3/1996

Thyroid Status in Patients with Symptomatic Benign Prostatic Hyperplasia (BPH) and prostatic Cancer (PC)

Libor Safarík*, Radovan Bílek**

* Dept. of Urology, lst Medical School, Charles University, Prague
** Institute of Endocrinology, Prague

Introduction

However strange it may sound, the connection of thyroid gland with prostate and it's diseases should not be a neglected issue anymore. Since 1952, when Lundquist and Seedorf detected in human seminal plasma the proteolytic activity similar to that of pepsinogen, and others (Hirsch-Marie and Delafontaine, Reese at al.) confirmed that the fraction of pepsinogen has been discovered in extragastrointestinal localization, the search for the various substances either proteous or steroid nature in the prostatic gland does not seem to be ridiculous one. The thyroid status in various subpopulations, including children, pregnant women or areas with the shortage of iodine in the food is quite good mapped all around, but in recent review of thyroid diseases (Límanová et al, 1995), only two relatively small paragraphs are devoted to the influence of age or serious diseases on thyroid gland function. Prostatic gland is no more a forbidden topic; with aging mankind's population it turns to be of more concern not even among the men, but even among their women (Walsh). In fact due to prostatic enlargement and it's consequences, more then 300 000 men decide to agree with the operation in the U.S.A. annually (Guess) and 2 to 3 billion of dollars are each year spent on the diagnostics and therapy from health insurance (Mebust). That's why the growing interest from either clinicians on one hand and pharmaceutical industry on the other hand is paid to the elucidation of etiopathogenesis of the prostatic growth.

It is not without interest that while other parts of organism are slowly atrophying, prostate resumes its growth, which takes origin in so called periurethral and stromal nodules according to the McNeal's theory from 1978. So far, some growth factors have been blamed to cause this growth, but no single one is perhaps responsible. In Schreiber's review, the thesis that thyroid tissue might be originally a derivate of gastrointestinal system was submitted. Transition zone of the prostate, which is the supposed origin of the benign prostatic hyperplasia is also derivate of entodermal tissue, which is the basic embryonal tissue of gastrointestinal system. If it is true, there should be no wonder that gastointestinal polypeptides might be detected in the prostate and might be of some importance in various pathological situations. Similarly to the steroid hormones - testosteron, dihydrotestosterone or oestradiol - triiodothyronine (T3) acts directly in the cell nucleus using its receptor. Thyroxine (T4), though released in much more higher amount into the plasma, serves mainly as prohormone, or in other words, as reservoir for conversion into its active metabolit - T3.

The influence of T3 on protein metabolism is equivocal in general. It raises the catabolism of many tissues up, causing the negative nitrogen ratio. In muscles the synthesis of proteins is mainly enhanced, which may be mediated by insulin-like growth factor 1-IGFI (Límanová). In prostate, the main growth factor influencing stromal growth is basic fibroblast growth factor. Story cultured prostatic cells in androgen free medium, but in presence of growth factors. He found that stromal cells synthesize basic fibroblast growth factor (bFGF, FGF2) and keratinocyte growth factor (KGF, FGF7). Basic FGF is a potent mitogen for prostatic stroma (PS) but a weak mitogen for prostatic epithelium (PE). Begun confirmed it in his article on bFGF writing that bFGF is a potent mitogen for mesenchymal cells, including fibroblasts cultured from prostate, and it has been postulated that it plays a role in the development of benign prostatic hyperplasia. In lipid metabolism, there is reversed influence on the plasmatic level of lipoproteins, the higher thyroid hormones are, the lower levels of VLDL, LDL, or even HDL and total cholesterol are detected.

Methods

In the submitted article we would like to outline some features which have been obtained from the research of the tissue of patients, beeing operated on for the symptomatic infravesical obstruction due to prostatic enlargement, both benign and malignant. The total number of patients accounts for 89, benign prostatic hyperplasia (BPH) were classified at 77 patients (87 %), prostatic cancer (PC) was detected in 12 patients (13 %) - Fig 1

For the statement of hormones and growth factors levels, the samples of blood were centrifuged immediately and stored at -20°C in a freezing box, until the analysis was performed. The tissues were stored in a deep freezer (-80°C) and they were homogenisated in an ice salina before analysis. After centrifugation the contents of tissue hormones in a supernatant were determinated in the same way as the hormones in serum. The hormones of the thyroid gland in serum or tissue in patients with BPH or prostatic cancer were performed using: thyroxine (RIA, code RI 241), triiodothyronine (RIA, code RI 271 ), the pituitary hormone TSH by ILMA (code LI 022), all from Immunotech a.s., Prague, Czech Republic, and basic fibroblast growth factor (bFGF) in tissue by ELISA, code RPN 2158, Amersham Int. U.K. The volume of the prostate was measured by transabdominal way using ultrasound probe 3.5 MHz. The number of patients with BPH and PC in single decades were as follows - Fig. 2

View figure 1 (7 k)

View figure 2 (15 k)

Results

There have been calculated regress equation in order to assess the power of the relation between the variables mentioned above. As far as the age of the patients is mentioned, out of relation: age / TSH, age / TSHT, age / T3 and age / T4, the only signiflcant relation at p < 0.05 revealed to be age vs. TSHT in prostate (r = 0.22, y = 10.66 - 614.01, N = 78) in the whole group of patients (when devided in to BPH and PC, the relation was insignificant). The decline of T3 with age was impressive, but insignificant in both BPH + PC and BPH alone, while relation age vs. T4 is equivocal. The age vs. T3 was r = - 0.22, y = -0.01 x + I.77, N = 65.

Considering the relations between sonographically measured volume and TSH, TSHT, T3 and T4, no significant relation at least at the level p < 0.05 was found despite the fact, that in case of sono / T3 in the whole group of BPH and PC only a "close shave" prevented the significant relation (r = 0.14, y = 7.07x + 33.07, N = 79) and in the BPH subgroup being expressed even closer, though insignificant (r = 0.16, y = 8.56x + 32.41, N=65).

As far as the relation between TSH, TSHT, T3 and T4 was considered (TSH / T3 and TSH / T4 were excluded due to the well known reasons), the strongly positive correlation was found between TSH and TSHT (r = 0.46, y =144.02x - 2.35). Further interesting correlation - the negative one - was found between TSHT and T4 for both: BPH + PC and even stronger for BPH alone (r = -0.22, y = -4.39x + 519.60, N = 78, and r = - 0.30, y = -6.26x + 656.96, N = 64 respectively).

Taking bFGF into account, then only positive correlation has been found between basic fibroblast growth factor and the level of thyroxine in the plasma (r = 0.25, y = 0.14x + 4.08, N = 79). The results are demonstrated in Fig. 3

View figure 3 (19 k)

Summary

According to our results, there seems to be several trends concerning possible relation of thyroid hormones on the metabolism of aging, but despite growing prostatic gland. With the advancing age, the plasmatic level of TSH is slowly declining, but the prostatic tissue concentration of TSHT was proved to be growing higher. If it is a matter of more precise clearance or the local synthesis de novo remains to be determined. While the influence of triiodothyronine (T3) on the sonographically measured mass of the prostate was nearly proved to be significant at the p < 0.05, it could be possible, that in other sample of patients, the bigger one, the possitive correlation may appear. The correlation was even closer to this cut-off level of 95% limit, when only BPH patients were considered. Furthermore, with advancing age the serum level of T3 was sharply declining and also approached nearly the 95% limit. If it is due only of the small sample remains to be stated, but in this case advancing age may change the ration T3 / T4 in favor of the latter. The significant positive correlation between T4 and bFGF has been demonstrated, but more other factors involved seem to be pertinent, as no positive correlation has been found between TSHT and T4 (r = -0.30, y = -0.0lx + 82.66, N = 64). In this challenging area of endocrinological connections of prostatic metabolism and thyroid hormones in advanced age further research is needed.

Contact address:

Dr. L. Safarík
Dept. of. Urology
1st Medical School
Charles University Prague
Ke Karlovu 6, Praha 2

Acknowledgements

The work was financed by funds from IGA R (Grants No. 0849-3, 2742-3) and GA R (Grant No. 0994).

Literature:

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[7] Reese JH, McNeal JE. Redwine EA. Samloft LM. Stamey TA: Differential distribution of pepsinogen II between the zones of the human prostate and seminal vesicle. J Urol 1986, 136: 1148-1152.

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[10] Walsh PC: The Prostate. Johns Hopkins Book, 1995.