Endocrine system of the body consists of any endocrine glands which produce metabolic changes through the secretion of the chemicals called hormones. Pituitary gland along with hypothalamus is considered to be the ‘Master’ gland of the body. Hormones produced by different endocrine glands have different mechanism of actions. They are interrelated to each other and often regulate the secretion of one another.

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Role of Hypothalamus

Hypothalamus is an area in the brain which controls a lot of functions of the body. It also affects the section of various endocrine glands, specifically the secretion of pituitary gland.

Pituitary gland itself controls the section of various other endocrine glands like gonads, adrenals, thyroid, etc. Releasing hormones are produced in the hypothalamus, which stimulates the pituitary gland cells to produce stimulating hormones, which directly affects the secretion of hormones from the endocrine gland.

Like thyroid releasing hormone, gonadotrophic releasing hormone, corticotrophin releasing hormone stimulates the production of thyroid stimulating hormone, FSH and LH and adrenocorticotropic hormone, respectively from the pituitary gland.

Like stimulating hormones, inhibitory hormones or factors are also produced. These help in the regulation of these hormones in the body. Positive and negative feedback mechanisms regulate the amount of hormone in the blood.

Hypothalamic–Pituitary–Gonadal (HPG) Axis

hypothalamus pituitary testicles axis

Image: “Hypothalamus-pituitary-gonadal axis.” by Testosterona-ciclo.png: Acracia derivative work: Boghog2 – Testosterona-ciclo.png. License: CC BY-SA 3.0

The hypothalamic–pituitary–gonadal axis (HPG axis) includes the hypothalamus, pituitary gland, and gonadal glands working together in a loop, through which production of hormones can be regulated. These glands work as if they are a single entity.

The downstream products of the hypothalamic–pituitary–gonadal pathway are regulated through the negative feedback mechanism. Spermatogenesis, i.e. the production of sperms in the testes, is stimulated by the gonadotropin-releasing hormone (GnRH) from the Arcuate nucleus in the hypothalamus.

How does the gonadal axis work?

The hypothalamus secretes GnRH in a pulsatile fashion, which travels down to the anterior pituitary gland, binds the receptors on the pituitary gland.

LH (luteinizing hormone) and FSH (follicle stimulating hormone) are released from the pituitary gland. Both these hormones enter the blood stream to the testes where LH stimulates the Leydig cells to produce testosterone, which acts on the Sertoli cells stimulating the production of sperms.

LH binds the LH receptors and promotes the conversion of cholesterol to pregnenolone through protein kinase activity. Pregnenolone is a precursor of testosterone. Testosterone is also required for other important biological processes like development of primary and secondary sexual characteristics, increase libido, epiphyseal closure.

FSH stimulates the Sertoli cells to produce androgen binding globulin (ABG) and inhibin. ABG binds to the testosterone from the Leydig cells and keeps it available in the seminiferous tubules and other target tissues.

Inhibin has more of a negative feedback role; it helps in regulating spermatogenesis and inhibition of FSH, LH and GnRH production.

Raised testosterone level in the blood stimulates the release of inhibin, which causes negative feedback on the pituitary and hypothalamus, decreasing the production of the pituitary gland.

Inhibition of the enzyme aromatase results in an increase in the FSH production suggesting that FSH regulation is more dependent on estradiol than testosterone.

In females

GnRH promotes the release of LH and FSH which act on the ovaries and produce estrogen and inhibin. Decrease in testosterone and DHEA, with raised estrogen leads to the female primary sexual characteristics in the fetal stage. Later in the pubertal age development, female secondary sexual characteristics occur.

Estrogen regulates the menstrual cycle and inhibin inhibits the hormone activin, which actually stimulates GnRH production.

LH surge promotes ovulation and estradiol promotes the growth of endometrium. Increased levels of estrogen and inhibin produce negative feedback changes on pituitary and hypothalamus.

menstrual cycle and hormonal changes

Image: “Menstrual cycle and hormonal changes.” by Npatchett. License: CC BY-SA 3.0

Role of Androgen-Binding Protein (ABP)

ABP is synthesized by the Sertoli cells and later secreted in the seminiferous tubules. This binds to the testosterone and keeps a high concentration of testosterone in the testes. Roughly the concentration of the hormone, testosterone, is 50 times more in the testes as compared to the blood.

Metabolic fate of testosterone

  1. Binds to the androgen receptors in the target tissues
  2. Converted to DHEA–dihydrotestosterone at the target tissues by the action of 5-alpha-reductase
  3. Or converted to estradiol by the action of aromatase.

Primary sexual characteristics: include the growth and development of testes and penis in males

Secondary sexual characteristics: include the development of facial and pubic hair, increased muscle mass, voice changes with the development of larynx.

Maturation of HPG axis in males

GnRH secretion starts in the intrauterine life in the fetal stage of life. This leads to the primary sexual characteristics. Its production decreases in the neonatal period and childhood, until puberty when pulsatile secretion of GnRH occurs and testosterone is produced. Secondary sexual characteristics are produced in the body.

After puberty till the adult stage of life, the production of GnRH and testosterone increases and in later part of adulthood it starts decreasing.

Hypothalamic–Pituitary–Gonadal (HPG) Axis Differentials

Due to disturbance of hypothalamic–pituitary–gonadal (HPG) axis, the development of sexual characteristics is delayed leading to many different complications in males and females. It can be due to central cause, i.e pituitary or hypothalamic disturbance or due to local primary disease of the gonads.

Associations of this condition include:

  1. Hypospadias
  2. Micropenis
  3. Cryptorchidism
  4. Mumps
  5. Use of various drugs

To find the cause of hypogonadism, following investigations should be done:

  1. FSH level
  2. LH level
  3. Prolactin level
  4. Estradiol levels
  5. Seminal fluid examination
  6. Thyroid function test
  7. Karyotyping

Still, if the diagnosis cannot be made, testicular tissue testing (testicular biopsy) and LH releasing hormone stimulation test can be done.


Female hypogonadism

Causes of hypogonadism in females are almost the same as that of males, except that instead of Klinefelter’s syndrome, Turner syndrome occurs in females. Features of Turner syndrome include short stature, webbed neck, high arch palate, short fourth metacarpals, and wide spaced nipples.

Male hypogonadism

Primary hypogonadism or hypergonadotrophic variety

The type of hypogonadism in which pituitary and hypothalamus are working normally but the problem lies within the gonads, is called primary hypogonadism. Causes of primary hypogonadism include:

  1. Genital trauma
  2. Autoimmune destruction
  3. Mumps orchitis
  4. Side effects of drugs:
    1. Cyclosporine
    2. Chemotherapeutic agents
  5. Congenital disorders
    1. Klinefelter’s syndrome
    2. Bilateral anorchia

Secondary hypogonadism or hypogonadotropic variety

The type of hypogonadism in which pituitary or hypothalamic secretions are decreased leading to decreased growth of gonads and other characteristics is called secondary hypogonadism.

Causes include:

  1. Idiopathic
  2. Post infectious state of CNS
  3. Prolactinoma
  4. Damage to the hypothalamus or pituitary via radiations, tumor, infiltrative trauma
  5. Hereditary hemochromatosis
  6. Congenital disorders like Kallman’s syndrome
  7. Side effects of drugs:
    1. Opiates
    2. Glucocorticoids
    3. Leuprolide (used in prostate cancer)

Signs and symptoms of hypogonadism

Hypogonadism can begin during

  • Fetal development,
  • Before puberty or
  • During adulthood.

Signs and symptoms of the disease depend on when the condition develops:

During fetal development:

  • Impaired growth of the external sex organs occurs in fetal life leading to any of the following:
    • Female genitals
    • Ambiguous genitals — genitals that are neither clearly male nor clearly female
    • Underdeveloped male genitals.

At Puberty:

  • It leads to delayed puberty, incomplete or lack of normal development. It can cause:
    • Decreased development of muscle mass
    • Lack of deepening of the voice
    • Impaired growth of body hair
    • Impaired growth of the penis and testicles
    • Excessive growth of the arms and legs in relation to the trunk of the body
    • Development of breast tissue (gynecomastia)

In adulthood:

  • Hypogonadism may alter masculine physical characteristics and impair normal reproductive function. Signs and symptoms may include:

As testosterone decreases, men have symptoms like females have after menopause: fatigue, decreased sex drive, difficulty concentrating and hot flashes.

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