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Medical BiochemistryMedical Biochemistry

Sarah J. Breese McCoy, Ph.D.

December 9, 2005

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Biochemistry of Hormones II: Biochemistry of Hormones II: Steroid HormonesSteroid HormonesOverview/Clinical CorrelationsOverview/Clinical Correlations

Chapter 22

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Overview: Steroid SynthesisOverview: Steroid Synthesis

All steroid hormones are made from pregnenolone.

Pregnenolone is made from cholesterol.

Cholesterol is made acetyl CoA (20%) or absorbed ready-made from diet (80%).

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Overview: Steroid SynthesisOverview: Steroid Synthesis

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Overview: Steroid SynthesisOverview: Steroid Synthesis

Cholesterol (C 27)

Pregnenolone (C 21)

Progesterone (C 21)

Aldosterone (C 21)

Cortisol (C 21)

Androgens (C 19)

Estrogens (C 18)

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Overview: Steroid SynthesisOverview: Steroid Synthesis

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Clinical Correlate: Clinical Correlate: Congenital Adrenal HyperplasiaCongenital Adrenal Hyperplasia

21B hydroxylase deficiency

Adrenals cannot make enough glucocorticoids or mineralocorticoids.

Female fetuses are virilized.

Salt wasting or hypoglycemia can be fatal w/o treatment.

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Overview: Steroid Mech. Action, Overview: Steroid Mech. Action, Positive Transcriptional EffectPositive Transcriptional Effect

Enter cell Bind to receptor; dimerize Enter nucleus Attach to DNA in promoter region, upstream of

gene to be copied Stimulate transcription of the gene Translation of mRNA into protein Protein (enzyme or receptor) affects cell

metabolism

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Clinical Correlate: Vitamin Clinical Correlate: Vitamin DD

Vit D induces the synthesis of Ca-binding protein (calbindin 9K) in enterocytes, which aids in the absorption of Ca from the intestinal lumen.

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Clinical Correlate: Vitamin Clinical Correlate: Vitamin DD

Vit D deficiency in children leads to rickets, a calcium deficiency marked by malformed, “soft” bones.

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Clinical Correlate: AldosteroneClinical Correlate: Aldosterone

Aldosterone from the adrenal cortex stimulates renal tubule cells to (1) make more Na+ channels, (2) make more Na+/K+ pumps, and (3) make more mitochondrial enzymes for ATP synthesis (to run the Na+/K+ pumps).

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Clinical Correlate: AldosteroneClinical Correlate: Aldosterone

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Clinical Correlate: T3/T4Clinical Correlate: T3/T4

In muscle, liver, and kidney, T3 induces the synthesis of Na-K pumps and probably also ATPase, which break down ATP to release energy to run the pumps.

Thus, more ATP/O2 are consumed and BMR ↑.

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Clinical Correlate: T3/T4Clinical Correlate: T3/T4

In Graves Disease, the thyroid makes too much T3/T4.

Two of the symptoms related to the mechanism on the previous slide are heat intolerance and weight loss without dieting.

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Overview: Steroid Mech. Action, Overview: Steroid Mech. Action, Negative Transcriptional EffectNegative Transcriptional Effect

Enter cell Bind to receptor; dimerize Enter nucleus1. Attach to DNA, displacing a positive

transcription factor, stopping production of some protein, OR

2. Attach directly to positive transcription factor, blocking its binding to DNA

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Overview: Steroid Mech. Action, Overview: Steroid Mech. Action, Negative Transcriptional EffectNegative Transcriptional Effect

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Clinical Correlate: Clinical Correlate: Oral ContraceptionOral Contraception

Review: GnRH (hyp) → FSH/LH (pit) → ovulation (ovary)

Birth control pills contain steroids that suppress ovulation by preventing the hypothalamus from releasing GnRH.

GnRH production is the result of transcription/translation of the KISS-1 gene in the hyp neuron cell nucleus.

High, sustained levels of estrogens, progestins, or androgens serve as negative transcriptional factors for KISS-1 gene transcription.

Bottom line: No KISS-1 gene transcription → no kisspeptin protein production→ no GnRH release→ no LH release→ no ovulation→ no pregnancy

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Bottom Line for Medical BiochemBottom Line for Medical Biochem

It is easier to diagnose and treat disease if you fully understand the relevant biochemistry.

Learning concepts is more important than memorizing details.