Gonadal Hormones

• Gonadal Function


  The function of the gonads (testes and ovaries)
• Testes


  • Paired, ovoid organs that hang from the inguinal canal by the spermatic cord
  • Comprised of seminiferous tubules and an interstitium
  • Serve dual functions: production of sperm and production of reproductive steroid hormones
• Genes important for normal gonadal differentiation

  • Steroidogenic factor 1 (SF-1)
  • Antimüllerian hormone (AMH)
  • Insl3
• Testes are located outside the body, encased by a muscular sac
• Blood flow and temperature regulation of testes is vital for uninterrupted sperm production
• Testes


  • Seminiferous tubules contain germ cells and Sertoli cells, responsible for sperm production
  • Interstitium contains Leydig cells that produce testosterone
• Puberty


  Transition from nonreproductive to reproductive state, associated with adrenarche and gonadarche
• Sperm production and movement

  1. Spermatogonia undergo mitosis and meiosis to form mature sperm

  2. Sperm move through tubuli recti, rete testes, ductuli efferentes testes, epididymis, and vas deferens
• Sertoli cells


  Polyfunctional cells that aid in development and maturation of sperm
• Testosterone


  Predominant hormone secreted by testes, controlled primarily by FSH and LH
• Hormonal control of testicular function


  1. Hypothalamus releases GnRH, which stimulates pituitary to release LH and FSH

  2. LH binds to Leydig cells and stimulates testosterone synthesis

  3. FSH acts on Sertoli cells to stimulate protein synthesis, inhibin, and androgen-binding protein
• Testosterone action


  Enters cell, converts to DHT, complexes with intracellular receptor and binds to nuclear receptor to effect protein synthesis and cell growth
• Testosterone effects on prenatal development

  1. Stimulates differentiation of male genital tract

  2. Causes regression of female primordial genital tract via AMH from Sertoli cells
• Testosterone effects on postnatal development

  Leads to development of secondary sex characteristics at puberty
• Hormonal regulation of male sexual development

  1. Hypothalamic GnRH stimulates LH release

  2. Testosterone production by Leydig cells

  3. Testosterone exposure leads to differentiation of male genital tract

  4. Sertoli cells produce AMH to regress female primordial genital tract

  5. 5α-reductase converts testosterone to DHT in scrotal skin
• Tanner staging


  System to stage development of male genital and pubic hair

  
• Effect of testosterone on spermatogenesis

  1. Stimulation of Leydig cells to produce testosterone

  2. Testosterone and FSH have paracrine effects on seminiferous and Sertoli cells to induce spermatogenesis

  3. Exogenous testosterone abuse reduces intratesticular testosterone and sperm production
• Effects of testosterone on secondary sexual characteristics

  • Growth-promoting effects on various target tissues
  • Maintenance of secondary sex characteristics into late adulthood
  • Prostate enlargement
  • Scalp hair regression
• Failure to develop or loss of secondary sexual characteristics should prompt evaluation for hypogonadism
• Causes of delayed puberty

  • Klinefelter's syndrome
  • Bilateral gonadal failure
  • Primary testicular failure
  • Anorchia
  • Vanishing testicles
  • Chemotherapeutic agents
  • Irradiation
  • Trauma
  • Infection (mumps orchitis)
  • Constitutional delayed puberty
  • Hypothalamic dysfunction
  • Malnutrition
  • Chronic systemic illness
  • Severe obesity
  • Central nervous system tumors
  • Hypopituitarism
  • Kallmann's syndrome
  • Isolated GH deficiency
  • Hyperprolactinemia
  • Hypothyroidism
  • Prader-Willi syndrome
  • Laurence-Moon syndrome
  • LEOPARD syndrome
  • Bloom syndrome
  • Germ cell neoplasia
  • Male pseudohermaphroditism
  • Ataxia–telangiectasia
  • Steroidogenic enzyme defects
• Hypergonadotropic hypogonadism


  Characterized by low testosterone, elevated FSH or LH, and impaired sperm production

  
• Klinefelter's syndrome


  • Most common human sex chromosome abnormality
  • Small, firm testes
  • Gynecomastia
  • Elevated LH and FSH
  • Azoospermia and sterility
  • Increased aromatase activity and elevated estrogen
  • Reduced bone density and increased breast cancer risk

  
• Testicular feminization syndrome


  • Severe form of androgen resistance syndrome
  • Lack of androgen and unopposed estrogen effects lead to female phenotype
  • Undescended testes require prompt removal to prevent malignant transformation
  • No response to exogenous testosterone
• 5α-reductase deficiency


  • Reduced DHT levels lead to female phenotype until puberty
  • Male internal genitalia develop in response to testosterone
  • DHT is essential for prostate and external genitalia development
• Myotonic dystrophy


  • Autosomal dominant disorder
  • Primary hypogonadism, frontal balding, diabetes, muscle weakness and dystonia
  • Testicular failure typically presents in 20s and 30s
  • Germ cell compartment failure followed by Leydig cell failure
• Mumps orchitis

  1. Develops in a third of postpubertal males with mumps

  2. Usually unilateral, so permanent sterility is rare

  3. Occurs within 4-6 days of parotitis, may precede or be the only manifestation
• Sertoli cell-only syndrome


  • Lack of germ cells
  • Small testes, high FSH, azoospermia, normal testosterone
  • May arise from Y chromosome microdeletions
• Hypogonadotropic hypogonadism


  Low testosterone with low or inappropriately normal FSH/LH

  
• Kallmann's syndrome


  • X-linked recessive disorder
  • Impaired migration of GnRH neurons and olfactory nerves
  • High incidence of microphallus, cryptorchidism, and small testes
• Hyperprolactinemia


  • Impairs FSH and LH pulsatile secretion via disruption of GnRH release
• Hypogonadism in type 2 diabetes

  • Low free or total testosterone with inappropriately low LH
  • Associated with insulin resistance, low SHBG, inflammation, and elevated estradiol
• Age-related decline in testosterone, with 19% hypogonadism at age 60, 28% at 70, and 49% at 80
• Acquired hypogonadism can follow pituitary injury from tumors, trauma, vascular injury, autoimmune disease, or hemochromatosis
• Long-term opioid use can cause severe hypogonadotropic hypogonadism
• Long-term or continuous use of narcotics has been linked to severe hypogonadotropic hypogonadism (due to μ-opioid receptor–mediated decreased GnRH pulsatile production) and even decrease in male fertility (decreased sperm motility, decreased sperm counts, and abnormal sperm morphology)
• It is unclear if sleep apnea leads to hypogonadotropic hypogonadism (due to hypoxemia and sleep deprivation), or if the obesity (which is often present in men with sleep apnea) leads to decreased testosterone levels
• Testosterone replacement therapy (especially high-dose testosterone) may worsen preexisting sleep apnea, possibly due to increased oxygen consumption
• The Endocrine Society guidelines recommend not starting testosterone replacement therapy in men with untreated severe OSA, until first starting them on CPAP
• Hypogonadism


  Both clinical and biochemical features must be met to make the diagnosis
• Testosterone concentrations have a circadian rhythm and the time of sampling must be considered. Morning samples between 8 and 10 AM are recommended to match values from reference interval studies