liseje Male Gonadal Hormones: Biosynthesis, Metabolism, and Pharmaceutical Agents

Learning Objectives for Male Gonadal Hormones

Biosynthesis Review: Examination of how gonadal steroid hormones are biosynthesized beginning with cholesterol and the key enzymes involved in their metabolism.
Enzymatic Roles: Understanding the role of $5\alpha\text{-reductase}$ and aromatase inhibitors in hormonal pathways.
Pharmacology of Testosterone Derivatives: Background on specific drugs including testosterone propionate, testosterone cypionate, and testosterone ethanate.

General Overview of Gonadal Steroid Hormones

Definition: Hormones that affect the development of reproductive organs and sexual characteristics.
Anatomical Context (Male): * Penis * Bladder * Lymph nodes * Seminal vesicle * Rectum * Prostate gland * Urethra * Epididymis * Testicle * Scrotum
Anatomical Context (Female): * Lymph nodes * Uterus * Ovaries * Fallopian tubes * Vagina

Reference Materials for Steroid Hormones

Primary References: * Goodman & Gillman's: The Pharmacological Basis of Therapeutics, 13th Edition, Chapters 44, 45, and 46. * Foye’s Principles of Medicinal Chemistry, 7th Edition, Chapter 28. * Biochemistry, 8th Edition (2015), Chapter 26, pages 789-794 (Berg, Tymoczko, Gatto, Jr., and Stryer).

Steroid Hormones Nomenclature and Carbon Classification

Origin: All sex steroids are cholesterol derivatives containing $27$ carbons ( $C_{27}$ ).
Structural Groups by Carbon Count: * 21 Carbons ( $C_{21}$ ): Pregnane derivatives, which include Progestins and Corticoids. * 19 Carbons ( $C_{19}$ ): Androstaten derivatives, which include Androgens. * 18 Carbons ( $C_{18}$ ): Estrane derivatives, which include Estrogens.

Corticosteroid Biosynthesis in the Adrenal Gland

General Features: * Synthesis occurs in different zones of the adrenal gland. * The zona glomerulosa (orange box) unique pathways synthesize mineralocorticoids. * The inner zona fasciculata and zona reticularis (gray box) pathways are involved in glucocorticoid and androgen precursor synthesis.
Zona Reticularis Specificity: This zone does not express $3\beta\text{-HSD}$ ( $3\beta\text{-hydroxysteroid dehydrogenase}$ ) and thus preferentially synthesizes DHEA (Dehydroepiandrosterone).
Key Enzymes and Intermediates: * Cholesterol side-chain cleavage enzyme (Desmolase): Initial step from cholesterol. * $3\beta\text{-Hydroxysteroid dehydrogenase}$ : Converts pregnenolone to progesterone and DHEA to androstenedione. * $17\alpha\text{-Hydroxylase}$ : Essential for the pathway leading to cortisol and sex steroids. * $21\alpha\text{-Hydroxylase}$ : Involved in the synthesis of aldosterone and cortisol. * $11\beta\text{-Hydroxylase}$ : Involved in the final steps of mineralocorticoid and glucocorticoid synthesis. * $18\text{-OH Steroid dehydrogenase}$ : Specific to the aldosterone pathway. * $17\text{-OH Steroid dehydrogenase}$ : Relevant to androgen production.
Daily Production Levels: * DHEA: $0.05-0.150\,mg/day$ . * Adrenal Cortical Hormones (Total): $15-30\,mg/day$ .

Testosterone Production Pathway in the Testis

Comparison to Adrenal Synthesis: The production of androgens from cholesterol is identical to the adrenal pathway, with the exception that the process continues further.
Testicular Progression: While the adrenal gland produces androstendione (adrenal androgen), the testis continues the conversion: * Substrate: Androstenedione. * Enzyme: $17\beta\text{-hydroxysteroid Oxidoreductase}$ (a complex of enzymes). * Product: Testosterone.
Peripheral Conversion: Androgens released into the blood from the adrenal cortex can also be converted to testosterone in the testes and peripheral tissues.
Site Summary: * Testis, Ovary, and Adrenal Gland: Synthesize androstenedione. * Adrenal Gland: Primarily produces DHEA in the zona reticularis.

Mechanism of Aromatization of Androgens

Enzyme: Estrogen Synthetase (also known as Aromatase, a P-450 enzyme).
Substrate: Testesterone (verbatim spelling from Page 9).
Product: Estradiol.
Cofactors: The process requires $3$ successive steps involving $O_2$ and $NADPH$ .
Catalytic Center: Involves an iron-containing enzyme center $Enz(Fe^{3+})$ .

Potency and Metabolism of Male Steroid Hormones

Dihydrotestosterone (DHT): * Converted from testosterone in a number of target tissues. * DHT is the most potent male steroid hormone. * Activity is $10$ times that of testosterone.
Testosterone as a Prohormone: Due to its lower relative potency compared to DHT, testosterone is sometimes classified as a prohormone.
Key Metabolic Enzymes: * $5\alpha\text{-reductase}$ : Converts testosterone to DHT (the major active metabolite). * Aromatase: Converts testosterone to estradiol (an inactive metabolite in the context of androgenic action, but active as an estrogen).

Physiological Pharmacokinetics of Testosterone

Circulation Binding States: * ~ $44\%$ bound to SHBG (Sex-Hormone Binding Globulin). * ~ $54\%$ bound to Albumin. * ~ $2\%$ exists as Free hormone.
Oral Administration: Oral testosterone is rapidly absorbed but is immediately metabolized by the liver, making it clinically ineffective in its natural form; thus, synthetic androgens are required for clinical use.
Tissue Dominance: DHT is the dominant androgen in many tissues and governs growth characteristics.
Inhibitors: $5\alpha\text{-reductase}$ inhibitors are used to block the conversion of testosterone to DHT.

Sex-Hormone Binding Globulin (SHBG)

Chemical Nature: A glycoprotein produced in the liver and released into the bloodstream.
Function: Binds to androgens and estrogens. Progesterone, cortisol, and other corticosteroids are instead bound by transcortin.
Bioavailability: The level of SHBG determines hormone bioavailability; hormones in the "bound" form cannot interact with their receptors.
Production Sites: Liver (primary), brain, uterus, testes, and placenta.
Specialized Nomenclature: SHBG produced specifically in the testes is called Androgen-Binding Protein (ABP).
Relative Binding Affinity for SHBG: * Dihydrotesterone (DHT) > testosterone > androstenediol > estradiol > estrone. * DHEA binds weakly to SHBG.

Physiological and Developmental Effects of Testosterone

Direct Testosterone Effects: * Internal Genitalia: Wolffian development during gestation. * Skeletal Muscle: Increased mass and strength during puberty. * Erythropoiesis.
Indirect Effects via Dihydrotestosterone (DHT) (Mediated by Androgen Receptor): * External Genitalia: Differentiation during gestation, maturation during puberty. * Adult Health: Implicated in prostatic diseases in adulthood. * Hair Follicles: Increased growth during puberty.
Indirect Effects via Estradiol (Mediated by Estrogen Receptor): * Bone: Epiphyseal closure and increased bone density. * Libido.
Shared/Interactive Effects: * Bone Growth.

Modified Testosterone Drugs and Clinical Products

Testosterone Propionate

Type: Prodrug of testosterone; agonist of the androgen receptor.
Classification: Androgen and Anabolic-Androgenic Steroid (AAS).
Indications: Treating low testosterone levels in men and breast cancer in women.
Delivery: Intramuscular (IM) injection.
Frequency: Administered $2-3\times/week$ .
Duration of Action: $0.8-1.5\,days$ .
Structure Modification: Esterification at the $C_{17}$ position.

Testosterone Cypionate

Type: Prodrug of testosterone; agonist of the androgen receptor.
Classification: Androgen and Anabolic-Androgenic Steroid (AAS).
Indications: Low testosterone in men and hormone therapy for transgender men.
Delivery: Intramuscular (IM) injection.
Frequency: $1\times$ every $2-4\,weeks$ .
Duration of Action: $4-5\,days$ ( $IM$ ).
Structure Modification: Modification at the $C_{17}$ position.

Testosterone Ethanate

Historical Context: One of the oldest anabolic steroids, dating back to the 1950s.
Type: Prodrug of testosterone; agonist of the androgen receptor.
Classification: Androgen and Anabolic-Androgenic Steroid (AAS).
Indications: Low testosterone in men and breast cancer in women.
Delivery: Intramuscular (IM) injection.
Frequency: $1\times$ every $2-4\,weeks$ .
Duration of Action: $4-5\,days$ ( $IM$ ).
Structure Modification: Modification at the $C_{17}$ position.

Summary Table of Testosterone Drugs

Drug	Delivery	Frequency	Duration of Action
Testosterone Propionate	IM Injection	$2-3\times/week$	$0.8-1.5\,days$
Testosterone Cypionate	IM Injection	$1\times$ every $2-4\,weeks$	$4-5\,days$
Testosterone Ethanate	IM Injection	$1\times$ every $2-4\,weeks$	$4-5\,days$

Lecture Study Guide: Essential Questions

Biosynthesis: What happens in the biosynthesis of testosterone that is unique to the testes? (Conversion from androstenedione via $17\beta\text{-HSD}$ ).
Metabolism (DHT): What does $5\alpha\text{-reductase}$ metabolize testosterone to? (Dihydrotestosterone).
Pharmacology (Inhibitors): What do $5\alpha\text{-reductase}$ inhibitor drugs do? (Prevent the conversion of testosterone to its more potent metabolite DHT).
Metabolism (Estradiol): What is the role of the aromatase enzyme in the metabolism of testosterone? (Aromatization of the A-ring to form estradiol).
Drug Design: For the modified testosterone drugs (propionate, cypionate, ethanate), what role do the extra functional groups at $C_{17}$ serve? (They act as prodrug esters to extend the duration of action and improve delivery characteristics).
Carbon Structuring: Are androgens $C_{27}$ , $C_{21}$ , $C_{19}$ , or $C_{18}$ carbon-containing structures biosynthesized from cholesterol? (Androgens are $C_{19}$ structures).