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Thus, while GH is a positive regulator of extracellular matrix (ECM) synthesis (Kragstrup et al., 2011) which is important in morphogenesis (Rozario and DeSimone, 2010), there is still debate surrounding its role in the regulation of muscle mass in adults; however what may be key is the lack of effect on muscle function regardless of its impact on growth pathways and MPS. These increases in post RE GH levels are blunted in older adults, and a progressive decline in GH secretion and clearance is observed after the age of 40 y (Zaccaria et al., 1999). However, the proposed effects of estrogen may be defined by the stage of the menstrual cycle.
Better sleep and improved body composition have obvious downstream effects on mood and energy levels. Start with regular exercise, which boosts your body's sensitivity to hormones. Common options include TSH (thyroid-stimulating hormone) tests to evaluate thyroid function, as well as tests for growth hormone and IGF-1, which tend to decrease naturally as we age. For example, growth hormone secretion diminishes by about 14% per decade after age 30, while DHEA levels plummet to just 10–20% of their peak by the age of 80. This physical transformation correlates with a 50% drop in growth hormone production by the age of 60. Resistance training helps counteract muscle loss, and modest caloric restriction (reducing intake to 75–80% of baseline) can further support hormonal balance and insulin function. Free testosterone levels drop even faster due to a yearly 2.7% increase in Sex Hormone-Binding Globulin (SHBG), which limits hormone availability.
The latter is suggested to occur through increased expression of Pax7 and MyoD transcription factors (Thomas et al., 2010; Sambasivan et al., 2011) which induce satellite cell expansion, differentiation, and self-renewal of muscle function and mass (Kitajima and Ono, 2016; Chidi-Ogbolu and Baar, 2019). In addition, estrogen is also known to activate insulin/IGF-1 (Lee et al., 2004) and PI3K/Akt (Mangan et al., 2014) pathways, potentially enhancing the mechanisms regulating MPS (Hansen et al., 2012) and consequently muscle growth (Smith et al., 2014). While less studied in this sphere, endogenous oestrogens seem to have a metabolic role in regulating skeletal muscle; for instance, being critical for the regrowth of atrophied skeletal muscle (Sitnick et al., 2006)- an action mediated by the estrogen receptors, located within skeletal muscle tissue that function as transcription factors (Hansen and Kjaer, 2014). Oestrogens are steroid hormones, primarily produced in the ovaries from testosterone via an aromatase enzyme, of which women have four times the amount compared with men, until the menopause (Hansen and Kjaer, 2014). However, transient activation of ERK1/2 induced by testosterone was not found to be directly related to the hypertrophic signaling cascade; though activated ERK can phosphorylate co-activators of the intracellular receptor at the nuclear level (Bratton et al., 2012), through potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK (serine 118-Independent pathway) which promotes cellular growth (Feng et al., 2001; Estrada et al., 2003).
Two hormones that play a significant role in men's health are insulin-like growth factor 1 (IGF-1) and testosterone. However, the decade between 50–60 years of age is when declines in motor nerve conduction velocity CV increase (Wagman and Lesse, 1952), and it is possible that the decline in testosterone levels may mediate this process. Because animal and human research has suggested that testosterone is neuroprotective and exerts effects at a variety of the motoric segmental levels (i.e., the brain, spinal cord and motor neurons, etc.) (Bialek et al., 2004, Fargo et al., 2009), it is likely that age-related testosterone decline may lead to declines in strength and physical performance via the motoric system. " In the following sections, we review the current literature with a critical eye on whether testosterone and/or insulin-like growth factor 1 (IGF-1) impact motor system form and function. We also cite relevant studies from the robust body of non-human animal work that have examined the neuroprotective and/or neuroregenerative roles of testosterone and insulin-like growth factor 1 (IGF-1) on the motoric system, and the translational implications from animals to humans will be discussed. Unlike testosterone, which gets most of the attention, IGF-1 operates as the downstream executor of growth hormone’s effects — it’s the molecule that actually builds tissue. Causes include aging (somatopause), GH deficiency, protein undernutrition, sleep deprivation, severe insulin resistance, hypothyroidism, liver disease, and chronic inflammation.
The natural optimization strategies alone can produce IGF-1 levels that would surprise most people — and they come with zero side effects and zero cost beyond the lifestyle changes themselves. Only after all of these fundamentals are optimized should anyone consider pharmacological IGF-1 enhancement through MK-677, growth hormone secretagogues, or direct IGF-1 peptides. However, prolonged caloric restriction or chronic undereating actually reduces IGF-1 levels because the liver needs adequate caloric and protein substrate to produce IGF-1. Ashwagandha (Withania somnifera) may support IGF-1 indirectly through its effects on sleep quality and stress reduction.
Conversely, impaired testosterone responsiveness to RE in older adults, likely attenuates the AR response, due to lack of testosterone mediated AR increases, and subsequently, limits muscle mass gains with RET. Given the concentration of SHBG increases across the lifespan in men (Liu et al., 2007) and only increase after ~60 y in women (Maggio et al., 2008), bioavailable testosterone (free plus albumin-bound testosterone) concentrations decline even more markedly than total testosterone levels with aging (Matsumoto, 2002). That being said, the importance of testosterone in women remains unclear since while there is an indispensable role e.g., on bone health, in older males (Mohamad et al., 2016), a reduction in testosterone generally does not occur independently of other hormones (such as the oestrogens) in females (e.g., following the menopause) (Chakravarti et al., 1976). Whilst the majority of investigations into the role of testosterone in muscle adaptive response have been performed in males (reflecting male biology), the importance of circulating concentrations of testosterone in adult women should not be underestimated based on its biological role in the conversion of progesterone to the principal oestrogens—oestradiol and oestrone (Cui et al., 2013). In an attempt to better understand the discrepancies between testosterone and muscle adaptive responses, Phillips and colleagues devised a unique experimental approach, whereby they compared a "high" vs. "low" hormone environment (induced by working distinct muscle bulk) (West et al., 2010). For example, immediately following RE, serum testosterone levels peak ~from 13 (resting levels) to 38 (at ~30 mins) nmol.L−1 with a concomitant upregulation of AR mRNA and protein content within the muscle (Willoughby and Taylor, 2004; Hooper et al., 2017). RE has been shown to increase the concentration of these hormones which activate several different signaling pathways in the muscle.
This is the classic "bodybuilding style" training that produces significant metabolic stress and muscle damage — both signals that upregulate local IGF-1 production within the muscle itself. Insulin-like growth factor 1 (IGF-1) is one of the most powerful anabolic hormones in your body. IGF-1 mediates most of GH's anabolic and metabolic effects throughout the body and serves as the standard clinical proxy for overall growth hormone axis activity. Reference range, optimal functional medicine levels, and why IGF-1 is the primary mediator of growth hormone activity, a key longevity biomarker with a complex optimal range where both deficiency and excess accelerate aging and disease risk.
Indeed estrogen replacement has been shown to attenuate the age-related decline in muscle mass observed in postmenopausal women (Enns and Tiidus, 2010). Given that estrogen stimulates post-RE myogenesis, decreased estrogen levels in post-menopausal women may be a contributing factor to the development of sarcopenia, diminishing the rate of muscle repair and adaptive capacity in older women (Thomas et al., 2010). HSPs act as an index of cellular damage and activate inflammatory cell populations (e.g., neutrophils and macrophages) thereby regulating the extent of inflammatory responses after muscle injury (Senf et al., 2013).
If I have high IGF-1, does that guarantee high testosterone? Attempting to artificially manipulate IGF-1 levels, particularly through exogenous administration, carries significant risks. Focusing solely on IGF-1 for testosterone optimization is misguided. Attempting to directly boost testosterone solely by focusing on increasing IGF-1 is not a reliable or recommended approach. The relationship between IGF-1 and testosterone is indirect and mediated through several pathways.