Estrogen and Progesterone

1. Estrogen and Progesterone 부산백병원 산부인과 박영미

2. Natural human steroid hormones • Glucocorticoids • cortisol • Mineralocorticoids • aldosterone • Sex steroids • Androgens • Estrogens • Progestagens

3. Androgens • testosterone • dehydroepiandrosterone (DHEA) • dehydroepiandrosterone sulfate (DHEAS) • androstenedione • dihydrotestosterone (DHT) • Estrogens • estradiol • estrone • estriol • Progestagens • progesterone

5. Estrogen

6. Estrogens are a group of steroid compounds, functioning as the primary female sex hormone. • oral contraceptives • estrogen replacement therapy in post menopausal women • hormone therapy for transsexual women • Like all steroid hormones, estrogens readily diffuse across the cell membrane; inside the cell, they interact with estrogen receptors.

7. Functions : Significantly higher levels in women of reproductive age • The development of female secondary sex characteristics, such as breasts • The thickening of the endometrium • Regulating the menstrual cycle. • In males • maturation of sperm • healthy libido

8. Structural • promote formation of female secondary sex characteristics • stimulate endometrial growth • increase uterine growth • maintenance of vessel and skin • reduce bone resorption, increase bone formation • Protein synthesis • increase hepatic production of binding proteins • Coagulation • increase circulating level of factors 2,7,9,10, antithrombin III, plasminogen • increase platelet adhesiveness

9. Lipid • increase HDL, triglyceride, fat deposition • decrease LDL • Fluid balance • salt and water retention • Gastrointestinal tract • reduce bowel motility • increase cholesterol in bile • Cancer • About 80% of breast cancers rely on supplies of the estrogen to grow. • Increased risk of developing endometrial cancer has been noted with increased levels of natural estrogen • Suppression of production of estrogen is a treatment for these cancers.

10. Types of estrogen • The three major naturally occurring estrogens : estradiol, estriol, estrone • From menarche to menopause : the primary estrogen is 17β-estradiol • In postmenopausal women : more estrone is present than estradiol. • Estradiol is produced from testosterone and estrone from androstenedione. • Estrone is weaker than estradiol.

11. Estradiol

12. Production • During the reproductive years, most estradiol is produced by the granulosa cells of the ovaries • by the aromatization of androstenedione to estrone • by conversion of estrone to estradiol by 17β-hydroxysteroid reductase • Smaller amounts of estradiol are also produced by the adrenal cortex, and (in men), by the testes. • Also produced in the brain and in arterial walls. • In particular, fat cells are active to convert precursors to estradiol, and will continue to do so even after menopause.

13. Effects • Female reproduction • Growth hormone for tissue of the reproductive organs, • supporting the lining of the vagina, the cervical glands, the endometrium and the fallopian tubes • enhances growth of the myometrium • Maintain oocytes in the ovary • During the menstrual cycle, luteinizing hormone surge, inducing ovulation • In the luteal phase estradiol, prepares the endometrium for implantation

14. Sexual development • The development of secondary sex characteristics in women is driven by estrogens, specifically estradiol • breast development • changes in the body shape affecting bones, joints, fat deposition, fat structure and skin composition • These changes are • initiated at the time of puberty • most enhanced during the reproductive years • less pronounced with declining estradiol support after the menopause.

15. Bone • Individuals without estradiol (or other estrogens) • tall and eunuchoid as epiphysieal closure is delayed or may not take place. • bone structure is affected resulting in early osteopenia and osteoporosis. • Women past menopause • accelerated loss of bone mass due to a relative estrogen deficiency.

16. Brain • Estrogens can be produced in the brain from steroid precursors. • As an antioxidant, they have been found to have neuroprotective function. • The positive and negative feedback loop of the menstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropins.

17. Blood vessels • Improvement in arterial blood flow has been demonstrated in coronary arteries. • Oncogene • Estradiol supports certain cancers, notably breast cancer and cancer of the uterine lining. • Several benign gynecologic conditions that are dependent on estrogen such as endometriosis, leiomyoma, and uterine bleeding

18. Liver • It can lead to cholestasis • It affects the production of multiple proteins including lipoproteins, binding proteins, and proteins responsible for blood clotting • Pregnancy • The effect of estradiol, together with estrone and estriol, in pregnancy is less clear. • Promote uterine blood flow, myometrial growth, • Sitmulate breast growth and • At term, promote cervical softening and expression of myometrial oxytocin receptors

19. Therapy • Hormone replacement therapy • Severe side effects of low levels of estradiol in a woman's blood : Often such therapy is combined with a progestin • Treatment of infertility in women when there is a need to develop sperm-friendly cervical mucus or an appropriate uterine lining. • Maintain female hormone levels in male-to-female transsexuals.

20. Hormonal contraception • A synthetic form of estradiol, called ethinylestradiol is a major component of hormonal contraceptive devices • Combined forms of hormonal contraception contain ethinylestradiol and a progestin • the inhibition of GnRH, LH, and FSH. • prevent ovulation and thus prevent pregnancy • Other types of hormonal birth control contain only progestins and no ethinylestradiol.

21. List of estradiol medications • Oral versions : Estrace®, Activella®, Progynova®, estrofem® • Transdermal preparation : Alora®, Climara®, Vivelle®, Menostar®, Estraderm TTS® • Ointments : Estrasorb Topical®, Estrogel® • Injection : Lunelle® monthly injection • Vaginal ointment : Estrace Vaginal Cream®, Premarin Cream® • Vaginal ring : Estring® • Conjugated estrogen preparations : Premarin®.

22. Contraindications • women who are pregnant or are breastfeeding • women with unexplained uterine bleeding • certain forms of cancer • prone to blood clotting disorders • Side effects • uterine bleeding • breast tenderness • nausea and vomiting • chloasma • cholestasis • migraine headaches

23. Estrone

24. Estrone is produced primarily from androstenedione originating from the gonads or the adrenal cortex • In premenopausal women : more than 50% of the estrone is secreted by the ovaries • In prepubertal children, men and non-supplemented postmenopausal women : the major portion of estrone is derived from peripheral tissue conversion of androstenedione • Interconversion of estrone and estradiol : occurs in peripheral tissue

25. Bioassay data : the estrogenic action of estrone is much less than estradiol • Estrone is primary estrogenic component of several pharmaceutical preparations, including those containing conjugated and esterified estrogens • In premenopausal women : estrone levels generally parallel those of estradiol • After menopause : estrone levels increase, possibly due to increased conversion of androstenedione to estrone

26. Estriol

27. Estriol is produced almost exclusively during pregnancy • Estriol is the major estrogen produced in the normal human fetus • During pregnancy the production of estriol depends on an intact maternal-placental-fetal unit • Fetal-placental production of estriol leads to a progressive rise in maternal circulating levels reaching a late-gestational peak several orders of magnitude greater than non-pregnant levels

28. Estriol has been suggested to be less carcinogenic than estradiol and estrone in animal studies. • At doses effective for the relief of postmenopausal symptoms, estriol does not induce endometrial proliferation to the extent of the other estrogens. • Topical estriol : postmenopausal genital atrophic changes : urinary incontinence.

29. Estrogen receptor

30. Distribution All the ERs are widely distributed. • The ERα is found in endometrium, breast cancer cells, ovarian stroma cells, the hypothalamus. • TheERβ has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, endothelial cells.

31. Binding affinity Different estrogenic compounds have different binding affinities for alpha and beta ERs: • 17-beta-estradiol binds equally well to both receptors. • estrone and raloxifene bind preferentially to the alpha receptor. • estriol to the beta receptor.

32. Selective estrogen receptor modulators (SERM) : the concept is based on the ability to selectively activate or block one type of ER • Tamoxifen : ER agonist in bone and uterus : ER antagonist in breast tissue -> used as a breast cancer treatment

33. Disease : Cancer • Estrogen receptors are overexpressed in around 70% of breast cancer cases, referred to as "ER positive". • Two hypotheses have been proposed to explain why this causes tumorigenesis • Firstly, binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication leading to mutations • Secondly, estrogen metabolism produces genotoxic waste

34. The result of both processes : disruption of cell cycle, apoptosis and DNA repair -> tumor formation • ERα is certainly associated with more differentiated tumors, while evidence that ERβ is involved is controversial. • Different versions of the ESR1 gene : associated with different risks of developing breast cancer. • Estrogen and the ERs have also been implicated in ovarian cancer, endometrial cancer, colon cancer, prostate cancer

35. Progesterone

36. C-21 steroid hormone : involved in the female menstrual cycle, pregnancy and embryogenesis • Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen. • Progesterone should not be confused with progestins, which are synthetically produced progestogens

37. Synthesis • Synthesized from pregnenolone, a derivative of cholesterol • The precursor of the mineralocorticoid aldosterone • Conversion to 17-hydroxyprogesterone of cortisol and androstenedione. • Androstenedione can be converted to testosterone, estrone and estradiol.

38. Sources • Progesterone is produced in the adrenal glands, the gonads the brain, and, during pregnancy, in the placenta. • Increasing amounts are produced during pregnancy : • Initially, the source is the corpus luteum • After the 8th week production of progesterone shifts over to the placenta • The placenta utilizes maternal cholesterol as the initial substrate, • most of the produced progesterone enters the maternal circulation • some is picked up by the fetal circulation and is used as substrate for fetal corticosteroids. • At term the placenta produces about 250 mg progesterone per day.

39. Effects • Reproductive system : "hormone of pregnancy” : many roles relating to the development of the fetus • Converts the endometrium to secretory stage to prepare the uterus for implantation • Affects the vaginal epithelium and cervical mucus • If pregnancy does not occur, progesterone levels will decrease, leading to menstruation • Normal menstrual bleeding is progesterone withdrawal bleeding.

40. 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.

41. Nervous system • Progesterone belongs to the group of neurosteroids that are found in high concentrations in certain areas in the brain and are synthesized there. • Neurosteroids affect synaptic functioning, are neuroprotective, and affect myelinization. They are investigated for their potential to improve memory and cognitive ability. • Progesterone as a neuroprotectant affects regulation of apoptotic genes. Its effect as a neurosteroid works predominantly through the GSK-3 beta pathway, as an inhibitor.

42. Other systems • It raises epidermal growth factor-1 levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells • It increases core temperature during ovulation. • It reduces spasm and relaxes smooth muscle. • It acts as an antiinflammatory agent and regulates the immune response. • It reduces gall-bladder activity

43. It normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy • It assists in thyroid function, in bone building by osteoblasts, in bone, teeth, gums, joint, tendon, ligament and skin resilience by regulating various types of collagen, and in nerve function and healing by regulating myelin • It appears to prevent endometrial cancer by regulating the effects of estrogen

44. Medical applications • Both to address acute situations, and to address the long-term decline of natural progesterone levels • Because of the poor bioavailability of progesterone when taken orally, many synthetic progestins have been designed • However, the roles of progesterone may not be fulfilled by the synthetic progestins which in some cases were designed solely to mimic progesterone's uterine effects

45. Progesterone is used • to control anovulatory bleeding. • to prepare uterine lining in infertility therapy • recurrent pregnancy loss due to inadequate progesterone production • Progesterone is being investigated as potentially beneficial in treating multiple sclerosis • Progesterone receptor antagonists, SPRM (RU-486) can be used to prevent conception or induce medical abortions • Progesterone is used in hormone therapy for transsexual women, and some intersex women - especially when synthetic progestins have been ineffective or caused side-effect