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Testosterone Signaling

Introduction

Testosterone Structure

Testosterone is classified as an androgen within the class of steroid hormones. [1] Androgens are synthetic compounds that stimulate or control the development or maintenance of male characteristics in vertebrates. [2] Androgens, with testosterone in particular, have strong affinity for the androgen receptor. [3] Androgen receptors (AR) are 'nuclear receptors' which are activated by the binding of adrenergic hormones in the cytoplasm and then translocating into the nucleus. [4]

Classical pathway Androgenic: which is mainly responsible for the development of sex differences [5]
Non-classical pathway Anabolic: which is the metabolic pathway, responsible for muscle and bone growth [6]

Testosterone Properties

Molecular formula: C19H28O2

Molecular weight: 288.42442 g/mol

IUPAC Name: (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one

Pub Chem

History

1767 John Hunter performed the first intention testicular transplantation, however physiological effects were not studied as he was more interested in the techniques of tissue transplantation. [7]
1849 Arnold Berthold postulated that the physiological and behavioural changes of castration were due to a substance secreted by the testes, and further determined that this substance must interact with the body through transmission in the blood stream. [7]
1889 Charles Edouard Brown-Séquard prepared a solution of testicular extracts that he subcutaneously injected. After 3 weeks he reported an increase in strength and a decrease in memory loss, insomnia and other signs of aging. This extract become known as “the elixir of life”, and although other scientists were sceptical of its effects, this research promoted much more experimentation within the field of orgnotherapy. [8]
1902 William Bayliss and Ernest Starling recovered an extract from duodenal mucosa which they named secretin. They observed secretins physiological effect and postulated that the extract was a blood borne chemical messenger which acted on a target tissue to elicit the observed effect. William B. Hardy later proposed the term hormone for these chemical messages and in 1905 the name was first published in an article submitted by Starling in the lancet. [7]
1929 Adolf Butenandt isolated estrone-the first pure sex hormone, followed by androstenone. In 1934 Leopold Ruzicka synthesized androstenone. The work by Butenandt and Ruzicka not only proved that hormones could be isolated, but that they could be synthesized and therefore easily implemented in modern medicine. [7]
1935 Kàroly Gyula David, E. Dingemanse, J. Freud and Ernst Laqueur first isolated and named Tesosterone and published a paper titled: “On Crystalline Male Hormone from Testicles (Testosterone),” [9]. Later in that year, Adolf Butenandt synthesized testosterone and published “A Method for Preparing Testosterone from Cholesterol”. A week after Butenandts paper was published Ruzicka and A. Wettstein published their own article describing the synthesis of testosterone and therefore, in 1939 both Ruzicka and Butenandt were offered the Nobel prize for chemistry. Butenandt however, was forced to decline the award due to the Nazi government. [7]
1944 Heller and Myers report that the symptoms of Andropause (male climacteric) may be reversed by treatment with testosterone. [10]
1948 First clinical studies suggesting testosterone replacement therapy can be used as an effective antidepressant. [11]
1951 Charles D Kochakian published “Recent Studies on the Vivo and in Vitro Effect of Hormones on Enzymes” indentifying androgens as stimulators of the protein anabolic processes. Following the publication of this article, many scientists have looked into the use of androgen therapy to restore protein and stimulate growth in patients suffering from a number of diseases. [12]
1950’s Anabolic steroids such as testosterone become widely used by athletes to increase muscle mass. [13]
1960 Invention of the Radioimmunoassay allowed researches to efficiently measure the endogenous levels of testosterone. Shortly after this, methods were developed to measure testosterone through saliva samples. Saliva radioimmunoassays made research on humans simpler by avoiding blood assays for testosterone. [14]
1990’s Effective routes of administering testosterone alternative to injection are developed. These methods include patches, gels and buccal systems. [15]
1993 Morley reports that Testosterone replacement therapy in older men (over a short trial period) decreases cholesterol and increases hematocrit and muscle strength. [16]
1994 Department of Medicine at Columbia University reported that low levels of free testosterone correlate directly with an increased incidence of coronary artery disease. They also identified low testosterone as a risk factor for hypotension and obesity. [17]

Biosynthesis

Steroidogenesis

Similar to other classes of steroid hormones, testosterone is derived from Cholesterol. [18] through the following multistep pathway:

1) Pregnenolone is synthesised directly from cholesterol in the first step of the biosynthesis of testosterone. This step involves the oxidative scission of the sidechain of cholesterol, triggering the loss of six carbon atoms to give pregnenolone. [19] This process is facilitated by the cholesterol side-chain cleavage enzyme, P450scc [20], which utilises NADPH and O2. [21] This mitochondrial enzyme is a member of the cytochrome P450 superfamily of enzymes [22], and the gene name is CYP11A1. [23]
2) The second step involves the formation of dehydroepiandrosterone from pregnenolone by the removal of two carbon side chains. [24] This reaction is catalysed by the enzyme CYP17A, through its hydroxylase and lyase activity. [25] This protein is also a cytochrome P450 enzyme. [26]
3) Furthermore, the 3-hydroxyl group of dehydroepiandrosterone is oxidized by 3-β-HSD to produce androstenedione [27] The enzyme 3-β-HSD is encoded by the two genes HSD3B1 and HSD3B2, and it is the only enzyme in the adrenal pathway of corticosteroid synthesis that is not a member of the Cytochrome P450 family. [28]
4) 17-β hydroxysteroid dehydrogenase is the final enzyme involved in the pathway, which is responsible for the hydrogenation of androstenedione to form testosterone. [29] 17β-HSD is the rate-limiting enzyme in the production of testosterone. [30]

Regulation

Testosterone is regulated by the action of various hormones in the hypothalamus , pituitary as well as in the gonads. Certain hormones such as gonadotropin-releasing hormone (GnRH), luteinizing hormones (LH) and follicle stimulating hormones (FSH) are involved in the regulation of testosterone. [31]

The hypothalamic-pituitary-testicular axis is the system involved in controlling, maintaining, or up-regulating the amount of testosterone synthesised. [32]

When testosterone levels are low:

1) GnRH is released from from the ventral hypothalamus, which then travels down the hypothalamic-pituitary portal vein. [33]

2) This in turn stimulates the release of two tropic hormones from the anterior pituitary, namely LH and FSH. [33]

3) These hormones are then involved in the stimulation of the testis, and as result triggering the release of testosterone. [33]

When testosterone levels are high, a negative feedback loop acts on both the pituitary and hypothalamus, inhibiting the release of their respective tropic hormones. [34]

Signalling Pathway

The binding of testosterone to an androgen receptor within a cell

Testosterone is an androgen hormone made by leydig cells. Leydig cells activity in testosterone production is stimulated by luteinising hormone. It plays an important role but is not limited to, male reproductive development, differentiation and spermatogenesis. Testosterone has been shown to act in two main pathways often referred to as the classical and non-classical pathway. Through the classical pathway, testosterone acts via the androgen receptor (AR). These receptors can be found in high numbers in the testis on sertoli cells and on peritubular myoid cells and leydig cells in seminiferous tubules. Peritubular myoid cells are those that surround the borders of seminiferous tubules. [35]

Proteins involved in Testosterone Signalling

Several proteins are involved in testosterone signalling. Those outlined below have actions that affect the other.[36]

  • Gonadotrophin releasing hormone (GnRH)
  • Follicle stimulating hormone (FSH)
  • Luteinising Hormone (LH)

Gonadotrophin releasing hormone (GnRH) is a hormone that is made in the hypothalamus that is able to mediate the production of Follicle stimulating hormone (FSH) and Luteinising Hormone (LH) in the anterior part of the pituitary gland. The presence of luteinising hormone enables the production of testosterone.[37]


Structure of the Androgen Receptor

The androgen receptor is comprised of various domains that are similar to other receptors of its nuclear steroid family classification. The androgen receptor gene is located on the long arm of the X Chromosome.

Features of the androgen receptor include: [38]

  • 110 kda
  • Approximately 919 amino acids in length [1]
  • N-terminal domain
  • DNA- binding domain (DBD)
  • Hinge region that links the DBD and LBD regions together
  • Ligand or androgen binding domain (LBD)
Testosterone inducing CREB phosphorylation via non-classical pathway

The Classical Pathway

Through this pathway, androgen hormones such as testosterone or dihydrotesterone(DHT) bind with an AR resulting in a conformational change in the AR structure. DHT is a converted form of testosterone that is made by 5a-reductase, an enzyme found in the cytoplasm. Upon binding, of either hormone to the AR, an activated complex results with the detachment of heat shock proteins(2). The transformed androgen-receptor complex enables greater binding affinity of the structure to DNA protein elements found in the nucleus, in which are necessary for gene transcription [39]. These elements are known as adrogen response elements (AREs).

The Non-Classical Pathway

The non-classical pathway or otherwise referred to as nongenomic pathway describes testosterone signalling that occurs through various pathways in which do not involve androgen receptors. According to recent research, the androgen hormones including testosterone has been suggested to act via different signaling pathways. Testosterone has been found to cause signalling through molecules such as the mitogen-activated protein (MAP) kinase and its affect on cAMP response element binding protein (CREB)[40]. - Recent studies, have also shown the involvement of testosterone-AR binding to Src kinase, epithelial growth factor receptor (EGFR) [41] and calcium signalling [42].

Normal Function

Testosterone has many different functions, these function extend from early stages of life in both male and female to latest stages of life in both genders.Testosterone plays an important role in development of sexual organs in male fetal. Without testosterone and its derivatives. Fetal testicular Sertoli cells produce Mullerian inhibitory substance, which is responsible for the involution of the Mullerian ducts. These ducts without the presence of testosterone develop into the uterus, fallopian tubes, and cervix. Leydig cell in the testes of fetal produce testosterone. Subsequent differentiation of male external genitalia also requires the action of dihydrotestosterone (DHT)[43]

Testosterone plays an essential role in maintaining spermatogenesis and male fertilityif testosterone is absent, spermatogenesis does not proceed beyond the meiosis stage. After withdrawal of testosterone, germ cells that have progressed beyond meiosis detach from supporting Sertoli cells and die, whereas mature sperm cannot be released from Sertoli cells resulting in infertility. testosterone dose this by targeting the sertoli cell. In the Sertoli cell, testosterone signals can be translated directly to changes in gene expression (the classical pathway) or testosterone can activate kinases that may regulate processes required to maintain spermatogenesis (the non-classical pathway).[44]


Testosterone has many function during puberty in males, even though it has similar function in females but the effect is much more significant in males than in females. Levels of testosterone in blood increase significantly during puberty and results in enlargement of sebaceous glands, phallic enlargement, increase frequency of erection, increase body hair, loss of fat in the face, voice deepens, increase in strength, male fertility and bone growth throughout the body.[45]

Testosterone has many functions during the adulthood life in both sexes. As mentioned previously the effect in males is much more than females. Testosterone is necessary in adults for sperm development, helps to maintain muscle mass and strength, helps to regulate the thromboxane A2 receptors on megakaryocytes and helps to aggregation of platelets [46].

Testosterone has many important rules in different type of cancer. For many years it was assumed that prostate cancer is caused by a deficiency of testosterone, research has shown that if testosterone is absent in patients at risk of prostate cancer, the cancer grows faster but none of the results showed that testosterone is the cause of cancer. [47]. New studies has shown that testosterone helps to gain lean muscle in elderly men and helps loss extra fat in tissue throughout the body. One of the advantages of this property, is to help prevent cardiovascular diseases. Men with higher levels of testosterone have a lower risk of getting blood pressure, less obese and less likely to suffer a heart attack [48]. Testosterone helps in the regulation of sympathetic nervous system, when at danger helps stimulation of fight or flight reactions [49].

Testosterone acts on cells through intracellular receptors called ARs (androgen receptors). In this article the researchers show that a mouse type (IC-21) macrophage which lack the AR receptors but still shows specific responses to testosterone. as a response to testosterone there is rapid increase in ca2+ in the cells. this ca2+ is also achievable by plasma membrane-impermeable testosterone-BSA.It is not affected by the AR blockers cyproterone and flutamide, whereas it is completely inhibited by the phospholipase C inhibitor U-73122 and pertussis toxin. Binding sites for testosterone are detectable on the surface of intact IC-21 cells, which become selectively internalized independent on caveolae and clathrin-coated vesicles upon agonist stimulation. Internalization is dependent on temperature, ATP, cytoskeletal elements, phospholipase C, and G-proteins. Collectively, our data provide evidence for the existence of G-protein-coupled, agonist-sequestrable receptors for testosterone in plasma membranes, which initiate a transcription-independent signaling pathway of testosterone. [50]

Experimental and clinical studies have reported that testosterone has a critical role in the maintenance of homeostatic and morphologic corpus cavernosum components, essential for normal erectile physiology. Although the exact mechanisms mediated by testosterone in erectile function are still under investigation, recent research has suggested an important role in the regulation of endothelial cell (EC) biological functions. Besides stimulating the production of EC mediators, testosterone is also thought to promote the vasculogenic reendothelialization process, mediated by bone marrow-derived endothelial progenitor cells. Additionally, testosterone seems to modulate other erectile tissue components, including trabecular smooth muscle cells, nerve fibers, and tunica albuginea structure, all essential for the erectile process. This paper summarizes current data regarding testosterone-induced cellular and molecular mechanisms that regulate penile tissue components, focusing particularly on the role of testosterone in endothelial health and erectile function. [51]

Abnormal Function

Androgen insensitivity syndrome (AIS)

Androgen insensitivity syndrome (AIS) or also known as testicular feminization (Tfm)is a disorder that has been seen to commonly occur on the X chromosome. AIS occurs when a cell with androgen receptors is unable to respond to testosterone or dihydrotestosterone (DHT) due to unsuccessful binding. [52] A result of AIS as observed in rat studies and humans with AIS, changes on a phenotypic level occur. One which includes external genitalia being female-typical in appearance. [53][54]

Myxedema

Myxedema in men is thought to cause infertility and impotence. Testicular function was investigated in eight consecutive men with primary hypothyroidism (autoimmune thyroiditis in five patients and amiodarone therapy in three patients). All had impotence that preceded the onset of hypothyroidism and did not improve with thyroid therapy. Gonadal function tests showed a hypergonadotropic state in five patients and hypogonadotropic hypogonadism in three patients including one with no response to luteinizing hormone-releasing hormone. Luteinizing hormone bioactivity was decreased in six patients and increased in two subjects who also had increased luteinizing hormone immunoreactivity. Serum testosterone and testosterone/estradiol-binding globulin concentrations were low in four of the patients. It is concluded that abnormalities of gonadal function are common in men with primary hypothyroidism. [55]

Prostate Cancer

Testosterone replacement therapy has not been shown to cause cancer, but is known to increase the rate of growth if an existing prostate cancer condition exists. This detrimental effect is linked to testosterones interaction with the androgen receptor. The androgen receptor primarily functions to produce its transcriptional effects. However, studies have identified androgen receptors of prostate cancer cells to play an additional role in mediating cellular signalling. Treatment of prostate cancer cells with dihydrotestosterone results in rapid activation of mitogen-activated protein kinases, resulting in increased activity of the transcription factor E1K-1. As mentioned above, this process is rapid and is unaltered by androgen antagonists. Through this mechanism of action, testosterone can ultimately increase the rate of spread of an existing prostate cancer. [56]

Genetic Disorders

154 Genetic disorders have been linked to testosterone including AIS noted above NCBI OMIN. Mutations in any one of the steps of steroidogenesis are presumed to alter or block the development of the male phenotype. Most of the genes encoding the enzymes involved in this pathway have now been cloned, and mutations within their coding regions have in fact shown to block development of the male phenotype. [57]

Clinical Uses

Since testosterones isolation in 1935[58], it has been the subject of many scientific studies. Consequently, numerous clinical uses of testosterone have been identified.

Testosterone Replacement Therapy Testosterone is administered clinically via testosterone replacement therapy which aims to increase the level of “free” testosterone in the blood. The most reported use of this therapy is for treatment of hypogonadism; a condition in which the body’s concentration of testosterone is severely reduced[59].Testosterone replacement therapy in hypogonadal men has been associated with increased: bone density, muscle strength, mood elevation, sexual function, and some aspects of cognitive function.[16] This therapy has even been tested for use as a male contraceptive in the 1970's acting via feedback mechanisms on the hypothalmus to reduce spermatogenesis. [60]
HIV As implied above, testosterone is a promoter of protein restoration and tissue growth[61]. This principle has been utilised in testosterone based treatments of “wasting conditions” such as human immunodeficiency virus (HIV), in which participants show an increase is lean body mass prior to treatment.[62]
Osteoporosis Testosterones ability to increase bone density has also made it a suitable tool for treatment of osteoporosis. The mechanism by which testosterone achieves this is by slowing down bone reabsorption, rather than increasing bone formation.[63]
Alzheimers A study conducted at Rockerfeller University in New York determined that testosterone is actively involved in reducing the neuronal secretion of beta-amyloid peptides[64]. Alzheimer’s disease is caused by the deposition of beta-amyloid peptides in susceptible brain regions. Treatment of Alzheimers patients with testosterone has been shown to successfully increase spatial memory, constructional abilities and verbal memory.[65]
Depression Testosterone has also been known to exhibit anti depressant properties, however the exact mechanism by which testosterone produces these effects is still unknown. It has been observed that women are twice as likely to be affected by depression disorders and men with hypogonadism also suffer from depression and anxiety more than other men with normal levels of testosterone. Studies have discovered that a specific pathway in the hippocampus, a region of the brain involve in regulation of stress and memory formation plays an important role in mediating testosterone effects. To further investigate the mechanism by which testosterone achieves these effects, multiple experiments were done on adult male rats. Rats with reduced testosterone levels were shown to illustrate depressive behaviors that were consequently reversed upon treatment with testosterone replacement therapy. A pathway called MAPK/ERK2 was identified to play a major role in mediating the above mentioned effects. These results suggest that optimal functioning of this pathway is required for testosterone to produce its antidepressant effects and can help us to develop efficient testosterone based antidepressent therapies.[66]
Type 2 Diabetes Testsoterone has also been used clinically for treatment of type 2 diabetes. Low testosterone levels have been linked experimentally to insulin resistance and metabolic syndrome. Furthermore, insulin resistance in combination with type 2 diabetes and metabolic syndrome have ultimately been proven to promote increased deposition of visceral fat, which induces inflammatory cytokines associated with endothelial dysfunction and vascular disease. Therefore, testosterone therapy may not only act to prevent type two diabetes, but in the long term it can reduce the likelyhood of developing secondary conditions associated with diabetes.[67]
Video As research continues, many more clinical uses of testosterone are being trialed. The following video summarises some of the physiological effects associated with low testosterone levels and addresses some of the clinical uses of the hormone. Testosterone Video

Current & Ongoing Research

Current research recently focuses mainly on the effects of testosterone in the body. These effects extensively being studied in middle age and elder men to see what are the positives and negatives of using this hormone. In a recent research testosterone level and effects of testosterone replacement therapy was studied in aging men and below is a list of their findings.

  • Low testosterone is a very common condition in aging man and brings about medical conditions such as obesity, metabolic syndrome, Type 2 diabetes and high blood pressure.
  • Low testosterone levels increase the risk of death from cardiovascular disease in middle age men.
  • Testosterone replacement therapy helps to reduce body fat and so is a good way of treating diabetes.
  • Testosterone replacement therapy improves glucose control and reduces the amount of bad lipids and increase the good fats in the body.
  • Testosterone replacement therapy increases sexual desire and erectile function. [68]


Synthetic testosterone comes in many different forms. In a recent study, both injection and oral testosterone were compared to demonstrate their differing effects. These two forms of testosterone were administered to middle age men showing symptoms of low testosterone and Type 2 diabetes. The study was done on 52 men, who were divided into three groups: the first group was injected with testosterone, the second were administered capsules, and the final was a control group that was given placebo drugs. After 6 months the group that was given the capsule, was given the injection form and the other groups remained the same. Below is a summary of some of the key findings of this study after 1 year:


  • Improvement of the body’s sensitivity to insulin
  • Beneficial effect on waist circumference and body fat
  • Improved sexual function
  • After switching from oral testosterone to the testosterone injection for the second 6 months of the study, testosterone levels, insulin sensitivity, waist circumference and levels of body fat all improved.

This study was important because it shows that not all forms of testosterone are equally effective. This study showed for the first time that oral testosterone is not as effective in men with low testosterone and diabetes. Unlike the oral form, the injection form of testosterone brings back the level of testosterone to the appropriate level in the body and only requires about five injections per year to do so. Low testosterone levels can increase the risk of cardiovascular disease, diabetes, MetS and narrowing of arteries, returning the testosterone to its normal range helps to improve all the conditions mentioned above. This study suggests testosterone replacement therapy has a significant role in preventing, MetS, cardiovascular disease, diabetes and narrowing of arteries. [69]

In a study comparing a group of elderly men with normal testosterone levels to those with low testosterone levels, data showed that males with lower testosterone have increased weight and body fat percentage. Additionally, decreased muscle functioning and a lower metabolic rate, were associated with lower levels of testosterone. Bone Mineral density was measured but no significant difference was found. Men in the low testosterone group were less satisfied with overall quality of life, but no difference in quality of their sexual life in compare to the other group. Men in the low testosterone group were then randomly divided into two groups and treated with testosterone or a placebo drug. After one year, they found a significant difference between the two groups. Bone mass density was increased significantly in the group treated with testosterone however, testosterone treatment did not increase handgrip strength or strength in the knee, but in the placebo group hand grip strength was reduced such that at the end of the study there were significant differences between the groups. This suggests that testosterone can maintain hand grip strength that would otherwise have declined in elderly men.[70]

Use of testosterone is very common between the elite athletes, but the effects of these use has not been extensively studied, in a recent study the safety of the intramuscular injection formulation of testosterone and the oral form of testosterone and the associated risk for hypertension, polycythemia, prostate cancer, benign prostatic hypertrophy (BPH) and prostatism was monitored in 5000 males in UK that used testosterone. Results identified 202 cases of hypertension , 146 cases of polycythemia, 46 cases of prostate cancer, 106 High blood pressure and 251 cases of prostatism. Risks of prostate cancer and prostatism were similar in user of the two formulation, but risks were higher for hypertension and polycythemia in the injectable form compare to the oral testosterone.[71]

Glossary

  • Chromosome an organized structure of coiled DNA and proteins
  • Cytokines any of a class of immunoregulatory proteins (as interleukin, tumor necrosis factor, and interferon) that are secreted by cells especially of the immune system
  • Dihydrotestosterone: an androgen or male sex hormone.
  • Genome: the complete set of genetic material of an organism
  • G-protein coupled receptor cell surface receptors that are coupled to G-proteins
  • Human Immunodeficiency Virus (HIV) a virus that causes the immune system to fail.
  • Hypogonadism: Hypogonadism is a medical term for decreased functional activity of the gonads, thus resulting in lower amounts of testosterone
  • Meiosis a type of cell division that results in the number of chromosomes in gamete-producing cells being reduced to one half.
  • Osteoporosis a condition that causes decrease in bone mass with decreased density and enlargement of bone spaces producing porosity and brittleness
  • Peritubular: being adjacent to or surrounding a tubule
  • Phenotypeobservable physical characteristics of an organism as a result of the interaction of its genotype and the environment.
  • Sertoli cell a cell found in the seminiferous tubules of the male reproductive system, provides nourishment to spermatids.
  • Steroidogenesis: The biologic synthesis of steroid hormones.
  • Testosterone replacement therapy a hormone treatment where testosterone not made by the body is introduced counteract low or deficient levels within the body.
  • Transcription: the process of constructing a messenger RNA molecule using a DNA molecule as a template with resulting transfer of genetic information to the messenger RNA
  • Myxedema: Describes a specific form of cutaneous and dermal edema secondary to increased deposition of connective tissue components (like glycosaminoglycans, hyaluronic acid, and other mucopolysaccharides) in subcutaneous tissue as seen in various forms of hypothyroidism and Graves' disease.[1]:535 It is more common in women than in men.
  • corpus cavernosum: Either of the columns of erectile tissue forming the body of the clitoris or penis
  • Cholesterol: is an organic chemical substance classified as a waxy steroid of fat. It is an essential structural component of mammalian cell membranes and is required to establish proper membrane permeability and fluidity.
  • Hypothalamus:is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland (hypophysis).
  • Gonad:is the organ that makes gametes. The gonads in males are the testes and the gonads in females are the ovaries.
  • LH:is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH ("LH surge") triggers ovulation[3] and development of the corpus luteum.
  • FSH:is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body
  • Prostatism:is an inflammation of the prostate gland, in men.

Cholesterol

Images

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