K. Griffiths

Lignans and isoflavonoids in plasma and prostatic fluid in men: samples from Portugal, Hong Kong, and the United Kingdom.

Chinese men have lower incidences of prostate cancer compared to men from Europe and North America. Asians consume large quantities of soya, a rich source of isoflavanoids phyto‐oestrogens and have high plasma and urinary levels of these compounds. The mammalian lignans, enterolactone and enterodiol, are another group of weak plant oestrogens and are derived from seeds, cereals and grains. Vegetarians have high plasma and urinary concentrations of lignans.

Diet and its preventive role in prostatic disease.

Asian men have much lower incidences of prostate cancer and possibly of benign prostatic hyperplasia (BPH) than their Western counterparts. Vegetarian men also have a lower incidence of prostate cancer than omnivorous males. Both Asian and vegetarian men consume low-fat, high-fibre diets which provide a rich supply of weak dietary oestrogens. These plant or phyto-oestrogens have been proposed as chemopreventive agents, particularly for Asian men and to a lesser extent, for vegetarian men also. The three principal classes of phyto-oestrogens are the isoflavonoids, flavonoids and lignans. Many foods of plant origin contain varying amounts of these compounds and hundreds of plants manifest some degree of oestrogenic activity. Soya, a dietary staple in many parts of Asia, is a major source of the isoflavonoids, daidzein and genistein. Flavonoids are present in high concentration in many fruits, vegetables and crop species. In particular, apigenin and kaempferol are regarded as major flavonoids because of their common occurrence in plants, and their significant concentrations when present. Apples, onions and tea-leaves are excellent sources of flavonoids. Plant lignans are present in many cereals, grains, fruits and vegetables, and give rise to the mammalian lignans, enterodiol and enterolactone; however, the richest source is linseed (flaxseed) and other oilseeds. In addition to their oestrogenic activity, many of these plant compounds can interfere with steroid metabolism and bioavailability, and also inhibit enzymes, such as tyrosine kinase and topoisomerase, which are crucial to cellular proliferation.

Endocrine treatment in prostate cancer.

Over its natural course, prostate cancer is a heterogeneous tumour with a generally slow but constant rate of growth. The androgen dependence of the prostate gland was demonstrated more than half a century ago by the landmark studies of Professor C. Huggins and colleagues. They established that androgens are implicated not only in growth regulation of the normal gland but also in the pathogenesis of prostate cancer, and that this malignant tissue retains some degree of androgen dependence. This concept was supported by studies of symptomatic clinical cancer, with androgen ablative therapy bringing relief to the patient in more than 80% of the cases. The classical treatment consisted of either bilateral orchiectomy, or administration of diethylstilbestrol (DES). Other forms of therapy followed, involving successive waves of new compounds that either withdrew androgen support from the cancer or blocked the androgens from their receptors in the prostate cancer cells. Chronologically, the progestagens can be well recognised, with one in particular: The successful derivative, cyproterone acetate (CPA). There also have been a number of oral vs. parenteral estrogens, the development of the luteinizing hormone-releasing hormone agonists (LH-RHA), the introduction of the non-steroidal anti-androgens characterised by flutamide and casodex, and more recently, the introduction of the LH-RHA. Moreover, there have been multiple possible forms of combination treatment to obtain maximal androgen blockade (MAB). However, no major differences in treatment outcome have been reported during the last 5 decades and most treatment choices have been based on tradition, associated side effects, the preferences of a particular doctor and patient, together with economic considerations. Furthermore, endocrine treatment has never been shown to cure clinical prostate cancer, which consequently has led to initiatives to defer endocrine treatment or to use it intermittently or use it as a form of neo-adjuvant or adjuvant treatment with surgery or radiotherapy. The history of endocrine therapy is replete with clinical trials that do not represent the patient population in general, and these trials share the clinical fact that they ignore the 20% to 30% of all patients who lack an initial response to a given endocrine treatment. Thus, it is no wonder that prognostic factors determine the outcome more than the treatment itself. Important to current endocrine treatment, however, is the shift to earlier stages of prostate cancer at initial diagnosis. Integration of endocrine treatment at this earlier phase in the pathogenesis of prostate cancer will substantially alter the treatment strategy in relation to long-term benefit with regard to survival, associated side effects, and costs. This complex adjustment is enhanced by recent discoveries in the molecular biology of the prostate which show, on the one hand, that the dihydrotestosterone-androgen receptor (DHT-AR) complex is important in the regulation of gene expression, but also that a number of intrinsic factors (e.g., peptide growth regulatory factors) can, through various paracrine, autocrine or intracrine interactions, exercise a major influence on cellular homeostasis and the regulation of prostatic growth. Semin. Surg. Oncol. 18:52–74, 2000.

Low incidence of androgen receptor gene mutations in human prostatic tumors using single strand conformation polymorphism analysis

It is possible that structural changes of the androgen receptor (AR) contribute to the insensitivity of prostatic carcinomas to endocrine therapy. We have isolated DNA from 58 human prostate tumor specimens (31 carcinomas pretreatment, 13 carcinomas after relapse to hormonal therapy, and 14 benign prostatic hyperplasia), three established human prostate carcinoma cell lines and two transplantable human prostatic carcinoma xenografts. Twelve pairs of oligonucleotide primers were used to amplify the majority of the coding region of the AR gene and the products screened for mutations using single‐strand conformation polymorphism (SSCP) techniques. In one tumor sample a cystosine to guanine transition in exon F which leads to substitution of glutamic acid for the wild type glutamine at position 798 of the ligand binding domain was detected. The same mutation was also found in the patients genomic DNA and as been described in a patient with partial androgen insensitivity syndrome. Intronic mutations were detected in two of the benign prostatic hyperplasia samples, and a silent mutation at nucleotide 995 was found to be present in eight poorly differentiated carcinomas, one BPH specimen, as well as in the cell line DU145 (18% of the samples studied). In agreement with most of the literature, these studies indicate that AR mutations are rare both prior to therapy and even in androgen relapsed tumors.

6Phytoestrogens and diseases of the prostate gland

Abstract Both benign hyperplasia (BPH) and cancer of the prostate are manifest in men beyond the age of 50. Approximately 50% of men greater than 50 years of age will suffer from the symptoms associated with BPH, especially from bladder outlet obstruction. With the ever-increasing proportion of the population over 65 years of age worldwide, BPH is becoming an important medical problem as the world moves into the next millennium. Cancer of the prostate is the second most commonly diagnosed cancer after skin cancer in the male population of the United States, and the second most common cause of death from cancer after that of the lung. Overall, around the world the incidence of carcinoma of the prostate is increasing annually by 2–3%. Both race and geographical location have a profound influence of the prevalence of prostate cancer worldwide. Black men in the USA have the highest incidence, while the incidence is much lower in Asian men from China, Japan and Thailand. Although the prostate gland is androgen-dependent, it is now recognized that the biological actions of endocrine-related factors, such as androgens, oestrogens, glucocorticoids and certain dietary and environmental factors, are mediated within the gland by various growth regulatory factors. The growth regulatory factors such as epidermal growth factor (EGF), keratinocyte growth factors (KGF), fibroblast growth factors (FGFs) and insulin-like growth factors II and I are mitogenic and directly stimulate cell proliferation under the modulating influence of steroid hormones. Steroids are therefore essential but not directly responsible for cell proliferation. Certain plant compounds such as isoflavonoids, flavonoids and lignans have been proposed as cancer protective compounds in populations with low incidences of prostate diseases. In particular, soya contains the isoflavone genistein, a compound with many properties which could influence both endocrine and growth factor signalling pathways.

Certain aspects of molecular endocrinology that relate to the influence of dietary factors on the pathogenesis of prostate cancer

Isoflavonoids, flavonoids and lignans are natural oestrogenic compounds derived from soya, tea, fruits and vegetables and they have been proposed as chemopreventive agents in Asian men, in whom the incidence of prostate cancer is much lower than in men from the West. In addition to their weak oestrogenic activity, oestrogen antagonistic activity has also been described for some of these compounds. Furthermore, the lignan, enterolactone and the soya-derived isoflavone genistein are inhibitors of several steroid metabolising enzymes, such as aromatase, 5α-reductase and 17β-hydroxysteroid dehydrogenase. Genistein is a potent inhibitor of tyrosine kinases and along with flavonoids such as kaempferol and apigenin is also an inhibitor of topoisomerases I and II, enzymes which are crucial to cellular proliferation. Genistein is also an inhibitor of angiogenesis and many experimental in vivo and in vitro models, including those for prostate cancer, are growth inhibited by isoflavonoids, flavonoids and lignans. It is estimated that the traditionally eating Japanese male consumes approximately 20 mg of isoflavones per day, whereas for Western men, the daily consumption would be less than 1 mg/day. This is reflected in a high mean plasma concentration of genistein (180 ng/ml, n = 72) in Japanese men, compared to a level of <10 ng/ml for Western males.

Steroid analysis in saliva for the assessment of endocrine function.

Advances in steroid analytical techniques during the past three decades have played a principal role in the development of clinical endocrinology. The establishment of immunoassays, in particular, has proved to be a most significant step, as the colorimetric group assays for urinary steroids, such as the 17-hydroxycorticosteroids and the complex, tedious procedures for the analysis of steroids in plasma, by double isotope derivative techniques or electron capture gas liquid chromatography (GLC), stepped into history. The use of antisera raised against steroids has produced sensitive and specific immunoassays for most steroids of interest in plasma, assays that determine the concentration of the hormone in the lower picogram range, lo6 times more sensitive than those in the 1960s. Such techniques were comparatively simple and their use during the past decade has revolutionized the field of steroid endocrinology. The use of such assays to investigate the endocrine status of an individual, however, is not without problems. Despite attention directed to the need to assess the analytical performance of a laboratory, quality control procedures in many units remain undeveloped. Assay automation should increase precision, ensuring the practicality of adding adequate numbers of quality-control samples to monitor performance, but the end result is still often based on the interpretation of hormone concentrations of a single plasma sample. Single plasma analysis is clearly not ideal for the study of hormones that undergo circadian or circatrigintan (monthly) rhythms of secretion. Even circannual rhythms must be considered for certain hormones, such as prolactin,? and other hormones, such as estriol, although not exhibiting a regular circadian rhythm, can vary quite markedly in concentration throughout the day. The effects of such changes can be minimized by suitable sampling regimens involving painful multiple blood sampling or invasive catheterization. The development of highly sensitive immunoassays has however initiated the birth of a new exciting era in clinical endocrinology. Despite pioneering work by Shannon and his colleague^^^^ in the mid-l960s, suggesting the possible role of salivary steroid analysis for the assessment of adrenal function, the nonspecific Porter-Silber colorimetric procedure failed to realize the potential value of this form of analysis. Over the last few years, a research initiative at the Tenovus Institute in Cardiff has been directed to establishing the credibility of salivary steroid analysis and to determine its potential for the investigation of the endocrine status of an individual subject or patient by these relatively noninvasive procedures.

Steroid hormones and the pathogenesis of benign prostatic hyperplasia.

The pathogenesis of benign prostatic hyperplasia (BPH) is still poorly understood: there is, however, general acceptance that the condition is not premalignant and that it has an etiology distinct from that of cancer. Interest now focuses on the biochemistry of the target prostate cells and the propensity of the gland for uncontrolled growth. Dihydrotestosterone (DHT) is the active intracellular androgen formed from testosterone by 5 alpha-reductase. DHT concentrations appear a little higher in BPH tissue than in normal tissue, and there is no doubt that DHT-receptor complex modulates gene expression. Current studies suggest that DHT is essential but not sufficient for proliferation, and that other regulatory factors, including peptide growth factors, are prerequisite. The growth responsiveness of prostate tissue to androgens may be dependent on the balance between epithelial and stromal tissues, with biologic processes in the epithelium indirectly controlled by androgen-dependent mediators of stromal origin.

Finasteride in association with either flutamide or goserelin as combination hormonal therapy in patients with stage M1 carcinoma of the prostate gland

It was very reasonable to consider that the combination of the 5α‐reductase, finasteride, and a pure antiandrogen such as flutamide should provide an effective form of maximal androgen blockade (MAB). Finasteride decreases intraprostatic levels of 5α‐ dihydrotestosterone (DHT), and the antiandrogen would restrain the biological action of the residual DHT by interfering with its association with androgen receptor. This form of MAB should sustain the concentration of testosterone in plasma, thereby maintaining sexual function and reasonable quality of life. In order to investigate this, a randomized multicenter phase II clinical trial of patients with untreated M1 cancer of the prostate was developed and undertaken.

Steroid receptors in early breast cancer: Value in prognosis

Abstract The relationship of prognosis to oestradiol-17β receptor (ER) status of primary breast tumours has been studied (a) in 550 patients who presented consecutively to one surgeon (RWB) and (b) 421 patients dealt with by 15 surgeons, coordinated by DG. Patients in (a) were staged after a triple-node biopsy according to node involvement, those in (b) by the TNM system. All patients were followed-up without treatment until recurrence. In group (a), 82 patients have had local or regional recurrence, 42 of whom also developed distant metastases. 42 developed distant metastases without prior local recurrence. ER status was related to tumour grade, disease free interval and survival. Furthermore ER status, with stage and grade, can be used to select good or bad pronostic groups. The site of metastases, a clinical factor of prognostic significance also related to ER status, ER + tumours tending to recur to bone, ER − to the viscera. In group (b), ER status also related to recurrence and survival, ER +, lymph-node negative (LN−) patients had a good prognosis. Conversely ER − LN + had a poor prognosis. Of particular interest in the group (b) study, ER − LN− patients could be identified as a high risk group with a survival rate similar to all LN + patients.