Endocrine lec8

• Estrogens


  A family of hormones synthesized in a variety of tissues, 17 –β Estradiol is the primary estrogen of ovarian origin
• Estrogen biosynthesis


  1. Aromatization of androgens in a complex process that involves 3 hydroxylation steps each of which requires O2- and NADPH, the aromatase enzyme is thought to include a P450 mixed –function oxidase

  2. Estradiol is formed if the substrate of this enzyme complex is TT, whereas esterone results from the aromatization of androstenedione

  
• Theca cells


  Source of androstendione and TT, these are converted by the aromatase enzyme in granuloza cells to esterone and estradiol respectively

  
• Progesterone


  Produced and secreted by the corpus luteum, which also makes some estradiol

  
• Significant amounts of estrogens are produced by the peripheral aromatization of androgens in human males

  
• The peripheral aromatization of TT to E2 accounts for 80% of the production of E2
• In females, adrenal androgens are important substrates, since as much as 50% of the E2 produced in pregnancy comes from aromatization of androgenes

  
• The conversion of androstenedione to esterone is the major source of estrogens in postmenopausal female

  
• Aromatase activity is present in adipose cells and also in liver, skin, and other tissues
• The increased activity of Aromatase enzyme may contribute to the "estrogenization" that characterizes such disease as cirrhosis of liver, hyperthyroidism, aging, and obesity
• SHBG


  Binds estradiol about five times less avidly than it binds TT or DHT, while progesterone and cortisol have little affinity for this protein

  
• CBG


  Binds progesterone and cortisol with nearly equal affinity, but has little avidity for estradiol and even less for TT, DHT, or esterone

  
• The metabolic clearance rates of these steroids are inversely related to the affinity of their binding to SHBG, hence esterone is cleared more rapidly than estradiol, which in turn is cleared more rapidly than TT or DHT

  
• There is no storage of ovarian steroids and they are secreted when they are produced
• Estrogen metabolism


  The liver converts estradiol and esterone to estriol, the conjugated steroids are water soluble and don't bind to transport proteins, so excreted in bile, feces and urine

  
• Progesterone metabolism


  Metabolized by liver to several compounds and excreted in the urine as sodium-pregnanediol 20- glucuronide, so it is ineffective when given orally, other derivatives of 17-alpha hydoxy progesterone and 17alpha –alkyl-substituted 19-nortestosterone compounds have progesterone activity and avoid hepatic metabolism so can be used as contraceptive drugs

  
• Menstrual cycle


  The human menstrual cycle results from complex interactions between hypothalamus, pituitary and ovaries, normally varies between 25- 35 days in duration, divided into follicular phase, luteal phase and menstrual phase

  
• Follicular phase


  A particular follicle begins to enlarge under the influence of FSH, estradiol levels are very low during the first week but start to increase progressively as the follicle enlarges, LH is released either in response to the high level of estradiol in a positive feedback manner or in response to a sudden decline of estradiol, progesterone levels are very low, LH peaks at the end of the follicular phase and precedes ovulation by 16- 18 hrs

  
• Luteal phase


  After ovulation, the granuloza cells of the ruptured follicle luteinize and form the corpus luteum which produces progesterone and some estradiol, estradiol peaks about mid-way through the luteal phase and then declines, progesterone is required for the preparation and maintenance of the secretory endometrium that provides early nourishment for the implanted blastocyst, LH is required for the early maintenance of the corpus luteum

  
• Placental hormones


  HCG can be detected within few days from the commencement of the pregnancy, progesterone is synthesized in the first 6-8 weeks, estriol is synthesized in the highest amounts among other estrogens, placental lactogen has some biological properties of prolactin and growth hormone