Biochemistry of Reproductive Hormones PDF

# Biochemistry of Reproductive Tissues ## Introduction - The process of conversion of cholesterol into biologically active steroid hormone is known as steroidogenesis. - Cholesterol is a class of lipids belonging to the steroid family. - It is an essential molecule that is not required in the diet...

# Biochemistry of Reproductive Tissues ## Introduction - The process of conversion of cholesterol into biologically active steroid hormone is known as steroidogenesis. - Cholesterol is a class of lipids belonging to the steroid family. - It is an essential molecule that is not required in the diet, but cells can synthesize it from simpler precursors. ## Cholesterol structure: - The structure of cholesterol is shown in the image. ## Steroid hormone: - A steroid hormone is any type of steroid that acts as a chemical messenger to the cells. - There are two classes of steroid hormones: - Corticosteroids: - Glucocorticoids - Mineralocorticoid. - Sex steroids: - Androgens - Estrogens - Progesterone. ## Importance of Steroid Hormones: - Steroid hormones play an important role in growth, development, sexual differentiation, and reproduction. - Steroidogenesis is important in regulating these processes. ## The process of Steroidogenesis: - Steroidogenesis is a multi-step process that occurs in two organelles: - Endoplasmic reticulum - Mitochondria. - This process requires various enzymes and organelles. - The requirements for steroidogenesis are: **Requirements**: 1. Cholesterol (Raw material) 2. Enzymes 3. Organelles ## Cholesterol and Steroidogenesis 1. Cholesterol is a class of lipids belonging to the steroid family. 2. The first and rate-determining step in steroidogenesis is the transfer of cholesterol to the inner mitochondrial membrane (IMM). 3. The IMM contains a number of steroidogenic enzymes. 4. Low-density lipoprotein receptor (LDLR) and scavenger receptor BI (SR-BI) are required for the first two receptor steps. - These receptors bring lipo-protein particles having esterified cholesterol to the steroidogenic processing cell. 5. Low-density lipoprotein is a primary source of cholesterol for steroidogenesis in humans. - However, SR-BI mostly serves as a cholesterol provider receptor in rodents. 6. After processing of lipo-protein, the formed cholesterol movement out of the lysosome is facilitated by Niemann Pick type C1 (NPC1). - NPC1 is localized late endosomes along with lipid transfer protein MLN64 and NPC2. - These proteins travel along microtubule tracks. - The cytoskeleton plays a key role in directing the positioning of cholesterol in steroidogenic organelles, i.e., mitochondria and endoplasmic reticulum. ## Enzymes involved in steroidogenesis: 1. Steroidogenesis is an enzymatically active process that is involved by various types of enzymes. 2. Notable enzymes are: - CYP450 - HSDs. 3. All types of steroidogenic enzymes are functionally unidirectional, i.e., irreversible. - This means the accumulation of products doesn't drive flux back to the precursor, except HSDs. 4. HSDs reactions are mechanistically reversible and can run in either direction under certain conditions. ## CYP450 enzymes: 1. CYP450 stands for cytochrome pigment 450. 2. Belongs to the family of CYP enzymes and absorbs all lights at a wavelength of 450 nm. 3. Total of 57 CYP450 enzymes are present in the human genome. 4. There are two types of CYP450 enzymes: - Type 1: Targets mitochondria. There are 7 in number. - Type 2: Targets the endoplasmic reticulum. There are 50 in number. 5. Presence of heme in the center of these enzymes activates molecular oxygen. - These CYP450 also adds electrons from the reduced form of NADPH. 6. Out of 57, only 6 are involved in steroidogenesis. - These 6 enzymes are called CYP450s.c.c, cytochrome pigment 450 cholesterol sidescain cleavage enzyme. ## Hydroxysteroid dehydrogenases (HSDs): 1. Molecular mass = 35 to 45 kDa. 2. Do not have a heme group. 3. Requires NADH/NAD+ or NADPH/NADP+ as co-factors to oxidize or reduce a steroid. - The mechanism used includes two electrons via the hydride transfer mechanism. 4. Possess reversible activity. 5. Classified into two categories based on structures: - Short chain dehydrogenase/reductase (SDR): It is a beta-alpha-beta protein, where up to 7 parallel beta sterols fan across the center of the molecule, forming Rossmann folds. - Aldo-keto reductase (AKR): Soluble protein contains beta-triose phosphate isomerase. 6. In both types of HSDs, the active site consists of a critical pair of tyrosine and lysine residues that participates in proton transfer to steroid alcohol during catalysis. ## What are reproductive hormones? - Hormones responsible for: - Sexual development. - Maintenance of libido. - Menstruation in females. - The hypothalamus controls hormone production in the pituitary gland by means of gonadotropin-releasing hormone “GnRH”. ## Hormonal Axis: - The hormonal axis is controlled by interactions between the hypothalamus, the pituitary gland, and male/female gonads. - The gender of an individual determines whether or not a negative feedback mechanism is activated in the hormonal axis. - Dysfunction in this axis can result in widespread effects, such as: - Ambiguous genitalia - Delayed puberty - Loss of fertility. ## Gonadotropin: - Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary. - They include FSH and LH. - Gonadotropins are responsible for: - Normal growth - Sexual development - Reproductive function - They act on the gonads, controlling gamete and sex hormone production. ## Male Hormonal Regulation: - The important locations for LH and FSH are: **Important Location for LH and FSH:** 1. Sertoli cells (inside seminiferous tubules) 2. Leydig cells (outside seminiferous tubules) - **FSH** stimulates Sertoli cells to produce ABP (androgen binding protein). - **LH** stimulates Leydig cells to produce testosterone. - ABP binds testosterone and transports it in the seminiferous tubule fluid to the epididymis. - It is taken up by a receptor-mediated process into the principal cells of the initial segment and caput epididymis. - Adult human males produce about ten times more testosterone than adult human females. - However, females are more sensitive to testosterone. - Testosterone is secreted by the interstitial cells of Leydig. ## Sperm Production: - Sperm production is controlled by hormones: - **Testosterone** - **FSH** - **LH** - These hormones stimulate sperm production. - One sex cell divides into four sperm. - Each sperm has 23 chromosomes. ## Sperm Maturation: - Sperm cells fully mature in the epididymis. - The components of the sperm are: - Head: contains acrosome. - Midpiece: contains ATP. - Tail: allows mobility. ## Fertilization: - Fertilization occurs when a sperm cell joins an egg cell. - The sperm penetrates the egg. - Membrane keeps out other sperm. - The nucleus of the sperm joins with the egg. - This process forms a zygote. ## Hormonal Feedback in Males: - When the seminiferous tubules fail to produce sperm, the secretion of FSH by the anterior pituitary gland increases. - Conversely, when spermatogenesis proceeds too rapidly, the pituitary secretion of FSH diminishes. - Sertoli cells also release inhibin which decreases pituitary production of FSH. - Inhibin helps regulate the production of sperm. ## Peripheral effects of testosterone: - Testosterone is the principal male sex hormone and an anabolic steroid. - It is responsible for: - Maintaining libido - Stimulating bone and muscle growth. - Maintaining secondary sexual characters. - Maintaining accessory glands and the reproductive system, e.g., the prostate. ## Metabolism: Testosterone: - After secretion, testosterone circulates in the blood in three forms: 1. Testosterone bound (tightly) to SHBG - 80%. 2. Testosterone weakly bound to albumin. 3. Free testosterone (very small amount). - Within 30 minutes to several hours, the testosterone is either transferred to the tissues or degraded into inactive products and excreted. ## Female Reproductive System: - The female reproductive system consists of the following organs: **Organs Involved:** 1. Uterus - Endometrium - Myometrium - Perimetrium 2. Vagina. 3. Pair of fallopian tubes. - The ovary produces eggs and female hormones. - The fallopian tubes are where the sperm meets the egg. - The uterus is where the baby grows. - The cervix dilates during labor. ## Effect of FSH and LH in Females: - FSH stimulates the primary follicles in the ovary. - The primary follicles turn into secondary follicles, producing estrogen. - The secondary follicles then mature into follicles. - LH works on mature follicles and stimulates ovulation. - Ovulation results in the formation of the corpus luteum. - The corpus luteum produces progesterone and relaxin. ## Release of egg from ovary: 1. The egg is released from the ovary. 2. The egg reaches the mid point of the fallopian tube where it is fertilized by sperm. 3. The fertilized egg implants into the endometrium of the uterus. ## Female hormones Progesterone and estrogen: - These hormones help prepare the uterine membrane for the implantation of a fertilized egg. - Without implantation, the uterine membrane is shed down as menstruation. - This cycle repeats itself every 21-35 days. ## Female hormone relaxin: - During pregnancy, relaxin is released from the placenta and the lining of the uterus. - Relaxin levels rise after ovulation, during the second half of the menstrual cycle. - Relaxin relaxes the wall of the uterus by inhibiting contractions. - Relaxin promotes the implantation of the developing placenta. - In men, relaxin is secreted from the prostate gland and can be detected in the semen, but it is not generally found in the blood circulation. ## STD - Reproductive health: - STDs attack reproductive organs. - They can cause infertility. - Left untreated, some STDs can be fatal. - STDs can be avoided by abstinence or using a condom. ## Health and Hygiene: **Estrogen effects on health**: - Low estrogen causes osteoporosis because estrogen helps prevent calcium loss. - Estrogen raises HDL (good) cholesterol in the blood. - After menopause, the risk of heart disease rises sharply. - Hormone replacement therapy (HRT) can reduce some of the symptoms of menopause. **Disturbance of progesterone in females:** - Can cause: - Menstrual cycle irregularities or missed periods - Infertility - Acne - Nail and heel problems - Slow metabolism, leading to weight gain. - Migraines or headaches and mood swings - Low libido and hot flashes **High testosterone in men:** - Can cause: - Heart muscle damage - Prostate enlargement - High blood pressure - Increased risk of blood clots - Aggressive behavior - Mood swings, euphoria, irritability **Low testosterone in men:** - Can cause: - Low sex drive - Difficulty achieving and maintaining an erection - Hair loss - Increased body fat - Decreased bone mass - Affected memory