HPG Axis PDF

Hypothalamic–pituitary–gonadal axis HPG axis  Background The HPG axis plays a critical part in regulating Reproduction and fertility and formation of gonadal sex steroids Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus arcu...

Hypothalamic–pituitary–gonadal axis HPG axis  Background The HPG axis plays a critical part in regulating Reproduction and fertility and formation of gonadal sex steroids Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus arcuate nucleus. The anterior portion of the pituitary gland produces luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the gonads produce estrogen and testosterone.  GnRH peptide hormone that activates gonadotrope cells, Its receptor is G-protein-coupled receptor that stimulates Phosphoinositide phospholipase C, which goes on to mobilize calcium and protein kinase C. This results in the activation of proteins involved in the synthesis and secretion of the gonadotropins LH and FSH. GnRH is degraded by proteolysis within a few minutes.  GnRH activity is very low during childhood, and is activated at puberty or adolescence GnRH is released in a pulsatile fashion  Pituitary gonadotropin The anterior pituitary gonadotrope cells responds to GnRH by secreting gonadotropins: – FSH= Follicular Stimulating Hormone – LH = Luteinizing Hormone Although the effects of FSH and LH are quite different in males and females, a certain analogy exists : Gonadotropins act via two-cell system in males and females. These gonadotropins then stimulate the synthesis and secretion of sex steroids in the gonads: estradiol and progesterone in females, and testosterone in males  Negative feedback of sex steroids in both sexes causes inhibition at both the hypothalamus and the pituitary  During early puberty in boys, both FSH and LH levels increase and thus, the Leydig cells proliferate and plasma levels of testosterone increase Immature Sertoli cells, they proliferate actively during the early postnatal period in response to FSH and other growth factors The total number of Sertoli cells that is generated during this stage will have a direct effect on sperm production in adult life, since each Sertoli cell is capable of supporting a certain, fixed number of developing germ cells  Luteinizing H Luteinizing hormone (LH) belongs to the glycoprotein hormone the LH receptor is belongs to the G protein-coupled receptor primarily present in Leydig cells associated with increase cAMP and initiation of steroidogenesis and testosterone formation  androgen action on Sertoli cells is critical for proper testicular maturation and normal spermatogenesis progression sexual hormone production by the Leydig cell.  Follicle-stimulating hormone (FSH) pituitary glycoprotein hormone. The primary target of FSH in the testis is the Sertoli cell. Via this action on Sertoli cells, FSH indirectly increases the number of Leydig cells, which is a key part of pubertal development FSH bind to G protein-coupled receptor, activates the cAMP on Sertoli cells of the testis stimulating transcription of specific genes, and increased proteins important for synthesis and action of steroid hormones, including the following: - Androgen-binding protein (ABP) - P-450 aromatase a key steroidogenic enzyme that converts testosterone, into estradiol. - Growth factors and other products that support sperm cells and spermatogenesis (I. e acting on Sertoli cells to increase the number of LH receptors on Leydig cells thus result in an increase in testosterone production). - Inhibins, which exert negative feedback on the axis  Androgen Testosterone together with its potent metabolite, dihydrotestosterone (DHT), are the principal androgens in the circulation of mature male Testicular testosterone secretion is principally governed by luteinizing hormone (LH) through its regulation of the rate-limiting conversion of cholesterol to pregnenolone within Leydig cell mitochondria by the cytochrome P-450  Testosterone is secreted at adult levels during three periods of male life: - rapidly during the first trimester of intrauterine life (coinciding with masculine genital tract differentiation), during early neonatal life as the perinatal androgen surge (with still undefined physiologic significance), and continually after puberty. - somatic changes of male puberty are triggered by the striking increases in testicular secretion of testosterone, rising ~30-fold over levels in pre-pubertal children and in women or After middle age, there are gradual decreases in circulating testosterone as well as increases in gonadotrophin and sex hormone–binding globulin 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 adrenal androgens make a proportionately larger contribution to the much lower circulating testosterone concentrations in children and women  Most testosterone in the circulation is bound to specific binding proteins. About 45% of plasma testosterone binds to sex hormone–binding globulin (SHBG) ~55% binds to serum albumin and corticosteroid-binding globulin A small fraction of the total circulating testosterone circulates free.  Once it diffuses into the cell, testosterone either binds to a high-affinity AR in the nucleus or undergoes conversion to DHT, which also binds to the AR The androgen-AR complex is a transcription factor that binds to hormone response elements on DNA estradiol for exerting most of its effects on bone, and for its role in regulating the release of GnRH and gonadotropins from the hypothalamus and pituitary Binding of either hormone to androgen receptors facilitates the dissociation of heat-shock proteins (HSP), as well as a change in receptor conformation that results in receptor phosphorylation and dimerization, and exposure of zinc finger DNA binding domains that are able to interdigitate into the DNA helix in regions where specific androgen response elements (ARE) are located.  Androgen effects on organ systems. induction and maintenance of male secondary sexual characteristics increased muscle protein synthesis, amino acid utilization, and maximum skeletal muscle strength. Androgens have been shown to increase erythropoietin (EPO) and hematocrit. Testosterone increases BMD and osteoblast growth while concurrently decreasing apoptosis of osteocytes Testosterone increases T cell maturation, decreases the proliferation of autoantibodies,  - Androgens decrease the activity of LPL resulting in a decline in lipogenesis (Weimar et al. 2002). -The nervous system responds to testosterone by increasing ant-inflammatory markers including IL-10 remyelination of neurons -Androgens also decrease the concentration of ROS and Aβ plaques in the nervous system -they can also drive tumor growth. Most notably, the role of the androgen receptor (AR) in prostate cancer has been extensively studied. Recent data suggest that AR signaling may also be important in breast cancer, glioblastoma, and additional tumor types men do experience a gradual decline in their serum testosterone levels (see Fig. 54-5) imageN54-6 and that this decline is closely correlated with many of the changes that accompany aging: decreases in bone formation, muscle mass, growth of facial hair, appetite, and libido  Symptoms of Hypogonadism in Adult Men Anemia Breast discomfort Loss of skeletal muscle mass Reduced bone mineral density or bone mass Reduced sperm levels (oligospermia) Abdominal adiposity, increased body fat & BMI Sexual dysfunction (erectile dysfunction, reduced libido, difficulty achieving orgasm, infertility) Fatigue Depression & Irritability Hot flashes Testicular atrophy Causes of Primary Hypogonadism Klinefelter's Syndrome. Resulting from a congenital abnormality where two or more X chromosomes are present in addition to one Y chromosome. The extra X chromosome causes abnormal development of the testicles with underproduction of testosterone. Undescended testicles. An abnormality that develops at the time of birth. If not corrected, it can result in testicular malfunction with reduced production of testosterone. Mumps. Mumps is an RNA virus that can cause a wide range of inflammatory conditions, including inflammation of the testicles (mumps orchitis) that can resuslt in long-term damage resulting in reduced testosterone production. Hemochromatosis. Iron overload can cause both testicular failure and dysfunction of the pituitary, resulting in reduced production of testosterone. Physical Testicular Injury. Because the testicles are located outside the abdomen they are prone to injury. Damage can impair testosterone production, especially if both testicles are affected. Cancer & Cancer Chemotherapy. Cancer, cancer radiation therapy and chemotherapy can affect gonadal tissue, resulting in reduced production of sperm & testosterone. Normal Aging. While a slow gradual decline in serum testosterone with age Causes of Secondary Hypogonadism Kallmann Syndrome. Pathology affecting the normal development of the hypothalamus, which control the secretion of LH & FSH can cause hypogonadism. This syndrome is also typically associated with an impaired ability to smell (anosmia). Pituitary disorders. Abnormalities of the pituitary, including pituitary tumors can impair release of FSH & LH, affecting testicular function. Treatment of brain tumors with surgery and radiation therapy can also negatively impact pituitary function and cause hypogonadism. Inflammatory Disease. Inflammatory conditions including tuberculosis can affect the hypothalamus and pituitary, causing hypogonadism HIV Infection. HIV infection can cause hypogonadism by effects on either the hypothalamus, pituitary or testes. Obesity. Obesity is associated with hypogonadism. Multiple mechanisms appear to be involved involving estradiol and leptins. Increased production of estradiol due to aromatase activity in fat tissue can reduce the release of GnRH due to negative feedback on the hypothalamus. Increased leptin levels also affect the hypothalamus and result in a negative impact on gonadotropin secretion Stress. Stress, excessive physical activity and weight loss have been associated with hypogonadism caused by increased release of cortisol