The Hypothalamus is an area of the brain which controls a lot of functions in the body. It also affects sections of various endocrine glands, specifically the secretion of pituitary glands. Relevant to the hypothalamic-pituitary-gonadal axis, the hypothalamus secretes GnRH that travels via the hypophyseal portal system to the anterior pituitary.
Other hormones secreted from the hypothalamus include thyrotropin-releasing hormone, corticotrophin-releasing hormone, and growth-releasing hormone, all of which exert their effects on the pituitary gland.
The Pituitary Gland
Under the influence of GnRH, the pituitary gland itself controls the secretion of gonadotropic hormones such as LH and FSH that exert the final effects of the axis.
Similarly, other endocrine glands like the adrenals and thyroid glands are also activated by hormones from the pituitary gland which include thyroid stimulating hormones and adrenocorticotropic hormone.
Like, in other 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 hormones in the blood.
Hypothalamic–Pituitary–Gonadal (HPG) Axis
The hypothalamic-pituitary-gonadal axis (HPG axis) includes the hypothalamus, pituitary gland, and gonadal glands working together in a loop, through which the 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 and binds to 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 bloodstream flow 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 the development of primary and secondary sexual characteristics, increasing libido and epiphyseal closure.
FSH stimulates the Sertoli cells to produce androgen binding globulin (ABG) and inhibin. ABG binds to 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 inhibiting FSH, LH and GnRH production.
Raised testosterone levels in the blood stimulate the release of inhibin, which causes negative feedback on the pituitary and hypothalamus, decreasing the production hormones in the pituitary gland.
Inhibition of the enzyme, aromatase, results in an increase in FSH production suggesting that FSH regulation is more dependent on estradiol than testosterone.
GnRH promotes the release of LH and FSH which act on the ovaries and produce estrogen and inhibin. A decrease in testosterone and DHEA, with raised estrogen, leads to 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 usually 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 the pituitary and hypothalamus.
Role of Androgen-Binding Protein (ABP)
ABP is synthesized by Sertoli cells and is later secreted in the seminiferous tubules. This binds to testosterone and maintains a high concentration of testosterone in the testes. The concentration of the hormone, testosterone, is approximately 50 times more in the testes than in the blood.
Metabolic fate of testosterone
- Binds to the androgen receptors in the target tissues
- Converted to DHEA–dihydrotestosterone at the target tissues by the action of 5-alpha-reductase
- Or converted to estradiol by the action of aromatase
Primary sexual characteristics: include the growth and development of the testes and penis in males.
Secondary sexual characteristics: include the development of facial and pubic hair, increased muscle mass and voice changes, as well as the development of the larynx.
Maturation of HPG axis in males
GnRH secretion starts in the intrauterine life in the fetal stage of life. This leads to primary sexual characteristics. Its production decreases in the neonatal period and in the childhood stage until puberty when the pulsatile secretion of GnRH occurs and testosterone is produced. Secondary sexual characteristics are produced in the body after puberty until the adult stage of life, the production of GnRH and testosterone increases and, in the latter part of adulthood, it starts decreasing.
Hypothalamic–Pituitary–Gonadal (HPG) Axis Differentials
Due to the disturbance of the 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 a central cause, i.e pituitary or hypothalamic disturbance or due to local primary diseases of the gonads.
Associations of this condition include:
- Use of various drugs
To find the cause of hypogonadism, the following investigations should be done:
- FSH level
- LH level
- Prolactin level
- Estradiol levels
- Seminal fluid examination
- Thyroid function test
Still, if a clear diagnosis cannot be made, testicular tissue testing (testicular biopsy) and LH releasing hormone stimulation tests should be done.
Causes of hypogonadism in females are almost the same as those of males, except that instead of Klinefelter’s syndrome, Turner syndrome occurs. Features of Turner syndrome include short stature, webbed neck, high arch palate, short fourth metacarpals, and wide-spaced nipples.
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:
- Genital trauma
- Autoimmune destruction
- Mumps orchitis
Side effects of drugs:
- Chemotherapeutic agents
- Klinefelter’s syndrome
- Bilateral anorchia
Secondary hypogonadism or hypogonadotropic variety
The type of hypogonadism in which pituitary or hypothalamic secretions are decreased leading to the decreased growth of gonads and other characteristics is called secondary hypogonadism.
- Idiopathic causes
- Post-infectious state of CNS
- Damage to the hypothalamus or pituitary via radiations, tumor, infiltrative trauma
- Hereditary hemochromatosis
- Congenital disorders like Kallman’s syndrome
Side effects of drugs:
- Leuprolide (used in prostate cancer)
Signs and symptoms of hypogonadism
Hypogonadism can begin during:
- Fetal development
- Before puberty
- During adulthood. Signs and symptoms of the disease depend on when the condition develops
During fetal development:
Impaired growth of 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
- Under-developed male genitals
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)
Hypogonadism may alter physical masculine characteristics and impair normal reproductive function.
Signs and symptoms may include:
- Erectile dysfunction
- Decrease in beard and body hair growth
- Decrease in muscle mass
- Development of breast tissue (gynecomastia)
- Loss of bone mass (osteoporosis)
As testosterone decreases, men have symptoms similar to those that females have after menopause: fatigue, decreased sex drive, difficulty concentrating and hot flashes.