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Classification

Physiology/Endocrine Background

• Introduction
• Ovarian Function
  • Gonadal Activity Stages
  • Puberty: mechanisms leading to ovarian function
    • Onset: Role of Neuronal Maturation
  • One Year Later
  • The Cycle
  • Menopause
  • Anomalies in Ovarian Function
    • minor disturbances
    • common causes of chronic abnormalities

Estrogens

• Some commonly used estrogens
• Estrogen Biosynthesis/Metabolism
• Estrogenic activity
• Natural estrogens
• Anatomical site of estrogen synthesis
• Sources of natural estrogen
• Synthetic estrogen
• Pharmacokinetics
  • Conversion steps
  • Biliary excretion
• Physiological Effects
  • Mechanism: Sequence
    • Estrogen receptors
    • Estrogen-Estrogen-Receptor Complex
    • Hormone Action
    • Genomic Effects
    • Membrane Estrogen Receptors
  • Female Maturation
    • Stimulation-Development
    • Endometrial Effects
    • Metabolic Effects
    • Plasma Lipid Effects
  • Blood Coagulation
• Estrogen: Clinical Uses
  • Primary Hypogonadism
  • Treatment
  • Post-menopausal hormonal therapy
    • osteoporosis
  • Bone: Estrogen replacement
  • Cardiovascular Issue
  • Hot flushes
  • Atrophic vaginitis
  • Cancer
  • Alternatives to estrogen therapy
  • Miscellaneous Uses
• Estrogens: Adverse Effects
  • Cancer
  • Diethylstilbesterol
• Estrogens: Contraindications

• Progestins
  • Progestational Compounds
  • Progesterone
    • Synthesis
  • Synthetic progestins I
  • Pharmacokinetics
    • Hepatic metabolism
  • Physiological Mechanisms
    • Progesterone Effects: Metabolic
    • Other Progesterone Effects
    • Synthetic progestins II
  • Clinical Uses
    • Therapeutic Uses
    • Diagnostic Uses
• Other Ovarian Hormones
  • Testosterone
  • Inhibin & Activin
  • Relaxin
• Hormonal Contraception
  • Overview
  • Two types of preparations
  • Implants
    • Norgestrel
    • Medroxyprogesterone
  • Pharmacological Effects
  • Ovarian Effects
  • Uterine Effects
  • Effects on the Breast
  • CNS Effects
  • Endocrine Effects
  • Effects on Blood
  • Hepatic Effects
  • Effects on Lipid Metabolism
  • Effects on Carbohydrate Metabolism
  • Cardiovascular Effects
  • Skin
• Clinical Uses
  • oral contraception
  • endometriosis
  • dsymenorrhea
• Adverse Effects
  • Introduction
  • Mild Adverse Effects
  • Moderate Adverse Effects
  • Severe Adverse Effects
    • Venous Thromboembolism
    • Myocardial Infarction
    • Cerebrovascular Disease
    • Gastrointestinal Disorder
    • Depression
    • Cancer

Menu II

• Introduction: Ovary {Estrogens; Progestins; Other ovarian hormones; Oral contraceptives; Inhibitors & Antagonists, & Ovulation-Inducing Agents}
• Ovarian Function:gametogenic/hormonal activities
• Gonadal Activity Stages:
  • Quiescent time: rapid body growth; maturation
  • Puberty: initiation of ovarian cyclic function {menstrual cycle}; duration 30 to 40 years
  • Menopause: failure of ovarian responds to gonadotropins (anterior pituitary gland secretion) ® end of cyclic bleeding

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Puberty: Mechanism and ovarian function

•  Onset --Neuronal Mechanism: rationale
  • immature gonad already can be stimulated by gonadotropins (already in hypothalamus)
  • pituitary: already responsive to hypothalamic gonadotropin-releasing hormones
  • Consequently: amygdala maturation may result in:
    1.  removal of hypothalamic median eminence cellular inhibition
    2.  thereby permitting pulsed (with appropriate frequency & amplitude) gonadotropin-releasing hormone (GnRH) release
    3.  and resulting in stimulation of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release.
  •  FSH & LH release (initially small amounts) inducing estrogen secretion (small amounts) cause:
    1. breast development
    2. changes in adipose tissue distribution (fat distribution)
    3. growth spurt (ending in epiphyseal closure - long bones)

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• One Year Later:
  • increased estrogen levels induce:
    • endometrial change
    • periodic bleeding
  • Within a few cycles (perhaps anovulatory): normal cyclic function occurs

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• The Cycle:
  • Vesicular follicles (each containing an ovum) enlarge, responding to FSH
  • 5-6 days later: one follicle begins to mature more rapidly
    1.  this follicle's granulosa cells multiply
       • estrogen synthesis (LHinfluence) and release rate increases ­
       • estrogen reduces ¯ FSH release
       • estrogen causes  regression of smaller, less mature follicles
    2.  Ovarian Follicle -- Composition
       • ovum + fluid-filled antrum lined by theca and granulosa cells
       • Peak estrogen secretion: just before midcycle
         • granulosa cells  initiate progesterone secretion
         •  These effects induce:
           • the brief surge in LH/FSH release leading yo ovulation
    3.  Follicle ruptures:
       • Ovum released into abdominal cavity;near uterine tube
       • cavity of ruptured follicle:
         1. fills with blood (corpus hemorrhagicum)
         2. luteinized theca and granulosa cells proliferate
         3. these cells replace blood and form the corpus luteum
       •  Corpus luteum cells produce (for the remainder of the cycle or longer pregnancy obtains):
         • estrogens
         • progesterone
  • If pregnancy does not occur:
    • corpus luteum degeneration (hormone production stops)® corpus albicans
    • endometrium (which proliferated during follicular phase) is shed during menstruation

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• Menopause:
  • Cause:
    • ovarian follicle exhaustion
    • few, nonfunctional ova remain; supply exhausted because of:
      • ovulation during reproductive life
      • atresia (majority)
  • Endocrine consequences:
    • reduced estradiol/other hormone production
    • consequent negative feedback loss on hypothalamic-pituitary centers
    • consequent increase in plasma gonadotropins (FSH first and achieving high levels than LH which increases later)
  • Postmenopausal ovaries: small; residual cells: stromal
  • cyclic uterine bleeding stops
  • ending of ovarian gametogenic/endocrine secretory function
  • mean age: 52 years (U.S.)
  • Estrogen levels may persist due to:
    • adrenal/ovarian steroid conversion. Examples:
      • androstenedione leading to estrone and estradiol (in adipose, perhaps other nonendocrine tissues)
  • Preceding menopause:
    • longer intervals between menses
    • increased plasma FSH and LH levels
    • Ovary: less responsive to gonadotropins

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• Anomalies in Ovarian Function:
  • Cyclic function disturbances: -- Possible causes
    • Some anomalies (minority) due to:
      •  inflammatory/neoplasms destroy: ovaries, uterus or pituitary
    •  Minor disturbances (amenorrhea/anovulatory periods) -- self-limiting. Maybe associated with: emotional or environmental changes
      •  Disorders induce alterations in control of hypothalamic releasing factor secretion
      • Anovulatory disturbance associated with:
        •  excessive dieting
        •  extreme exercise-- e.g. distance running
    •  Common causes of chronic ovulatory anomalies:
      • Pituitary prolactinomas
      • Tumor/syndromes can cause excessive ovarian/adrenal androgen production
        • Androgens (e.g.,from adrenocortical sources) may modify normal ovarian function
        • Ovarian tumors may be androgen-producing:
          • arrhenoblastomas
          • Leydig cell tumors
          • estrogen-producing granulosa cell tumors

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