowledge there were no reports evaluating similar aim to our study.
Prostatic cysts rarely occurring in young men are classified as congenital and acquired (10-11). The congenital cyst are cysts arising from the prostatic utricle with enlargement of the verumontanum and developing either from Muller ductus located in midline between the prostate and the rectum or from Wolff ductus located laterally between the prostate and the rectum (12). Cysts located in the midline of the prostate are mullerian duct or utricular cysts. The mullerian duct cysts are of mesodermal origin not communicating with prostatic urethra or seminal vesicles, and it never contains sperm. Utricular cyst is of endodermal origin, the ejaculatory ducts can be localized in the lateral wall of the cyst, communication with the prostatic urethra is common and sperm may be present (13); and are the most common congenital prostatic cysts. They may be associated with pseudohermaphroditism, hypospadias (14-17), cryptorchism or unilateral renal agenesis (17). Symptomatic prostatic cysts usually present with recurrent urinary tract infections, chronic pelvic pain syndrome, infertility, or ejaculatory pain in addition to low semen volume, hematospermia, and painful testes (10). In our study, all patients were asymptomatic, and diagnosis of prostatic cyst has been made during regular follow up of prostate by transrectal ultrasonography. All patients had midline prostatic cyst which support the diagnosis of either mullerian duct or utricle cysts. The definite distinction between utricular or mullerian cyst was not possible on ultrasonography images unless providing puncture (presence of both cyst and sperm prove utricle cyst). Prostatic calculi are not very common in young men. They consist of calcified corpora amylacea (18). They are associated with chronic inflammation, epithelial damage and obstruction of the glandular tissue on histological examination (19). Prostatic calculi are asymptomatic in most cases, but large calculi may lead to urinary inflammation, prostatitis, urinary retention or chronic pelvic pain syndrome (20-21). Chronic irritation of the prostatic tissue and local infection likely initiate a development of malignant tumor. There were no symptoms related to prostatic calculi in study patients. Diagnosis of prostatic calculi was performed by regular transrectal ultrasonographies of prostate. Any patient underwent infection of the urinary tract.
Changes in echogenity in prostate tissue always arouse suspicion of cancer. Normal prostate development, as well as preserving its structure and function depends on the presence of androgens (22). Endocrine dependence of prostate demonstrated experimentally in castrated animals Hunter early in 1786 (23). At 40 of the 20th century it was confirmed by Huggins et al. (24). Androgens via the androgen receptor regulate the expression of many genes affecting especially the prostatic tissue the cell differentiation and proliferation, cell cycle regulation and cell death - apoptosis (25). Data on long term effects of hormone replacement therapy in young men are not available. A man treated by testosterone therapy, is monitored using a standard monitoring plan. It is important if the treatment is efficient and leads to symptom improvement of testosterone deficiency, but equally important is early detection of treatment advert events (26). The most difficult problem in monitoring hypogonadal men with hormone replacement therapy are the criteria for carrying out a prostate biopsy. Changes in echogenity of prostate tissue in young patients are alarming. In these patients, we have reduced since mid 2011 replacement doses of testosterone in half and are continuously careful monitored. In the case of progression we will perform a biopsy under transrectal ultrasound. It is necessary to seriously entertain the idea if the doses commonly used for testosterone replacement therapy are supraphysiological for patients with congenital hypogonadism.
The study presents long term results of complex treatment in patients with disorders of onset and progress of puberty and spontaneous sexual development in adolescence. Throughout the long term testosterone replacement therapy we found in 71 % of patients changes in prostatic tissue in transrectal ultrasonography. We diagnosed the newly formed cysts, calcifications and changes in echogenity of tissue that in some patients had progressive trend. These findings have considerable clinical importance for patients. Interdisciplinary cooperation of endocrinologist and andrologist may within the long term follow up significantly contribute to clarification of the influence of testosterone replacement therapy on prostate development, expand knowledge about the development of human prostate and long term safety of androgen replacement in men with hypogonadism, in whom the treatment was iniciated in adolescence. The results can be considered as a priority. Further follow up and expansion of the number of patients is considered to be necessary.
LIST OF ABBREVIATIONS
FSH follicle stimulating hormone
HRT hormone replacement therapy
LH luteinizing hormone
PSA prostate specific antigen
SD standard deviation
The study was funded by the Internal Grant Agency of the Ministry of Health, grant No. NS9983. The study was approved by the Ethical Committee of the 3rd Faculty of Medicine, Charles University in Prague.
DEPARTMENT OF CORESPONDING AUTHOR
Department of Urology, 3rd Faculty of Medicine, Charles University in Prague
Ruska 87, 100 00 Prague 10
Phone/fax: +420 267 162 999
1. Griffin JE, Wilson JD. Disorders of the testes and male reproductive tract. In: Wilson JD, Foster DW, eds. Williamęs Textbook of Endocrinology, 8th ed. Philadelphia: Saunders 1992; 799–852.
2. Vermeulen A, Kaufman J. Aging of the hypothalamopituitary testicular axis in men. Horm Res 1995; 43: 25–28.
3. Ambler G. Androgen therapy for delayed male puberty. Curr Opin Endocrinol Diabetes Obes 2009; 16: 232–239.
4. Walvoord E. Sex steroid replacement for induction of puberty in multiple pituitary hormone deficiency. Pediatr Endocrinol Rev 2009; 6: 298–305.
5. Pozo J, Argente J. Ascertainment and treatment of delayed puberty. Horm Res 2003; 60: 35–48.
6. Lee PA. Puberty and its disorders. In: Lifshitz F, Pediatric endocrinology, 4th ed. New York: Marcel Dekker 2003; 231.
7. Rogol A. New facets of androgen replacement therapy during childhood and adolescence. Expert Opin Pharmacother 2005; 6: 1319–1336.
8. Bertelloni S, Baroncelli G, Garofalo P, Cianfarani S. Androgen therapy in hypogonadal adolescent males. Horm Res Paediatr 2010; 74: 292–296.
9. von Elm E, Altman D, Egger M, Pocock S, Gotzsche P, Vandenbroucke J, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Gaceta Sanitaria 2008; 22: 144–150.
10. Dik P, Lock T, Schrier B, Zeijlemaker B, Boon T. Transurethral marsupialization of a medial prostatic cyst in patients with prostatitis-like symptoms. J Urol 1996; 155: 1301–1304.
11. Ishikawa M, Okabe H, Oya T, Hirano M, Tanaka M, Ono M, et al. Midline prostatic cysts in healthy men: incidence and transabdominal sonographic findings. Am J Roentgenol 2003; 181: 1669–1672.
12. Sivaraman L, Sivasubramani S. Prostatic cysts. Ann R Coll Surg Eng 1978; 60: 476–478.
13. Van Poppel H, Vereecken R, De Geeter P, Verduyn H. Hemospermia owing to utricular cyst: embryological summary and surgical review. J Urol 1983; 129: 608–609.
14. Shima H, Ikoma F, Terakawa T. Developmental anomalies associated with hypospadias. J Urol 1979; 122: 619–621.
15. Devine C, Horton C, Scaff J. Epispadias. Urol Clin North Am 1980; 7: 465–476.
16. Ritchye M, Benson R, Kramer S. Managment of Mullerian duct remnants in the male patient. J Urology 1988; 140: 795–799.
17. Gevenois P, Vansinoy M, Sintznoff S. Cysts of the prostate and seminal vesicles – 11 cases. Am J Roentgenol 1990; 155: 1021–1024.
18. Hwang EC, Choi HS, Im CM, Jung SI, Kim SO, Kang TW, et al. Prostate calculi in cancer and BPH in a cohort of Korean men: Presence of calculi did not correlate with cancer risk. Asian J Androl 2010; 12: 215–220.
19. De Marzo AM, Nakai Y, Nelson WG. Inflammation, atrophy, and prostate carcinogenesis. Urol Oncol 2007; 25: 398–400.
20. Bedir S, Kilciler M, Akay O, Erdemir F, Avci A, Ozgok Y. Endoscopic treatment of multiple prostatic calculi causing urinary retention. Int J Urol 2005; 12: 693–695.
21. Geramoutsos I, Gyftopoulos K, Perimenis P, Thanou V, Liagka D, Siamblis D, et al. Clinical correlation of prostatic lithiasis with chronic pelvic pain syndromes in young adults. Eur Urol 2004; 45: 333–337.
22. Wilding G. Endocrine control of prostate cancer. Cancer Surv 1995; 23: 43–62.
23. Hunter J. Observations on the structure situated between the rectum and bladder, called vesiculae seminales. Coll. Works of J. Hunter, Vol. 4. London: J.F. Palmer 1786; 31.
24. Huggins C. Effect of orchiectomy and irradiation on cancer of the prostate. Ann Surg 1942: 6: 1192–1200.
25. Stárka L, Heráček J, Kuncová J, Sachová J, Urban M, Bendlová B. Receptor pro androgeny a karcinom prostaty. DMEV 2005; 7: 125–131.
26. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536–2559.