Androgens and Functions in Man

Endocrine Functions

  • Androgens play a crucial role in various biological processes within the male body.

Learning Objectives

  • Understand the following:

    • Synthesis of testosterone.

    • Biological effects of testosterone.

    • Androgenic effects of testosterone.

    • Therapeutic use of testosterone.

    • Anti-androgen therapy.

Testosterone

Production and Secretion

  • Source: Primarily produced from cholesterol by Leydig cells in testes.

  • Secretion Phases:

    • At adult levels during the 1st trimester (1).

    • During neonatal life (2).

    • Continually after puberty (3).

  • Transport in Plasma:

    • Bound to albumin and serum sex-hormone binding globulin (SSBG).

Conversion and Activity

  • Testosterone is convertible to the more potent 5α-dihydrotestosterone (DHT), responsible for several responses in the urinary-genital tract (e.g., benign prostate hyperplasia).

  • It binds to and activates a single androgen receptor (AR), which is found in various tissues including:

    • Reproductive tissue.

    • Skeletal muscle.

    • Brain.

    • Kidney.

Synthesis Pathway in Leydig Cells

  • Process: Testosterone synthesis from cholesterol involves:

    1. Endocytosis of LDL (Low-Density Lipoproteins).

    2. De novo cholesterol synthesis from acetyl-CoA.

    3. Utilization of five enzymes:

      • 20,22-desmolase: Converts cholesterol to pregnenolone.

      • 17α hydroxylase (CYP17): Converts pregnenolone to 17α-hydroxypregnenolone.

      • 17,20-desmolase: Converts 17α-hydroxypregnenolone to dehydroepiandrosterone (DHEA).

      • 17β-hydroxysteroid dehydrogenase: Converts DHEA to androstenediol.

      • 3β-hydroxysteroid dehydrogenase: Converts androstenediol to testosterone.

Control of Testosterone Synthesis

Hormonal Control

  • Hypothalamus: Releases GnRH (Gonadotropin-Releasing Hormone).

  • Anterior Pituitary Gland: Releases:

    • FSH (Follicle-Stimulating Hormone).

    • LH (Luteinizing Hormone), which stimulates the testes and acts upon:

      • Sertoli cells (support sperm production).

      • Leydig cells (stimulate testosterone production).

  • Positive feedback loop influences the secretion of testosterone and derived hormones such as estradiol and DHT.

Plasma Testosterone and Metabolism

Levels and Binding

  • Circulating testosterone:

    • Free (1-2%).

    • Bound to Serum SSBG (~45%).

    • Bound to Albumin (~55%).

  • Biologically Active Metabolites: Affect various target tissues.

  • Only the free and loosely bound to albumin fractions of testosterone exhibit biological activity.

Metabolic Pathway

  • Dihydrotestosterone: Formed by the action of 5α-reductase in various tissues including:

    • Prostate.

    • Scrotum.

    • Penis.

    • Bone.

Biological Effects of Testosterone

Developmental Roles

  • In foetus: Promotes male reproductive tract development and external genitalia (sex differentiation).

  • In pre-pubertal children: Can prematurely close epiphyses of long bones.

  • In puberty: Promotes development of:

    • Primary sexual characteristics: Enlargement of male genitalia.

    • Secondary sexual characteristics: E.g., body shape, muscle growth, and facial/pubic hair, deepening of voice.

Adult Effects

  • Physiological impacts include:

    • Retention of salt and water.

    • Skin changes: Thickening and darkening.

    • Increased activity of sebaceous glands.

    • Increments in body weight and muscle mass.

    • Enhanced sense of well-being, increased libido, and physical vigor.

  • Note: Exogenous testosterone can paradoxically inhibit spermatogenesis.

Testosterone Deficiency

Diagnosis and Treatment

  • Testosterone deficiency can result from testicular disorders, confirmed through hormone assays.

  • Indicators: High LH with low testosterone levels suggest hypothalamic-pituitary disorders, while low levels of both suggest conditions like genitalia ambiguities and infertility.

  • Androgen Replacement Therapy (ART): Aim is to restore tissue androgen exposure, usually for the lifetime of the patient.

Clinical Spotlight on Conditions

  • Uses of Androgenic Steroids:

    • Andropause: Characterized by a slow and subtle decline in total and free testosterone levels with age, affecting 60% of men over 65, potentially related to impotence.

    • Male Hypogonadism: To develop or maintain secondary sex characteristics.

Therapeutic Androgen Preparations

Androgen Replacement Forms

  • Testosterone (Histerone): Oral administration leads to absorption and rapid catabolism in hepatic circulation.

  • Transdermal patches and synthetic testosterone preparations available:

    • Testosterone propionate (Neo-Hombreol®).

    • Testosterone enanthate (Delatestryl®).

    • Testosterone undecanoate (Andriol®).

Hormone Preparations

  • 17α-alkylated testosterone for oral use includes:

    • Methyltestosterone (Oretin Methyl).

    • Oxandrolone (Oxandrin).

    • Stanozolol (Winstrol).

    • Fluoxymesterone (Halotestin).

    • Danazol (Danocrine).

Symptoms and Signs of Hypogonadism

Symptoms Include:

  • Decreased libido.

  • Erectile dysfunction.

  • Infertility.

  • Fatigue and weakness.

  • Depression and irritability.

  • Vasomotor phenomena.

Signs Include:

  • Decreased body hair and muscle mass.

  • Smaller prostate and testes.

  • Gynaecomastia: enlargement of breast tissue.

  • Osteoporosis: reduced bone density.

  • Anaemia: decreased red blood cell count.

Diagnosis Criteria

  • Normal testosterone levels range: 300-1000 ng/dl.

  • Hypogonadism diagnosis: testosterone levels < 300 ng/dl with one or more symptoms noted above.

Spotlight on Disease: Adult Male Hypogonadism

Causes Include:

  • Autoimmune Disorders:

    • Addison’s disease (adrenal insufficiency).

    • Hypoparathyroidism (underproduction of parathyroid hormone).

  • Genetic Disorders:

    • Klinefelter syndrome (extra X chromosome).

  • Other Factors: Severe infections, liver and kidney diseases, hemochromatosis (iron overload).

Therapy for Adult Male Hypogonadism

Testosterone Preparations Overview

Compound

Standard Adult Dose

Monitoring

T enanthate

250 mg i.m. every 2-3 weeks

Midway between injections

T undecanoate

1000 mg i.m. every 12 weeks

At the end of the dosing interval

T propionate

200 mg i.m. every 2-3 weeks

Nadir levels monitored

Injectable Forms

  • Short Acting: Gaining wide clinical experience, with fluctuations in serum testosterone levels leading to local side effects.

  • Long Acting: Stable plasma levels but monitoring challenges for dose adjustment due to lower nadir levels than normal range.

Oral and Transdermal Forms

  • Oral T undecanoate: Varies by dosing schemes for timing adjustments based on biological response.

  • Transdermal patches and gels: Vary in application timing and monitoring post-application absorption levels.

Androgen Replacement Therapy (ART) Precautions

Adverse Effects and Risks

  • Generally uncommon:

    • Precautions for older men due to potential urinary obstruction.

    • Risks of epiphyseal closure for prepubertal boys, which can stifle growth.

    • Caution with injections concerning bleeding disorders, epilepsy, and other health conditions.

Androgen Blockade Therapies

Conditions and Indications

  • Prostate Cancer: Anti-gonadotropin-releasing hormones (e.g., GnRH analogues) to suppress testosterone and inhibit tumor growth.

  • Male to Female Gender Transition: Involves estrogens and anti-androgens for feminizing hormone therapy.

  • Conditions of Hyperandrogenism in Women: Use of combined oral contraceptives and anti-androgens to reduce ovarian androgen secretion, especially in cases of severe acne.

Concluding Notes

  • Continual evaluation of therapy for effectiveness and safety remains essential in the realms of androgen replacement and blockade practices.