Pathophysiologic and Endocrine Aspects

The Journal of International Medical Research 1990; 18 (suppl I): 8 - 10
Pathophysiologic and
Endocrine Aspects
G. Sica
Institute of Histology and General Embryology,
Catholic University of s. Cuore, Rome, Italy
Androgens regulate development and functional maturation of the
prostate. A lack of androgens at puberty impairs normal prostate
growth and causes regression and atrophy of the gland in adults.
Orchidectomy or indirect androgen suppression by hypophysectomy
or administration of oestrogens reduces prostatic weight and secretion. As far as prostatic cancer is concerned, significant improvement
occurs in the clinical conditions of patients affected by advanced neoplasia subjected to castration or oestrogen administration. Recently,
other endocrine manipulations have been proposed, but the response
to these treatments strictly depends on the composition of the neoplastic population. Prostatic cancer consists of cells that are sensitive to or
dependent on hormones and others that are hormone-independent.
Biological activity of hormones, particularly androgens, is mediated
via intracellular receptors, which are not easy to measure in prostatic
tissue. Androgen receptor level can be modulated in prostatic cancer
cells by natural interferon-f3, opening new perspectives in the therapy
of prostatic cancer.
Les androgenes assurent Ie develcppement et la regulation de la maturation fonctionnelle de la prostate. Un deficit en androgenes au
moment de la puberte affecte Ie developpement normal de la prostate
et, it l'age mur, est synonyme de regression et d'atrophie. Une orchidectomie ou une suppression indirecte des androgenes par hypophysectomie ou par administration d'oestrogenes reduit l'acttvite de la prostate; ces therapies ont done ete les traitements de choix du cancer
prostatique metastatique, Plus recemment, it a He propose d'autres
manipulations endocrines. Le cancer prostatique consiste en cellules
qui sont sensibles ou dependantes des androgenes et en d'autres qui
sont independantes des androgenes et ainsi plus ditliciles it traiter. Des
recepteurs d'androgenes cytosoliques et nucleaires ont ainsi ete etu-
Address for correspondence: Professor G. Sica,
Instituto Di Istologia, Universita Cattolica, Largo F
Vito 1,00168 Rome, Italy.
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Pathophysiologic and endocrine aspects
dies en faisant appel a des Iigandes synthetiques dans Ie cadre d'un
dosage d'echange. Le rapport entre les taux de recepteurs et la reponse
a la therapie et I'identification des groupes chez qui une reponse a ete
obtenue feront I'objet d'un debat, Le niveau des recepteurs peut etre
modifie in vitro par I'interferon-B a une dose de 100 a 1000 UI/ml dans
les cellules PC-3 derivees du cancer prostatique humain. L'auteur de
Particle discute I'efflcacite de Pinterferon-B dans Ie traitement du cancer prostatique.
Gli androgeni regolano 10 sviluppo e la maturazione funzionale della
prostata. La carenza di androgeni in eta puberale ostacola il normale
sviluppo della ghiandola e ne causa, nell'adulto, una riduzione ponderale associata ad atrofia degli elementi secernenti. L'orchiectomia 0 la
soppressione androgenica prodotta in via indiretta mediante ipofisectomia 0 somministrazione di estrogeni riduce il peso e l'attivita secretoria della prostata. Per quanta concerne il carcinoma della prostata,
Ie condizioni cliniche di pazienti affetti da neoplasia in fase avanzata
traggono notevole giovamento dalla castrazione 0 dalla somministrazione di estrogeni. Recentemente, altri tipi di trattamento endocrino
sono stati proposti, ma la risposta esempre condizionata dalla composizione della popolazione neoplastica. Essa infatti e data da cellule
ormono-sensibili, da cellule del tutto dipendenti dagli ormoni e da
cellule svincolate dal controllo ormonale. L'attlvita biologica degli
ormoni, nella fattispecie degli androgeni, e mediata da recettori intracellulari, che, nel tessuto prostatico, sono difficilmente dosabili. II
livello dei recettori per gli androgeni PUQ essere modulato in Iinee
cellulari di cancro della prostata dal beta interferone naturale. Questa
possibilita apre nuove prospettive nel trattamento del carcinoma
prostatico.
KEY WORDS: Prostatic cancer; pathophysiology; hormonal effects; interferon-S
rr'he prostate comprises a conglomerate
~ of between 30 and 50 glands, which are
surrounded by interstitial tissue containing
muscle, and elastic and collagen fibres.
These fibres provide support and firmness
for the epithelial component. The prostate
depends on the combined action of various
hormones for growth, with the most important role being played by androgens,
which regulate development and functional
maturation of the prostate. If androgens are
not produced at puberty normal development of the prostate is impaired, whereas if
androgen deprivation takes place in adult
life the prostate undergoes regression and
atrophy, leading to a reduction in secretion.
Androgen suppression induced by orchidectomy or indirectly brought about by hypophysectomy or the administration of
oestrogens results in a reduction in the
weight of the prostate, with a loss of metabolic and functional activity.
Since Huggins and Hodges showed in
1941 that prostatic cancer was affected by
androgens.t-" androgen withdrawal has
become the treatment of choice in the
majority of cases for metastatic prostatic
cancer.' In addition to orchidectomy and
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G. Sica
the administration of oestrogens, in patricular diethylstilboestrol, other endocrine
manipulations, including the administration of anti-androgens, progestogens, antioestrogens and luteinizing hormone releasing hormone analogues, have been proposed as alternatives for the treatment of
prostatic cancer." Combined therapies and
hormonal associations have been suggested
more recently, the aim of therapy being to
obtain a more efficient and less toxic treatment.
When considering the hormone sensitivity of prostatic cancer, it is important to
note that the neoplastic cell population is
composed of androgen-dependent, androgen-insensitive and androgen-independent
cells. This heterogeneity may explain the
different responses of cancer to endocrine
therapy. At present, the most urgent need is
for a treatment for hormone-insensitive
prostatic cancers.
It is generally accepted that the biological activity of steroidal hormones is medi. ated via intracellular proteins (receptors)
present in the target tissues; therefore, attempts have been made to develop a
method to predict the responsiveness of
prostatic cancer to endocrine manipulations, with particular emphasis on the
measurement of androgen receptors. Many
obstacles, however, have delayed the development of a reliable assay for the determination of androgen receptors in human
prostatic tissue. Some problems have been
resolved using synthetic ligands, these ligands being employed in an exchange assay under conditions that minimize degradation of the androgen receptor. The receptors are mainly located in the nucleus; therefore, for the determination in prostatic tissue, receptors in both the nucleus and cytoplasm must be assayed. At present, the
relationship between androgen receptor
concentrations in prostatic cancer and
response to therapy is not clear and the
ability of androgen receptors to identify
response groups is under discussion.'
An interesting approach to the modulation of hormone sensitivity in prostatic
cancer, at least in vitro, is represented by
the possibility of using natural interferon-S
to enhance androgen receptors. It has been
demonstrated that interferon-B at concentrations ranging from 100 to 1000 IU/ml
can increase androgen receptor concentrations in PC-3 cells derived from a human
prostatic cancer when evaluated by a whole
cell assay.
Further investigations need to be
undertaken to establish the dose and the
modalities of interferon-B treatment, which
could be used in vivo to achieve-the same
receptor enchancement as observed in vitro.
Information derived from these studies, therefore, provides new perspectives in the
treatment of prostatic cancer, particularly
in those tumours which are receptor-negative.
REFERENCES
1. Huggins C: Studies on prostatic cancer. II. The
effects of castration on advanced carcinoma of
the prostate gland. Arch Surg 1941; 43: 209 - 223.
2. Huggins C, Hodges CV: Studies on prostatic cancer. II. The effects of castration, estrogen and androgen injections on serum. Cancer Res 1941; 1:
293.
3. VACURG: Treatment and survival of patients
with cancer of the prostate. Surg Gynecol Obst
1967; 124: 1011.
4. Bono AV, Pozzi E, Robutelli della Cuna G, et al;
Prostatic cancer - survey of hormonal treatment
in Europe. J lnt Med Res 1990; 18 (suppll): 11 25.
5. Barrack ER, Tindall OJ: A critical evaluation of
the use of androgen receptor assays to predict the
androgen responsiveness of prostatic cancer. In:
Current Concepts and Approaches to the study of
Prostatic Cancer. New York: Alan R. Liss, 1987;
155 -187.
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