Lecture 4 Endo

Bioregulation: Synthesis, Metabolism, and Action of Steroid Hormones and Thyroid Hormones

Overview of Endocrine Components and Activity

• Bioregulation: The regulation of biological function at the hormonal level, including the synthesis, metabolism, and action of specific groups of hormones.

• Types of Hormones:

  • Steroid Hormones

  • Thyroid Hormones

Key Glands and Hormones in The Endocrine System

• Adrenal Cortex

  • Produces steroid hormones such as cortisol, aldosterone, and androgens.

• Pituitary Gland

  • Anterior Pituitary: Secretes ACTH, GH, TSH, MSH, prolactin, and FSH/LH (gonadotropins).

  • Posterior Pituitary: Releases oxytocin and ADH (antidiuretic hormone).

• Kidney: Involved in the action of hormones such as ADH.

• Target Organs: Hormonal action occurs in the skin, bone, muscle, breast, testis, and ovary.

Steroid Hormones

Structure of Steroid Nucleus

• Stereoisomers: The different spatial arrangements of the same atoms.

• Delta 4: Describes the double bond between Carbon 4 and Carbon 5.

• Visual Representation: Reference Figure 3-17 for detailed structure.

Synthesis Pathways

• Progesterone Synthesis Pathway:

  • Progresses through various enzymatic steps.

  • Reference Figure 3-22 detailing the pathway.

• Corticosteroid Synthesis from Progesterone: Details on how progesterone is converted into corticosteroids. Reference Figure 3-23.

• Androgen Synthesis:

  • Key Steps:

  • Begins with Pregnenolone.

  • Pathways include the A5-pathway leading to DHEA and the A4-pathway leading to Testosterone.

  • Enzymes Involved:

  • 38-HSD, P450c17, 3β-HSD.

  • Final Products: Testosterone (T), Dehydroepiandrosterone (DHEA), 5α-Dihydrotestosterone (DHT), etc.

  • Reference the figures detailing synthesis processes between pages 5 and 6.

Estrogen Synthesis

• Synthesis of Estrogens from Androgens:

  • Involves conversion of testosterone to estradiol through the activity of aromatase.

  • the knowledge of steroid metabolites allows scientists to better understand the nuances of hormone regulation and potential therapeutic targets in conditions related to estrogen imbalance. This pathway highlights the importance of androgen conversion in various tissues, including the ovaries, adrenal glands, and adipose tissue, which can significantly influence reproductive health and hormonal balance.

  • Reference to Figure 3-25.

  • the definition of steroid metabolites is a broad term that refers to the various byproducts formed during the metabolic processing of steroid hormones, which can influence physiological functions and the biosynthesis of other hormones.

Hormone Transport and Binding

Steroid Hormone Carrier Proteins

• Types of Carrier Proteins:

  • Corticosteroid Binding Globulin (CBG): Carries glucocorticoids.

  • Sex Hormone Binding Globulin: Transports estradiol and testosterone.

  • Thyroid Binding Globulin: Binds thyroid hormones.

• Key Concept: Any free hormone not utilized by target cells is excreted.

Chaperone Proteins and Hormonal Action

• Role of Chaperone Proteins:

  • Also referred to as ‘Heat Shock Proteins’, they are bound to unoccupied receptors.

  • Release upon hormone binding to facilitate the formation of zinc finger proteins that assist in transcription processes.

• Glucocorticoid Receptor with HSP90: The complex involved in steroid hormone signaling.

• homodimers vs heterodimers in the context of hormone receptors play a significant role in the regulation of gene expression; homodimers consist of two identical receptor molecules, while heterodimers are formed by two different types of receptors, often leading to distinct functional outcomes in transcriptional regulation.

Mechanism of Steroid Hormone Action

• Activation Mechanism: Encompasses hormone-response elements that facilitate genomic actions of steroid-activated transcription factors.

  • Reference Figure 3-26 for detailed visual explanation.

  • Zinc Fingers: Conformational structures allowing binding to DNA. Reference Figure 3-28 for structure and function.

Thyroid Hormones

Synthesis of Thyroid Hormones

• Formation: Thyroid hormones (T3 and T4) are synthesized from thyroglobulin by follicular cells in the thyroid gland, utilizing iodine, specifically through the action of the enzyme thyroid peroxidase (TPO).

• Key Components:

  • Mono-iodotyrosine (MIT), Di-iodotyrosine (DIT), and how they combine to form T3 (3,5,3'-Triiodothyronine) and T4 (3,5,3',5'-Tetraiodothyronine).

Thyroid Hormone Action

• Mechanism of Action:

  • Hormones travel via blood to target cells, producing various metabolic effects, including increased protein synthesis through thyroid hormone response elements (TRE).

  • Reference to Figure 3-33 outlining these mechanisms.

  • Mention of deiodination processes, especially in peripheral tissues, is significant for T4 conversion to the more active T3 form.

Understanding and Applications

• Questions for Understanding:

  • How do second messengers amplify signals in the absence of nuclear receptors?

  • What do elevated levels of aromatase indicate?

  • How can steroid hormones function through membrane receptors?

  • Implications of knowing steroid metabolites for research purposes.

  • Mechanisms of removal for glucuronides pertaining to steroid hormones.

• Environmental Considerations:

  • Bacteria in wastewater treatment and implications for gluconates/sulfates in endocrine disruption.

Summary

• Key Takeaways:

  • Understanding the synthesis, metabolism, and mechanisms of steroid and thyroid hormones is crucial in biomedicine and endocrinology.

  • The roles these hormones play have far-reaching effects on various bodily functions, from metabolism to reproductive health.

1⃣ Gluconate conjugates with estrogens or progesterone to form glucuronides (water-soluble). How are these removed from the body?

When steroid hormones like estrogen or progesterone are no longer needed, they are metabolized in the liver.

One major pathway is glucuronidation:

• The liver attaches glucuronic acid to the hormone.

• This forms a glucuronide conjugate.

• The conjugated hormone becomes water soluble.

Because steroid hormones are normally lipid-soluble, they cannot easily be excreted in urine. Making them water-soluble allows the body to eliminate them.

These glucuronides are removed by:

➤ Kidneys → Urine

Water-soluble conjugates circulate in blood and are filtered out by the kidneys.

➤ Bile → Feces

Some are secreted into bile, enter the intestine, and leave in feces.

So the key answer:

2⃣ Bacteria in wastewater treatment plants remove gluconates/sulfates. What effect does this have?

When humans excrete hormone conjugates (glucuronides or sulfates), they enter wastewater.

Certain bacteria in wastewater treatment plants:

• Break the conjugated bond

• Remove the glucuronide or sulfate group

• Convert the hormone back into its active (lipid-soluble) form by removing the polar groups, allowing it to re-enter cellular membranes and engage with specific hormone receptors.

This process can:

• Reactivate steroid hormones

• Allow them to re-enter the environment

• Contribute to endocrine disruption in aquatic organisms

For example:

• Fish exposed to reactivated estrogens may develop reproductive abnormalities.

So the effect is:

3⃣ Which hormone is most prone to endocrine mimicking compounds?

all sex hormones have homodimers

The hormone most vulnerable to endocrine mimics is:

➤ Estrogen

Specifically:

• Estradiol

Why?

• Estrogen receptors are less structurally selective.

• Many environmental chemicals resemble estrogen’s structure.

• Estrogen receptors strongly influence development and reproduction.

Common endocrine mimics include:

• BPA

• Phthalates

• Certain pesticides

These compounds bind estrogen receptors and mimic or block estrogen’s effects.

So the answer is:

4⃣ Where does most deiodination of Thyroxine (T4) occur, and what happens after?

The cytoplasm of the target cell is where most deiodination of Thyroxine (T4) occurs, converting it to its more active form, Triiodothyronine (T3), which then enters the nucleus to regulate gene expression.

Thyroid hormones are released mainly as:

• Thyroxine (T4)

T4 is mostly inactive (prohormone form).

The majority of deiodination occurs in:

➤ Peripheral tissues (especially the liver and kidneys)

An enzyme called type 1 or type 2 deiodinase removes one iodine atom from T4.

This converts T4 into:

• Triiodothyronine (T3)

T3 is the active form of thyroid hormone.

After conversion:

• T3 enters cells

• Binds thyroid hormone receptors in the nucleus

• Alters gene transcription

• Increases metabolism, protein synthesis, and energy use

Some T4 can also be converted into:

• Reverse T3 (rT3) — inactive form

So the summary:

Quick Summary Table

Second messengers provide amplification of signal. Without second messengers how does signal become amplified with nuclear receptors?

 What would high levels of aromatase indicate?

 Steroid Hormones also appear to work through membrane receptors. How do we know this?

 What does the knowledge of steroid metabolites allow scientists to do?