1. 1 Medical Biochemistry Sarah J. Breese McCoy, Ph.D. December 9, 2005

2. 2 Biochemistry of Hormones II: Steroid Hormones Overview/Clinical Correlations Chapter 22

3. 3 Overview: Steroid Synthesis u All steroid hormones are made from pregnenolone. u Pregnenolone is made from cholesterol. u Cholesterol is made acetyl CoA (20%) or absorbed ready-made from diet (80%).

4. 4 Overview: Steroid Synthesis

5. 5 Cholesterol (C 27) Pregnenolone (C 21) Progesterone (C 21) Aldosterone (C 21) Cortisol (C 21) Androgens (C 19) Estrogens (C 18)

6. 6 Overview: Steroid Synthesis

7. 7 Clinical Correlate: Congenital Adrenal Hyperplasia u 21B hydroxylase deficiency u Adrenals cannot make enough glucocorticoids or mineralocorticoids. u Female fetuses are virilized. u Salt wasting or hypoglycemia can be fatal w/o treatment.

8. 8 Overview: Steroid Mech. Action, Positive Transcriptional Effect u Enter cell u Bind to receptor; dimerize u Enter nucleus u Attach to DNA in promoter region, upstream of gene to be copied u Stimulate transcription of the gene u Translation of mRNA into protein u Protein (enzyme or receptor) affects cell metabolism

9. 9

10. 10 Clinical Correlate: Vitamin D u Vit D induces the synthesis of Ca- binding protein (calbindin 9K) in enterocytes, which aids in the absorption of Ca from the intestinal lumen.

11. 11 Clinical Correlate: Vitamin D u Vit D deficiency in children leads to rickets, a calcium deficiency marked by malformed, “soft” bones.

12. 12 Clinical Correlate: Aldosterone u 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).

13. 13 Clinical Correlate: Aldosterone

14. 14 Clinical Correlate: T3/T4 u 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. u Thus, more ATP/O 2 are consumed and BMR ↑.

15. 15 Clinical Correlate: T3/T4 u In Graves Disease, the thyroid makes too much T3/T4. u Two of the symptoms related to the mechanism on the previous slide are heat intolerance and weight loss without dieting.

16. 16 Overview: Steroid Mech. Action, Negative Transcriptional Effect u Enter cell u Bind to receptor; dimerize u Enter nucleus 1. 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

17. 17 Overview: Steroid Mech. Action, Negative Transcriptional Effect

18. 18 Clinical Correlate: Oral Contraception u Review: GnRH (hyp) → FSH/LH (pit) → ovulation (ovary) u Birth control pills contain steroids that suppress ovulation by preventing the hypothalamus from releasing GnRH. u GnRH production is the result of transcription/translation of the KISS-1 gene in the hyp neuron cell nucleus. u High, sustained levels of estrogens, progestins, or androgens serve as negative transcriptional factors for KISS-1 gene transcription. u Bottom line: No KISS-1 gene transcription → no kisspeptin protein production→ no GnRH release→ no LH release→ no ovulation→ no pregnancy

19. 19 Bottom Line for Medical Biochem u It is easier to diagnose and treat disease if you fully understand the relevant biochemistry. u Learning concepts is more important than memorizing details.