The Effects of Sex Hormones on Skeletal Muscles during Aging
Harris & Emberley (2014) defined sex hormones as a class of steroid hormones regulating the function and growth of the reproductive organs or stimulate secondary sexual characteristics development. They include estrogen, testosterone, and Dihydrotestosterone (DHT). Sex hormones, estrogen, and testosterone play a fundamental role in the function and regulation of skeletal muscle (Griggs et al, 1989).
There are two types of skeletal muscles, type I fibers and type II fibers. Type I fibers also referred to as slow oxidative fibers or slow-twitch fibers contain many mitochondria and large amounts of myoglobin and many capillaries of blood. These fibers have a slow velocity of contraction, split ATP at a slow rate, and are resistant to fatigue. On the other hand, Type II fibers also referred to as fast oxidative fibers or fast-twitch fibers have very many mitochondria, large amounts of myoglobin, and many capillaries of blood. Moreover, Type II fibers split ATP at a rapid rate, has a high capacity of ATP generation through oxidative metabolic processes, are resistant to fatigue, and have a faster velocity of contraction.
The female sex hormone estrogen is secreted by the ovaries. Testosterone, a male sex hormone, is secreted by the testis. Estrogen is the dominant hormone in females and testosterone is dominant in males (Griggs et al, 1989). Estrogen hormone has protective effects on different types of skeletal muscle injuries. Enns & Tiidus (2010) indicated that estrogen may influence the contractile properties of muscles and attenuate post-exercise muscle damage indices. Moreover, estrogen stimulates muscle repair and the regenerative process such as proliferation and activation of the satellite cells. Enns & Tiidus (2010) further asserted that estrogen may exert its protective effects on the skeletal muscle by playing the role of an antioxidant hence limiting the oxidative damage; binding to the receptors of estrogen hence governing the downstream genes regulation and molecular targets, and acting as a stabilizer of the membrane by intercalating within the membrane phospholipids. The estrogen concentration in women declines as women enter menopause, and this results in negative outcomes including delay in recovery from skeletal muscle injuries and greater injury of skeletal muscles. Muscle mass and strength decrease is believed to occur faster in women with menopause than in older men and this is due to differences in hormonal levels where estrogen levels in women tend to decrease with a mean age of 51yrs compared to men (Harris & Emberley, 2014). Women in the menopausal period stop producing eggs which mark the ends of their menstrual cycle and fertility. Menopausal periods are categorized into two phases; pre-menopausal and postmenopausal. During pre-menopausal periods, estrogen levels slowly drop even though women are still experiencing regular menstrual periods and are capable of giving birth (Hickey, Elliott & Davison, 2012). During the postmenopausal period, women experience a fast and constant drop in estrogen levels. In this period, women stop ovulating marking the end of their fertility and they also experience a lot of discomfort in their bodies (Hickey, Elliott & Davison, 2012). The decreasing estrogen levels in these two phases convey a direct effect on peripheral tissues like a skeletal muscle (Maltais, Desroches & Dionne, 2009). A current study conducted by Pöllȧnen et al (2011), suggested that women in pre-menopausal stages have better muscle strength, power, and larger muscles than women in post-menopausal periods. This suggested that estrogen might have a direct effect on skeletal muscle, but this research is still uncertain.
According to Herbst & Bhasin (2004), the testosterone hormone decreases fat mass and increases lean body mass in young men. Testosterone hormone in young men induces hypertrophy of the skeletal muscle leading to improved leg power and muscle strength. As the men age, they lose muscle mass because of the natural decline in testosterone levels. A significant reduction in testosterone hormone can also result in sarcopenia (Pöllȧnen et al., 2011). Sarcopenia is characterized by muscle weakness and is caused by decreasing circulating levels of sex hormones in skeletal muscles and bones. Sarcopenia in men (mass weakness) is associated with a decrease in testosterone (Pöllȧnen et al., 2011). Similarly, Dihydrotestosterone (DHT) is a male sex hormone that is converted to testosterone using 5-α reducates enzyme. It is 90% responsible for changes and the development of male sex characteristics (Phillips et al, 1993). In skeletal muscle, through the non-genomic pathway, physiological levels of DHT affects the fast twitch and slow twitch fibers of skeletal muscle by increasing tetanic contractions and twitching of the fast-twitch fibers but then it decreases them in slow-twitch fibers (Phillips et al, 1993). Skeletal muscles are also capable of converting estrogen to androgens through a pathway involving steroidogenic enzymes (Prentice et al, 2009).
As people, age, steroid sex hormones like estrogen, testosterone, and DHT are said to affect muscle strength and power. This proposal will address: first the influence of estrogen replacement therapies on skeletal muscle in both post-menopausal and pre-menopausal women. Second, the effects of testosterone replacement therapy on older men and athletes.
2.0 Body: comparison and analysis of relevant research articles
1. The use of HRT and why women use HRT
Hormonal replacement therapy (HRT) is a medication that contains hormones that the body of a woman stopped producing after menopause and is used to treat the symptoms of menopause. HRT is normally given to some of the women whose progesterone and estrogen levels significantly dropped because of menopause. Bagger (2004) stated that when the levels of estrogen and progesterone drop especially when the women approach menopause, some women may boost their levels of hormones artificially to reduce certain symptoms of menopause. Estrogen hormone helps maintain bone density, regulate vaginal moisture, and skin temperature. Therefore, a drop in the levels of estrogen can cause urinary problems, vaginal dryness, thinning hair, night sweats, sleep problems, moodiness, irregular periods, lower fertility, memory and concentration difficulties, hot flushes. Fat accumulation in the abdomen and breast getting smaller. Bakour & Williamson (2015) pointed out that some of these symptoms may occur in peri-menopause before the start of menopause. The main function of the Progesterone hormone is to prepare the womb of a woman for possible pregnancies in addition to protecting the endometrium. There is a higher risk of developing endometrial cancer when the progesterone levels go down (Enns & Tiidus, 2010).
Even though several studies Goldstein (2010) has linked HRT with life-threatening conditions such as ovarian cancer, breast cancer, and other illness conditions, doctors still prescribe it in some conditions. There are several benefits as to why women use HRT, key among them being the treatment or prevention of osteoporosis, and the relief of menopausal symptoms.
(a) Improvement in skeletal muscles function and reduction in osteoporosis risks
According to Hickey, Elliott & Davison (2012), HRT improves the functions of the skeletal muscles. In a study conducted by Hickey, Elliott & Davison (2012), the findings indicated that HRT improves the functions of muscles in women, up to the muscle fibers. Even though women showing the symptoms of menopause, Hickey, Elliott & Davison (2012) found out that even though the muscle fibers did not show any change in size, the HRT users’ muscles showed greater strength by generating maximum force than the non-HRT users. It is believed that at least in part, using HRT reduces modifications of the contractile proteins of the muscle linked to aging. In addition to skeletal muscles, HRT is effective in the preservation of the mineral density of the bone. Stevenson et al (2006) stated that taking HRT amongst women leads to osteoporosis reduction in the hip and spine and this could explain why women use HRT.in a study conducted by Marjoribanks et al (2012), taking HRT by women have decreased significantly the incidences of fractures with the long-term use of HRT. According to Hickey, Elliott & Davison (2012), HRT is the first line of treatment for the management and prevention of osteoporosis in women with the symptoms of menopause and who are aged below 50 years. Even though the density of the bone declines after HRT discontinuation. Bagger (2004) in their study demonstrated that women taking HRT for a few years around menopause have a long protective effect for several years after stopping using HRT. To determine whether HRT administration for 2- 3 years in the early years of postmenopausal provide long-term visits, such as prevention of bone fractures and prevention of bone Loss, Bagger (2004) studied a group of 347 healthy women in post menopause with normal bone mass who had completed earlier one of four HRT trials that are placebo-controlled and who were reexamined after stopping HRT for 5, 11 or 15 years. 263 of those women received either placebo or HRT for 2-3 years with no further treatment of bone sparing until follow-up. Moreover, the remaining 84 women in the study reported either current or prolonged HRT use at reexamination. The mineral density of the bone at the spine (L1 to L4) and mineral content of the bone in the forearm was then measured at baseline, the end of the trial, and follow-up. Bagger (2004) assessed, at the follow up the radiological presence of the vertebral fracture and collected new information on the non-vertebral fractures incidences. When a comparison was done with that of women treated with placebo, bone mineral content and bone mineral density in women treated with HRT continued to show higher values significantly (>5%) even several years after the HRT stoppage. After the treatment stoppage, the rate of loss of bone returned to normal rates of post-menopause. In summary, limited HRT administration in the early years of post-menopause offers long-lasting benefits for postmenopausal bone loss prevention and osteoporotic fractures (Bagger, 2004).
(b) Urogenital symptoms improvement
Women in premenopausal or menopause also use HRT to improve their urogenital menopause symptoms. Several studies have indicated that HRT improves vaginal dryness significantly and also sexual function. Moreover, HRT is very much effective in improving the related symptoms of vaginal atrophy (Sturdee et al, 2010). Panay et al (2013) indicated that women also use HRT in relieving the symptoms of urinary frequency since it has a proliferative effect on the urethral and bladder epithelium. Goldstein (2010) also observed that HRT improves vaginal symptoms, decrease the vaginal pH, and vaginal atrophy. Moreover, there is an improved maturation of the epithelia with HRT compared to non-hormonal gels and placebo and that could explain the reasons why women use HRT. In a study conducted by Goldstein (2010) on how to recognize and treat urogenital atrophy in postmenopausal women, Goldstein (2010) observed that it results from menopausal estrogen deficiency and has several clinical effects which include sexual dysfunction, vaginal dryness, recurrent urinary infections, and urinary incontinence. Goldstein (2010) further asserted that estrogen therapy either administered systematically or locally provides significant relief. Local vaginal estrogen therapy in low dose, in the form of rings, creams, and vaginal tablets has been shown to reduce vaginal dryness and dyspareunia, restore normal cytology of the vagina, and restorative the vaginal pH
(c) Reduction in cardiovascular diseases
HRT also reduces the risks of heart attack and heart failure. Bakour & Williamson (2015) asserted that women who receive the HRT immediately after the commencement of their menopause have a lower likelihood of developing heart failures and heart attacks. This could also explain the reasons why women use HRT. Even though the relationship between cardiovascular diseases and HRT is still controversial, Hickey, Elliott & Davison (2012) asserted that the duration and timing of HRT and the pre-existing cardiovascular disease have a likelihood of affecting the outcomes. A study conducted by Prentice et al (2009) quoted trial research done by Women health initiative (WHI) found out that there was a slight increase in coronary heart disease incidences in the first year after commute enforcement of HRT. The women in the trial were taking the conjugated equine estrogens without or with medroxyprogesterone acetate (Prentice et al, 2009). In another recent study by Schierbeck et al (2012), the results demonstrated that HRT reduces coronary heart disease incidences by around 50% if it commenced within years of the menopausal years. Similarly, Schierbeck et al (2012) showed that women who receive HRT early after menopause had a significant reduction in mortality risk without any apparent increase in the risk of stroke, venous thromboembolism, or cancer.
2. How HRT effects, skeletal muscle of post-menopausal women compared to pre-menopausal women
In the previous randomized controlled trials, post-menopausal HRT administration for 6 to 1 year has shown improvement in mobility and an increase in the strength of the muscles in young postmenopausal women (Sipilä et al, 2001; Skelton et al, 1999, Taaffe et al, 2005). However, 27 and 46 in their studies documented that amongst the older women there was no improvement in mobility and muscle strength with HRT treatment. Skeleton et al (1999) on their randomized controlled trials investigated the effects of HRT on muscle composition and muscle cross-sectional areas. The results indicated no change in the cross-sectional area of the muscle adductor policy after one year of cyclical norgestrel and estrogen treatment amongst women with a mean age of 61 years although there was a significant strength gain on the same muscle.
Similarly, Sipilä et al (2001) also did a double-blind randomized controlled test among early post-menopausal women and the results showed a significant mean increase of 6% in the cross-sectional area of the knee extensor muscle after continuous treatment with combined progestin and estradiol compared to the controlled subjects. In the same study, Sipilä et al (2001) examined the thigh muscle density by CT and recorded an increase after HRT. This suggested decreased intramuscular content. Additionally, the relative fat proportion within the knee compartment of the extensor muscle remained unchanged in the women under HRT, while it increased amongst the controlled group (Sipilä et al, 2001).
Pöllänen et al (2015) conducted a study to examine the relationship between characteristics of muscles in pre-menopausal (n=8) and intramuscular steroid hormones and in the postmenopausal pairs of monozygotic twin sisters (n=16, eight pairs of twin sisters), discordant for estrogen use based on the replacement of hormones. Pöllänen et al (2015) assessed the isometric strength of the skeletal muscles by measuring the strength of knee extension. Moreover, the explosive muscle power of the lower body was assessed as the height of the vertical jump. From the study. Intramuscular estrogen, testosterone, DHEA, and DHT proved to be independent, significant predictors of power, and strength explaining the variation of 59-64% in the strength of knee extension and 80-83% of the vertical jumping height variation in women. The study by Pöllänen et al (2015) suggests that intramuscular sex steroids are associated with power and strength regulation in muscles of women.
3. Changes in muscle mass after menopause
Menopause is linked with the natural estrogen decline which increases the fat mass of the visceral, decreases the mass density of the bones, muscle strength, and muscle mass. In their study review, Maltais, Desroches & Dionne (2009) examined the menopause transition role and associated decrease in the status of hormone regarding the changes. Furthermore, the study overviewed the efficiency of nutrition and physical exercise on sub-characteristics of muscle.
According to Harris & Emberley (2014), the role of estrogen in the maintenance of muscle mass remains unclear. For instance, in a study done by Trenkle (1976), estrogen was reported to stimulate the growth of muscles in developing cattle and sheep. However, in a study done by Ihemelandu (1980), estrogen was found to be hindering the growth of the skeletal muscles of the developing rodents. In women, Petrofsky et al (1976) and Seeley et al (1995) found that estrogen does not affect muscle mass. Similarly, in a study done by Philip et al (1993), the results indicated that women who are deficient in sex hormones which includes the post-menopause women had less specific strength in their adductor pollicis muscle (force/muscle cross-sectional area), compared to their aged-matched women who were under HRT.
Pamela (n.d) pointed out that an average woman during their menopausal transition can expect to gain 2-5 pounds of muscle, especially in the lower tummy. The major reason for weight gain among women is estrogen decline. Healthtalk.org. (2015) also elaborated that fat cells in the buttocks, thigh, and hip have estrogen receptors. In most women, estrogen drives most storage of fat to the lower body parts, and therefore as the levels of estrogen begin to decline, it loses its hold on the storage of fat below the waist. Instead, the fat begins to be deposited around the waistline
4. The use and why athletes use testosterone replacement therapy
According to Gregory et al (2003), there is an increasing number of males using testosterone therapy to help in the treatment of erectile dysfunction, fatigue, and loss of sex drive, and also to enhance their physical performance as these are the most common symptoms of low testosterone in the body. Testosterone therapy is normally used in treating male hypogonadism or simply low testosterone. This is a condition where the body fails to make hormones that are enough because of a problem with pituitary glands or the testicles (Griggs et al, 1989).
Athletes tend to use testosterone replacement therapy to enhance their physical performance during sports. This is because testosterone hormone allows the athletes to increase their muscle mass and also performance (Herbst and Bhasin, 2004). Herbst and Bhasin (2004) indicated that bodybuilders and athletes use supplements that boost testosterone to increase their strength as well as improve their recovery time. This practice is also referred to as doping (Herbst and Bhasin, 2004).
Leaner body mass helps control weight and increases energy which athletes require. Evidence shows that testosterone treatment can increase muscle strength and size and decrease fat. This effect is much greater where testosterone therapy is combined with strength training exercises. In a study done by Snyder et al (1999) on 108 men who are aged over 65 years and under the treatment of testosterone for 36 months, the results indicated that testosterone therapy decreased fat significantly. Especially in the legs and arms. Moreover, these same men under the study have an increase in their lean mass majorly around their trunk.
Another reason why athletes tend to use testosterone replacement therapy is for stronger bones which help in supporting their internal organs and muscles hence boosting their athletic performance. A drop in testosterone levels leads to a drop in bone density, and this raises the risk of osteoporosis or weaker bones among the athletes. The argument is echoed by another study by Snyder (1999) which indicated that testosterone replacement therapy can make older men with low testosterone levels increase their bone density.
5. The effects of testosterone replacement therapy in athletes’ skeletal muscles
Testosterone replacement therapy has the ability to increase muscle mass and muscle strength on the skeletal muscle of the athletes. It works by increasing the protein synthesis of the muscle. Griggs et al (1989) conducted a study on the effects of testosterone on muscle protein synthesis and muscle mass. The researchers the pharmacological dose effect of testosterone enanthate on total body potassium and muscle mass, and muscle protein synthesis, and whole body in normal male subjects. Among the 9 subjects, estimated muscle mass by creatine exertion increased. Estimation of the total body potassium by 40k counting increased among all participants. A primed infusion protocol that is continuous with L-[1-13C] leucine was applied in determining the whole body oxidation and leucine flux. Furthermore, the estimation of the protein synthesis of the whole body was done from nonoxidative flux. Lastly, the synthesis rate of the muscle protein was determined by measuring the incorporation of [13C] leucine into the obtained muscle sample by needle biopsy. The results from the study indicated that testosterone therapy increased protein synthesis of the muscle in all subjects, leucine oxidation slightly decreased, but a whole-body synthesis of protein did not significantly change. Additionally, muscle morphometry did not show significant increases in the diameter of the muscle fiber. This study suggested that testosterone increases muscle mass is by increasing the synthesis of the muscle protein (Griggs et al, 1989).
Gregory et al (2003) also conducted a study on the effects of testosterone replacement therapy on the skeletal muscle after injury of the spinal cord. Using a randomized controlled study design and settings in Georgia, USA, and Athens, Gregory et al (2003) took soleus, gastrocnemius, tibialis anterior, vastus lateralis, and triceps branch muscles from 12 young Charles River male rats after sham surgery or complete SCI after 11 weeks. The rats were given TRT after surgery and their muscle samples sectioned and fibers quantitatively analyzed for alpha-glycerol-phosphate dehydrogenase (GPDH), succinate dehydrogenase (SDH), and actomyosin ATPase (qATPase) and qualitatively analyzed for myosin ATPase activities. The results of the study showed a decrease in the average size of fibers in affected muscles. Additionally, there was an SDH decrease and an increase in qATPase and GPDH activities across the muscles of the four hind limbs of the SCI animals. Moreover, the size of fiber in the TRI was increased by SCI (31+/-2%). This shows that TNT has an effect on muscle mass, and it increases muscle mass (Gregory et al, 2003).
In summary, the literature review looked at the effects of sex hormones on skeletal muscles during aging. It discussed the role of each sex hormones in the skeletal muscles before discussing the muscle reduction in pre-menopause and post-menopause period and how estrogen hormone is associated during these periods. Similarly, the literature review briefly highlighted the reduction of muscle mass as men age and how testosterone is associated with muscle reduction. Additionally, the paper reviewed several articles by comparing and analyzing their data under five different groupings. That is the use of HRT and why women use HRT; How HRT affects the skeletal muscle of post-menopausal women compared to pre-menopausal women; Changes in muscle mass after menopause; the use and why athletes use testosterone replacement therapy; and the effects of testosterone replacement therapy in athletes’ skeletal muscles.
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