Oestrogen

oestrogen in obs and gynecology

1. OESTROGEN & PROGESTERONE dR. p. sneha 1 st year pg Guided by dr.c.rama mani md Hod of dept of obg

2. Active hormones of ovary are steroid hormones derived from cholesterol. These include oestrogen , progesterone,testosterone and androstenedione Cholesterol is a building block in steroidogenesis and all steroid producing tissues except placenta are capable of synthezising cholesterol from two carbon precursor acetate.

3. Steroid hormone production involves at most 17 enzymes and occur in abundant smooth endoplasmatic reticulum found in steroidogenic cells. Ovary is deficient in 21 hydroxylase and 11 beta hydroxylase ,therefore it is unable to produce corticosteroids.

4. Biosynthesis In females, synthesis of estrogens starts in theca interna  cells in the ovary, by the synthesis ofandrostenedione from  cholesterol. Androstenedione is a substance of weak androgenic activity which serves predominantly as a precursor for more potent androgens such as testosterone as well as estrogen. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted either immediately into estrone , or into testosterone and then estradiol in an additional step. The conversion of androstenedione to testosterone is catalyzed by  17β- hydroxysteroid dehydrogenase (17β-HSD), whereas the conversion of androstenedione and testosterone into estrone and estradiol, respectively is catalyzed by aromatase, enzymes which are both expressed in granulosa cells. In contrast, granulosa cells lack  17α-hydroxylase and  17,20-lyase, whereas theca cells express these enzymes and 17β-HSD but lack aromatase. Hence, both granulosa and theca cells are essential for the production of estrogen in the ovaries.

5. HISTORY In 1929 Adolf Butenandt and Edward Adelbert Doisy independently isolated and determined the structure of oestrogen . The first orally effective oestrogen EMMENIN derived from late pregnancy urine of canedian women was introduced in 1930 by Collip and Ayerst laboratories.

6. Natural oestrogens are c18 steroids. Main sources are theca and granulosa cells of graffian follicles and corpus luteum while the adrenal cortex is the secondary source of supply During pregnancy placenta is the source Some oestrogens are also produced in smaller amounts by other tissues such as liver adrenal glands and the breast These secondary sources of oestrogens are especially important in post menopausal women Fat cells produce oestrogens as well

7. Oestrogen is secreted as oestradiol . It is bound to albumin by 30% and sexhormone binding globulin by 69% and only 1% is biologically active It acts by binding to cytoplasmic receptors in the cells It is inactivated by liver and excreted as conjugates of oestrone oestradiol and oestriol in the urine and bile 85% in urine and 10% in feaces

8. Mechanism of action After dissociation from the binding sites that is from albumin and sex hormone binding globulin steroid hormones diffuses across the cell membrane and bind to the nuclear receptor protein with high affinity. Two oestrogen sub types ER α ER β α Receptor 1.Classical oestrogen receptor 2.N-terminal portion of α receptor contains a region that promotes transcription activation Β receptor 1.Homologus to α receptor 2.Contains repressror domain.

9. These receptor isoforms vary in structure ,chromosomal location ,distribution. The activated steroid receptor complex interacts with nuclear chromatin to initiate hormone specific RNA synthesis. This results in synthesis of specific proteins and number of physiological functions.

10. The plasma oestradiol levels raises approximately 6-7days before ovulation from 50 mcg daily to peak level of 300 – 600 mcg about 2 days before ovulation and approximately 24 hrs before LH peak level upto 350 pg /ml. There after the oestradiol concentration falls to 150-200 mcg daily. But a small raise is seen again in the mid luteal phase. Urinary excretory levels follow the pattern seen in the plasma. The oestradiol peak seen before the ovulation is not a good marker for indicating ovulation as LH, because follicular maturation does not always end in ovulation

11. Types Steroidal The three major naturally occurring estrogens in women are  estrone (E1 ),  estradiol(E2 ), and  estriol (E3). Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity . During menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels . Though estriol is the most plentiful of the three estrogens it is also the weakest, whereas estradiol is the strongest with a potency of approximately 80 times that of estriol .

12. Thus, estradiol is the most important estrogen in non-pregnant females who are between the menarche and menopause stages of life.  Another type of estrogen called  estetrol (E4 ) is produced only during pregnancy . All of the different forms of estrogen are synthesized from  androgens, specifically testosterone  and androstenedione , by the enzyme aromatase.

13. Nonsteroidal Synthetic substances of this kind are known as  xenoestrogens . Plant products with estrogenic activity are called phytoestrogens. Those produced by fungi are known as  mycoestrogens . Unlike estrogens produced by mammals, these substances are not necessarily steroids.

14. Actions of oestrogen Feminization and secondary sexual characters Specific action on the genital tract 1.vulva and vagina a.Development of vulva. b.Vascular stimulation of vulva and vagina c.Epithelial stimulation of vulva and vagina d.cornification of superficial layers of vagina.oestrogen raises the karyopicnotic index in vaginal cytology. e.deposition and metabolism of intracellular glycogen in vaginal epithelium.

15. 2.uterus a.Causes myoplasia of myometrium and cervix. b.Increases uterine vascularity c.regenerates the endometrium after mensturation and is responsible for proliferative hyperplasia of endometrium. d.stimulant effect on the glands of endocervix and their mucus secretion.

16. 3.Fallopian tubes a.oestrogen stimulates the tubal musculature which is infact morphologically specialized myometrium. 4. Ovary no action

17. BREAST Hypertrophy of the ductal and parenchymal tissue of the breast,increased vascularity,areolar pigmentation, but no galactogenic effect,large doses suppress lactation. Action on other endocrine glands. Oestrogen suppress FSH and thyrotropic hormones. It can be used to inhibit ovulation as also production of milk in the puerperal patient.It is stimulant to LH and there by corpus luteum formation. Skeletal system It increases calcification of bone and closure of epiphysis in the adolescent and is antagonist to somatotropin

18. Water and sodium metabolism Oestrogen tends to cause water and sodium retention. An example is premensural tension which is caused by congestion and water retention. Blood cholesrerol Increases HDL and triglycerides decreases LDL and fat deposition

19. Coagulation Increase circulating level of factors 2, 7, 9, 10, plasminogen Decrease  antithrombin  III Increase platelet  adhesiveness Protein synthesis Increase hepatic production of binding proteins

20. Gastrointestinal tract Reduce bowel motility Increase cholesterol in bile Melanin Increase  pheomelanin , reduce  eumelanin Cancer Support hormone-sensitive breast cancers Lung function Promotes lung function by supporting alveoli (in rodents)

21. Pharmacokinetics Naturally occurring oestrogens These agents and their esterfied or conjugated derivatives are readily absorbed through GIT, skin and mucous membrane. Taken orally , oestradiol is rapidly metabolized and partially inactivated by microsomal enzymes of liver. Synthetic oestrogen analogues These compounds such as ethinyl oestradiol and mestranol are well absorbed after oral administration. Mestranol is quickly demethylated to ethinyl oestradiol,which is metabolized more slowly than naturally occurring oestrogens by the liver and oeripheral tissues. Being fat soluble they are stored in adipose tissue,from which they are slowly released. Therefore synthetic oestrogen analogues have prolonged action and higher potency compared to those of natural oestrogens .

22. Metabolism Oestrogens are transported in blood bound to serum albumin or SHBG. Bio availability of oestrogen taken orally is low due to 1 st pass metabolism in the liver. To reduce 1 st pass metabolism the drugs may be administered via trans dermal root , intra vaginally,or by injections. They are hydroxylated in the liver to derivatives that are subsequently glucuronated or sulfated . The parent drugs and their metabolites undergo excretion into bile and are then reabsorbed through the intra hepatic circulation. Inactive products are excreted in the urine.

23. Indications Short term use for menopausal symptoms. Premarin 0.625mg or evalon 1-2 mg daily for 3 -4 months is effective. Oestrogen cream is prescribed for local symptoms such as dry vagina and urethral syndrome. Long term hormonal replacement therapy prevents or delays osteoporosis and is also cardio protective. Oestrogen cream is also prescribed in vulvo vaginitis in children,senile vaginitis and urethral syndrome in menopausal women. Oral contraceptives Dysfunctional uterine bleeding

24. Intersex,the patient suffering from turner syndrome and testicular feminizing tumor should receive oestrogen combined with progestogens cyclically through out life to develop secondary sexual characters,to avoid cardiovascular accidents and osteoporosis. Oestrogen is used in prostratic cancer.

25. Side effects Nausea vomiting when given orally. Mastalgia,water retention and increase in weight. Thrombo embolism ,cerebral thrombosis Endometrial and breast cancer if given for a long period with out progestrogen . Hepatic adenoma , gall bladder disease.

26. Preparation and their doses. 1.oral Doses in common use indications Etinyloestradiol 0.01,0.02,0.05,1 mg Irregular menses,OC pills Conjugated equine oestrogen 0.625mg,1.25mg HRT Micronized oestrogen 1-2mg Menorrhagia,irregular menses Combined pills contraceptives

27. injectable Conjugated equine oestrogen 25mg slow iv menorrhagia Tropical vaginal Dienoestrol cream,evalon cream 0.01% in cream base Senile vaginitis,urethral syndrome Trans dermal patches 17 beta- oestradiol (3-7 days) 0.03-0.1mg HRT Combined E+MPA 0.625mg+5 mg HRT Oestradiol implant 25,50,100mg Long acting HRT -6 monthly

28. Progesterone

29. Progesterone is an endogenous steroid hormone  involved in the  menstrual cycle, pregnancy, and embryogenesis of humans and other species .  It belongs to a group of steroid hormones called the  progestogens ,and is the major progestogen in the body. It is also a crucial metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a  neurosteroid .

30. History Willard Myron Allen co-discovered progesterone with his anatomy professor George Washington Corner at the University of Rochester Medical School in 1933. The name  Progesterone   derived from   Proge stational   Ster oidal ket one.

31. Sources Progesterone is produced in high amounts in the ovaries (by the corpus luteum) from the onset of puberty to  menopause. It is also produced in smaller amounts by the adrenal glands after the onset of  adrenarche  in both males and females . To a lesser extent, progesterone is produced in nervous tissue, especially in the brain, and in  adipose tissue, as well.

32. During pregnancy , progesterone is produced in high amounts by the ovaries and placenta. At first, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropin ( hCG ) from the conceptus . A fter the 8th week, production of progesterone shifts to the placenta . The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term the placenta produces about 250 mg progesterone per day.

33. In mammals, progesterone ( 6 ), like all other steroid hormones, is synthesized frompregnenolone  ( 3 ), which in turn is derived from cholesterol ( 1 ) Cholesterol ( 1 ) undergoes double oxidation to produce 20,22-dihydroxycholesterol ( 2 ). This vicinal  diol  is then further oxidized with loss of the side chain starting at position C-22 to produce pregnenolone ( 3 ). This reaction is catalyzed by cytochromeP450scc. The conversion of pregnenolone to progesterone takes place in two steps. First, the 3-hydroxyl group is oxidized to a  keto  group ( 4 ) and second, the double bond is moved to C-4, from C-5 through a keto /enol  tautomerization  reaction .  This reaction is catalyzed by 3beta-hydroxysteroid dehydrogenase/delta(5)-delta(4)isomerase.

34. levels In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. Progesterone levels tend to be < 2 ng/ml prior to ovulation, and > 5 ng/ml after ovulation. If  pregnancy occurs, human chorionic gonadotropin is released maintaining the corpus luteum allowing it to maintain levels of progesterone . Between 7–9 weeks the placenta begins to produce progesterone in place of the corpus luteum, this process is named the luteal-placental shift. After the luteal-placental shift progesterone levels start to rise further and may reach 100-200 ng/ml at term After delivery of the placenta and during lactation, progesterone levels are very low.

35. Function Progesterone is the most important progestogen in the body, the result of its action as a potent agonist of the nuclear progesterone receptor  ( nPR ). In addition, progesterone is a non-selective ligand of the recently discovered membrane progesterone receptors ( mPRs ),as well as a ligand of the  PGRMC1(progesterone receptor membrane component 1. Progesterone modulates the activity of  CatSper  ( cation channels of sperm)  voltage-gated Ca 2 +  channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis). I t has been suggested that substances that block the progesterone binding site on CatSper channels could potentially be used in male contraception.

36. Progesterone has a number of physiological effects that are amplified in the presence of estrogens . Estrogens through estrogen receptors (ERs) upregulate the expression of PRs .  E levated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis , with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production, which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.

37. Progesterone is sometimes called the "hormone of pregnancy ",  and it has many roles relating to the development of the fetus. Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal  epithelium and   cervical mucus, making it thick and impenetrable to sperm. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation . Normal menstrual bleeding is progesterone-withdrawal bleeding . If ovulation does not occur and the corpus luteum does not develop, levels of progesterone may be low, leading to  anovulatory dysfunctional uterine bleeding .

38. During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy. Progesterone decreases contractility of the uterine smooth muscle . In addition progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production. A drop in progesterone levels is possibly one step that facilitates the onset of labor.

39. Progesterone plays an important role in mammary gland development in females . In conjunction with prolactin, it induces lobuloalveolar maturation of the breasts during pregnancy to allow for milk production, and thus lactation and breastfeeding, after childbirth .

40. Progesterone, like  pregnenolone  and  dehydroepiandrosterone (DHEA ), belongs to an important group of endogenous steroids called  neurosteroids . It can be synthesized within the central nervous system and also serves as a precursor to another major neurosteroid ,  allopregnanolone . Neurosteroids are neuromodulators, and are  neuroprotective , neurogenic, and regulate neurotransmission and myelination .   The effects of progesterone as a neurosteroid are mediated predominantly through its interactions with non-nuclear PRs, namely the mPRs and PGRMC1.

41. Progesterone raises epidermal growth factor-1 (EGF-1) levels, a factor often used to induce proliferation. Progesterone increases core temperature ( thermogenic function) during ovulation . Progesterone reduces spasm and relaxes smooth muscle.  Bronchi are widened and mucus  regulated. (PRs are widely present in  submucosal tissue.) Progesterone acts as an anti inflammatory agent and regulates the immune response. Progesterone reduces gall-bladder  activity.

42. Progesterone normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy. Progesterone may affect gum health, increasing risk of gingivitis (gum inflammation). Progesterone appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen. Progesterone plays an important role in the signaling of insulin release and pancreatic function, and may affect the susceptibility to diabetes or gestational diabetes.

43. Actions ENDOMETRIUM: Progesterone causes secretory hypertrophy and decidual formation,if the endometrium has been previously primed with oestrogen . PREGNANCY: Progesterone initially from the corpus luteum and later from the placenta. Uterus: Progesterone cause myohyperplasia of the uterus. They increase the strength but diminish the frequency of uterine contraction.

44. FALLOPIAN TUBE: Progestogens cause hyperplasia of the muscular lining of the fallopian tube and make peristalatic contractions more powerful as well as increase the secretions by tubal mucous membrane. CERVIX: Progestogens cause hypertrophy of cervix and makes cervical mucous more viscus .it renders the internal os competent and holds the pregnancy at term

45. VAGINA : During early pregnancy the vagina becomes violet colored due to venous congestion. The epithelial cells fail to mature and cornified . They are classically basophilic with fairly large nuclei and folded edges. Karyopicnotic index falls below 10%. PITUTARY: The exact actions of progestogens on pituitary is not known. Progestogens may inhibit the production of FSH and suppress ovulation.

46. SMOOTH MUSCLE: progestogens relax smooth muscles ,the uterine muscles therefore relax in pregnancy. FLUID RETENTION : Progestogen cause water and sodium retention and is contributory factor in premenstrual tension and weight gain. ANABOLIC EFFECT: Progestogens exert anabolic effect and this partly accounts for some of the weight gain.

47. VIRILIZATION: While part of administrated progestrogen is metabolized oestrogen .,it is also partly metabolized to testosterone. If administrated to a patient during pregnancy some progestogens have virilizing effect upon a female foetus .

48. Metabolism It is metabolized in liver and excreated in the urine as sodium pregnanediol glucuronide. Natural progesterone is not active orally,and is given only by im injection in oil base. Progesterone acts on target tissues only when the latter are primed with oestrogen , as oestrogen produces progesterone receptors.

49. Progestogens are synthetic compounds belonging to two main groups.: The oestrone or 19-norprogestins which are structurally similar to testosterone and pregnane or 17-acetoxy compounda are mainly incorporated in oral contraceptive pills and pregnane compounds used in pregnancy and DUB.

50. Classification Pure progesterone Pregnane , lynestrenol . Estrane (derivatives of testosterone)– norethisterone,norethinyndiol . Gonane - levonorgestrel , norgestrel . Third generation progesterone- desogestrel,gestodene,norgestimate Hibrids - drospirenone

51. Classification of progestogens Progesterone derivative Progesterone content progesterone Natural progesterone Pregnane progestogens 17 α hydroxyl progesterone caproate Medroxy progesterone acetate Chlormanidone acetate Cyproterone acetate Norpregnane progestogens Nomegestrol acetate Gestonorone caproate Stereoisomer of progesterone: Retroprogesterone derivatives Dydrogesterone 19norprogesterone derivatives Demegestone Promegestone Nestorone Trimegestone

52. Alkyl derivatives of 19 nortestosterone A. Estrone steroids Norethisterone Norethisterone acetate Norethynodrel Ethynodiol diacetate Lynestrenol Norgestrel B.Gonane steroids Levonorgestrel Desogestrel Etonogestrel Gestodine Norgestimate Norelgestromin dienogest Spironolactone derivatives Drospirenone Unsaturated 19 norsteroid Gestrinone

53. Third generation progesterone are less androgenic and cause less metabolic disorders but increase the risk of thrombosis. Hibrids have anti androgen and anti mineralocorticosteroid efeect are used in premensural tension causes hyperkalemia by decreasing potassium excretion in the urine . less water retention and weight gain. They have no influence on lipid profile and have good control on mensural cycles.

54. Progesterons are administerd Orally Singly or with oestrogen Intra muscular injection monthly or three monthly as contraceptive. Implants,norplant Iucd impregnated with levonorgesterol progestasert , mirena Vaginal tables and rings Skin patches

55. Therapeutic applications Pure progesterones can be used in threatened and recurrent abortions and in corpus luteal phase deficiency. High dose of injections are used in advanced endometrial ca Contraception Dysfunctional uterine bleeding. Dysmenorrhoea , premensural tension syndrome Endometriosis Endometrial ablation in DUB Amenorrhoea ,progesterone challenge test Post coital pill with oestrogen in HRT Postponement of mensuration

56. contraindications Undiagnosed vaginal bleeding Breast cancer Breast tumor Thromboembolism

57. Side effects Nausea ,vomiting Head ache , mastalgia Water retention,cramps in the legs ,weight gain Hirsutism in androgen related compounds Depression Increased LDL and cardiovascular accidents Deep venous thrombosis ,pulmonary embolism with desogestrol and gestodene . Breast tumors and cancers