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Somatopause, Weaknesses of the Therapeutic Approaches and the Cautious Optimism Based on Experimental Ageing Studies with Soy Isoflavones

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Somatopause, Weaknesses of the Therapeutic Approaches and the Cautious Optimism Based on Experimental Ageing Studies with Soy Isoflavones EXCLI Journal 2018;17:279-301 – ISSN 1611-2156 Received: November 06, 2017, accepted: March 10, 2018, published: March 21, 2018 Review article: SOMATOPAUSE, WEAKNESSES OF THE THERAPEUTIC APPROACHES AND THE CAUTIOUS OPTIMISM BASED ON EXPERIMENTAL AGEING STUDIES WITH SOY ISOFLAVONES Vladimir Ajdžanović1*, Svetlana Trifunović1, Dragana Miljić2, Branka Šošić-Jurjević1, Branko Filipović1, Marko Miler1, Nataša Ristić1, Milica Manojlović-Stojanoski1, Verica Milošević1 1 Department of Cytology, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia 2 Clinic for Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia * Corresponding author: Vladimir Z. Ajdžanović, PhD, Department of Cytology, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Despot Stefan Blvd. 142, 11060 Belgrade, Serbia, Tel: +381-11-2078-321; Fax: +381-11-2761-433, E-mail: [email protected] http://dx.doi.org/10.17179/excli2017-956 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). ABSTRACT The pathological phenomenon of somatopause, noticeable in hypogonadal ageing subjects, is based on the growth hormone (GH) production and secretion decrease along with the fall in GH binding protein and insulin-like growth factor 1 (IGF-1) levels, causing different musculoskeletal, metabolic and mental issues. From the perspective of safety and efficacy, GH treatment is considered to be highly controversial, while some other therapeutic ap- proaches (application of IGF-1, GH secretagogues, gonadal steroids, cholinesterase-inhibitors or various combi- nations) exhibit more or less pronounced weaknesses in this respect. Soy isoflavones, phytochemicals that have already demonstrated the health benefits in treated elderly, at least experimentally reveal their potential for the somatopausal symptoms remediation. Namely, genistein enhanced GHRH-stimulated cAMP accumulation and GH release in rat anterior pituitary cells; refreshed and stimulated the somatotropic system (hypothalamic nuclei and pituitary GH cells) function in a rat model of the mild andropause, and stimulated the GH output in ovariec- tomized ewes as well as the amplitude of GH pulses in the rams. Daidzein, on the other hand, increased body mass, trabecular bone mass and decreased bone turnover in the animal model of severe andropause, while both isofla- vones demonstrated blood cholesterol-lowering effect in the same model. These data, which necessarily need to be preclinically and clinically filtered, hint some cautious optimism and call for further innovative designing of balanced soy isoflavone-based therapeutics. Keywords: somatopause, therapy, experimental ageing, soy isoflavones INTRODUCTION While the temporal one is general and intuitively clear, reflecting the time flow, the Ageing represents a complex two other dimensions are interconnected and phenomenon characterized by the temporal, have some gender-related specificities. social and psychophysiological dimension. Female ageing is outlined by initial continuity 279 EXCLI Journal 2018;17:279-301 – ISSN 1611-2156 Received: November 06, 2017, accepted: March 10, 2018, published: March 21, 2018 of the process, leading to the fertility-related hypogonadism (LOH) (Vance, 2003; milestone – the menopause, a “point of Morales, 2004; Singh, 2013). To be precise, discontinuity“ or the specific life transition primary hypogonadism (testicular failure) as associated with an increase in various health well as the secondary hypogonadism risk factors including cardiovascular issues, (hypothalamic-pituitary-gonadal axis failure) osteoporosis, diabetes or cancer (Perry et al., entirely represent the phenomenon of 2015; Koebele and Bimonte-Nelson, 2016). andropause (Golan et al., 2015). Similarly to Some psychological disorders considering the menopausal women, various psycho- low moods, depression, anxiety states, social issues like depression, lack of insomnia, changes in cognition or reduction motivation, lower psychological vitality, of sexual interest also accompany the post- anxiety, irritability, insomnia, difficulty in menopausal period of life (Pearce and concentrating, memory impairment, decreas- Hawton, 1996; Santoro et al., 2015). An ed work performances, low dominance and abrupt and permanent cessation of the ovarian decreased libido are observable in the ageing function is responsible for the menopausal men (Amore, 2005). transition (Calabrese et al., 2014; Ajdžanović The neuroendocrine regulation of the et al., 2017a). Ovarian cell loss begins even ageing process is attracting intensive attention prenatally in numerous female mammals, of the investigators during the current epoch deriving exponential depletion of primary of a dramatic increase in the elderly people follicles and oocytes, associated with loss of share (Jones and Boelaert, 2015). Ageing- fecundity by midlife (Finch, 2014). In the induced extinction/dysfunction of the post-menopause, follicle-stimulating hormo- regulatory hippocampal, hypothalamic and ne levels are significantly higher, estradiol limbic neurons and synapses and the levels are fallen, while inhibin B and anti- compensatory gliosis (Mani et al., 1986; Mullerian hormone are undetectable (Burger Ferrari et al., 2001) are followed with a et al., 2007). Reconsideration of the role and decrease of hormonal secretion within purpose in life, personality, interpersonal majority of the neuroendocrine axes, reduced relationships or body image influence the sensitivity of tissues to hormonal actions and experience of menopause in the social terms the loss of normal circadian rhythms (Jones (Deeks, 2004). On the other hand, male and Boelaert, 2015). Additionally to ageing is progressive and gradual in its previously mentioned, ageing-related essence, while low free testosterone is the key structural and functional disorders of the characteristic of the hormonal status of ageing reproductive system (menopause and males (Gray et al., 1991; Chahal and Drake, andropause) as well as the hypothalamic- 2007; Ajdžanović et al., 2015a, 2016). So far pituitary-adrenal (HPA) axis perturbations accumulated data indicate ageing-induced during ageing (adrenopause) linked with decrease in the Leydig cell steroidogenic metabolic syndrome and cardiovascular capacity with an increase in cyclooxygenase- issues, hypogonadal ageing subjects 2 activity and its’ tonic inhibition of frequently suffer from the loss of growth axis steroidogenic acute regulatory gene express- function (somatopause), associated with ion; lowered Sertoli cell function and number, reductions in skeletal muscle and bone decline in seminiferous tubule volume and mass/strength (Ferrari and Mantero, 2005; sperm content, as well as raised germ cells Lombardi et al., 2005; Golan et al., 2015; apoptosis rate (Wang et al., 2002; Wang and Jones and Boelaert, 2015). The impression is Stocco, 2005). Diminished endogenous that the somatopausal perspective of testosterone production, enabling circulating musculoskeletal issues in elderly received free testosterone lower than 220 pmol/L, insufficient attention within the research grounds a specific multi-symptomatic circles. syndrome known as andropause or late-onset 280 EXCLI Journal 2018;17:279-301 – ISSN 1611-2156 Received: November 06, 2017, accepted: March 10, 2018, published: March 21, 2018 Hormone replacement therapy (HRT) of When it comes to the focus of the ageing subjects appears to be an biomedically-oriented part of the scientific acceptable medical approach, considering community, the past two decades have been that the irreversible age-related changes at the in the sign of massive investigation at the field tissue/organic level almost entirely exclude of plant-derived, preferably safe and the causal therapy modalities (Beg et al., effective, alternatives to HRT. A complex 2008; Shifren and Shiff, 2010; Ajdžanović et array of polyphenolic, bioactive non-nutrients al., 2015a, 2016). Significant benefits isolated from vegetables, legumes, cereals, pertinent to the prevention of menopausal fruits or tea, also known as phytochemicals, osteoporosis as well as the management of a have demonstrated significant health benefits certain psychological disorders, frequent in upon consumption either as an integral part of this period of female life, are observed upon the food or as a food supplement/alternative menopausal estrogen therapy (Al-Safi and remedy (Adlercreutz and Mazur, 1997; Santoro, 2014; Cauley, 2015). In line with Setchell, 1998; Tham et al., 1998; Chanet et this, the affirmative aspects of testosterone al., 2012). application to ageing males have included the Soy isoflavones (commonly genistein, prevention or reversion of bone deterioration, daidzein and equol – Figure 1) represent glucocorticoid hypersecretion, sexual dys- diphenolic, estrogen-like compounds that function and depression (Myers and may exist without or with glucose residues Meacham, 2003; Amore et al., 2009; attached (aglycones or 7-O-β-D glucosides). Ajdžanović et al., 2017b). Treatment with They perform weak estrogenic and anti- growth hormone (GH) during ageing was estrogenic activity both in vitro and in vivo considered as a possible “fountain of youth”, (Price and Fenwick, 1985). Also, soy hence as some good solution in improving the isoflavones manifest tyrosine kinase functional status of elderly (Clayton
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