Male Hormones and Androgens

• Male hormones, androgens, are vital for reproductive health, physical development, and overall well-being.

Primary Hormones

• Testosterone is the primary male sex hormone, mainly produced in the testes.
• Testosterone drives puberty, sperm production, muscle mass, bone density, libido, and red blood cell production.
• Dihydrotestosterone (DHT) is derived from testosterone and is crucial for fetal genital development.
• DHT may be linked to male-pattern baldness and prostate enlargement in adulthood.
• Androstenedione is a precursor to testosterone and estrogen and influences hormonal balance.

Regulatory Hormones

• Gonadotropin-Releasing Hormone (GnRH) is secreted by the hypothalamus.
• GnRH stimulates the pituitary to release Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH).
• FSH supports sperm production via Sertoli cells.
• LH triggers testosterone synthesis in Leydig cells.

Other Relevant Hormones

• DHEA/DHEA-S are adrenal precursors to testosterone and estrogen, with imbalances potentially disrupting hormonal equilibrium.
• Estrogens (Estrone, Estradiol) are present in small amounts in men.
• Elevated estrogen levels in men correlate with gynecomastia, obesity, and prostate issues.
• Progesterone balances DHT and estrone effects and supports nervous system calmness.

Functions and Imbalances

• Testosterone and FSH/LH regulate spermatogenesis and fertility in reproductive health.
• Deficiencies in testosterone and FSH/LH can cause infertility, low libido, or erectile dysfunction.
• Physical effects of testosterone maintains muscle mass, bone density, and fat distribution.
• Testosterone imbalances may lead to fatigue, osteoporosis, or weight gain.
• Low testosterone is linked to depression, irritability, and increased cardiovascular risk affecting metabolic and mental health.

Testing and Treatment

• Hormone panels (saliva or blood tests) evaluate testosterone, DHT, and estrogens.
• Hormone panels diagnose conditions like andropause or hypogonadism
• Treatments include hormone replacement therapy (testosterone, DHEA) or medications like Clomid to boost sperm production.

Regulation and Feedback

• Inhibin (from Sertoli cells) and testosterone suppress GnRH, FSH, and LH to maintain hormonal balance through negative feedback.
• Male hormonal health relies on a balance of androgens, regulatory hormones, and estrogens/progesterone.
• Disruptions in the hormonal system can affect fertility, physical vitality, and mental well-being.

Key Functions of Testosterone

• Testosterone drives fetal male genital development via conversion to DHT.
• Testosterone initiates puberty and maintains sperm production.
• Testosterone supports libido and erectile function in both sexes.
• Testosterone enhances muscle mass, strength, and recovery by promoting protein synthesis.
• Testosterone maintains bone density, which reduces osteoporosis risk.
• Testosterone stimulates red blood cell production.
• Testosterone regulates fat distribution and metabolism, and low levels correlate with metabolic syndrome.
• Testosterone influences mood, cognition, and energy levels.

Regulation of Testosterone

• The hypothalamus releases GnRH, and the pituitary secretes LH and FSH in the Hypothalamic-Pituitary-Gonadal (HPG) Axis.
• LH stimulates Leydig cells in testes to produce testosterone.
• FSH supports spermatogenesis via Sertoli cells.
• High testosterone inhibits GnRH and LH to maintain balance through negative feedback.

Production of Testosterone

• Testosterone is synthesized from cholesterol in Leydig cells in testes via enzymes (CYP11A1, 3β-HSD, CYP17A1).
• Small amounts of testosterone are produced in adrenal glands (both sexes) and ovaries (females).

Imbalances and Disorders

• Symptoms of low testosterone (hypogonadism) include reduced libido, muscle loss, fatigue, depression, and infertility.
• Causes of low testosterone are aging, obesity, and pituitary/testicular disorders such as Klinefelter syndrome.
• High testosterone in women is linked to PCOS (acne, hirsutism).
• High testosterone in men is rare; may indicate tumors or steroid abuse.

Testing and Management

• Diagnosis of testosterone imbalances involves blood tests (morning samples for accuracy).
• Blood tests measure total/free testosterone, LH, and FSH.
• Treatment includes hormone replacement therapy (HRT), lifestyle changes (weight loss, exercise), or medications like Clomid.

Gender Differences

• Women have lower testosterone levels (~10% of males).
• Testosterone supports bone health, libido, and muscle strength in women.
• Imbalances in women cause menstrual irregularities or virilization.
• Testosterone's multifaceted roles underscore its importance in overall health.
• Imbalances in testosterone require targeted clinical intervention.

Sperm Production via Testosterone

• Testosterone directly stimulates spermatogenesis (sperm production) in the testes.
• Higher testosterone levels exhibit increased sperm concentration (+46%) and total sperm count (+44%).

Sexual Function via Testosterone

• Testosterone maintains libido and erectile function by supporting nitric oxide production and vascular health.

Physical Health via Testosterone

• Testosterone supports muscle mass, bone density, and fat metabolism, indirectly benefiting reproductive health.

Negative effects of low testosterone

• Low testosterone correlates with decreased sperm count, motility, and DNA integrity.
• Men over 35 experience age-related declines in testosterone and semen parameters.
• Low testosterone impairs sexual arousal and erectile capacity (ED).
• Obesity and metabolic syndrome exacerbate testosterone deficiency, creating a cycle that further harms fertility.

Paradoxical Effects of Testosterone Therapy

• Exogenous testosterone (e.g., TRT) disrupts the hypothalamic-pituitary-testicular axis.
• TRT reduces FSH/LH secretion and halting natural sperm production, lowering sperm counts to near-zero levels.
• Sperm production may recover after discontinuing TRT, but recovery time varies.

Lifestyle and Environmental Influence

• Men engaged in regular heavy lifting or manual labor have higher testosterone levels and improved sperm parameters.
• Excess body fat lowers free testosterone and increases estrogen conversion, impairing fertility.

Age-Related Decline

• Testosterone levels decrease by ~1% annually after age 40.
• This decrease contributes to reduced semen quality and fertility

Testosterone Deficiency and Sperm

• Testosterone is essential for spermatogenesis (sperm formation) in the testes.
• Deficiency leads to decreased sperm count and may cause oligospermia (low sperm concentration) or azoospermia (absence of sperm).
• The testes require locally high testosterone concentrations for sperm development.
• Low systemic testosterone disrupts the microenvironment, impairing germ cell maturation.

Impaired Sperm Quality

• Low testosterone correlates with reduced sperm motility (movement capability).
• Deficiency increases abnormal sperm shapes (teratozoospermia), reducing fertilization potential.
• Testosterone deficiency elevates oxidative stress, causing sperm DNA fragmentation and compromising genetic material stability.

Hormonal Feedback Disruption

• Exogenous testosterone replacement therapy (TRT) suppresses the hypothalamic-pituitary-testicular axis.
• TRT halts endogenous testosterone and sperm production entirely.

Secondary Effects

• Low testosterone often coexists with obesity or metabolic syndrome.
• This situation exacerbates sperm dysfunction through inflammation and estrogen dominance.
• Age-related testosterone decline (starting around 35) progressively worsens semen parameters.

Clinical Evidence

• Men with testosterone deficiency have 30–50% lower sperm counts compared to those with normal levels.
• Borderline low testosterone levels correlate with suboptimal sperm health.
• Testosterone deficiency directly impairs testicular function.
• The direct impairment reduces sperm quantity/quality and disrupts hormonal regulation, all of which contribute to male infertility.

Impaired Spermatogenesis

• Testosterone is essential for maintaining the testicular microenvironment required for sperm formation.
• Deficiency disrupts germ cell maturation, leading to reduced sperm count (oligospermia) or complete absence (azoospermia)
• The testes rely on locally high testosterone concentrations (up to 100x blood levels) to support sperm cell division and maturation.
• Low systemic testosterone compromises the sperm cell division and maturation process.

Hormonal Axis Disruption

• Testosterone deficiency disrupts the hypothalamic-pituitary-gonadal (HPG) axis.
• This reduces luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion.
• LH stimulates Leydig cells to produce testosterone, while FSH supports Sertoli cells in sperm nourishment.
• Low LH/FSH further exacerbates testosterone depletion and sperm production failure.

Abnormal Sperm Development

• Low testosterone correlates with poor sperm motility and increased abnormal morphology (e.g., misshapen heads, defective tails).
• This reduces fertilization potential.
• Oxidative stress from testosterone deficiency damages sperm DNA integrity.
• This increases fragmentation rates.

Secondary Effects of Androgen Deficiency

• Obesity-related testosterone deficiency increases estrogen conversion.
• This suppresses gonadotropin release and worsening spermatogenic dysfunction.
• Age-related decline (starting around 35–40 years) progressively reduces testosterone and semen quality.

Iatrogenic Suppression

• Exogenous testosterone replacement therapy (TRT) suppresses natural HPG axis activity.
• TRT halts endogenous testosterone and sperm production.

Clinical Evidence

• Men with low testosterone levels exhibit 30–50% lower sperm counts and 4–18% reduced normal sperm morphology compared to those with normal levels.
• In congenital conditions like Klinefelter syndrome, testosterone deficiency leads to testicular atrophy and irreversible infertility.
• Testosterone deficiency disrupts hormonal regulation, impairs sperm cell maturation, and degrades semen quality.
• This directly contributes to male infertility.

Biological Role of Androstenedione

• Androstenedione is produced in the adrenal glands and gonads (testes in males, ovaries in females).
• It serves as a precursor for synthesizing testosterone and estrogens (e.g., estrone) in the body.

Clinical Relevance of Androstenedione

• Elevated androstenedione levels may indicate adrenal disorders (e.g., congenital adrenal hyperplasia) or gonadal tumors.
• Androstenedione was marketed as a supplement to enhance muscle mass and erectile function, though clinical trials have questioned its efficacy.

Regulation and Effects of Androstenedione

• Androstenedione which regulates sexual differentiation, libido, and secondary sexual characteristics in both sexes - is part of the androgen family
• Androstenedione is a critical intermediate in steroid hormone metabolism, with clinical significance in diagnosing endocrine disorders and historical interest in performance enhancement.

Hormone Levels via Androstenedione

• Short-term supplementation (300 mg/day) transiently increases serum testosterone levels by ~34%, but levels often return to baseline within hours. (Men)
• Chronic use suppresses natural testosterone production via hypothalamic-pituitary-gonadal axis inhibition. (Men)
• Androstenedione converts to estrone via aromatase, elevating estrogen levels.
• This imbalance increases risks of gynecomastia (breast growth) and testicular atrophy. (Men)
• Androstenedione supplementation raises testosterone levels by ~200%, leading to masculinization effects (e.g., hirsutism, voice deepening). (Women)
• Conversion to estrone exacerbates hormonal imbalances, potentially causing menstrual irregularities and polycystic ovary syndrome (PCOS)-like symptoms. (Women)

Muscle Growth via Androstenedione

• Despite transient testosterone spikes, studies show no significant improvement in muscle mass or strength in healthy men.
• Hypogonadal men may see modest gains in fat-free mass and strength, but effects are dose-dependent and inconsistent
• Elevated testosterone may temporarily enhance muscle mass (Women).
• Gaining muscle can come as a cost of adverse effects like abdominal fat accumulation and virilization (Women)

Risks of Androstenedione

• Supplements worsen lipid profiles, reducing HDL ("good" cholesterol) and increasing LDL ("bad" cholesterol).
• Long-term use correlates with liver/kidney toxicity and increased cancer risk.
• In men, exogenous androstenedione reduces endogenous testosterone production, potentially causing infertility.
• Risks of hormonal imbalance, organ damage, and metabolic dysfunction outweigh potential gains.

GnRH Stimulation of Gonadotropins

• GnRH is released in pulsatile patterns from the hypothalamus.
• It triggers the anterior pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
• FSH acts on Sertoli cells in the testes to support spermatogenesis (sperm cell maturation) and produce androgen-binding proteins.
• LH stimulates Leydig cells to produce testosterone, which is critical for sperm development and maintaining the testicular microenvironment.

Impact of GnRH Deficiency

• In conditions like Kallmann syndrome (GnRH neuron migration failure), low GnRH leads to hypogonadotropic hypogonadism (HH).
• Characteristics of the above include reduced FSH/LH, undescended testes, and absent sperm production.
• Without pulsatile GnRH, the testes remain prepubertal, with small volume