The study of naturally occurring mutations in humans and induced mutations in mice that cause sex reversal has been instrumental in the cloning and functional analysis of genes involved in gonadal differentiation. Several genes required for this complex developmental process have now been identified. The genes LIM1, WT1 and FTZ-F1 have been demonstrated to be involved in the formation of the gonads prior to their differentiation as testes or ovaries. Subsequent sex-specific gonadal differentiation appears to be mediated by the SRY and SOX9 genes in the testis, and the DAX-1 gene in the ovary.
Testosterone-induced nitrogen retention in castrated male animals, eunuchoidal men, prepubertal boys and women, and the sex-related differences in the size of the muscles between male and female animals, have been cited as evidence that testosterone has anabolic effects. Recent studies have reported that replacement doses of testosterone in hypogonadal men and supraphysiological doses in eugonadal men increase fat-free mass, muscle size and strength. These effects have provided the rationale for exploring these anabolic applications in sarcopenic states. Although emerging data demonstrate modest gains in fat-free mass in HIV-infected men given replacement doses of testosterone, we do not know whether testosterone supplementation can produce clinically meaningful changes in muscle function and disease outcome in patients with wasting disorders.
Plants abound in essential phytochemicals produced for their various vital functions. The same compounds seem also to be crucial for human health and disease. Recent human epidemiological and laboratory animal and cell studies on cancer and heart disease have highlighted the phytoestrogens—naturally occurring principles that share with steroidal oestrogens an ability to activate oestrogen receptors. The best known non-steroidal phytoestrogens include the isoflavones daidzein, genistein, formononetin and biochanin A, the coumestan coumestrol, and the lignans secoisolariciresinol and matairesinol. Acknowledging the potentially chemoprotective role of these non-nutrients, we have quantified all biologically important isoflavonoids and lignans in cereals, oilseeds and nuts, legumes, vegetables, fruits, berries and beverages such as tea, coffee and wine. In this chapter, we present a review of our studies on staple plant foods, indicating that plants contain, besides a wide range of chemicals with a number of biological properties, biologically active phytoestrogens—precursors of hormone-like compounds found in mammalian systems.
Acquired growth hormone resistance (AGHR) may be defined as the combination of a raised serum growth hormone (GH) concentration, low serum insulin-like growth factor-1 (IGF-1) concentration and a reduced anabolic response to exogenous GH. A wide range of conditions exhibit the syndrome to a variable degree, including sepsis, trauma, burns, AIDS, cancer, and renal or liver failure. The primary defect seems to be a reduction in IGF-1 concentration which then leads to increased GH concentration by a loss of negative feedback. It is not clear whether IGF-1 concentration falls because of decreased production or increased clearance from the circulation, or both. Treatment to reverse the biochemical defect by restoring IGF-1 levels, either by the administration of GH or IGF-1, has resulted in improvements in a wide range of metabolic parameters and, more recently, to definite clinical benefit in well-defined groups, such as patients with AIDS. These results cannot be extrapolated to other groups with AGHR as a recent unpublished report suggested increased mortality in critically ill patients treated with GH. Research needs to focus on the molecular basis of AGHR if we are to develop therapies for catabolism.
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.
While there have been ample studies of a cross-cultural nature and experimental evaluations establishing the cardioprotective effect of soy protein, efforts to clarify the proportion of those benefits related to its phytoestrogen content are relatively recent. In most cases, the general approach to evaluating the role of soy's phytoestrogens has been to compare the cardiovascular benefits of isolated soy protein with a comparable soy protein isolate that has been alcohol extracted. Based on that approach, soy phytoestrogens appear to lower low-density lipoprotein concentrations while increasing plasma concentrations of the high-density lipoproteins. Particularly noteworthy with respect to the high-density lipoprotein effects are the increases in apolipoprotein A-1. Phytoestrogens may also prevent the oxidation of lipoprotein particles. The soy phytoestrogens favourably influence coronary artery reactivity. They also inhibit the progression of atherosclerosis in the coronary, iliac and common and internal carotid arteries. The cardiovascular benefits of soy phytoestrogens appear to be equal for males and females.
The congenital adrenal hyperplasias are the commonest cause of ambiguity of the external genitalia at birth, although sexual differentiation in these disorders is strictly normal. The masculinized genetic female is invariably the result of 21-hydroxylase deficiency. The molecular features are well characterized and the phenotypic correlates are generally concordant. Prenatal treatment by maternal dexamethasone administration can successfully prevent virilization of the external genitalia in an affected female fetus. Placental aromatase is a ran and recently characterized alternative cause of a masculinized female which should be considered in the absence of fetal adrenal hyperplasia and maternal androgen-secreting tumours. The investigation of abnormal sexual development requires an initial karyotype analysis and serum 170H progesterone measurement to determine whether 21-hydroxylase deficiency is the likeliest cause. Thereafter, the presence of a 46,XY karyotype: determines the mode of investigation according to androgen production and action. Obtaining appropriate samples for DNA, biochemical and immunohistochemical analyses is essential if the diagnostic yield for the investigation of abnormal sexual development is to be improved.
Practically all plant foods contain small amounts of the diverse phytoestrogen molecules that have the potential to improve health. Phytoestrogens, especially the soy-derived isoflavones, are receiving great scrutiny as food supplements for the purposes of both enhancing the health of tissues and preventing several common diseases, such as cardiovascular diseases, cancers of reproductive tissues and osteoporosis. Investigations of isoflavones, in particular, have recently become more prominent because of their oestrogenic activities. These actions may be as either partial oestrogen agonists or anti-oestrogens (inhibitors of natural oestrogen activity). For example, the isoflavones of soy, mainly genistein and daidzein, have been shown by at least three different laboratories to conserve bone in ovariectomized rodent models, and they probably have similar conservatory effects in higher mammalian species. Nevertheless, the only positive effects of phytoestrogens on bone observed so far in post-menopausal women have been small and limited to the lumbar vertebrae. Additional information on human studies currently in progress is needed before the efficacy of these preparations in human subjects is known.
There are many hormonal changes that occur with ageing in humans, of which the most dramatic and intriguing change occurs for the adrenal androgenic steroid dehydroepiandosterone (DHEA). There are tantalizing epidemiological data demonstrating a significant association between the changes in circulating DHEA level and changes in the incidence of malignancy, atherosclerosis, Alzheimer's disease and other age-related changes. The pharmacological effects in animals such as rodents and rabbits have demonstrated many beneficial effects, for example increased immune function, the prevention of atherosclerosis, cancer, diabetes and obesity, and the improvement of memory. Clinical studies carried out in small groups of subjects have clearly demonstrated that the administration of DHEA to the elderly increases many hormone levels, including that of insulin-like growth factor-1, (free and total) testosterone, dihydrotestosterone, oestrone and oestradiol. It remains to be clearly defined whether these changes are clinically beneficial, and there is only insufficient information on the side-effects on long-term use. Results from short-term intervention studies in small groups of subjects have not demonstrated any convincing beneficial effects so far. A judgement on whether DHEA replacement has a place in preventing age-related disabilities could be determined only on the basis of results from studies of long-term DHEA replacement in elderly people.
Normal ageing is associated with a decline in lean body mass, muscle mass and strength. The functional consequences of these changes may be significant and include falls, fractures, loss of mobility and increasing dependency. The anabolic actions of testosterone on muscle have been known for over 60 years, and replacement studies in young hypogonadal men have shown that testosterone can improve muscle mass and strength. In addition, the supraphysiological replacement of testosterone in young eugonadal men has also been shown to increase muscle mass and improve strength. Although the data are limited, studies of testosterone replacement in healthy older men with relative testosterone deficiency have demonstrated some modest improvements in muscle mass and strength, although the clinical and functional relevance of the muscle changes have yet to be determined. More data and experience are needed before testosterone can be advocated for the prevention or reversal of sarcopenia in the ageing male.
Endocrine disrupters are exogenous substances that cause adverse effects in the endocrine system. Sexual differentiation is regulated by reproductive hormones. Male differentiation is critically dependent on normal androgen action, which in turn depends on normal production of luteinizing hormone. Other essential hormones include follicle-stimulating hormone, anti-Müllerian hormone, and insulin-like hormone 3 (insl-3). Estrogens influence transcription of insl-3 and affect sexual differentiation both directly and indirectly. Diethylstilbestrol is the best known endocrine disrupter and has caused abnormalities of sexual differentiation in both exposed male and female human fetuses. There is a growing group of chemicals that have weak estrogenic properties, but, in addition, there are several antiandrogenic compounds that have been shown to disturb sexual differentiation in experimental animals. It is a challenge for endocrinologists to find out whether or not these chemicals or mixtures of them are involved in any of the abnormalities of human sexual differentiation.
It is now recognized that growth hormone (GH) deficiency in adults represents a distinct clinical syndrome that encompasses reduced psychological well-being as well as specific metabolic abnormalities. The latter features, which include hypertension, central obesity, insulin resistance, dyslipidaemia and coagulopathy, closely resemble those of metabolic insulin resistance syndrome. The increased cardiovascular morbidity and mortality demonstrated in these GH-deficient (GHD) adults reinforce the close association between the two syndromes. Replacement of GH in GHD adults has resulted in a marked reduction of central obesity and significant reduction in total cholesterol but little change in other risk factors, in particular insulin resistance and dyslipidaemia. The persistent insulin resistance and dyslipidaemia, together with the elevation of plasma insulin levels and lipoprotein (a) with GH replacement in these subjects are of concern. Long-term follow-up data are required to assess the impact of GH replacement on the cardiovascular morbidity and mortality of GHD adults. Further exploration of the appropriateness of the GH dosage regimens currently being employed is also indicated.
Animal models of gonadal hormone influences on the sexual differentiation of brain and behaviour are reviewed and discussed as a basis for predicting hormonal influences on human neurobehavioural development. Behavioural outcomes in clinical intersex cases, including congenital adrenal hyperplasia, androgen insensitivity syndrome, enzymatic deficiencies and situations in which hormones have been prescribed during pregnancy are reviewed. It is concluded that the prenatal or neonatal hormone environment contributes to the development of human behaviours that show sex differences, particularly childhood play behaviour, sexual orientation and core gender identity. There also is some evidence for influences on aggression and cognition. It is also concluded that additional research is needed to determine why some intersex patients assigned and reared as girls are not successful in this identity and role.
Androgens have an important physiological role in women. Not only are they the precursor hormones for oestrogen production in the ovaries and extragonadal tissues, but they also appear to act directly, via androgen receptors, throughout the body. Androgen levels decline with increasing age in women, who may experience a variety of physical symptoms secondary to androgen depletion, as well as physiological changes that affect their quality of life. In this chapter, the changes in androgens as women age are reviewed, and the rationale for physiological androgen, specifically testosterone replacement, in women is addressed.
Puberty describes the complex physiological transition between childhood and adulthood. Dramatic physical changes occur, most notably the development of secondary sexual characteristics and the pubertal growth spurt. During the adolescent growth spurt, growth velocity increases from pre-pubertal rates of 4-6 cm per year to as much as 10-15 cm per year. Accompanying the increase in gonadal steroids is an increase in amplitude of growth hormone secretory bursts. Evidence suggests that adequate growth hormone and gonadal steroids are both necessary for the attainment of a normal pubertal growth velocity, and the complex interplay between these two hormonal axes is under intense investigation. Delayed onset of puberty, or constitutional delay of growth and adolescence, is a common phenomenon presenting particularly in boys. Physiologically, it represents an extension of the normal pre-pubertal hypogonadotropic hypogonadal state. Without intervention, these children will spontaneously undergo puberty and often reach their genetic height potential, but their delay compared with that of their peers is often of concern to the children and their families. Recent evidence suggests long-term physiological benefits of early androgen replacement therapy in these boys, including maximizing attained bone mineral density. Androgen replacement therapy in male adolescents with constitutional delay of growth and adolescence is beneficial psychologically as well as physiologically and should be initiated promptly.
There has been much recent interest in the relationship between androgens and bone mineralization in men. Increases in serum androgens during puberty allow for skeletal maturation and the attainment of peak bone mass, and the persistence of normal testosterone secretion during adulthood is important for the maintenance of bone density. Testosterone deficiency is associated with heightened bone turnover and is a major risk factor for osteoporosis in men. The administration of testosterone to androgen-deficient men leads to an increase in bone mass, particularly in the trabecular bone compartment, and a reduction in levels of surrogate markers of bone turnover, suggesting that androgens have a dampening effect on bone remodelling. In addition, the administration of androgens to eugonadal men with idiopathic osteoporosis, with resulting supraphysiological testosterone concentrations, may lead to increases in bone mineral density. The risk of osteopenia due to androgen deficiency and the benefits of testosterone substitution therapy or supraphysiological administration on bone will be reviewed.
Phytoestrogens are paradoxical. Because of their structural similarity to the physiological oestrogens, they have been assumed to increase the risk of breast cancer. However, nations where the largest amounts of phytoestrogens are consumed in the diet have the lowest incidence of and rate of death from breast cancer. Although these epidemiological observations do not prove that phytoestrogens have anti-cancer properties, many preclinical experiments support this concept. Some indicate that early life exposure to phytoestrogens may be critical for breast cancer prevention. Clinical studies to define the effect of phytoestrogens on breast cancer recurrence are underway. The recent discovery of a second class of oestrogen receptors, with a differential distribution among the tissues, may enable an explanation of the phytoestrogen paradox. These receptors have opened a way of utilizing phytoestrogens in the treatment of oestrogen-sensitive chronic diseases such as atherosclerosis and osteoporosis.
Phytoestrogens are paradoxical. Because of their structural similarity to the physiological oestrogens, they have been assumed to increase the risk of breast cancer. However, nations where the largest amounts of phytoestrogens are consumed in the diet have the lowest incidence of and rate of death from breast cancer. Although these epidemiological observations do not prove that phytoestrogens have anti-cancer properties, many preclinical experiments support this concept. Some indicate that early life exposure to phytoestrogens may be critical for breast cancer prevention. Clinical studies to define the effect of phytoestrogens on breast cancer recurrence are underway. The recent discovery of a second class of oestrogen receptors, with a differential distribution among the tissues, may enable an explanation of the phytoestrogen paradox. These receptors have opened a way of utilizing phytoestrogens in the treatment of oestrogen-sensitive chronic diseases such as atherosclerosis and osteoporosis.
