DOWNLOAD PDF MECHANISMS OF ACTIONS OF TESTOSTERONE ENANTHATE

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1 Chapter 1 : Testosterone Enanthate - FDA prescribing information, side effects and uses Testosterone Enanthate Injection, USP provides Testosterone Enanthate, USP, a derivative of the primary endogenous androgen testosterone, for intramuscular administration. In their active form, androgens have a beta-hydroxy group. Esterification of the beta-hydroxy group increases the duration. The triggering conditions sharp change in brightness is a partial inhibition of testosterone enanthate dosage I of h channels, which causes a transient change in the brightness in a limited area of the visual field photopsia. The main pharmacodynamic property of testosterone enanthate dosage is dose-dependent slowing of the testosterone cypionate vs enanthate heart rate. This leads to a reduction of the load on the myocardium due to a decrease in myocardial oxygen demand. Pharmacokinetics testosterone enanthate dosage is the S-enantiomer shows no biological conversion in studies in vivo. N-desmetilirovannoe testosterone enanthate dosage derivative is the major active metabolite. Absorption and bioavailability testosterone enanthate dosage is rapidly and almost completely absorbed from the gastrointestinal tract after ingestion fasting with achieving maximum concentration C max in plasma after about 1 hour. It is recommended to take the tablets during meals in order to reduce the concentration variability. Metabolism testosterone enanthate dosage largely metabolized in the liver and intestine by oxidation with cytochrome P ZA4 isoenzyme CYP3A4. The metabolism of this active metabolite also occurs with the participation of isoenzyme CYP3A4. Conversely, strong inducers and inhibitors of cytochrome P can significantly affect the concentration of testosterone enanthate dosage plasma. Excretion of metabolites occurs equally through the intestines and kidneys. Special patient groups Patients elderly pharmacokinetic indices AUC and the C max were not significantly different in patients 65 years and older, 75 years or older and the general population of patients. Data on the use of testosterone enanthate dosage in patients with moderate hepatic insufficiency points on a scale Child-Pugh are limited and do not allow to draw a conclusion about the features of the pharmacokinetics of testosterone enanthate dosage in this group of patients, and in patients with severe hepatic insufficiency more than 9 points on a scale Child -Pyu no. The relationship between the pharmacokinetic and pharmacodynamic properties of slowing the heart rate is directly proportional to the increase in the blood plasma concentration of testosterone enanthate dosage and the active metabolite S when taken in doses of mg twice daily. High concentrations of testosterone enanthate dosage in blood plasma, which can be achieved with the simultaneous use of testosterone enanthate dosage with potent inhibitors isoenzyme CYP3A4, can lead to a marked slowing of the heart rate, however, this risk is reduced while the use of a moderate inhibitor of CYP3A4. Such megadoses are used primarily by football players and powerlifters. Who does not believe, let him try to see the bodybuilding champions in the off-season or the period of muscle building, when they absorb incredible amounts of testosterone no ester. Indications Treatment of stable angina in adults with normal sinus rhythm: Contraindications Hypersensitivity to testosterone enanthate dosage or any ancillary components of the formulation. Severe hypotension systolic blood pressure BP of less than 90 mm Hg and diastolic blood pressure less than 50 mmhg. Severe hepatic insufficiency more than 9 points on a scale Child-Pugh. Unstable or acute heart failure. The presence of pacemaker operating in a mode of constant stimulation. The simultaneous use of strong inhibitors of the cytochrome P ZA4, such as antifungal agents group of azoles ketoconazole, itraconazole, macrolide antibiotics clarithromycin, erythromycin for oral, josamycin, telithromycin, HIV protease inhibitors nelfinavir, ritonavir and nefazodone. Age 18 years effectiveness and safety of the drug in this age group has not been studied. Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome. Application of pregnancy and during breastfeeding Pregnancy Animal studies have demonstrated the presence of reproductive toxicity, embryotoxicity and teratogenicity. It is not known whether testosterone enanthate dosage penetrates into breast milk. If necessary, use Bravadin during lactation should stop breastfeeding. Dosing and Administration Inside, twice a day morning and evening during food intake. After weeks of therapy, the dose may be increased to 15 mg per day 7. Chronic Page 1

2 heart failure recommended starting dose is 10 mg per day 5 mg 1 tablet twice a day. After 2 weeks of therapy, the dose may be increased to 15 mg per day 7. Patients older than 75 years, patients aged 75 years and older treatment should be started at a lower dose. The recommended starting dose is 2. In the future, the dose may be increased. The recommended initial dose â 10 mg per day 1 tablet of 5 mg twice a day. Abnormal liver function No dose adjustment is required in patients with mild hepatic insufficiency up to 7 points on a scale Child-Pugh. Caution should be exercised when using the drug Bravadin in patients with moderate hepatic impairment 7-9 points on a scale Child-Pugh. Children and adolescents The safety and efficacy of testosterone enanthate dosage in children and adolescents under the age of 18 years have not been established. Side effect The use of testosterone enanthate dosage has been studied in clinical trials involving almost 14, patients. The most common side effects were dose-dependent and have been associated with the mechanism of action of testosterone enanthate dosage. Violations of the organ of vision: Violations of the organ of hearing and labyrinth disorders: Violations of the heart and blood vessels: Disorders of the nervous system: Violations of the respiratory system, the chest and mediastinum: Violations of the skin and subcutaneous tissue disorders: Violations of the gastrointestinal tract: General disorders and at the injection site: Usually, such events provoked a sharp change in light intensity in the area of the visual field. Basically photopsia appeared during the first two months of therapy, followed by repetition. Intensity photopsias usually been mild or moderate. Photopsia stopped against the background of continued therapy Overdose overdose Bravadin drug may lead to severe and prolonged bradycardia. Treatment Treatment is symptomatic and severe bradycardia should be carried out in a specialized hospital departments. In the case of a combination of bradycardia with impaired hemodynamic necessary use of beta-agonists isoprenaline. If necessary â to set the pacemaker. Interaction with other drugs. Page 2

3 Chapter 2 : Testosterone Enanthate - Steroid Abuse The mechanism of action of the nandrolone esters and other anabolic steroids, and the effect of drug delivery systems on their biological activity have been studied by van der Vies (). The duration of action of the esters depends upon the rate of absorption from the site of administration. Mucuna pruriens Health benefits and mechanism of action Do you know? Today many Natural Testosterone boosting supplements include Mucuna extract as one of the major ingredients. This herbal ingredient helps to enhance muscles and increase testosterone levels. It is well known for its aphrodisiac properties and is also used to stimulate the deposition of proteins in muscles, as well as to help increase muscle strength and muscle mass and stimulate alertness and improve coordination. Its principle components are L-DOPA and the bioactive alkaloids mucunine, mucunadine, mucuadinine, prurienine and nicotine as well as b-sitosterol, glutathione, lectin, oils, venic and gallic acids. It is a plant native to many tropical regions of the world, especially India and Africa. It produces beautiful purple flowers that hang in long clusters, followed by clusters of bean pods. The mature pods have a hair-like velvety covering that may cause itching to people sensitive to mucunain. Commonly Used Names for Mucuna pruriens: In the United States Mucuna pruriens is primarily known as velvet bean, mucuna, or cow-itch. It was used extensively for livestock feed and as an enriching cover crop to re-nourish depleted soils. Soybeans provided greater economic value as a cash crop. In addition, inadequate methods for mechanically harvesting the long vine velvet beans drastically reduced velvet bean acreage in the US. Today, however,velvet beans have been re-discovered and are being widely sought after and used in several different venues. Agriculture â velvet beans are an excellent soil builder for restoring nutrient depleted soil. Velvet bean is a legume and uses nitrogen fixing bacteria in root nodules to produce nitrogen to improve the soil. Velvet beans are unsurpassed as a soil builder for restoring depleted garden soils. Velvet bean seed and foliage provide a high protein food source for cattle. Velvet beans are a superior deer food and are actively sought out by wildlife managers for planting in wildlife food plots; Herbal and Nutritional Supplement Products: Mucuna velvet bean has gained tremendous popularity as a health supplement and sports nutrition supplement. How it works Mechanism of action of Mucuna pruriens Mucuna increases L-Dopa levels and stimulates the deposition of growth hormone HgH by the pituitary gland, as well as stimulates the deposition of proteins in the muscles. Mucuna has white flowers, lavenders or purples; It is also known by some curious names as: Reported Uses and Benefits of Mucuna pruriens: Body building and Sports Supplement: Today many Natural Testosterone boosting supplement brands containing Mucuna extract are widely being used for enhancing muscles and increasing testosterone levels. Mucuna has been used for centuries as an aphrodisiac to increase libido in both men and women, primarily due to the dopamine inducing effect. Improves sense of well being and improves sleep: Dopamine is a neurotransmitter that promotes enjoyment and enhances interest in life. Helps reduce body fat and cellulite Helps to improve skin texture and appearance Increases energy levels Helps lower cholesterol levels Acts as a diuretic Coffee Substitute â Nescafe: The velvet fuzzy covering on the bean pods trichomes contain a compound called mucunain, which is a natural intestinal de-wormer Mucuna in the treatment of sexual dysfunctions Studies have also shown that Mucuna seeds can cause a significant increase in sperm count and ovulation in women. It is still used to increase libido in men and women because of its dopamine-inducing properties. Mucuna also showed to stimulate testosterone-enanthate induced by androgenic activity observed in a group of treated individuals. Page 3

4 Chapter 3 : Mucuna pruriens Health benefits and mechanism of action- Natural testosterone racedaydvl.co Testosterone Enanthate is a long-acting intramuscular form of the androgen testosterone. Testosterone inhibits gonadotropin secretion from the pituitary gland and ablates estrogen production in the ovaries, thereby decreasing endogenous estrogen levels. Advanced Search Abstract Testosterone supplementation increases muscle mass primarily by inducing muscle fiber hypertrophy; however, the mechanisms by which testosterone exerts its anabolic effects on the muscle are poorly understood. The prevalent view is that testosterone improves net muscle protein balance by stimulating muscle protein synthesis, decreasing muscle protein degradation, and improving the reutilization of amino acids. However, the muscle protein synthesis hypothesis does not adequately explain testosterone-induced changes in fat mass, myonuclear number, and satellite cell number. We postulate that testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage. The hypothesis that the primary site of androgen action is the pluripotent stem cell provides a unifying explanation for the observed reciprocal effects of testosterone on muscle and fat mass. AFTER nearly six decades of intense controversy 1, a consensus has emerged that androgens have direct anabolic effects on the mammalian skeletal muscle 2â Testosterone administration to androgen-deficient men is associated with an increase in lean body mass 2â 6, mostly due to skeletal muscle accretion 4. In addition, testosterone administration leads to a reduction in whole body and regional fat mass Table 1 3â 6. Testosterone effects on the muscle are linearly correlated with the administered dose and the prevalent circulating testosterone concentrations 7. Thus, administration of supraphysiological doses of testosterone to eugonadal men leads to further gains in muscle size and maximal voluntary strength 7, 8. Testosterone-induced increase in muscle size is associated with hypertrophy of both type I and II fibers 9, and an increase in the number of myonuclei and satellite cells Any proposal to explain the anabolic effects of testosterone should ideally reconcile all of these observed effects of testosterone administration on body composition and muscle morphology. Until recently, the dominant hypothesis had been that testosterone administration increases the synthesis rates of mixed skeletal muscle protein, including myosin heavy chain MHC 4, 11â However, this hypothesis does not explain all of the observed effects of androgens on body composition; hence, the mechanisms by which testosterone induces skeletal muscle mass remain poorly understood. There are several additional vexing issues related to the effects of testosterone on the muscle that have not been fully explained. Are androgen effects on muscle and fat mass mediated through similar or different mechanisms? What cell type within the skeletal muscle is the primary target of androgen actionâ is it the muscle fiber, satellite cell, or yet another androgen-responsive cell? Are androgen effects on the muscle mediated through an androgen receptor-mediated pathway? What signal transduction pathways are involved in mediating androgen effects on the muscle? Is 5-alpha reduction of testosterone necessary for mediating testosterone effects on the muscle? What is the role of aromatization of testosterone in mediating androgen effects on body composition? What is the mechanistic basis of the tissue-specific differences in androgen responsiveness? This review attempts to address these issues, and is a summary of the data and thoughts generated in our laboratories over the past decade on the anabolic effects of testosterone on skeletal muscle. Testosterone Induces Skeletal Muscle Fiber Hypertrophy Administration of replacement doses of testosterone to healthy young 2â 6 and older men with low testosterone levels 18â 21 and HIV-infected men with low testosterone levels 17, and administration of supraphysiological doses to eugonadal men, increases muscle size 7, 8. To evaluate whether testosterone-induced increase in muscle size is due to muscle fiber hypertrophy, we treated healthy young men with monthly injections of a long-acting gonadotropin-releasing hormone GnRH agonist to suppress endogenous testosterone secretion and weekly injections of 25, 50,,, or mg testosterone enanthate TE for 20 weeks. Muscle biopsies were obtained from vastus lateralis muscle in eugonadal men before and after 20 weeks of combined treatment with GnRH agonist and testosterone 7, 9. Page 4

5 Muscle volume measured by magnetic resonance imaging increased in proportion to the administered dose and the prevalent testosterone concentrations. The cross-sectional areas of both type I and II fibers also increased in direct correlation with the testosterone dose and total and free testosterone concentrations during treatment 9 Figure 1. The relative proportions of type I and type II fibers did not change significantly after treatment in any group. Thus, the increase in muscle volume in healthy eugonadal men treated with graded doses of testosterone is due to concentration-dependent hypertrophy of both type I and type II muscle fibers 9. Testosterone Increases Number of Myonuclei and Satellite Cells in Skeletal Muscle of Healthy Young Men We counted the number of myonuclei in biopsies of vastus lateralis obtained at baseline and after 20 weeks of treatment with a GnRH agonist and,, or mg weekly dose of testosterone enanthate. Testosterone administration was associated with a significant increase in myonuclear number. Because myonuclei in muscle fibers are contributed by satellite cells, we considered the possibility that testosterone administration increases satellite cell number. Accordingly, we quantitated the number of satellite cells by direct counting and by spatial orientation methods. Testosterone administration was associated with a dose-dependent increase in percent satellite cell number, obtained by direct counting, and absolute satellite cell number obtained by spatial orientation in men treated with mg and mg doses Figure 2 The change in percent satellite cell number correlated with changes in total and free testosterone concentrations Satellite cell and mitochondrial areas were significantly higher and the nuclear to cytoplasmic ratio lower after treatment with mg and mg doses These data demonstrate that testosterone-induced muscle fiber hypertrophy is associated with an increase in satellite cell number, a proportionate increase in myonuclear number, and changes in satellite cell ultrastructure. These alterations in satellite cell number and ultrastructure and muscle morphology cannot be explained by the muscle protein synthesis hypothesis. Testosterone Effects on Fat Mass Testosterone is an important determinant of whole body and regional fat mass. Hypogonadal men have higher fat mass in comparison with eugonadal controls 3. Induction of androgen deficiency in healthy men by administration of a GnRH agonist leads to an increase in fat mass In young, hypogonadal men, testosterone replacement therapy is associated with a decrease in fat mass 3â 6. Long-term studies of testosterone supplementation of older men have also demonstrated a decrease in fat mass 18, Serum testosterone levels are lower in middle-aged men with visceral obesity than in age-matched controls 22, Serum testosterone levels correlate inversely with visceral fat area 22, Testosterone replacement of middle-aged men with visceral obesity has been reported to decrease intraabdominal fat mass and improve insulin sensitivity 24, In our doseâ response studies, administration of graded doses of testosterone to men was associated with a dose-dependent decrease in fat mass 7. Loss of fat mass at higher doses was evenly distributed in the trunk and appendices and in the superficial and deep compartments. Until recently, testosterone effects on fat mass and metabolism have been assumed to be mediated by mechanisms that are distinct from those that mediate androgen effects on the muscle. Testosterone has been reported to inhibit lipid uptake and lipoprotein lipase activity in adipocytes, and stimulate lipolysis 21, in part by increasing the number of lipolytic beta-adrenergic receptors. In addition, testosterone inhibits the differentiation of preadipocytes to adipocytes. All of these hypotheses on the direct effects of testosterone on fat mass, although plausible, do not provide a unifying explanation for the reciprocal changes in muscle and fat mass. Testosterone Effects on Protein Synthesis Soon after the biochemical synthesis of testosterone, several groups investigated the anabolic effects of testosterone in animal models. During the s, Kochakian 26 first described the nitrogen-retaining properties of urinary androgens in the castrated dog. He recorded similar effects of androgens in the castrated male rat and found that the androgen stimulation not only resulted in nitrogen retention but also increases in body weight 26â These studies suggested that androgen effects were dose related, with higher nitrogen retention and weight gains observed with higher doses of androgens 26â Shortly after the initial animal studies, Kenyon and colleagues 29 studied the effects of testosterone propionate in eunuchoidal men, and eugonadal men and women. During androgen treatment, urinary nitrogen excretion diminished, with the greatest magnitude of effects observed in eunuchoidal men. These observations, combined with the results of the animal studies 26â 29, allowed the Page 5

6 early recognition of the anabolic effects of androgens. It is notable that Kenyon and others were not able to demonstrate sustained increases in nitrogen retention with testosterone supplementation in eugonadal men, an observation that sparked considerable skepticism for the next 50 years about the anabolic effects of supraphysiological doses of androgens in eugonadal men. Induction of androgen deficiency by administration of a long-acting GnRH agonist in healthy young men is associated with decreased rates of 13C-leucine appearance, a measure of proteolysis Lowering of testosterone concentrations in this study 14 was also associated with a significant decrease in nonoxidative leucine disappearance, a marker for whole-body protein synthesis. Conversely, testosterone supplementation stimulates the synthesis of mixed skeletal muscle proteins 4, 11â All of these studies of protein turnover have been performed in the fasting state in which the net balance between protein synthesis and breakdown is negative. Testosterone administration improves the muscle protein balance and reduces the loss of muscle protein during the fasting state 4, 12â However, none of the studies have demonstrated a clear improvement in muscle protein balance into the positive territory, which would indicate net protein accretion. It is possible that during the fed state, testosterone administration leads to net protein accretion. Testosterone improves the efficiency of reutilization of amino acids in the muscle The effects of testosterone administration on muscle protein breakdown have not been studied extensively. A recent study by Ferrando and colleagues 15 reported a significant decrease in muscle protein breakdown following testosterone supplementation in older men. In this study 15, the proteasome peptidase activity was decreased by testosterone administration, a finding consistent with the decrease in muscle protein degradation assessed by using labeled phenylalanine and measurements of arteriovenous differences. Thus, the net effect of testosterone administration is a greater net accretion of nitrogen because of the amelioration of protein loss during fasting, and by stimulation of protein anabolism with feeding Several observed effects of testosterone administration on body composition and muscle histomorphology are not easily explained by the muscle protein hypothesis. If muscle protein synthesis or degradation were the primary target of androgen action, then one would have to invoke a separate mechanism to explain the reduction in fat mass that occurs during androgen administration. Similarly, muscle protein hypothesis does not easily explain the observed increases in the number of myonuclei and satellite cells in the skeletal muscle during androgen treatment. Undoubtedly, muscle fiber hypertrophy could not occur without a net increase in protein accretion; however, it is likely that the increase in muscle protein synthesis is a secondary event in the cascade of molecular processes that culminate in muscle hypertrophy. Androgen receptors are expressed in all the skeletal muscles that have been examined 30, The level of expression varies in different muscle groups However, androgen receptors in most organ systems are nearly saturated at testosterone concentrations that are at or near the lower end of the normal male range 1. Indeed, many androgen-dependent functions in men are maintained at testosterone concentrations that are near the lower end of the male range 7. However, our doseâ response studies in healthy young men have demonstrated that the anabolic effects of testosterone on the muscle are linearly related to testosterone dose and circulating concentrations over a range that extends at least a log unit higher than the lower end of the normative range in men 7. If androgen receptors are saturated at relatively low testosterone concentrations, then how can we explain the effects of higher, supraphysiologic doses of testosterone on the muscle? This apparent discordance led to considerable skepticism about the biological plausibility of direct anabolic effects of testosterone on the muscle. These observations also led to speculation that the anabolic effects of testosterone on the muscle might not be mediated through an androgen-dependent mechanism. In animal models, glucocorticoids antagonize the anabolic effects of testosterone 32â 34 ; conversely, testosterone administration can prevent glucocorticoid-induced muscle atrophy. Testosterone binds glucocorticoid receptor with low affinity 33, and it is not clear whether testosterone has additional postreceptor effects on the glucocorticoid pathway. Administration of androgen receptor antagonists to men is associated with loss of muscle mass, suggesting that testosterone at the prevalent circulating concentrations is necessary for maintenance of skeletal muscle mass in men. These data also support the role of the androgen-receptor pathway in mediating androgen effects on the muscle. Androgen administration upregulates Page 6

7 the expression of androgen receptor in the skeletal muscle Therefore, it is possible that testosterone administration increases the responsiveness of the skeletal muscle to androgen action by upregulation of its own receptor. Although there is agreement that androgen receptors are expressed in the mammalian skeletal muscle, the exact cell type or types that express androgen receptors have not been identified. Much of the previous work on androgen receptor localization has been performed by using homogenized extracts of skeletal muscles, which precludes cellular localization. However, Doumit and colleagues 35 have demonstrated, by immunoblotting and immunohistochemical staining, that porcine satellite cells express androgen receptor immunoreactive protein. Unpublished data Sinha-Hikim and colleagues suggest that additional cell types in the human skeletal muscle also express androgen receptor; the precise nature of these additional cells that express androgen receptor has not been elucidated. Muscle Pluripotent Cell Differentiation As the Primary Target of Androgen Action Muscle growth and regeneration during postnatal development and hypertrophy is dependent on the addition of myonuclei to muscle fibers 36â Because the nuclei within the muscle fibers are postmitotic, new myonuclei are contributed by the satellite cells 36â An increase in satellite cell number is an essential antecedent of an increase in myonuclear number and muscle fiber hypertrophy 36â Therefore, it is not surprising that testosterone supplementation increases satellite cell number in the levator ani of rats 39, 40 and the skeletal muscle of men Page 7

8 Chapter 4 : Testosterone enanthate - Wikipedia Testosterone Enanthate Actions & Functions: As we talked about above, Testosterone Enanthate is classified as a single large ester testosterone chemical compound. Other examples of this would be Testosterone Cypionate and the fast acting Testosterone Propionate. In mammals, testosterone is primarily secreted in the testicles of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. It is the principal male sex hormone and an anabolic steroid. In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass, and the growth of body hair. In addition, testosterone is essential for health and well-being as well as the prevention of osteoporosis. Females also are more sensitive to the hormone. Testosterone is observed in most vertebrates. Fish make a slightly different form called ketotestosterone. Its counterpart in insects is ecdysone. These ubiquitous steroids suggest that sex hormones have an ancient evolutionary history. In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone effects can be classified as virilizing and anabolic, though the distinction is somewhat artificial, as many of the effects can be considered both. Testosterone effects can also be classified by the age of usual occurrence. For postnatal effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone. The prenatal androgen effects occur during two different stages. Between 4 and 6 weeks of the gestation. Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4â 6 months of age. The function of this rise in humans is unknown. It has been speculated that "brain masculinization" is occurring since no significant changes have been identified in other parts of the body. Surprisingly, the male brain is masculinized by testosterone being aromatized into estrogen, which crosses the bloodâ brain barrier and enters the male brain, whereas female fetuses have alpha-fetoprotein which binds up the estrogen so that female brains are not affected. Pre- Peripubertal effects are the first observable effects of rising androgen levels at the end of childhood, occurring in both boys and girls. Pubertal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males, these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the blood. Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels decrease in the later decades of adult life. It is speculated that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes. Fatherhood also decreases testosterone levels in men, suggesting that the resulting emotional and behavioral changes promote paternal care. However, causality cannot be determined in this relationship. Marriage or commitment could actually cause a decrease in T levels. Single men, who do not have relationship experience, have lower testosterone levels than single men with experience. It is suggested that these single men with prior experience are in a more competitive state than their non-experienced counterparts. Collectively, these results suggest that it is the presence of competitive activities rather than bond-maintenance activities that are more relevant to changes in T levels. Men producing more testosterone are also more likely to engage in extramarital sex. Testosterone levels do not rely on physical presence of a partner for men engaging in relationships same-city vs. Physical presence may be required for women who are in relationships for the testosterone-partner interaction, where same-city partnered women have lower testosterone levels than long-distance partnered women. It has been found that when testosterone and endorphins in ejaculated semen meet the cervical wall after sexual intercourse, females receive a spike in testosterone, endorphin, and oxytocin levels, and males after orgasm during copulation experience an increase in endorphins and a marked increase in oxytocin levels. Testosterone levels follow a nyctohemeral rhythm which peaks early each day, regardless of sexual activity Page 8

9 There are positive correlations between positive orgasm experience in women and testosterone levels where relaxation was a key perception of the experience. An increase in T levels has also been found to occur in both men and women who have orgasms that are masturbation-induced. Studies conducted on rats have indicated that their degree of sexual arousal is sensitive to reductions in testosterone. When testosterone-deprived rats were given medium levels of testosterone, their sexual behaviors copulation, partner preference, etc. Therefore, these mammals may provide a model for studying clinical populations among humans suffering from sexual arousal deficits such as hypoactive sexual desire disorder. In non-human primates it has been suggested that testosterone in puberty stimulates sexual motivation, which allows the primate to increasingly seek out sexual experiences with females and thus creates a sexual preference for females. Higher levels of testosterone were associated with periods of sexual activity within subjects, but between subjects testosterone levels were higher for less sexually active individuals. Men who have sexual encounters with unfamiliar or multiple partners experience large increases of testosterone the morning after. Men who watch sexually explicit films also report increased optimism and decreased exhaustion. Previous research has found a link between relaxation following sexual arousal and testosterone levels. Testosterone increases in men who engage in brief conversations with women. This result was seen in heterosexual men who had engaged in sexual activity in the 6 months prior to the study. Men who are exposed to scents of ovulating women maintained a stable testosterone level that was higher than the testosterone level of men exposed to nonovulation cues. Testosterone levels and sexual arousal in men are heavily aware of hormone cycles in females. This may be linked to the ovulatory shift hypothesis, where males are adapted to respond to the ovulation cycles of females by sensing when they are most fertile and whereby females look for preferred male mates when they are the most fertile; both actions may be driven by hormones. In a study, males were exposed to either visual or auditory erotic stimuli and asked to complete a cognitive task, where the number of errors on the task indicated how distracted the participant was by the stimuli. It concluded that men with lower thresholds for sexual arousal have a greater likelihood to attend to sexual information and that testosterone may have an impact by enhancing their attention to the relevant stimuli. Testosterone levels are shown to increase as a response to previously neutral stimuli when conditioned to become sexual in male rats. This reaction engages penile reflexes such as erection and ejaculation that aid in sperm competition when more than one male is present in mating encounters, allowing for more production of successful sperm and a higher chance of reproduction. Androgens may modulate the physiology of vaginal tissue and contribute to female genital sexual arousal. This was in comparison with the control conditions. When females have a higher baseline level of testosterone, they had higher increases in sexual arousal levels but smaller increases in testosterone, indicating a ceiling effect on testosterone levels in females. Sexual thoughts also change the level of testosterone but not level of cortisol in the female body, and that hormonal contraceptives may have an impact on the variation in testosterone response to sexual thoughts. Van Anders and Dunn also studied the link between testosterone and orgasms in women, and found a correlation between high T levels and positive orgasm experience. This occurred in both the partnered and solitary context of orgasm. There is a time lag effect when testosterone is administered, on genital arousal in women. In addition, a continuous increase in vaginal sexual arousal may result in higher genital sensations and sexual appetitive behaviors. Testosterone may prove to be an effective treatment in female sexual arousal disorders. There is no current androgen preparation or for the treatment of androgen insufficiency approved by the FDA at this point in time, but it has been used off-label to treat low libido and sexual dysfunction in older women. Testosterone may be a treatment for postmenopausal women as long as they are effectively estrogenized. Testosterone levels play a major role in risk-taking during financial decisions. The administration of testosterone makes men selfish and more likely to punish others for being selfish towards them. As testosterone affects the entire body often by enlarging; males have bigger hearts, lungs, liver, etc. In humans, masculinization of the fetal brain appears, by observation of gender preference in patients with congenital diseases of androgen formation or androgen receptor function, to be associated with functional androgen receptors. There are some differences between a Page 9

10 male and female brain possibly the result of different testosterone levels, one of them being size: A study conducted in found no immediate short term effects on mood or behavior from the administration of supraphysiologic doses of testosterone for 10 weeks on 43 healthy men. Another study found a correlation between testosterone and risk tolerance in career choice among women. Literature suggests that attention, memory, and spatial ability are key cognitive functions affected by testosterone in humans. Much of the literature, however, suggests a curvilinear or even quadratic relationship between spatial performance and circulating testosterone, where both hypo- and hypersecretion deficient- and excessive-secretion of circulating androgens have negative effects on cognition and cognitively modulated aggressivity, as detailed above. Testosterone depletion is a normal consequence of aging in men. The "evolutionary neuroandrogenic theory" focuses on the hormone testosterone as a factor influencing aggression and criminality and being evolutionary beneficial during certain forms of competition. In most species, males are more aggressive than females. Castration of males usually has a pacifying effect on their aggressive behavior. In humans, males engage in crime and especially violent crime more than females. The involvement in crime usually rises in the early teens to mid teens which happen at the same time as testosterone levels rise. Research on the relationship between testosterone and aggression is difficult since the only reliable measurement of brain testosterone is by a lumbar puncture which is not done for research purposes. Studies therefore have often instead used more unreliable measurements from blood or saliva. Most studies support a link between adult criminality and testosterone although the relationship is modest if examined separately for each sex. Nearly all studies of juvenile delinquency and testosterone are not significant. Most studies have also found testosterone to be associated with behaviors or personality traits linked with criminality such as antisocial behavior and alcoholism. About half the studies have found a relationship and about half no relationship. The testosterone derivative estradiol is known to correlate with aggression in male mice. Moreover, the conversion of testosterone to estradiol regulates male aggression in sparrows during breeding season. Different ethnic groups have different incidences of prostate cancer. Differences in sex hormones including testosterone have been suggested as an explanation for these differences. A study found ethnical differences between blacks and whites in the testosterone to sex hormone binding globulin ratio in blood from the umbilical cord in infants. The original and primary use of testosterone is for the treatment of males who have too little or no natural endogenous testosterone productionâ males with hypogonadism. Appropriate use for this purpose is legitimate hormone replacement therapy testosterone replacement therapy [TRT], which maintains serum testosterone levels in the normal range. However, over the years, as with every hormone, testosterone or other anabolic steroids has also been given for many other conditions and purposes besides replacement, with varying success but higher rates of side effects or problems. Examples include reducing infertility, correcting lack of libido or erectile dysfunction, correcting osteoporosis, encouraging penile enlargement, encouraging height growth, encouraging bone marrow stimulation and reversing the effects of anemia, and even appetite stimulation. By the late s testosterone was being touted as an anti-aging wonder drug e. Decline of testosterone production with age has led to interest in androgen replacement therapy. Page 10

11 Chapter 5 : Testosterone (medication) - Wikipedia Testosterone enanthate is used primarily in androgen replacement therapy. It is the most widely used form of testosterone in androgen replacement therapy. The medication is specifically approved, in the United States, for the treatment of hypogonadism in men, delayed puberty in boys, and breast cancer in women. It exists in both an oral and injectable format, and it sits on the third place pedestal among the top 3 anabolic steroids most widely used and most popular among bodybuilders and athletes. It is superseded only by Deca-Durabolin Nandrolone Decanoate in second place, and Dianabol Methandrostenolone in first place. Winstrol is probably most famous and well-known for its alleged use by Canadian Olympic sprinter Ben Johnson in the Seoul Summer Olympic games where he tested positive for it. However, its origins begin in when its details were first released in the medical and scientific community[1]. Winstrol was approved for an extensive list of medical treatments following its release onto the prescription drug market, ranging from tissue and muscle wasting diseases to an Oesteoporosis drug, as well as in the treatment of burn victims and children with stunted growth. Winstrol was not very effective as a treatment for anemia, however[3]. Its primary operation is through binding with the androgen receptor rather than non-receptor mediated activity[4], which is common with certain other anabolic steroids such as Dianabol or Anadrol. Winstrol also has a low affinity for binding with the Glucocorticoid-binding sites in addition to some activity that is independent of androgen receptors[5][6][7][8]. Winstrol also possesses a very low degree of Progestogenic activity in the body[8]. Advertisement An impressive and somewhat unique function that Winstrol exhibits is its ability to significantly lower SHBG Sex Hormone Binding Globulin levels in the body, allowing freer Testosterone and other anabolic hormones to be able to exert anabolic activity in muscle tissues[10]. It exhibits exceptional capability and a high degree of stimulating and facilitating protein synthesis[11][12]. Winstrol has also been observed to possess a capability of boosting collagen synthesis in the body[13]. It is, however, a derivative of Dihydrotestosterone DHT where it contains a Pyrazol group attached to the first cycloalkane ring known as the A-ring of the anabolic steroid structure. This is actually very noticeable when a picture of the chemical structure of Winstrol is laid side-by-side with its progenitor hormone DHT, even to an individual unfamiliar with chemistry. Specifically, this major modification classifies Winstrol as what is known as a Heterocyclic steroid. Unfortunately, DHT itself is rendered inactive almost immediately by two enzymes upon its entrance into muscle tissue. All anabolic steroids that belong to the family of DHT-derivatives such as Winstrol, Anavar, Primobolan, Masteron and several others contain modifications to their chemical structures that grant them significant activity and effectiveness within muscle tissue, where DHT itself unmodified would never survive metabolism there. The Pyrazol structure also grants Winstrol a significant shift in its anabolic and androgenic strengths to favor more of a stronger anabolic strength while greatly reducing its androgenic strength. This is what grants Winstrol with an incredibly strong disassociation of anabolic to androgenic effects. Winstrol also possesses a methyl group attached to the 17th carbon known as C17 Alpha Alkylation, which is the chemical structural modification that allows the anabolic steroid to survive the first pass through the liver when ingested orally, and allows the anabolic steroid to become further resistant to hepatic metabolism. It is also believed that Winstrol also possesses some very small measurable form of anti-progestogenic properties in regards to the Progesterone receptor, although this is not fully understood. In addition to some small antagonistic effects on the Progesterone receptor, it has been found that Winstrol also possesses low affinity for Glucocorticoid-binding site interactions, as well as activity that is independent of Androgen receptors, Progesterone receptors, and Glucocorticoid receptors. Winstrol has not been found to have any notable Progestogenic activity in the body as well. Winstrol possesses a very high binding affinity for SHBG Sex Hormone Binding Globulin, therefore granting far more of Winstrol as well as other anabolic steroids that may be stacked alongside it, such as Testosterone to freedom in the bloodstream in doing its job of signaling muscle growth. SHBG is a protein that attaches and binds to other sex hormones Testosterone, Page 11

12 Estrogen, or any synthetic anabolic steroid and renders them useless as long as SHBG is bound to that hormone. Winstrol has also demonstrated to not only prevent SHBG from binding with other anabolic steroids, but it has also demonstrated strong suppression of SHBG production in the body. For example, one particular study conducted on 25 male test subjects where Winstrol was administered orally resulted in a Resulting from this is an avoidance of the Estrogen-related side effects of water retention and the associated risks of elevated blood pressure, as well as other Estrogen-related side effects. Being a DHT-derivative, it is also unable to interact with the 5-alpha reductase enzyme, which is the enzyme responsible for the conversion of Testosterone into Dihydrotestosterone. As Winstrol is already a modified form of DHT, this cannot possibly occur. Winstrol exhibits a longer half-life as a result of its structural modifications, enabling the injectable format of Winstrol to possess a half-life of approximately 24 hours, and 9 hours for the oral preparation of Winstrol. In relation to Testosterone, Winstrol holds an androgenic strength rating of 30 with an anabolic strength rating of, which is quite significant considering this means Winstrol is slightly over three times the anabolic strength of Testosterone. In order for any individual to understand the meaning of these numbers and ratings, it must be understood that the base reference measurement for these strength ratings is the number one anabolic steroid Testosterone. Testosterone is utilized as the measuring stick or the measuring bar whereby all other anabolic steroids are referenced with and compared to much like the celcius scale of temperature measurement where the freezing point and boiling points of water is used as the baseline measurement for temperature. An important fact that must be reminded to the reader is the fact that both the injectable and oral preparations of Winstrol possess the exact same chemical structure. This is unlike nearly all other anabolic steroids, where oral preparations are always Calpha alkylated, and injectable preparations are absent of this methylation and often injectable compounds are also esterified to modulate the release rate and half-life. This presents some concerns that the reader must be aware of: The result is a greater amount of hepatotoxicity liver toxicity, and because both the injectable and oral preparations both possess the hepatotoxic modification of Calpha alkylation, they both will place an almost equal level of hepatotoxic strain on the liver. However, the injectable preparation avoids the first-pass through the liver, which allows it to be slightly less hepatotoxic than the oral Winstrol preparation â but hepatotoxic nevertheless, and its duration of use must also have limitations placed on it. Winstrol Side Effects The primary areas of concern when it comes to Winstrol side effects are, simply put: This means that no Estrogenic side effects should be experienced as a result of Winstrol use alone. Therefore, side effects such as gynecomastia, water retention and bloating, or other side effects as a result of Estrogen buildup are completely nonexistent here. Advertisement Although Winstrol does possess a weaker androgenic strength rating than Testosterone does, androgenic side effects are still a potential risk, though much lower, and may only effect users significantly if they are especially sensitive to androgens. One area of prominent concern is that of HPTA suppression, which is a given with the use of any anabolic steroid. Hepatotoxicity liver toxicity is also one effect that one should be conscious of with Winstrol, especially with use of the oral variant[15]. The injectable preparation of Winstrol has also raised concerns in studies, where severe hepatotoxicity was eventually experienced by otherwise healthy individuals[16]. It is therefore recommended to utilize Winstrol, especially the oral variant, for periods of no longer than 6 â 8 weeks at a time. Cardiovascular health concerns are particularly major when it comes to Winstrol side effects. Winstrol Cycles and Uses Winstrol cycles are normally intended for the purpose of fat loss, cutting, and pre-contest preparation where the end goal is to achieve very low body fat levels and a high level of definition in the physique. There are those who claim it can also be utilized for bulking, mass, and strength gaining, but there are other anabolic steroids that are generally cheaper and better suited for these purposes than Winstrol. It is generally accepted that Winstrol cycles should be reserved for cutting and fat loss. As such, Winstrol cycles normally include a base compound of similar use, normally something such as Testosterone Propionate for an 8 â 10 week cycle. Intermediate and advanced Winstrol cycles can also involve three compounds in total, normally a stack such as Testosterone Propionate, Trenbolone Acetate, and Winstrol either the oral or injectable preparation will do. It is important to also note Page 12