Endocrine System 4

What enzymes cleaves POMC?

Convertases

What are the four posttranslational peptides derived from POMC?

α-MSH, β-MSH, γ-MSH, which are melanocyte-stimulating hormones, and ACTH (Adrenocorticotropic Hormone)

What are the five melanocortin receptors, and what type of receptors are they?

MC1R, MC2R, MC3R, MC4R, MC5R, and they are 7-transmembrane (because it goes through the membrane 7 times), G-protein-coupled receptors (GPCRs).

What are the two melanocortin antagonists?

Agouti and agouti-related protein (AGRP).

What are two proteins that modulate melanocortin activity?

Mahogany and syndecan-3.

What opioid peptide is derived from POMC but is NOT part of the melanocortin system?

β-Endorphin, which is produced in the pituitary and functions in pain inhibition.

How does posttranslational processing of POMC exhibit tissue specificity?

• Different POMC peptides are produced by different cell types.

• The same POMC precursor can be cleaved into different hormones depending on the tissue, allowing it to regulate different physiological functions.

• Mutations in the POMC gene/processing are rare but possible

What are some examples of tissue specificity in the melanocortin system?

α-MSH that is produced in the brain inhibits food intake, and a mutation is linked to early-onset diabetes.

α-MSH that is produced in the skin acts on melanocytes to influence skin and coat color. A mutation leads to altered pigmentation.

MCR (melanocortin Receptors) that are produced in the adrenals, skin, brain, and penis. Penile MCR mutation is associated with sexual dysfunction.

How does α-MSH increase pigmentation in the skin?

1) α-MSH binds to MC1R, a G-protein-coupled receptor.

2) This activates adenylyl cyclase, which converts ATP to cAMP.

3) Increased cAMP activates PKA (protein kinase A).

4) PKA activates CREB (cAMP response element-binding protein).

5) CREB promotes the synthesis of MITF (microphthalmia-associated transcription factor).

6) MITF regulates the transcription of tyrosinase (Tyr) and DCT (dopachrome tautomerase), enzymes that lead to melanin synthesis.

How does the Agouti protein act as an antagonist?

In the skin:

• The Agouti protein binds to MC1R in the skin, preventing α-MSH from binding, blocking the pathway for melanin production

In the brain:

• Agouti protein binds to MC4R, disrupting normal signaling. This leads to overeating, obesity, hyperglycemia, and insulin resistance

What are some examples of MC1R mutations affecting pigmentation?

1) Yellow mice (caused by Agouti protein antagonizing MC1R).

2) Black jaguar (due to melanism, a dominant gene mutation in MC1R).

3) Red hair in humans (caused by two copies of a recessive mutation in MC1R, leading to reduced melanin production).

What leads to erectile dysfunction?

MC4R mutation leads to erectile dysfunction.

α-MSH analogs (agonists) are used to treat erectile dysfunction by enhancing MC4R signaling.

Example: Melanotan II, an α-MSH analog, binds to MC3R & MC4R in the brain to increase sexual function.

What are the two anterior pituitary hormones that are controlled by both a releasing hormone and an inhibiting hormone?

Prolactin and GH

What is the structure of the mammary glands?

• Each lobe is divided into smaller lobules.

• Lobules contain alveoli, which are tiny milk-producing glands.

• Milk flows from alveoli → secondary tubules → mammary ducts → lactiferous ducts → nipple.

• Right before lactation, milk accumulates in the lumen of the duct.

How are mammary glands developed and regulated during lactation?

1) Before birth: The placenta releases estrogen and progesterone, which stimulate the development of mammary ducts.

2) After birth: Estrogen levels drop, and prolactin levels increase, controlling milk production.

3) Milk release: Controlled by oxytocin, which is produced in the hypothalamus and stored in the posterior pituitary.

4) Suckling stimulus: Suckling on the mother's nipple stimulates prolactin production. Sometimes, just seeing or hearing the baby can trigger milk release.

What are some of the nutrients that are found in breast milk?

1) Proteins

2) Lipids

3) Carbohydrates

4) Vitamin A, B, D, E

5) Calcium, iron, zinc, selenium, etc.

6) Immunoglobin A (IgA)

7) Hormones, growth factors, chemokines

What hormone plays a role in trust?

Oxytocin

How does the SRY gene determine sex?

The SRY gene, which is located on the short arm of the Y chromosome under the pseudoautosomal region, induces embryonic gonads to become testes. The lack of it results in the development of ovaries.

How does fetal sex differentiation occur?

At 6 weeks:

• The fetus has a bipotential gonad, meaning it is undifferentiated.

At 10 weeks (male):

1. The gonadal tissue develops into testes

2. This stimulates the production of testosterone (androgen) from Leydig cells, and Müllerian Inhibiting Factor (MIF/AMH) from Sertoli cells.

3. MIF causes Müllerian duct to degenerate, preventing female reproductive structures from forming

4. Testosterone then maintains the Wolffian duct, helping it develop into the seminal vesicle, the vas deferens, and the epididymis

5. The enzyme 5α-reductase is then going to convert testosterone into DHT, which is essential for the development of the male external genitalia.

At 10 weeks (female):

1. Due to the lack of SRY, the gonadal tissue develops into ovaries.

2. Since there are no Sertoli cells nor testosterone, the Müllerian duct is maintained and the wolffian duct is degenerated.

3. The lack of MIF also causes the Müllerian duct to become the fallopian tube, uterus, and vagina.

How do external genitalia develop in males and females?

At 6 weeks:

• External genitalia in males and females are identical, consisting of the urogenital sinus, genital tubercle, urethral folds, and labioscrotal swellings.

For males:

• Testosterone and DHT develop the genital tubercle into the penis. The urethral folds fuse to form the penile urethra, and the labioscrotal swellings fuse to form the scrotum. DHT also promotes the development of the prostate.

For females:

• Without testosterone, the genital tubercle develops into the clitoris, and the labioscrotal swellings develop into the labia majora.

What is the chromosomal makeup of nucleated cells in the body?

With the exception of oocytes and sperm, all nucleated cells contain 46 chromosomes, making them diploid. This consists of 22 homologous pairs of autosomes, and 1 pair of sex chromosomes.

What is the chromosomal makeup of oocytes and sperm, and how is sex determined?

TOocytes and sperm are haploid, each containing half a set of 23 chromosomes. The zygote has a unique set of 46 chromosomes—one homologous chromosome from the mother and one from the father in each pair. If the sex chromosomes are XX, the individual will be female, whereas XY results in a male.

What are some abnormal SRY Recombinations?

1) XX male (with SRY on X chromosome)

2) XY female (no SRY)

What does testes development require?

It requires the insulin receptor family, which includes:

1. Insulin receptor (INSR)

2. Insulin-like growth factor 1 receptor (IGF1R)

3. Insulin receptor-related receptor (INSSR)

What does a mutation in the insulin receptor family result to ?

If there are mutations within all three receptors, even XY individuals with the SRY gene develop ovaries instead of testes and exhibit a completely female phenotype.

What are true hermaphrodites (intersex individuals)?

True hermaphroditism is a sexual development disorder where an individual has both ovarian and testicular tissue.

• It can occur with different chromosomal patterns (karyotypes), such as XX, XY, or a mix (mosaicism).

• This happens in every 1 out of 1500-2000 births.

What are true pseudohermaphrodites (intersex individuals)?

A pseudohermaphrodite (intersex individual) is a person with a congenital endocrine disorder where their external genitalia do not match their internal sex organs.

Eg. males with a defective 5a-reductase gene:

• This is the enzyme that converts testosterone to DHT.

• Since DHT is required for male external genitalia and prostate development, these individuals are born with female-appearing genitalia.

• At puberty, their testes start producing more testosterone, leading to masculinization, including the growth of male genitalia, voice deepening, and muscle development.

What happens during puberty?

• Puberty is a period of rapid growth and development, with earlier and more noticeable changes in females.

• It is triggered by the activation of the HPG axis (Hypothalamic-Pituitary-Gonadal axis), leading to gonadal maturation (ovaries/testes development).

• Adolescence follows, during which adult social and cognitive behaviors mature.

• These processes are regulated by interactions between the nervous system and gonadal steroid hormones.

What triggers the onset of puberty?

1. FSH & LH levels are high at birth due to GnRH (Gonadotropin-releasing hormone) and remain high for the first 6 months of life before dropping until puberty.

2. Puberty is triggered by a sharp increase in LH, which follows a pulsatile secretion pattern. LH secretion increases in frequency and amplitude, with higher levels at night than during the day.

3. This happens due to an increase in GnRH secretion, which is released from the hypothalamus and signals the anterior pituitary to release LH and FSH.

4. The increase in LH during puberty stimulates sex hormone production—testosterone from the testes and estradiol from the ovaries.

5. The rise in sex hormones leads to the development of secondary sex characteristics.

What is the role of Gonadotropin-releasing hormone (GnRH) in puberty?

1. It is released from the hypothalamus (Hypo) in pulses.

2. Children with GnRH deficiency will fail to mature.

3. Treatment will only work if administered in pulses similar to the natural secretion pattern.

4. An increase in pulsatile GnRH, either naturally or through treatment, triggers the start of puberty.

GnRH Activity Across Life

• Normal: High at birth, decreases in childhood, peaks again at puberty, then remains stable throughout life.

• Complete defect of GnRH secretion: No spikes; remains low at all times.

• Reversal of GnRH secretion defect: Initially low but treated, allowing a delayed peak that can be restored to normal.

• Relapse of GnRH secretion defect: Peaks with treatment but declines again when treatment stops too early.

• Partial defect of GnRH secretion: Attempts to peak at puberty but fails and declines.

• Adult-onset GnRH secretion defect: Normal through puberty, but decreases in adulthood when it should remain stable.

What are some variations in puberty?

• Genetic factors: Timing of puberty varies, but no specific genes have been identified.

• Environmental factors: Higher altitudes are linked to later puberty onset.

• Nutrition: Poor nutrition can delay puberty, while high-calorie diets may accelerate it.

• Chronic illness: Certain diseases can slow down puberty.

• Exposure to synthetic hormones and chemicals: Theoretical concern that environmental chemicals might influence puberty timing.

• Precocious puberty: Puberty starts much earlier than normal.