Hormone production rates can be calculated from either estimating metabolic clearance rate (from bolus injection or steady-state isotope infusion using high specific-activity tracers) and mean circulating testosterone levels (46, 47) or by estimation of testicular arteriovenous differences and testicular blood flow rate (48). These weak androgens, predominantly originating from the adrenal cortex, constitute a large circulating reservoir of precursors for conversion to bioactive sex steroids in extragonadal tissues including the liver, kidney, muscle, and adipose tissue. An androgen, or male sex hormone, is defined as a substance capable of developing and maintaining masculine characteristics in reproductive tissues (notably the genital tract, secondary sexual characteristics, and fertility) and contributing to the anabolic status of somatic tissues. While the benefits of incorporating proandrogenic herbs are wide-ranging—from improved endocrine function and fertility to broader systemic resilience—they must be used mindfully, in alignment with individual needs, timing, and constitution. Currently, the effect of medical treatment for AGA is not idealistic, stem cell-based regenerative medicine has shown potential for hair regrowth and follicle repair, but the long-term effect and mechanism of stem cell therapy is not quite explicit. Moreover, testosterone enhances endothelial function by promoting nitric oxide production, supporting the growth and repair of endothelial cells, and reducing inflammation. The research encompasses testosterone's effects on sexual function, bone health, muscle strength, depression, and vascular endothelium (Figure 1) and presents a detailed overview of the selection criteria. Research indicates that testosterone therapy may improve vaginal lubrication and overall sexual satisfaction in women with low testosterone levels . In males and females, testosterone can be aromatized to estrogen by the enzyme aromatase, influencing various physiological functions, including bone health and reproductive functions . When combined with other drugs, microneedles can further stimulate hair growth 61, 62. Alternatively, microneedle therapy is a minimally invasive procedure that employs multiple fine needles to create microneedles on the skin and stimulate new blood vessels, Wnt protein expression, and growth factors . Apart from the FDA-approved drugs, there are several treatments to combat hair loss. However, long-term use of finasteride can negatively impact sexual functions, such as decreased libido, decreased ejaculation, increased infertility, and erectile dysfunction . Finasteride affects hair growth by acting on DPCs by improving the aggregation behavior of stem cells and enhancing the expression of stem cell transcription factors Nanog and Sox-2 . Think of ARs as the lock on your front door and testosterone as the key. Various confounding factors as would be evaluated in standard clinical trials are not taken into consideration. Although the studies rate good on the NOS, the domains used are not univocal and there are some inherent limitations in using NOS for meta-analysis. The AAS use was unregulated and unsupervised AAS use and subjects in some studies resorted to polypharmacy. The full texts of the remaining 116 studies were screened, and 84 studies were further excluded. After removing 160 duplicates, 883 studies were screened against title and abstract. The quality assessment of studies as per the NOS scale was done separately for case–control and cohort studies under the subheadings of selection, comparability and exposure as outlined in the NOS coding manual. Two authors (PMM and GRT) analysed the studies for quality assessment consensually. As previously noted, this anti-androgen mechanism may help to reduce the risk of BPH, acne, and baldness. The endocrine effect is thought to be due to phytoestrogens and other chemicals found in licorice root, including the steroid glycyrrhizin and glycyrrhetic acid, which also have a weak anti-androgen effect (5, 6). Licorice affects the endocrine system because it contains isoflavones (phytoestrogens), which are chemicals found in plants that may mimic the effects of estrogen and relieve menopausal symptoms and menstrual disorders. High levels of DHT are a risk factor for conditions such as benign prostatatic hypertrophy (BPH), acne, and baldness. Red reishi, commonly known as LingZhi in Chinese, is a mushroom thought to have many health benefits. Thus, despite the marked adrenal decrease in women in A4 production with advanced age , the decrease in T at menopause may have a more effective result when lowering the androgen availability of postmenopausal women. This may explain the quantitative importance of A4, but also, probably—and mistakenly—includes the dubious “androgenic” contribution of the fairly maintained levels of DHEA to the “androgenization” often described for old women. The ovary does not cease its production of T in women for at least one decade after menopause , but the overall production of A4 by the adrenals decreases markedly, which converts T in the main androgen produced overall (as compared to A4) . What Are Androgen Receptors? Testosterone is responsible for bone growth, muscle production, sex drive, sperm production. Unlike the testis, which is an efficient androgen producer, the adrenal gland plays only a secondary role in active androgen in men. The adrenal glands synthesize an assortment of C19 steroids, of which DHEA and DHEAS have been have been the major focus and biomarkers of adrenal androgen excess. While there remains some controversy as to the relative impact of the adrenal versus ovary to PCOS androgen profiles, most authorities agree that, like the symptoms seen in PCOS, the source(s) of androgen excess is/are also variable. However, there is considerable support that the adrenal can contribute to the hyperandrogenism seen in PCOS. Beginning around theage of 35–40 years, circulating testosterone concentration levels decrease byapproximately 1%–3% per year (19).Approximately 20% of men older than 60 years and 50% of men older than 80 years have serumtestosterone concentrations below the normal range for young men (13). This may result from reduced testicular responses togonadotrophin stimuli with aging, coupled with incomplete hypothalamo-pituitarycompensation for the fall in total and free testosterone levels (17,18). Gonadotropin-releasing hormone (GnRH), produced and released by the hypothalamus,stimulates the production and pulsatile release of luteinizing hormone andfollicle-stimulating hormone in the anterior pituitary. A contradiction of aging exists upon comparison of muscle loss between older men and women.This contradiction may, in part, be explained by hormones prior to and following andropause inmen and menopause in women. Although these adverse effects may be transitory in some individuals, it is unclear who is more vulnerable to permanent harmful effects, nor is it known if the existing therapy can fully resolve these conditions in the long run. Moreover, viability and adequacy studies on public health policies and educational programs are warranted to reduce AAS’s mis-prescription and abusive use. Efforts should also be made to test harm reduction strategies to prevent AAS-induced damage, as well as new pharmacological treatments for the recovery of fertility and sexual dysfunction. Some studies suggest that adolescents should be the focus of educational policies and harm reduction interventions, given that there is a high prevalence of addiction in this age group, and the use of AAS tends to increase throughout life (Sagoe et al., 2014; Kanayama and Pope, 2018). The pharmacologically increased T will probably inhibit the secretion of GnRH and gonadotropins, at least on a system in which the low T levels should (and could) activate the eventual higher production of GnRH—and then LH—to enhance the natural synthesis of T. Theoretically, giving T as a drug helps sustain its circulating levels, but its maintenance along time may make redundant the natural HHG regulation of its synthesis, affecting, this way, the critical function of producing spermatozoa for reproduction . Figure 5 presents a general view of the main system controlling the circulating levels of T (and in general, of the principal androgens). This strong controlling relationship between glucocorticoids and androgens/estrogens is critically centered in the adrenal cortex (as explained in Section 5.2), thus, the shared (but opposite) adrenal control of corticosteroids and androgens also has a brain connection, or an additional control node, in the hypothalamus. The circulating levels of T, E2, KT and DHT modulate the pulse secretion of GnRH (gonadotropin-releasing hormone) from the hypothalamus 345,346,347 directly into the hypophysis portal vein system , despite GnRH regulatory effects extending to other organs of the HHG (hypothalamus–hypophysis–gonads) axis . A series evaluating anastrozole for treatment of secondary hypogonadism in 69 older men followed for 1 year confirmed a generally low rate of adverse events although one instance each of new diagnosis hepatitis, pulmonary embolism, and embolic stroke was reported.91 A similar observation of pulmonary embolism incidence was confirmed in a more recent series after only 12 weeks of treatment.90 In addition, some data have suggested potentially worse skeletal bone health with anastrozole use in older men, presumably based upon lower estrogen levels.92 Taken collectively, AIs may result in a positive influence on the HPG axis after TRT or AAS use, but in the absence of more robust clinical data and an uncertain side effect profile with long-term use, AI use may be limited to an adjunctive role only in those who have abnormally low T/E ratios. Their use clinically in men is off-label and has focused upon improving male infertility and symptoms of hypogonadism, particularly in obese men or in those with a serum testosterone-to-estrogen (T/E) ratios 64 In addition, AIs can be prescribed for use with exogenous testosterone or hCG to mitigate side effects of hyperestrogenemia such as gynecomastia. In men, normal binding of estrogen at these receptors functions as an indirect negative feedback mechanism of endogenous testosterone production to downregulate GnRH and subsequently pituitary gonadotropin production. Producers exert their influence at the level of the hypothalamus, prompting it to release gonadotropin-releasing hormone (GnRH). While negative feedback governs most hormones, there are key exceptions that operate under positive feedback. It consists of an interconnected network of tissues, glands, and organs that work together to regulate virtually every function in the body. Testosterone has clear dose-dependent effects, extending from below to well above the physiological concentrations without evidence of a plateau, on muscle size and strength (but not performance function or fatigue) in young (348) and older (349) men with similar magnitude of ultimate effect (350). For hereditary angioedema, newer mechanism-based, more specific and costly therapies such as purified or recombinant C1 inhibitor and bradykinin or kallekrein antagonists may overtake the traditional role of 17α-alkylated androgens such as danazol for long-term prophylaxis of hereditary angioedema (311, 312, 345) or endometriosis. Similarly, in anemia due to marrow failure androgens reduce transfusion dependence but do not improve survival from the underlying marrow disorders. In this case, the main differencing factor may be found in the irreversible phenolic nature of the estrogen A-ring, necessarily affecting the shape of the receptor’s binding site. Despite all being nuclear receptors, the structural genetic and regulative differences are not the same, and are largely marked by their physiological agonists. This common structure of receptors is not shared by the ER, or estrogen-related receptors (3-B) group comprising only the ERα, β and γ types . The other form of pre-receptor androgen activation is conversion of testosterone to estradiol by the enzyme aromatase (220) which diversifies androgen action by facilitating effects mediated via ERs (221). Such negative feedback involves both testosterone effects via androgen receptors as well as aromatization to estradiol within the hypothalamus (217, 218). All components of the hypothalamo-pituitary testicular (HPT) axis are established during fetal life and its first activation is during the neonatal period manifested as a transient surge lasting several months in circulating testosterone (“mini-puberty”) reaching adult male levels and creating androgen imprinting in non-reproductive tissues. The metabolic clearance rate of testosterone is reduced by increases in circulating SHBG levels (57) or decreases in hepatic blood flow (e.g. posture) (49) or liver function. The pharmacokinetics and pharmacodynamics of androgen esters is therefore primarily determined by ester side-chain length, volume of oil vehicle, and site of injection via hydrophobic physicochemical partitioning of the androgen ester between the hydrophobic oil vehicle and the aqueous extracellular fluid (654). This depot product relies on retarded release of the testosterone ester from the oil vehicle injection depot because esters undergo rapid hydrolysis by ubiquitous esterases to liberate free testosterone into the circulation. The most widely used testosterone formulation for many decades has been intramuscular injection of testosterone esters (figure 5), formed by 17β-esterification of testosterone with fatty acids of various aliphatic and/or aromatic chain lengths, injected in a vegetable oil vehicle (653). Education and Support Therefore, it is important that clinicians recognize previous TRT or AAS use in patients presenting for infertility treatment. Concurrently, awareness of a more pervasive use of anabolic-androgenic steroids (AAS) within the general population has been appreciated. The use of testosterone replacement therapy (TRT) for hypogonadism continues to rise, particularly in younger men who may wish to remain fertile. Your provider compares total testosterone to SHBG to find the amount of androgen in your blood. Issues with androgen levels can lead to delayed or early (precocious) puberty in children. In this study, the authors confirmed increases in testosterone but failed to reach any of their other clinical endpoints.But the reality is that for many people, limiting exposure to, and the harmful effects of, endocrine system disruptors is possible.Patients that have complicated medical conditions managed by multiple medications may also benefit from nutraceuticals, rather than adding more medical therapies with potential drug‐drug interactions or lowering the threshold for development of side effects.Although these adverse effects may be transitory in some individuals, it is unclear who is more vulnerable to permanent harmful effects, nor is it known if the existing therapy can fully resolve these conditions in the long run.Ideally, they stimulate the AR to increase muscle mass and body protein (consequently, facilitating leanness) 145,147, with limited effects on many of the other functions of T (largely sex-related) .Dermal patches are available and this is the method of choice for the treatment of hypogonadism 1,7.Seven studies15,22,26,27,28,29,30 comprising 327 participants compared the FSH in AAS users and naïve population.The presence of these hormones was confirmed in a 1971 study published in Experientia (Krehula and Kolbah), which identified multiple androgenic steroids in Pine Pollen.Clomiphene citrate is a SERM that has been used in the treatment of men with azoospermia, oligozoospermia, and unexplained infertility, in addition to treating male hypogonadism. Working in concert with the body, Producers foster endogenous hormone production, underscoring their importance in a holistic model of supporting health, wellness, and vitality. This understanding offers insight into their potential applications and how they can be used—independently or synergistically—to support healthy hormone levels. The HPG Axis also regulates sex hormones in females, specifically estrogen and progesterone production. In males, the regulation and production of testosterone is primarily orchestrated through the Hypothalamus–Pituitary–Gonadal (HPG) Axis, governed by negative feedback. Although androgenetic alopecia (AGA) does not significantly effect physical health, it can have serious negative impact on the mental health and quality of life of the patient. Androgenetic alopecia is the most common cause of hair loss aggravated by increased life pressure, tension, and anxiety. Continued exploration of testosterone's role may lead to improved therapeutic strategies that enhance the quality of life and health outcomes across diverse populations. Also, it is important to know that reduced testosterone levels are correlated with a higher incidence of atherosclerosis, coronary artery disease, and cardiovascular events, as well as decreased heart rate 35,36. Mechanisms of Action of Androgens However the first major clinical trial of leuprolide, a GnRH analog, failed to demonstrate neuromuscular benefit in swallowing (247) and further studies of selected subgroups and therapeutic targets are warranted (248, 249). Although the extreme length of the polyglutamine repeat does determine mild androgen resistance, these men usually have normal reproductive function including fertility and virilization prior to diagnosis in mid-life (242). Among healthy people, where the glutamine repeat polymorphism has alleles of lengths between 5 and 35 (population mean ~21), the length of the glutamine repeat is inversely proportional to AR transcriptional efficiency so that this polymorphism dictates genetic differences between individuals in the androgen sensitivity of their target tissues (233). However, a link between withaferin A intake and increased T levels has not been observed.In a study by Zhou et al., injection of dermal papilla cell‐derived exosomes in mice was shown to accelerate the onset of hair follicle anagen phase and delay catagen phase, while simultaneously stimulating the expression of beta‐catenin and sonic hedgehog growth factors.116 Chang‐Hun Huh et al. demonstrated increased mean hair density and thickness among 20 patients after 12 weeks of exosome treatment.If biochemical abnormalities are detected, treatment with 17α-alkylated androgens should cease and safer androgens may be substituted without concern.Aromatase inhibitors are a class of drugs that act by blocking aromatase P450 enzymes, consequently normalizing the testosterone/E2 ratio and improving spermatogenesis (56).It’s typically reserved for men who require testosterone therapy but wish to maintain fertility or natural testicular function.Kovac et al. reported that very few users (15.2%) regret the AAS use despite side effects such as hypogonadism due to lack of awareness. TD increases with age, with approximately a 1% annual decrease in free testosterone levels after age 30 (6, 7). Testosterone replacement therapy is an important treatment option for men with low testosterone and symptomatic hypogonadism. Overview of key insights gained into androgen receptor (AR) biology in males from Global AR Knockout (ARKO) male mice. Other treatment approaches involving inhibition of histone acetylation or acceleration of AR degradation remain experimental.81 Should the preclinical studies identifying muscle as a site of direct mutant AR toxicity82 be confirmed in humans, this may allow targeting the periphery rather than the central nervous system (CNS) for treatment. Conversely, testosterone treatment to alleviate androgen deficiency symptoms in men with Kennedy’s disease carries the risk of accelerating the progression of muscle weakness via enhanced mutant AR aggregation. However, the different effects on body composition and metabolic environment caused by prolonged treatment of humans with different AcT at pharmacological levels (see Section 7.3) suggest that this is, yet, a dark zone of our knowledge, affecting, precisely, the androgens most widely used in clinical practice. Similarly, fluid overload from sodium and fluid retention due to cardiac or renal failure or severe hypertension is rare and probably confined to high dose pharmacological androgen therapy (799) whereas controlled clinical trials suggest androgens may improve cardiac function and quality of life (394), rather than having detrimental effects, in men with chronic heart failure. The main biochemical measures available for monitoring of androgenic effects include hemoglobin and trough reproductive hormone (testosterone, LH, FSH) levels. Virtually all androgenic side effects are rapidly reversible on cessation of treatment apart from inappropriate virilization in children or women in which voice deepening, terminal body hair, or stunting of final height may be irreversible. However, supraphysiological doses of synthetic androgens in pharmacological androgen therapy or the massive doses of androgen abusers as well as unphysiological use of androgens in chidren or women may produce unwanted androgenic side effects. The main differences in clinical effects between both types of treatment, however, were those derived from cardiovascular protection/damage. The apparently marked beneficial effects of transdermal T on insulin resistance and the increase in insulin sensitivity, which were necessarily observed under relative short-term treatment (gel), can be directly related to the implication of E2 in the control of glucose metabolism (and lipid oxidation). Thus, I decided to just list the articles directly available, and pair the papers with the effects most commonly described of androgens in the series studied. The assumption of pharmacological equivalence is essentially based on the control observations of increased T levels after months or years of substitutive treatment using T or exogenous AcT. Any comparison with the effects on endogenous androgens T, KT and DHT (but also including E2) is again absent. The degree of urogenital sinus derivative development together with testis descent provide clinical clues to the degree of androgen sensitivity. The severity of androgen insensitivity can be categorized most simply as complete, partial and mild although a more detailed 7 stage Quigley classification based on degree of hypospadias, phallic development, labioscrotal fusion and public/axillary hair is also described (1, 232). Androgen receptor transcriptional activation is governed by a large number of coregulators (251, 252) whose tissue distribution and modulation of androgen action remain incompletely understood. Specific binding of the dimerized, ligand-bound androgen receptor complex to tandem androgen-response elements initiates gene transcription so that the androgen receptor acts as a ligand-activated transcription factor. Ligand binding leads to shedding of heat shock proteins 70 and 90 that act as a molecular chaperone for the unliganded androgen receptor (250). In combination with harm reduction strategies, some pharmacological approaches could potentially restore male fertility and sexual function in AAS users. Noteworthy, the erectile dysfunction post-AAS cycle could be boosted by the sharp increase in libido during the cycle. These data reinforce the negative (although partially transitory) effects of AAS abuse on male fertility. 3.3. Patient cost We will include randomised controlled trials (RCTs), quasi‐RCTs and cohort studies, with no restrictions based on language of publication, date of publication, or publication status. Thus it is unclear why those estradiol doses should be kept low in order to make the addition of androgen antagonists like CPA or spironolactone necessary. The adverse events of high estradiol doses described in studies from the 1980s and 1990s should be re‐evaluated because those studies used ethinyl estradiol and premarin (equine estradiol) (Prior 1989), instead of bioidentical 17‐beta‐estradiol, and progestins instead of bioidentical progesterone. However, clinical evidence suggests that this can result in adverse events; for example, CPA has significant potential for causing depression and for worsening depressive symptoms (Seal 2012). This dual approach—increasing free testosterone and reducing estrogenic conversion—ensures that more testosterone remains both available and active within the system. Maximizers operate through a nuanced interplay with the body’s endocrine regulation systems, specifically targeting the mechanisms that govern the bioavailability and activity of testosterone. Together, these actions preserve testosterone, reduce estradiol accumulation, and restore a more favorable hormonal environment. While estrogen plays essential roles in both sexes, its excess—especially alongside diminished testosterone—can lead to a range of metabolic, mood-related, and reproductive concerns. One of the major obstacles to doing so is aromatization—the enzymatic conversion of testosterone into estradiol, a potent form of estrogen. If you’re exploring options to support your long-term health, Ehormones MD offers professional guidance and care tailored to your individual needs. While these changes are expected, there are clinically guided options available that can help support your health and well-being over time. Trever is just 1 of over 3,000 satisfied Ehormones MD patients nationwide. A medical consultation can help determine the most appropriate treatment options based on individual symptoms and health goals. Description of the effect - AAS use negatively impacted the gonadotrophin levels and had lower sperm motility and testicular size. Most AAS users need additional medications to mitigate detrimental effects on fertility. The erectile function improved with AAS use, but on withdrawal, there was decreased libido and erectile dysfunction. These levels remained low for 3–6 months after stopping AAS. EDCs are defined by their ability to mimic, block, or alter the normal function of hormones, often by binding to hormone receptors, modifying hormone synthesis, or interfering with hormone metabolism. Emerging research suggests that intentional cold exposure—such as cold showers, ice baths, or cryotherapy—may positively influence androgen receptor sensitivity. RAW Pine Pollen™ provides additional phytoandrogenic, nutritional, and micronutrient support through essential vitamins, minerals, and amino acids that may promote androgen receptor sensitivity—complementing adaptogens like Tongkat Ali and Ashwagandha. Cortisol binds to the androgen receptor, blocking testosterone’s ability to “unlock” and enter the cell. The adipose tissue, bone marrow, hair follicles, and umbilical cord are the sources of regenerative pluripotent stem cells. Therefore, stem cells have been widely used in the treatment of various diseases such as diabetes, myocardial infarction, Alzheimer's disease, and Parkinson's disease . Stem cells are a class of self-replicating, multipotential undifferentiated cells, a relatively primitive class of cells that can differentiate into cells with multiple functions under certain conditions . Table 2. Risk of bias assessment of included studies. Ideally, they stimulate the AR to increase muscle mass and body protein (consequently, facilitating leanness) 145,147, with limited effects on many of the other functions of T (largely sex-related) . 4 The synthesis of 11-keto-androgens from 11OH precursors requires oxidation, whereas the formation of active 11OH-corticosteroids requires reduction (Section 5.2); thus, the synthesis of active functional GC is probably not compatible with that of (also active) 11-keto-androgens. Other acronyms; AR (androgen receptor); ER (estrogen receptor); SHBG (sex-hormone binding globulin); GC (glucocorticoid). The EA (estrogenic androgens), Ane (5-androsterone) and other androgen metabolites—not described in Section 3—have not been included in the table because of their unclear functions and few (and/or) chemically variable molecule representatives. Obviously, most androgens bind to the AR, but it is unclear whether the AcT can bind the AR on the main specific agonist site; DHEA also binds the ER , and the AP binds neither of these receptors . They are used in the treatment of anemia, severe burns, wasting syndrome in patients suffering from AIDS , osteoporosis , or breast cancer 39,43. It was developed for the treatment of wasting diseases, especially for patients losing bone strength and mass . Metenolone has weak androgenic and oestrogenic activity and low hepatotoxicity and has been discontinued for medicinal use in many countries. It is used in the treatment of hypogonadism, delayed puberty , female breast cancer , and anemia . Other side-effects include mental disorders, increased aggressiveness, and hepatotoxicity. Studies have shown successful treatment with this new method and have exhibited consistent improvements in testosterone deficiency (29). Due to the need for a surgical procedure for implantation and the sequela of side effects, this form of TRT is usually not recommended as first-line treatment (28). It is recommended that three to six 75mg pellets should be implanted every 4-6 months (150 mg-450 mg) to achieve stable testosterone levels in the normal range (14). Subdermal pellet implants (Testopel®) are a viable option for testosterone replacement and result in stable testosterone levels. Other proposed theories include a mechanism of action similar to that of minoxidil with blood flow promotion in the scalp via NO production and reduced follicular inflammation.99, 100 Other common side effects of flutamide include hot flashes and potentially increasing the effect of warfarin.91 Rare side effects include pericardial effusion, congestive heart failure, and allergic reactions.22 The drug is available as a 2.5 mg tablet, and it can be cut in halves or quarters to achieve optimal safe dosing for the treatment of AGA. If used properly, patients can expect to see hair growth within 4–8 months which stabilizes after 12–18 months.36 If a patient terminates treatment, progressive hair loss can be expected within 12–24 weeks.37 For patients that have early or mild‐to‐moderate hair loss, and want to avoid oral medications due to the potential systemic side effects, topical therapies may serve as a viable first‐line option or adjuvant for the treatment of AGA. Multiple studies have shown that men who experience premature loss of hair often exhibit emotional distress and express significant concern to their peers and family.16, 17 Studies have also shown that the psychological impact in women is more devastating than in male counterparts.18 Androgenetic alopecia, also known as male or female pattern baldness, is the most common type of hair loss and affects at least 80% of men and half of women by age 70, with the incidence increasing with age.1, 2, 3 Although commonly encountered by practicing dermatologists and hair specialists, it can be one of the most challenging conditions to address as treatment selection often involves a complex consideration of multiple factors and ethical decision‐making. Although chronic androgen deficiency protects against prostate disease (130, 782, 783), prostate size of androgen-deficient men receiving androgen replacement therapy is restored to, but does not exceed, age-appropriate norms (784, 785). Serial evaluation of bone density (especially vertebral trabecular bone) by dual photon absorptiometry at 1- to 2-year intervals may be helpful as a time-integrated measure to verify the adequacy of tissue androgen effects (420, 572). Blood testosterone measurements are valuable before treatment for diagnosis and after start of treatment to check adequacy of dosage if in doubt and, during long-term treatment, only to evaluate changes in treatment dosage or product. Allergy to the vegetable oil vehicle (sesame, castor, arachis) used in testosterone ester injections is very rare, and even patients allergic to peanuts may tolerate arachis (peanut) oil. Endogenous testosterone is reportedly a risk factor for thromboembolism in a two sample Mendelian randomization study (756) but not confirmed in a 10-year follow-up of 1350 Norwegian men in a population-based study (757). In common with mutations in many other genes, making a clear distinction between the most minor grades of clinical pathology and a silent, functionally insignificant polymorphism is challenging and depends on reproducing experimentally the functional consequences of the mutation in an authentic biological system. The blood LH and testosterone concentrations are usually but not always elevated although the androgen sensitivity index, the product of serum LH and testosterone concentrations, is more consistently raised. If pubertal progression is inadequate, exogenous testosterone may be useful but higher than usual dosage may be required to get satisfactory effects. Many of the AAS users reported in various studies included in the current review practiced polypharmacy. Coward et al. reported a cohort of 382 men with profound hypogonadism (testosterone 50 ng/dl or less). In addition, increased libido, improved sexual performance, virility and alleviated ageing process were the most cited reasons for starting or restarting AAS. In a prospective study done by Katz et al., ADAM scores improved in all but one question (i.e., change in height) (18).In addition to supporting the cardiovascular system and somewhat reducing the risk of cancer and type 2 diabetes (8), green tea may also have an important anti-androgen effect because it contains epigallocatechins, which inhibit the 5-alpha-reductase conversion of normal testosterone into DHT.The main metabolic function of E2 is probably its role in the control of energy balance and substrate energy partition, in part by controlling insulin action in the regulation of glucose metabolism 3,9,726.It also delves into alternative and investigational therapies for TD that aim to mitigate the undesired effects of male infertility and hypothalamic-pituitary-gonadal axis disruption by increasing endogenous testosterone (Table 1).This conversion is catalyzed predominantely by type 2 5α-reductase (SRD5A2) and occurs in the target androgen tissues, including the prostate (72).This is sometimes complemented by the addition of an AR antagonist to achieve so-called complete androgen blockade, although the incremental benefit of this combined approach using first-generation AR antagonists is marginal.67 ADT is not curative, and after a median of 1–2 years of ADT, clinical progression occurs.68 While this has traditionally been thought to represent androgen-independent prostate cancer, this is now known to be generally incorrect.Treatment of embryonic zebra fish with aromatase inhibitor 4-hydroxyandrostenedione,binding to the aromatase enzyme and thereby inhibiting the conversion of testosterone orandrostenedione to estradiol, denervates the zebra fish trunk muscles (84). These findings do not materially change the unfavorable balance of evidence for testosterone treatment for functional causes of a low serum testosterone in the absence of pathological hypogonadism. The improvement in sexual function, about 1/3 increase over baseline sexual activity, waned during the year’s treatment and there was no concomitant improvement in either vitality or physical activity compared with placebo. However, as observational studies cannot ascribe causality it remains likely that such reductions in blood testosterone may be a consequence rather than a cause of the increased mortality. A relatively short androgenic drug treatment may allow for the ulterior recovery of testicular function , but excessively long-term treatments may induce more severe and enduring damage to the HHG axis regulation, affecting fertility and even inducing sterility 390,391. These hormones play a key role in the regulation of the ovarian cycle in females, but also control, respectively, the testicular synthesis of androgens in Leydig cells and spermatogenesis by the Sertoli cells , the latter with the necessary intervention of T and E2 . At least in women, their main site of production are the adrenal glands 66,229,230, via 11β-hydroxylase 45,231, which also promote the specific synthesis of GC (by oxidizing C11) that characterizes this group of hormones. Additionally, high androgen levels can come from stress which will cause more DHEA to be produced which can combine with testosterone to make DHT which causes hair loss, oily skin, and acne. Furthermore, the review highlights Investigational therapies to increase endogenous testosterone such as Selective androgen receptor modulators and Leydig stem cell transplantation, respectively. Arora et al. (2019) was the first study of its kind to show successful ALC differentiation, increased testosterone production, and preservation of the HPG axis with subcutaneous autograft of LSCs in hypogonadal mice (75). Whether this approach will lead to increased longevity remains unanswered, however,mounting evidence suggests that significant gains in health through enhanced functionalperformance is an approach worth further investigation. Testosterone therapies, and to a lesser extent estradiol and GHreplacement, have increased substantially over the past several years and are widely used asfunction promoting therapies in older men and women (36) by increasing protein anabolism and reducing protein catabolism in skeletalmuscle. Because part of the decreases inmuscle size, loss of bone, and increases in fat might be related to changes in theendocrine system, additional androgens or estrogens in combination with exercise maycombat the extra decline in muscle strength that occurs with andropause andmenopause. Continuous use of finasteride for up to six months is required to reduce an enlarged prostate, but the effects can last for up to twelve months after the drug is discontinued. Finasteride and dutasteride (67 and 68, Figure 12) are both 4-aza-derived 5α-reductase inhibitors that find use in the treatment of prostate cancer, and enlarged prostate (benign prostatic hyperplasia). Cardiovascular problems, hepatotoxicity, and the development of some brain tumours were reported as rare adverse effects. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. As research continues to advance, we can look forward to even more innovative and effective treatments in the future. By taking these steps and exploring the alternatives outlined in this guide, you’re not just preventing testicular atrophy—you’re investing in your long-term health, vitality, and well-being. What works best will depend on individual factors such as age, overall health, specific medical conditions, and personal goals. Women with NCCAH present with menstrual irregularities and hyperandrogenism, often leading to a misdiagnosis of PCOS. When there are no abnormalities found on investigation, i.e. elevated testosterone or DHEA-S and normal ovaries on ultrasound in a woman under the age of 40 years and not on hormonal contraception, and there are no menstrual abnormalities, the diagnosis of idiopathic hirsutism is made.69 Treatment is directed toward controlling hirsutism with shared decision making to ensure the woman’s perceived areas of concern are adequately addressed. We discuss the 3 most common diagnoses in premenopausal and postmenopausal women. This unique phytochemical profile allows Pine Pollen to act directly on androgen receptors, offering an immediate, non-synthetic method of supporting testosterone levels. Because of this similarity, they can bind to androgen receptors and mimic the actions of endogenous hormones like testosterone. Elevated SHBG levels—common with aging, chronic inflammation, or metabolic dysfunction—further reduce the pool of free testosterone, limiting its physiological effects. Their role is particularly relevant when testosterone is present but underutilized, or when estrogen levels interfere with androgenic expression. Certain supplements may interact with medications, potentially altering their effectiveness or causing unwanted effects. If you are taking any medications, consult with your healthcare provider before using supplements. Testosterone, epitestosterone and androstenedione in the pollen of scotch pine (P. silvestris L.). Sex hormones and corticosteroids in pollen of Pinus nigra. Mild side effects include scalp pain, headache, and burning sensation, but these effects usually subside in 10–15 min post‐injection and do not warrant use of topical anesthesia or pain medications.109 Vibration or cool air is typically sufficient to alleviate any significant pain that a patient may feel from the treatment. PRP is generally indicated for patients with early‐stage AGA, as intact hair follicles are present and a more significant hair restorative effect can be achieved. Low‐level laser therapy (LLLT) was discovered serendipitously in the 1960s when mice irradiated with a low fluence red laser were found to grow hair. Maintenance of spermatogenesis before beginning or during TRT or AAS use For hair loss, early prevention, diagnosis, and treatment are internationally recognized. A study that recruited 1,000 healthy men between the ages of 20 and 35 and developed a customised questionnaire to determine basic physical and smoking habits found that the prevalence of AGA was higher among smokers than non-smokers, and that the severity of AGA was not related to smoking intensity. Some in vitro human studies have shown increased markers of oxidative stress and increased sensitivity to oxidative stress in dermal papilla cells of balding scalp compared to non-balding scalp . Further studies have demonstrated the important impact of Treg cells on the maintenance of HFSC and that immune cells are essential for hair regeneration . No use, distribution or reproduction is permitted which does not comply with these terms. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. It also causes an increase in oestradiol levels (Rose 1977), so that further virilisation is prevented and feminisation occurs (WPATH 2011). Several hormonal substances and combinations are used clinically for HRT in transitioning women. We know of no studies identifying the ratio of patients who undergo HRT, nor do we know of studies investigating how much time passes between the start of transition (respectively the decision to transition) and the start of HRT. Meanwhile, antiandrogens such as spironolactone or cyproterone acetate are commonly taken orally. By addressing the root cause, not simply just the symptom (or the hormone imbalance for that matter), we can find long-term, sustained healing. Testosterone is produced from the ovaries and DHEA from the adrenal glands. It is commonly believed that erectile dysfunction can be genetic, permanent or require heavy medication to fix. Vitamins are crucial nutrients for many cellular processes, including repair of tissue damage and the growth of new cells. Aphrodisiacs do not only act as a sexual enhancer, but increase energy and strength. If requested by clinicians, compounding pharmacies may formulate dutasteride topical solutions, although literature is sparse regarding its utility in treating androgenetic alopecia. The International Post‐Finasteride Syndrome Foundation was established to provide public education and support for those patients living with PFS.59 This drug can be purchased over the counter which has made it much more cost‐effective for patients. Some patients report an unpleasant residue after applying the foam, in which case a solution formulation may be preferred. Minoxidil is available in both 2% and 5% solutions and in foam preparation, so clinicians and patients have flexibility to select their preferred strength and formulation. The LH receptor has the structure of a G-protein linked receptor with its characteristic seven transmembrane spanning helical regions and a large extracellular domain which binds the LH molecule. Cholesterol originates predominantly by the de novo synthesis pathway from acetyl‑CoA with luteinizing hormone regulating the rate‑limiting step, the conversion of cholesterol to pregnenolone within mitochondria, while remaining enzymatic steps occur in smooth endoplasmic reticulum. Both activities reside in a single, multifunctional protein with the directionality of pathway flux determined by enzyme co-factors, notably electron supply from NADPH via the P450 oxidoreductase (POR), a membrane-bound flavoprotein serving diverse roles as a reductase, and cytochrome b5 (10, 11). The highly tissue-selective regulation of the 17,20 lyase activity (active in gonads but inactive in adrenals) independently of 17-hydroxylase activity (active in all steroidogenic tissues) is a key branch-point in steroidogenic pathways. In general, in a healthy population, the normal level of testosterone hormone in men is an average of 264 to 916 ng/dL .As measurement of “free” or “bioavailable” testosterone is laborious, calculational formulae with limited validation (93, 110, 114) have been widely used; however, these estimates for “free” ( ) or “bioavailable”(118, 119) testosterone are not accurate in large scale evaluation.We will use the reference management tool Covidence to identify and remove potential duplicate records of relevant studies ().Licorice affects the endocrine system because it contains isoflavones (phytoestrogens), which are chemicals found in plants that may mimic the effects of estrogen and relieve menopausal symptoms and menstrual disorders.Some research has demonstrated decreases in sperm count and spermatogenesis in both rats and humans while others have shown no alteration in sperm with daily finasteride at 1 mg daily.60, 61, 62 Studies that demonstrated decreased concentrations of sperm with finasteride use typically showed reversal or improvement 3–4 months after treatment termination.62, 63 A multicenter, randomized, double‐blinded study demonstrated a mean reduction in sperm count and motility after 6 months of treatment.Gynecomastia is a feature of androgen deficiency but may appear during androgen replacement therapy, especially during use of aromatizable androgens such as testosterone that increase circulating estradiol levels at times when androgenic effects are inadequate (e.g., a too low or infrequent dose or unreliable compliance with treatment).This combined approach aims to provide the benefits of testosterone supplementation while preserving natural testicular function.When advising patients on appropriate treatment options, it is important to discuss monthly and 5‐year treatment expenses to estimate a real world and lifelong cost. Where the HRT is not expected to be successful, which can be the case for facial bone structure, breast development and genitalia, surgical methods and techniques for permanent hair removal and hair transplantation may be used for further approximation of the body to a female body type (WPATH 2011). Hormone replacement therapy (HRT) aims to suppress the development of male attributes or reverse male attributes that have already developed. This proposed systematic review and meta‐analysis focuses on ‘transgender women in transition from male to female’, a definition meant to include anyone starting with a sex that is commonly perceived as male with the goal to adapt their gender expression to something commonly and/or individually perceived as female. Currently there is uncertainty about the value of hormone therapy as a sole intervention or when combined with surgery. However, studies and surveys suggest a prevalence of male‐to‐female (MTF) transsexuality of around 0.001% (Pauly 1968), to 0.6% (Joseph 2017), depending on time and location. MSC exosomes have also shown promise in hair restoration as they contain potent cytokines and growth factors that promote hair growth.113, 114 Initial studies have demonstrated that MSC exosomes induce proliferation and migration of human dermal papilla cells and secretion of VEGF and IGF‐1 in vitro.115 Moreover, mice intradermally injected with MSC exosomes underwent telogen to anagen conversion, suggesting hair growth stimulation in vivo. Light therapy is ideal for patients who prefer non‐invasive options, or for those who lack a flexible schedule to come into the office for regular treatments. It has shown efficacy in treating AGA and acne vulgaris in female patients.96 Although cyproterone acetate and topical minoxidil are both safe and effective options, CA may be a superior choice when patients have other signs of hyperandrogenism and elevated BMI.95, 97 The most common side effect of bicalutamide is mild and transient elevation of liver enzymes.92 Two retrospective reviews also suggested bicalutamide as a safe and effective option for female pattern hair loss with 95% adherence.93, 94 The most common side effects of OB were mild hepatic injury, peripheral edema, and gastrointestinal complaints. Adverse effects were detected in about 30% of the participants, but they were all tolerable.79 Another prospective study using a 5 mg once daily regimen showed 100% improvement at week 12 and 24 with 43% patients achieving excellent improvement.22 Pirmez et al. suggested that very low dose oral minoxidil (0.25 mg once daily) may be less effective in treating moderate AGA and higher dosage might be needed. The Critical Role of Androgen Receptor Sensitivity This is taking a root cause approach when it comes to understanding our health and hormones. Your androgens are metabolized (or broken down) by utilizing either the 5 alpha or 5 beta pathways. Elevated levels can be due to blood sugar imbalances which cause a surge of insulin in the blood which will signal the ovaries to produce more testosterone. High androgen levels are a common indicator of polycystic ovarian syndrome, (PCOS). Testosterone and DHEA are both androgen hormones. According to the free hormone hypothesis (78-80), recently restated and updated (62), the free (non-protein bound) fraction of testosterone is the most biologically active with the loosely protein-bound testosterone constituting a less accessible but mobilizable fraction, with the largest moiety tightly bound to SHBG constituting only an inactive reservoir. Other modifiers of circulating SHBG levels include up-regulation by acute or chronic liver disease and androgen deficiency and down-regulation by obesity, protein-losing states (65), non-alcoholic fatty liver disease (73, 74) and, rarely, genetic SHBG deficiency(75-77). As a product of hepatic secretion, circulating SHBG levels are particularly influenced by first-pass effects on the liver of oral drugs including sex steroids. Moreover, the review compares the core impacts of these therapy options on hormone levels and modulation of HPG axis. The manuscript reviews the alternative therapies to increase endogenous testosterone replacement which includes but not limited to Selective estrogen receptor modulators, gonadotropins, and Aromatase inhibitors, respectively. Zhang et al. (2017) identified that transplanting human p75+ LSCs into EDS-treated rats (inducing ALC dysfunction) successfully replaced the impaired ALCs and partially restored testosterone production (74). Other studies have shown great promise in increasing testosterone production at more upstream regulation points. Beattie et al. (2015) demonstrated increased testosterone production in rat models by directly stimulating aged ALCs with translocator protein (TSPO), a ligand involved in transporting cholesterol from the cytosol to mitochondria (71). Instead, the aim is to support holistic health—including the other triads—by encouraging optimal, healthy levels of androgenic hormones. The first triad of the Androgenic Approach encompasses the physical lifestyle modifications that are absolutely essential for restoring and maintaining health—including endocrine health and androgenic hormone production. However, before diving into this topic, it’s important to clarify that using proandrogenic herbs to support androgen hormone levels is just one of several necessary interventions to maintain health. Notable phytosterols include the androgenic sterols (phytoandrogens) found in Pine Pollen, which can mimic the activity of male sex hormones. The term proandrogenic refers to the use of specific phytotherapeutic herbs, functional mushrooms, or other compounds, that positively influence androgen hormone levels. This coordinated hormonal cascade—initiated at the level of the hypothalamus—demonstrates how Producers can naturally enhance endogenous testosterone production. LH travels to the Leydig cells of the testes, stimulating the production of testosterone. Through modulating the endocrine signaling process, particularly through their influence on the hypothalamus, Producers stimulate the body's own mechanisms for hormone production. When levels fall below the ideal range, production ramps up—the furnace kicks back on. However, the effective use of proandrogenic herbs requires a more nuanced and in-depth understanding of their mechanisms. Acne is unusual during testosterone replacement therapy being mainly restricted to a few susceptible individuals during establishment of treatment with shorter-acting intramuscular testosterone esters, probably related to their generation of transient supraphysiologic testosterone concentrations in the days after injection (570, 655). In a few untreated hypogonadal men, mainly in newly diagnosed older men, initiation of androgen treatment with standard doses occasionally produces an unfamiliar and even intolerable increase in libido and erection frequency. The higher prevalence of adverse behavioral effects reported among androgen abusers may be related not only to the massive androgen doses but also to high levels of background psychological disturbance (527), drug habituation (557), and anticipation (741) which predispose to behavioral disturbances reported during this form of drug abuse (727, 742). However, such adverse behavioural reactions were not observed in larger studies of testosterone administration to unpaid healthy men (666, 669, 739, 740). Testosterone is the main androgen in all people. Their levels can change throughout the day. Testosterone is the most common androgen. They help start puberty and play a role in reproductive health and body development. This article does not contain any studies with human or animal subjects performed by any of the authors. In a recent comparison study done on HCG and different forms of testosterone, it was noted that HCG leads to a lesser increase in estrogen than exogenous testosterone. The investigators were unable to reach the study’s primary end point, but they demonstrated a significant increase in lean body mass, testosterone and estradiol. One study demonstrating support for HCG as a treatment modality for hypogonadism was conducted on healthy Australian men. LL-37 increased the expression of EGR1, activated MAPK, and the LL-37 pretreated ASCS-CM strongly promoted hair growth in vivo . It significantly increased the secretion of insulin-like growth factor binding proteins (IGFBP-1 & IGFBP-2), M-CSF, M-CSF receptor, platelet-derived growth factor receptor-β (PDGFR-β), and VEGF . Similarly, a 3-month pilot study involving 15 volunteers using hUC-MSC-conditioned medium indicated that 86.6% of the volunteers had hair regeneration, with no side effects or adverse reactions . Subsequently, a 16-week clinical trial involving 30 patients with mild to moderate hair loss was conducted. Although men have two to three times the prevalence (430) as well as earlier onset and more severe atherosclerotic cardiovascular disease than women, the precise role of blood testosterone and of androgen treatment in this marked gender disparity is still poorly understood (309).This is backed by a study published in The Journal of Clinical Endocrinology & Metabolism, where men and women given GH, like CJC-1295, had improved sex drive and testosterone levels.The elevation of T levels by the majority of these so-called boosters seems to be negligible.This systematic review has provided a comprehensive examination of testosterone's physiological roles, emphasizing the need for further research to address existing gaps in knowledge.Lastly, in the setting of severe hyperandrogenism, ovarian and adrenal vein sampling can be used when both pelvic and adrenal imaging are negative.52 Right and left ovarian and adrenal veins are accessed and testosterone is measured to determine a left to right difference.Instead practical gonadotropin therapy uses hCG, a placental heterodimeric glycoprotein which has a much longer duration of action allowing it to be administered every two or three days.In male mice, aromatization of testosterone must occur locally within bone as circulating estradiol levels are too low to activate ERs ; however, the role of local vs circulating estradiol effects on male bone remain to be clarified.Structural studies of the AR’s LBD shows it has similar tertiary conformation as other steroid receptors (most closely resembling PR) with 12 stretches of α helix interspersed with short β pleated sheets. As a large amount of testosterone remains on the skin after topical application, transfer of testosterone by direct skin contact is a risk for an intimate partner ( ) or children ( ). For non-scrotal patches, the smaller size and application to less permeable non-scrotal (trunk, proximal limb) skin limit testosterone absorption. Despite its clinical advantages and popularity, this simple, non-patented technology has limited commercial marketing appeal and, consequently, is not widely available apart from compounding chemists and niche manufacturers (598). Recent studies using a smaller (75 mg) implant reproduce these features although requiring administration of a larger number of pellets ( ). The testosterone response to resistance exercise and training in aging women is similar(either an acute increase or no change) to that for younger women (128), whereas others found that in middle-aged and older women whoare untrained, total and free testosterone do not change acutely in response to high(131,145) or moderate (146) volumeresistance exercise. Kvorning andcolleagues (142) have shown that the Leydigcells are likely involved in the acute resistance exercise–induced increase intestosterone in men, but women do not have Leydig cells. Findings on the testosterone response to a bout of heavy resistance exercise in womenare equivocal with both increases (131,135–137) and no changes observed (138–141). Estrogens promote the developmentof female genital organs and features, growth of the endometrium, and inhibit thesecretion of follicle-stimulating hormone by the pituitary. Hormonal changes and theirpotential effects on inflammation may, in part, affect conditions, such asatherosclerosis, cardiovascular diseases, metabolic syndrome, and type 2 diabetes.Although the role of sex hormones on aging and age-related diseases is still unclear,there are clear age associations, which are likely reducing healthy aging and negativelyimpacting longevity. To date, finasteride and minoxidil are the only two FDA-approved drugs for the treatment of AGA . UV exposure also induces oxidative DNA damage and cytotoxicity in human hair follicle cells . Furthermore, it has been suggested that obesity is not only a risk factor for hair loss, but may synergize with repetitive hair cycles or aging-induced changes that significantly inhibit HFSC self-renewal . Additionally, saffron is another known aphrodisiac that can improve hormone regulation and increase vitality, energy, and libido while improving metabolic functions and is beneficial for weight loss. It has been shown to naturally increase norepinephrine and dopamine production in the brain, affecting mental health and promoting feelings of calmness, focus, and confidence. It produces a large amount of unique glycoproteins that allow greater production of testosterone and is used to help regulate fertility in males. These unique plants have been the heart of many studies which aimed to show their benefits in male sexual performance, treating erectile dysfunction and premature ejaculation. Ehormones MD maintains contemporaneous medical records, readily available to the patient, and subject to the patient’s consent, available to his or her other healthcare provider(s). Ehormones MD managed physicians do not provide any prescriptions unless a clinical need exists at the time of physician assessment. Contact Ehormones MD today to learn more about your personalized health options. There is as yet no information regarding its efficacy in endocrine disease states such as PCOS, however, one small-scale study has demonstrated this prolactin reducing effect in a group of healthy males, and the implication is that it could be of use in mild hyperprolactinemia (16, 17). Reduction in prolactin levels affects FSH and estrogen levels in females and testosterone levels in men. In that study, the inhibitory effect of an isopropanolic extract of black cohosh (iCR) on cell growth in androgen-sensitive LNCaP and androgen-insensitive PC-3 and DU 145 prostate cancer cells was investigated. The current review has shown that higher T doses are protective for erectile functions during their use, but there can be decreased libido and ED after discontinuing T. HCG is known to preserve testicular function and prevent testicular atrophy. Microdissection testicular sperm extraction (micro-TESE) may be used for the exceedingly rare case of unrelenting azoospermia that does not resolve despite a thorough attempt at medical treatment. For patients with histopathological abnormalities (namely, sperm maturation arrest), IVF-ICSI has been used but there is no published data confirming the success. Conservative or medical management forms the initial protocol for the management of AAS-induced male infertility. It was studied as an agent for use in the treatment of weight loss and short stature but concerns about its toxicity prevented it from being marketed as a pharmaceutical compound . Unlike most other anabolic steroids, THG binds to glucocorticoid receptors, which may result in serious complications due to weight loss. Desoxymethyltestosterone (DMT; 26, Figure 6) is an orally active 17α-methylated derivative of dihydrotestosterone. Another very specific side effect is the so-called trenbolone cough (particularly prevalent in trenbolone acetate), a phenomenon whose mechanism has not yet been satisfactorily explained, and is believed to be related to the interaction with prostaglandin receptors. Trenbolone acetate is still used in animals to stimulate muscle growth and appetite . Small testicular size (reference range 15–25 ml, approximately 4.5 cm × 3.0 cm) is seen in virtually all cases of male hypogonadism, except those of recent onset. Androgen deficiency may be suspected by certain clinical features (which includes decreased libido, hot flushes, etc.), however, the diagnosis needs to be confirmed by appropriate laboratory testing. The synthesis and pulsatile release of the gonadotropic hormones (follicle stimulating hormone FSH and luteinizing hormone LH) from the anterior pituitary are regulated by gonadotropin-releasing hormone (GnRH), which is synthesized by the hypothalamus. Testosterone is essential to the development of primary and secondary male sex characteristics during puberty and for the maintenance of these characteristics during adult life.