Pathophysiology

Pathophysiology

I-24. Male hypogonadism and androgen insensitivity syndrome

男性性腺機能低下症とアンドロゲン不応症

Male Sex Hormone Regulation

  • GnRH (hypothalamus) → LH + FSH (pituitary):
    • LH → Leydig cells → testosterone.
    • FSH → Sertoli cells → spermatogenesis + inhibin (negative feedback).
  • Testosterone metabolism: → DHT (via 5α-reductase: external genitalia, prostate, sebum/acne, hair, baldness); → estradiol (via aromatase: bone mass, epiphyseal closure, gynecomastia). Direct effects: GnRH/FSH/LH feedback, spermatogenesis, muscle mass, RBC formation, central obesity, dyslipidemia.

Classification of Hypogonadism

  • Primary (testis): ↑LH/FSH (no feedback); decreased spermatogenesis may dominate.
  • Secondary (pituitary) & Tertiary (hypothalamus): ↓LH/FSH → ↓testosterone + spermatogenesis.
  • Androgen insensitivity: normal hormones, but target tissue is insensitive.

Tertiary (Hypothalamic) Hypogonadism

  • Congenital: Kallmann syndrome (anosmia — olfactory + GnRH neurons share origin); congenital hypogonadotropic hypogonadism (normosmia).
  • Acquired:
    • Hyperprolactinemia (↓GnRH).
    • Functional (obesity/T2DM): ↑adipose aromatase → estradiol → ↓GnRH; ↓SHBG → testosterone filtered by kidney → ↓testosterone → ↓spermatogenesis, ↓muscle/motivation → ↑body weight (vicious cycle).
    • Heavy exercise/stress, malignancy, eating disorders.
    • Congenital adrenal hyperplasia: ↑ACTH → ↑adrenal androgens → feedback blocks GnRH → ↓testicular testosterone → ↓spermatogenesis (androgens still act peripherally).

Secondary (Pituitary) Hypogonadism (rare)

  • Congenital: isolated LH deficiency (↑FSH, ↓virilization/spermatogenesis); isolated FSH deficiency (↑LH, normal puberty, no spermatogenesis); combined LH/FSH (GnRH receptor mutation).
  • Acquired: pituitary tumor, trauma, vascular problems, iatrogenic (surgery/radiotherapy).

Primary (Testicular) Hypogonadism

  • Hypergonadotropic (↑LH/FSH): Klinefelter (47-XXY), FSH/LH receptor mutation, impaired testicular development (anorchia, cryptorchidism), radio/chemotherapy, trauma, torsion/varicocele, mumps.
  • Gynecomastia common: ↑LH/FSH → ↑testicular aromatase → androgens→estradiol → ↑prolactin → estradiol + prolactin → gynecomastia.

Symptoms by Timing

  • Depend on when deficiency occurs.
  • Before puberty: testosterone needed for epiphyseal closure → continued growth → long extremities, very tall (eunuchoid).

Androgen Insensitivity Syndrome

  • Normal hormone regulation but target tissue insensitive to androgens.
  • Normally testosterone + AMH (in males) suppress Müllerian duct → male organs. Without testosterone effect: Müllerian duct would form female organs.
  • With absent testosterone receptors but AMH present: small testes (form early), otherwise external female characteristics; female internal organs don’t develop (suppressed by AMH). Abdominal testes risk malignant transformation → should be removed.

一問一答

▶How is male reproductive hormone secretion regulated?

GnRH → LH + FSH. LH → Leydig cells → testosterone; FSH → Sertoli cells → spermatogenesis + inhibin (negative feedback).

▶What are the actions of testosterone's metabolites DHT and estradiol?

Via 5α-reductase, DHT acts on external genitalia, prostate, sebum/acne, and hair/baldness; via aromatase, estradiol supports bone mass, epiphyseal closure, and can cause gynecomastia.

▶How are primary, secondary, and tertiary hypogonadism distinguished?

Primary (testis): ↑LH/FSH. Secondary (pituitary) and tertiary (hypothalamus): ↓LH/FSH → ↓testosterone + spermatogenesis.

▶What is Kallmann syndrome?

Congenital tertiary (hypothalamic) hypogonadism with anosmia, because olfactory and GnRH neurons share a common origin.

▶What is the vicious cycle of functional hypogonadism in obesity/T2DM?

↑Adipose aromatase → estradiol → ↓GnRH; ↓SHBG → testosterone filtered/lost → ↓testosterone → ↓muscle/motivation → ↑weight, worsening the cycle.

▶Why does hyperprolactinemia cause hypogonadism?

Prolactin inhibits GnRH, reducing LH/FSH and thus testosterone and spermatogenesis.

▶How does congenital adrenal hyperplasia cause male hypogonadism?

↑ACTH → ↑adrenal androgens → negative feedback blocks GnRH → ↓testicular testosterone and ↓spermatogenesis (peripheral androgen effects persist).

▶What causes acquired secondary (pituitary) hypogonadism?

Pituitary tumor, trauma, vascular problems, or iatrogenic damage (surgery/radiotherapy) reducing LH/FSH.

▶What is the cause and karyotype of Klinefelter syndrome?

Primary (hypergonadotropic) hypogonadism due to a 47,XXY karyotype, with ↑LH/FSH.

▶Why is gynecomastia common in primary testicular hypogonadism?

↑LH/FSH → ↑testicular aromatase → androgens converted to estradiol → ↑prolactin; estradiol + prolactin → gynecomastia.

▶Why does prepubertal hypogonadism cause a tall, eunuchoid body habitus?

Testosterone (via estradiol) is needed for epiphyseal closure; its deficiency allows continued long-bone growth → long extremities and tall stature.

▶What is androgen insensitivity syndrome?

Normal hormone regulation but target tissue is insensitive to androgens (e.g., absent androgen receptors), so virilization fails despite normal/high testosterone.

▶Why do patients with complete androgen insensitivity have female external but no female internal organs?

Absent androgen receptors prevent male external development (→ female-appearing externalia), but AMH from the testes still suppresses the Müllerian ducts, so female internal organs don't form.

▶Why should abdominal/undescended testes in androgen insensitivity be removed?

Because intra-abdominal testes carry a risk of malignant transformation.

▶What are the direct (non-metabolite) effects of testosterone?

Negative feedback on GnRH/FSH/LH, spermatogenesis, increased muscle mass, RBC formation, and effects on central obesity and dyslipidemia.

▶What hormone pattern characterizes primary hypogonadism, and why?

↑LH/FSH with ↓testosterone, because the failing testis cannot provide negative feedback or respond to gonadotropins.

▶What acquired insults can cause primary testicular hypogonadism?

Radio-/chemotherapy, trauma, testicular torsion, varicocele, cryptorchidism, and mumps orchitis.

▶What roles do FSH and inhibin play in the testis?

FSH stimulates Sertoli cells to support spermatogenesis; Sertoli cells secrete inhibin, which provides negative feedback on FSH.

▶How can isolated LH versus isolated FSH deficiency present?

Isolated LH deficiency: ↑FSH with reduced virilization/spermatogenesis. Isolated FSH deficiency: ↑LH, normal puberty, but absent spermatogenesis.

▶How can stress, heavy exercise, or eating disorders cause hypogonadism?

They suppress hypothalamic GnRH (tertiary hypogonadism), lowering LH/FSH and testosterone.