HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]1MALE REPRODUCTIVE HORMONESThe reproductive hormonal axis in male consists of three main components: the hypothalamus, thepituitary gland and the testis. This axis normally functions in a tightly regulated manner to produceconcentrations of circulating hormones required for normal male sexual development, sexualfunction and fertility. Hormones produced by this axis include the hypothalamic gonadotropinreleasing hormone GnRH , pituitary gonadotropins FSH and LH and testicular steroids.These hormones function in an integrative way to ensure normal development and regulation ofmale reproductive system. Dysfunction in this axis can result in widespread effects such asambiguous genitalia, delayed puberty and loss of fertility. This easy briefly reviews the properties,function and regulation of male reproductive hormones as well as common disorders associatedwith their abnormalities.GONADOTROPIN-RELEASING HORMONEGonadotropin-releasing hormone (GnRH) is small neuropeptide .It is composed of 10 amino acids, so it iscalled decapeptide hormone.GnRH is synthesized as part of a large prohormone that is cleaved enzymatically and further modified withinthe secretory granules. GnRH is degraded by proteolysis within few minutes, so it has a short half-life,approximately 2-4 min.The gene, GnRH1, for the GnRH precursor is located on chromosome 8.Production & Secretion of GnRHGnRH is considered a neurohormone, a hormone producedin a specific neural cell that are distributed diffuselythroughout the hypothalamus and released at its neuralterminal. A key area for production of GnRH is the preopticarea of the hypothalamus, which contains most of the GnRH-secreting neurons.GnRH secretion is pulsatile in all vertebrates. in periodicpulses usually occurring every 1–2 hours. These GnRH-containing neurons project to the median eminence wherethey release GnRH from their axon terminals into thehypophysial portal system, Figure 1.In the portal capillaries, GnRH travels to the anterior pituitarygland.Pulsatile activity can be disrupted by hypothalamic-pituitary disease, either dysfunction (i.e.,hypothalamicsuppression) or organic lesions (trauma, tumor).Function of GnRHThe portal blood carries the GnRH to the pituitary gland, which contains the gonadotrope cells (consideredas receptors of GnRH). GnRH activates its receptor, gonadotropin-releasing hormone receptor (GnRHR), aseven-transmembrane G-protein-coupled receptor that stimulates the beta isoform of Phosphoinositidephospholipase C, which goes on to mobilizecalcium and protein kinase C. This results in the activation ofproteins involved in the synthesis and secretion of the gonadotropins LH and FSH.So, from the previous paragraph, the main function of GnRH is Stimulation of the synthesis and secretion ofluteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the anterior pituitary gland.Figure 1 Hypothalamic hypophysial portal system.
HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]2The pathway of hormones in male from the hypothalamus to the pituitary gland to the target organ is : -- Hypothalamus → GnRH → Pituitary → FSH → Testes → Spermatogenesis.- Hypothalamus → GnRH → Pituitary → LH → Testes →Testosterone.Requirement for pulsatile GnRH secretion:The Importance of pulsatile secretion of GnRH to stimulate release ofLH and FSH. The secretion of both LH and FSH sharply decline as GnRHsecretion is changed from pulsatile to continuous, but restoring pulsatilesecretion of GnRH rapidly restores secretion of both hormones, Figure2.Activity Of GnRHGnRH activity is very low during childhood, and is activatedat puberty adolescence.GnRH is found in organs outside of the hypothalamus and pituitary , its role in other life processesis poorly understood.The body carefully controls the production of testosterone. Chemical signalsfrom tow location – the pituitary gland and the hypothalamus.Thehypothalamus controls hormone production in the pituitary gland by means ofgonadotropin – releasing hormone "GnRH".This hormone tells the pituitary gland to make follicle – stimulating hormone "FSH" and luteinizing hormone"LH".GONADOTROPINS HORMONES IN MALESFollicular stimulating hormone (FSH)Luteinizing hormone (LH)Secretion of gonadotropins hormones:Both FSH and LH are secreted from the anterior pituitary gland by same cells called gonadotropes cellsunder the stimulation of gonadotropin releasing hormone (GnRH), Figure 3.GnRH is secreted by the hypothalamus under the feedback inhibiting mechanism of thetestosterone and inhibin hormones.GnRH is secreted intermittently a few minutes at time once every 1 to 3 hoursThe intensity of this hormone’s stimulus is determined in two ways: by the frequency of thesecycles of secretion and by the quantity of GnRH released with each cycleThe secretion of LH by the anterior pituitary gland is also cyclical, with LH following fairlyfaithfully in the pulsatile release of GnRH. Conversely FSH secretion increases anddecreases only slightly with each fluctuation of GnRH secretion instead it changes moreslowly over a period of many hours in response to longer-term changes in GnRH.So duo to the much closer relation between GnRH secretion and LH secretion, GnRH is also widely known asLH releasing hormoneIn the abscens of GnRH the gonadotropes cells almost don’t secrete LH or FSH.GONADOTROPINS METABOLISMThe gonadotropins are a family of closely related heterodimeric glycoprotein hormones present in mammals,which are important to the correct functioning of the reproductive system, but much less information is availableconcerning their metabolic processing.In mammals, the glycoprotein hormones consist of a common ALPHA subunit and BETA subunit.The solved crystal structure of human chorionic gonadotropin (hCG) showed that each of the gonadotropinsubunits is densely disulfide bridged, resembles the other in structure, and also has structural homology to thedisulfide-knot growth factor proteins.Elevated prolactin levelsdecrease GnRH activity.Figure2Figure 3
HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]3The disulfide-knot feature leads to protease generation of disulfide-bridged core fragments (the main urinarymetabolites of the gonadotropins), which retain significant immunogenic features that render them measurablein many assays forintact subunits.The hypothesis of this study was that urinary excretion of such stable and discrete glycoprotein coremetabolic fragments of similar or identical structures is a common degradative pathway in both humans andnonhuman species.Function of Gonadotropins hormonesLH and FSH exert their effect on their target tissues in the testes mainly by activating the cyclic adenosinemonophosphate second messenger system which activates specific enzymes in the respective target cells.Luteinizing hormone (LH) stimulates the interstitial (Leydig) cells in the testes to secrete the Testosteronehormone.The amount of secreted testosterone increase approximately in direct proportion to the amount of LH. SO themainly function of LH in the males is determining of secondary sexual characteristics by stimulation thesecretion of Testosterone.Follicle stimulating hormone (FSH) stimulates the Sertoli cells in the semineferous tubules of the testes togrow and secrete various spermatogenesis substances, At the same time the testosterone anddihydrotestosterone diffuse into the semineferous tubules to act on the spermatogenesis. This mean to initiatethe spermatogenesis both FSH and testosterone are requiredRegulation of FSH secretion(Negative Feedback Control of Semineferous Tubule Activity- Role of the Hormone Inhibin)When the semineferous tubules fail to produce sperm, secretion of FSH by the anterior pituitary glandincreases markedly. Conversely, when spermatogenesis proceeds too rapidly, pituitary secretion of FSHdiminishes. The cause of this negative feedback effect on the anterior pituitary is believed to be secretion bythe Sertoli cells of still another hormone called inhibin This hormone has a strong direct effect on the anteriorpituitary gland to inhibit the secretion of FSH and possibly a slight effect on the hypothalamus to inhibitsecretion of GnRH.Potent inhibitory feedback effect on the anterior pituitary gland provides an important negative feedbackmechanism for control of spermatogenesis, operating simultaneously with and in parallel to the negativefeedback mechanism for control of testosterone secretion.TESTOSTERONEis a steroid hormone from the androgen group. In mammals, testosterone is primarily secreted in thetestes of males and the ovaries of females, although small amounts are also secreted by the adrenalglands. It is the principal male sex hormone and an anabolic steroid. Testosterone is evolutionarilyconserved through most vertebrates.On average, an adult human male body produces about ten times more testosterone than an adult humanfemale body, but females are, from a behavioral perspective (rather than from an anatomical or biologicalperspective), more sensitive to the hormone. However, the overall ranges for male and female are very wide,such that the ranges actually overlap at the low end and high end respectively.SecretionIt secretes by the interstitial cells of Leydig, Figure 5, which are almost nonexistent in testes during childhoodwhen the testes secrete almost no testosterone, but they are numerous in the newborn male infant for the firstfew months of life and in adult male any time after puberty, at both these times the testes secrete largequantities of testosterone, Figure 4.
HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]4Figure 4 The secretion by age. Figure 5 The secretion by interstitial cells.Metabolism:After secretion of the testosterone it will circulate in theblood as:1. Testosterone bound (tightly) to SHBG – 80%2. Testosterone weakly bound to Albumin3. Free Testosterone (very small amount).For 30minutes to several hours by that time thetestosterone either is transferred to the tissues or it willdegraded into inactive products that are subsequentlyexcreted.The effect on target tissuesMechanisms: by activation of the androgen receptor(directly or as DHT), and by conversion to estradiol andactivation of certain estrogen receptors.The amplification pathway Free testosterone (T) istransported into the cytoplasm of target tissue cells,where it can bind to the androgen receptor, or can bereduced to 5α-dihydrotestosterone (DHT) by thecytoplasmic enzyme 5-alpha reductase, Figure 7. Thisenzyme expressed by two genes I and II. Type onefound in liver, kidney and skin, while type two found inthe prostate and to less extend in the skin. DHT bindsto the same androgen receptor even more strongly thanT, so that its androgenic potency is about 5 times that ofT. The T-receptor or DHT-receptor complex undergoes astructural change that allows it to move into the cellnucleus and bind directly to specific nucleotidesequences of the chromosomal DNA. The areas ofbinding are called hormone response elements (HREs) ,and influence transcriptional activity of certain genesproducing the androgen effects, Figure6 . It is importantto note that if there is a 5-alpha reductase deficiency, thebody (of a human) will continue growing into a femalewith testicles.Figure6 An anabolic-androgen steroid binds to anandrogen receptor located in the cytoplasm and is thencarried into the nucleus, where it instructs DNA totranscribe mRNA and, further, undergo translation toenhance the process of protein synthesis and ultimatelymuscle or bone growth.Figure 7 Pathways of testosterone action.
HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]5Androgen receptors occur in many different tissues especially prostate gland, external genitalia in the adult.Both males and females respond similarly to similar levels of testosterone.The diversification pathway of testosterone action allows testosterone to modulate its biological effects viaestrogenic effects that often differ from androgen receptor mediated effects. The diversification pathway,characteristic of bone and brain, involves the conversion of testosterone to estradiol by the enzyme aromatase,Figure 7.The bones and the brain are two important humans tissues where the primary effect of testosterone is byway of aromatization to estradiol. In the bones, estradiol accelerates maturation of cartilage into bone, leadingto closure of the epiphyses and conclusion of growth. In the central nervous system, testosterone is aromatizedto estradiol. Estradiol rather than testosterone serves as the most important feedback signal to thehypothalamus (especially affecting LH secretion). In many mammals, prenatal or perinatal "masculinization" ofthe sexually dimorphic areas of the brain occurs by the estradiol derived from testosterone and this areaprograms later male sexual behavior.Finally the inactivation pathway occurs mainly in the liverwith oxidation and conjugation to biologically inactivemetabolites that are excreted by the liver into the bill and bythe kidney into the urine.Factors influence the testosteroneThe testosterone used in women to treator prevent loos of bone density and totreat certain kinds of depression .Figure 8 Factors influence the testosterone
HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]6Figure 9 Testosterone functional roles on thebody.FUNCTION OF TESTOSTERONE:During fetal development:1- Causes formation of the prostate gland, seminal vesiclesand male genital ducts. 2- Suppressing the formation of femalegenital organs. 3- Just before birth, it causes the descent of thetestes from the abdominal cavity into scrotal sac.During puberty development:1 -Causes enlargement of penis, scrotum and testes. 2-Influence the secondary male sex characteristics asaggressive behavior and body hair patterns (over pubis, faceand chest). 3- Stimulates maturation of sperm cell. 4-Stimulates bone growth by increases the total quantity of bonematrix and causes calcium retention. 5- Stimulates proteinbuildup in muscles production muscular development, typicalof males with more bulk and firmness in their muscularphysique. and 6- Causes enlargement of the thyroid cartilage , resulting in the visible Adams apple in malesand deepening of the voice due to hypertrophy of laryngeal mucosa and enlargement of the larynx .REGULATING MALE REPRODUCTIONThe hypothalamic pituitary gonadal hormones are a critical partin the development and regulation of body system, Such asreproductive and immune system.The hypothalamic produces gonadotropin–releasing hormone(GnRH), the anterior portion of pituitary gland produces luteinizinghormone (LH) and follicle –stimulating hormone (FSH) and gonadsproduces estrogen and testosterone.( GnRH) secreted by hypothalamus that located in brain , travelsdown the anterior part of pituitary gland via hypophysial portalsystem and bind to receptor on the secretary cells ofadenohypothysis . In response to (GnRH) stimulation these cellproduce (LH) and (FSH) which travel into blood stream. These twohormones play an important role in communicating to the gonads.In male (LH) stimulate the interstitial cells located in the test is toproduce testosterone and (FSH) play role in spermatogenesis.The production of (GnRH) (LH) (FSH) are similar but the effectof these hormones are different, ( FSH) stimulate sustertacularcells to release androgen binding protein which promotetestosterone binding , ( LH ) binding to interstitial cells causingthem to secrete testosterone .Testosterones is required for normal spermatogenesis andinhibits the hypothalamus, inhibin is produced by spermatogenesiscells.Figure 10 Feedback regulation of hypo-thalamic-pituitary-testicular axis in male.
HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]7In general, androgen (testosterone one of them) promote protein synthesis and growth of these tissue withandrogen receptor, testosterone effect can be classical as vitalizing and anabolic effect. Anabolic effectsinclude growth of muscle mass and strength and stimulation of bone maturation.Androgenic effect: include maturation of sex organ particular the penis and the formation of scrotum in thefetus and after birth (usually at puberty) a Deeping of voice, growth of the beard and axiliary hair and pubichair.MALEHORMONALDISORDERSThe most important male sex hormone istestosterone, which influences sperm production,fertility, and sex drive. Male sex hormones alsopromote the development of secondary sexualcharacteristics at puberty. Over- or underproductionof male sex hormones may be due to a variety offactors, including inherited disorders, long-termillnesses, tumors, or lifestyle factors.Male sex hormones, or androgens, are producedmainly by the testes but also by the adrenal glands.The production of male sex hormones is controlledby hormones secreted by the pituitary gland. In turn,the pituitary gland is under the control of thehypothalamus. The changes that occur at pubertyare controlled by the sex hormones. The early or lateonset of puberty in boys, which may be a symptom ofunder- or overproduction of male sex hormones,Table 1.Hypogonadism, in which male sex hormones areunderproduced. In boys, this condition can suppresssexual development; in men, hypogonadism lowerssperm production and fertility, Table 2. TheGynaecomastia, breast enlargement in males thattemporarily affects nearly half of all boys during puberty. Male hormonal disorders may lead to sexualproblems and can sometimes be a cause of infertility.Abnormal puberty in malesVery early or late onset of puberty, usually due to a hormonal imbalance.The natural process of sexual development and maturation that takes place over several years is known aspuberty. In boys, puberty is normally characterized by enlargement of the genitals; development of hair on theface, in the armpits, and in the pubic region; a growth spurt, in which the body gets bigger and more muscular;and deepening of the voice. Puberty in boys usually begins between the ages of 10 and 14. Abnormal pubertystarts either earlier than normal (precocious puberty) or later (delayed puberty). Precocious puberty is rare andTable 1 Symptom of under- and overproduction oftestosterone.
HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]8is usually an indication of an underlying hormonal disorder. Delayed puberty is more common and less likely toindicate a serious underlying condition.Precocious puberty is caused by the overproduction of male sex hormones in a young boy. Boys in whompuberty is delayed are usually just late developers, a tendency that often runs in families. However, delayedpuberty may also be caused by the underproduction of male sex hormones. Rarely, there is a moreserious underlying cause, such as a brain tumour pressing on the hypothalamus or pituitary gland,or a chromosome disorder, such as Klinefelter’s syndrome, in which the sex organs do not developnormally.Some long-term illnesses, such as Crohn’s disease, kidney failure, cystic fibrosis, and diabetes mellitus, canalso cause delayed puberty and growth.Certain lifestyle factors, such as excessiveexercise and an inadequate diet, may delaythe onset of puberty. Rarely, a pituitarytumour may lead to either precocious ordelayed puberty.Early or late puberty should be investigatedby a doctor, who will carry out a physicalexamination to see if puberty has started orhow far it has progressed. A blood test mayalso be performed to measure hormone levels and to check for a chromosomal abnormality. X-rays of the wristand hand may be used to assess bone maturity, and ultrasound scanning of the testes or adrenal glands mayalso be carried out to look for abnormalities. If a pituitary tumour is suspected, MRI or CT scanning may beperformed. If tests identify an underlying cause for abnormal puberty, it will be treated. For example,precocious puberty may be treated with drugs that block the production of male sex hormones or inhibit theiraction. These drugs may be given in the form of injections, implants under the skin, or nasal sprays. If delayedpuberty runs in the family, treatment may not be needed. In many other cases, puberty is induced by givinginjections of testosterone. Some boys benefit from counselling for psychological problems caused by abnormalpuberty. Abnormal puberty is often treatable, but lifelong treatment may be neededHypogonadism in malesUnder activity (Reduced activity) of the testes, resulting in low levels of the sex hormone testosterone andimpaired production of sperm.In boys who have not reached puberty, testicular growth and the development of secondary sexualcharacteristics (such as growth of facial, armpit, and pubic hair, muscle growth, and deepening of the voice)may be delayed or arrested.Abnormal development of the testes due to a chromosome disorder, such as Klinefelter’s syndrome, maycause hypogonadism (primary hypogonadism), as may failure of the pituitary gland to produce sufficienthormones, which may be the result of a pituitary tumor.(secondary hypogonadism), Table 2.If hypogonadism occurs after puberty, the only effect may be infertility (see Abnormal puberty in males).The doctor will carry out a physical examination to determine whether the genitals and secondary sexualcharacteristics have developed normally. A blood test may be done to measure the levels of testosterone andother hormones and to look for a chromosomal abnormality. Treatment is aimed at the underlying cause. ForTable 2 Type of hypogonadism.
HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]9example, synthetic male hormones may be used to treat disorders of the testes. If underactivity of the pituitarygland is the cause, pituitary hormones may be given. A pituitary tumour may be removed surgically. In boys,hormone treatment stimulates puberty, including growth and sexual development; in men, it encourages growthof facial hair, muscle strength, potency, and sex drive. Side effects of treatment with hormones may includetemporary breast development (see gynaecomastia" If the genitals are normal, treatment may improve sexualpotency and fertility; if hypogonadism is due to a testicular disorder, fertility is rarely achieved.GynaecomastiaNoncancerous enlargement of one or both breasts in males.All males produce small amounts of the female sex hormone estrogen. If too much estrogen is produced,breast enlargement, called gynaecomastia, occurs. One or both breasts may be affected, Figure 11. Thecondition is common in newborn boys and affects 1 in 2 male adolescents. It is usually temporary in both ofthese age groups. Older men can also be affected.Gynaecomastia An excess of the female sex hormone estrogen in theblood may cause one or both male breasts to enlarge. Gynaecomastiain the newborn occurs when the fetus has been exposed to themother’s estrogen within the uterus. Increased levels of estrogen,resulting in breast enlargement, are also common during puberty.Drugs that affect levels of female sex hormones, such asspironolactone and corticosteroids, may lead to enlargement of the breasts. Some drugs for prostate cancermay have the same effect.The symptoms of gynaecomastia may include Tender and swollen breast or breasts. Firm or rubbery button oftissue that can be felt underneath the nipple and discharge from the nippleOne breast may enlarge more than the other. The symptoms listed above should always be investigated sothat breast cancer can be excluded.Newborn boys do not need treatment, and gynaecomastia usually disappears within a few weeks. In mostadolescents, the condition disappears in less than 18 months without any treatment. In older men, the doctorwill ask about lifestyle factors and carry out a physical examination. He or she may arrange for tests tomeasure hormone levels and to look for evidence of breast cancer. The treatment and outlook depend on theunderlying cause, but, if gynaecomastia persists, the excess tissue may be removed surgically.MaleinfertilityA small percentage of male infertility is caused by hormonal problems. The hypothalamus-pituitary endocrinesystem regulates the chain of hormonal events thatenables testes to produce and effectivelydisseminate sperm. Several things can go wrongwith the hypothalamus-pituitary endocrine system:1- The brain can fail to release gonadotrophic-releasing hormone (GnRH) properly. GnRHstimulates the hormonal pathway that causestestosterone synthesis and sperm production.2- A disruptionin GnRH release leads to a lack of testosterone and a cessation in sperm productionUnlike the causes of female infertility, which aremore easily identifiable, the cause of infertility can bedifficult to determine in some men. A cause isdiscovered in only 1 in 3 men investigated.Figure 11 Gynaecomastia.
HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]103- The pituitary can fail to produce enough luteinizing hormone (LH) and follicle stimulating hormone(FSH) to stimulate the testes and testosterone/sperm production. LH and FSH are intermediates in thehormonal pathway responsible for testosterone and sperm production.4- The testes’ Leydig cells may not produce testosterone in response to LH stimulation.5- A male may produce other hormones and chemical compounds which interfere with the sex-hormonebalance.REFERECESBooks:- Guyton & Hall Textbook of medical physiology "tenth edition"- Delmars Fundamentals of Anatomy and Physiology by Donald C.Rizzo,PH.D.Web sites:-Wikipedia and free encyclopedia.- Micro anatomy of endocrine gland (http://www.studyblue.com)- Cold Spring Harbor Laboratory Press-- PPP HealthCare- http://www.stanford.edu/class/siw198q/websites/reprotech/New%20Ways%20of%20Making%20Babies/causemal.htm- http://www.livestrong.com/article/174398-male-testosterone-facts/- http://www.foxnews.com/health/2012/12/17/dealing-with-low-testosterone/- http://men.webmd.com/testosterone-15738- www.tbeeb.net/- http://genesdev.cshlp.org/content/14/24/3075.fullhttp://genesdev.cshlp.org/content/14/24/3075.full24.5.2013