Hypothalamic pituitary gonadal axis

Endocrine control systems

HPG is one of 3 major endocrine system controls

1. HPA axis: Pigmentation, Chronic fatigue syndrome, Insomnia , Hypotention (CMV)
2. Hypothalamic–pituitary–gonadal axis (HPG) (Infertility: MTB, HPV, MMP)
3. Hypothalamic–pituitary–thyroid axis (HPT) (Hypothroidism,

Physiology

• HPG axis is also known as Hypothalamic–Pituitary–Ovarian/ Testicular axis
• It refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity.
• HPG axis plays a critical part in reproductive and immune systems.
• GnRH is secreted from the hypothalamus by GnRH-expressing neurons.
• The anterior portion of the pituitary gland produces LH and FSH
• Gonads produce estrogen and testosterone.
• Release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology.
  • LH acts on Leydig cells in the male testes and theca cells in the female.
  • FSH acts on Sertoli cells in the male and follicular cells in the female.
  • Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis.

• The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH.
• GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

Location and regulation

Females

• In females FSH and LH act primarily to activate the ovaries to produce estrogen and inhibin and to regulate the menstrual cycle and ovarian cycle.
• Estrogen forms a negative feedback loop by inhibiting the production of GnRH
• Inhibin acts to inhibit activin, which is a peripherally produced hormone that positively stimulates GnRH
• Follistatin, which is also produced in all body tissue, inhibits activin and gives the rest of the body more control over the axis.

Males

• In males LH stimulates testicular interstitial cells to produce testosterone,
• FSH plays a role in spermatogenesis.
• Only small amounts of estrogen are secreted in males.

Both sexes

• Recent research has shown that a neurosteroid axis exists, which helps the cortex to regulate the hypothalamus's production of GnRH.
• In addition, leptin and insulin have stimulatory effects and ghrelin has inhibitory effects onGnRH secretion from the hypothalamus.
• Kisspeptin also influences GnRH secretion.

Reproduction

Females

• In females, the positive feedback loop between estrogen and LH help to prepare the follicle in the ovary and the uterus for ovulation and implantation.
• When the egg is released, the empty follicle sac begins to produce progesterone to inhibit Hypothalamus / Anterior pituitary thus stopping the estrogen-LH positive feedback loop.
• If conception occurs, the placenta will take over the secretion of progesterone; therefore the mother cannot ovulate again.
• If conception does not occur, decreasing excretion of progesterone will allow the hypothalamus to restart secretion of GnRH.
• These hormone levels also control the uterine (menstrual) cycle causing the proliferation phase in preparation for ovulation, the secretory phase after ovulation, and menstruation when conception does not occur.
• Activation of the HPG axis in Males / Females during puberty also causes individuals to acquire secondary sex characteristics.

Males

• In males, the production of GnRH, LH, and FSH are similar, but the effects of these hormones are different.
• FSH stimulates sustentacular cells to release androgen-binding protein, which promotes testosterone binding.
• LH binds to the interstitial cells, causing them to secrete testosterone.
• Testosterone is required for normal spermatogenesis and inhibits the hypothalamus.
• Inhibin is produced by the spermatogenic cells, which, also through inactivating activin, inhibits the hypothalamus.
• After puberty these hormones levels remain relatively constant.

Life cycle

The activation and deactivation of the HPG axis also helps to regulate life cycles. At birth FSH and LH levels are elevated, and females also have a lifetime supply of primary oocytes. These levels decrease and remain low through childhood. During puberty the HPG axis is activated by the secretions of estrogen from the ovaries or testosterone from the testes. This activation of estrogen and testosterone causes physiological and psychological changes. Once activated, the HPG axis continues to function in men for the rest of their life but becomes deregulated in women, leading to menopause. This deregulation is caused mainly by the lack of oocytes that normally produce estrogen to create the positive feedback loop. Over several years, the activity the HPG axis decreases and women are no longer fertile.

Although males remain fertile until death, the activity of the HPG axis decreases. As males age, the testes begin to produce less testosterone, leading to a condition known as post-pubertal hypogonadism. The cause of the decreased testosterone is unclear and a current topic of research. Post-pubertal hypogonadism results in progressive muscle mass decrease, increase in visceral fat mass, loss of libido, impotence, decreased attention, increased risk of fractures, and abnormal sperm production.^{[citation needed]}

Sexual dimorphism and behavior

Sex steroids also affect behavior, because sex steroids affect the brains structure and functioning. During development, hormones help determine how neurons synapse and migrate to result in sexual dimorphisms. These physical differences lead to differences in behavior. While GnRH has not been shown to have any direct influence on regulating brain structure and function, gonadotropins, sex steroids, and activin have been shown to have such effects. It is thought that FSH may have an important role in brain development and differentiation.

Testosterone levels have been shown to relate to prosocial behavior. This helps create synaptogenesis by promoting neurite development and migration. Activin promotes neural plasticity throughout the lifespan and regulates the neurotransmitters of peripheral neurons. Environment can also affect hormones and behavior interaction.

Clinic

• WHO group I of ovulation disorders: Hypothalamic–pituitary failure
• WHO group II of ovulation disorders: Hypothalamic–pituitary dysfunction.
  • WHO group II is the most common cause of ovulation disorders, and the most common causative member is PCOS.

Hypogonadotropic hypogonadism

• HH is a Hypothalamic–pituitary failure. Like adrenal insufficiency, we could dived this problem into two parts. Primary and secondary Hypogonadism. Oophoritis should be considered as primary hypogonadism since the simple inflammation of ovaries is the core of pathology. HH could be the secondary and tertiary form because of involvement of Pituitary and Hypothalamus.
• HH is due to problems with either the hypothalamus or pituitary gland affecting HPG axis.
  1. Hypothalamic disorders result from a deficiency in the release of GnRH
  2. Pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary.

Two types

HH has two types considering its etiology

Congenital HH

• CHH is due to genetic abnormalities resulting in non-functional GnRH secreting neurons or gonadotropic cell dysfunction in the anterior pituitary. CHH is divided into 2 subtypes depending on the condition of the olfactory system, anosmic HH (Kallman syndrome) and normosmic HH.

• CHH is a genetically heterogenous disorder with cases reported as being X-linked, recessive and autosomally inherited.

Acquired HH

AHH is an acquired form of the disease often occurring after sexual maturation and is not related to genetic defects including

• Sarcoidosis
• Lymphocytic hypophysitis
• Pituitary adenomas
• Craniopharyngiomas and other CNS tumours.

AHH and Prolactin

• Most of these patients have multiple pituitary hormone deficiencies.
• Hyperprolactinaemia is the most common cause of AHH.
• It is a well-established cause of infertility in both male and female mammals.
• Prolactin inhibits GnRH neurons and therefore inhibits the subsequent release of LH, FSH and sex steroids.
• It could be considered as ttertiary hypogonasism. Since GnRH deficit is the core of pathological effects.
• PCOS:

HPG and PCOS

Recently PCOS is classified into 4 clinical subtypes. Adrenal PCOS which is distinguished by high DHEA-S from Insulin-resistance PCOS. I think insulin resistance would be be the starting point of Insulin-resistance PCOS, because Insulin could increase GnRH and GnRH could increase Androgen and Strogen, which are very high in that form of PCOS. On the opposite site we have Adrenal PCOS, which is not an appropriate name. Because in both form we have adrenal hyperactivity, but here in adrenal type there is primary adrenal corext hyperactivity. Androgens are not increasing but DHEA-s is only increasing. It likes Cushing syndrome