Kuliah Pakar Gangguan Haid_ Biokimia

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ASPEK BIOKIMIA HORMON SEX WANITA

(the female sex hormones)

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Diagram of hypothalamic-pituitary-ovarian axis (an overview)

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3 types ovarian steroid hormones

• Estrogen : the granulosa cells

• Progestagens :corpus luteum

• Androgens :the thecal and stromal cells

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Ovarian steroid hormones

• Belong to a large family of steroid compounds• Composition is based on : a four ring structure, containing :

- 3 cyclohexane rings (A,B,C)- 1 cyclopentana ring (D)

• Clasified on the basis of their structure and principal biological function. 3 major types : Estrogens, progestagens, and androgens.

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Structural formulas of Estrogens

• Are C18-steroids• Structurally, estrogens are derivatives of the parent hydrocarbon estrane,

which is an 18-carbon molecule with an aromatic ring A and a methyl group at C-13

• Estrogens possess a phenolic hydroxyl group at C-3, which gives the compounds acidic properties

• The phenolic ring A and the oxygen function at C-17 are essential for biological activity

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Structural formulas of Estrogens

• Do not possess a methyl group at C-10 (as do androgens)• May possess a ketone (estrone) or hydroxyl group (estradiol) at C-17 and

frequently at C-16 (estriol). More than 20 estrogens have been identified, but only l7β-estradiol (also denoted as E2) and estriol (also denoted as E3) are routinely measured clinically.

• The principal and most potent estrogen is estradiol-17β

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Sturctural formulas of important estrogens

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Estrogen biosynthesis• Source : - Non pregnant women : ovary (the majority) and

adrenals- Pregnant women : placenta (major source)- Post-menopausal women : almost all by the adrenals

• Acetate, cholesterol, progesterone and testosterone can all serve as precursors of estrogen.

• Cholesterol is derived from circulating plasma lipoproteins or stored lipid in adipose tissue

• LDL is the primary source• The rate-limiting step is the initial conversion of cholesterol to

pregnenolone.• FSH and LH are required for estrogen synthesis.

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Estrogen biosynthesis in the human ovary

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Estradiol metabolism

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Estrogen production

• In the normal, nonpregnant woman, estradiol is produced at the rate of 100 to 300µg/day.

• The production of estrone ranges from 100 to 200 µg/day.

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Transport of estrogen hormones

• Steroid transport molecules include specific globulins and albumin

• Sex hormone-binding globulin (SHBG) : - β-globulin - synthesized by the liver - high affinity, low capacity binding

• Albumin : low affinity, high capacity• Plasma estradiol bound to : - Albumin ±60%

- SHBG ±38% - free 2-3%

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Structural formula of Progesterone

• Progesterone (pregn-4-ene-3,20-dione) is a carbon 21 (C21) steroid compound with a molecular weight 314,47 daltons.

• The progestational activity is characterized by a keto group at C3 and a double bond between C4 and C5 (delta 4 - ∆4),

• The two-carbon side chain (CH3CO) on C-17 is not thought to be important for its physiological action

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Progesterone biosynthesis• Source : - Non pregnant women : ovary (the majority) and

adrenals- Pregnant women : placenta (major source)

- Post-menopausal women : almost all by the adrenals

• Progesterone hormones are synthesized from cholesterol through pregnenolone, and this cholesterol is taken from the circulation in the form of low-density lipoprotein cholesterol (LDL)

• Initiation and control of luteal secretion of progesterone are regulated by LH and FSH.

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Progesterone biosynthesis

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Transport of progesterone hormones

• Progesterone is only slightly soluble in blood, due to its hydrophobic cyclopentanophenanthrene ring structure, and is therefore bound to cortisol-binding globulin (transcortin) for transport.

• This binding affinity is relatively low, and therefore progesterone is rapidly cleared from blood

• Production rate:fertile women = 0.8-2.5 mg/day during follicular phase,

15-50 mg in the luteal phase

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Metabolism of progesterone• Progesterone is degraded in

the liver to inactive metabolites through conjugation with glucuronic acid, which are excreted in urine as water-soluble glucuronides.

• Based on the degree of reduction, there are three groups of progesterone metabolites : 1. pregnanediones 2. pregnanolones3. pregnanediols

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Structural formula of Androgen

• Androgen is a 19-carbon steroid, with a molecular weight 288,42 daltons

• Ovarian theca cells secrete androgens, including :- testosterone - androstenedione (converted metabolically to testosterone and the parent structure of estrone)- Dehydroepiandrosterone (DHEA) : the primary precursor of estrogens

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Androgen biosynthesis

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Metabolism of androgen

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Transport of androgen hormones

• The binding proteins include the specific sex hormone binding globulins (SHBG) and albumin

• SHBG : high affinity, low capacity binding• Albumin : low affinity, high capacity• In women, testosterone is bound to : - SHBG ± 66-78%

- Alb ±20-30% - free 2-3%

• Production rate : - testosterone 0.25 mg/day - androstenedione 3 mg/day (cycling)

1.6 mg/day (menopause) - DHT 0.056 mg/day

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Mechanisms of action of steroid hormones

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Estrogen and progesterone changes during the normal menstrual cycle

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Estrogen and progesterone changes during the normal menstrual cycle

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Estrogen’s metabolic effects

• Regulate menstrual cycle• Stimulate proliferation of endometrium• Affect calcium homeostasis and have a beneficial effect on

bone mass• Develop of secondary female sex characteristics e.g. fat

distribution, breasts, body hair• Increase concentrations of SHBG, corticosteroid-binding

globulin and thyroxine-binding globulin• Play a preventive role in coronary heart disease

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Progesterone’s metabolic effects

• Prepare uterus for pregnancy• Promotes implantation of fertilized egg• Maintain the pregnancy • Develop mammary glands

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Androgen’s metabolic effects

• Mainly to be converted into estrogen• Prevent bone loss, as well as sexual desire and satisfaction• Develop of secondary female sex characteristics, e.g. hair

growth in the pubic and underarm areas

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Thank You