Hormonal Regulation of Puberty

Hormonal Regulation of Puberty

• The hypothalamic-pituitary-gonadal (HPG) axis regulates puberty via a complex hormonal cascade
• The process starts in the brain and leads to the production of androgens and estrogen
• Androgens and estrogens are the key sex hormones driving physical and reproductive changes during puberty

Hormonal Cascade Overview

• The hypothalamus increases secretion of gonadotropin-releasing hormone (GnRH), which initiates puberty
• GnRH released in a pulsatile manner ensures proper pubertal development
• GnRH stimulates the anterior pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the two key gonadotropins
• LH and FSH affect the gonads. In males, LH stimulates Leydig cells in the testes to produce testosterone (an androgen)
• In females, FSH and LH stimulate ovarian follicles, which then produce estrogens, mainly estradiol

Roles of Androgens and Estrogens

• Males predominantly produce androgens (e.g. testosterone) but females produce smaller amounts in the adrenal glands and ovaries
• Androgens stimulate male secondary sex characteristics, growth of external genitalia, growth spurts, and epiphyseal plate closure
• Androgens also influence libido and aggression
• Females primarily produce estrogens (e.g., estradiol), but males produce small amounts via testosterone conversion
• Estrogens stimulate female secondary sex characteristics, regulate menstruation, and help with maturation of reproductive systems
• Estrogens contribute to the pubertal growth spurt and epiphyseal closure
• These promote feedback effects on the HPG axis, initially positive for LH surge and later negative to regulate GnRH

Feedback Regulation

• Negative feedback from rising testosterone or estrogen levels regulates GnRH, LH, and FSH secretion
• In females, positive feedback from estrogen at mid-cycle causes an LH surge and triggers ovulation
• Rising testosterone or estrogen inhibit GnRH, LH, and FSH through negative feedback
• High estrogen mid-cycle in females causes positive feedback, leading to LH surge then ovulation

Differences in Secondary Sex Characteristics

• Boys(driven by testosterone): Facial hair grows on the upper lip, chin, and cheeks
• Boys: Lthe arynx and vocal cords enlarge, causing the voice to "break"
• Boys display increased Muscle mass, especially in the upper body and shoulders
• Boys develop Body hair on the chest, back, arms, legs, and underarms
• Boys: Pubic hair appears at the base of the penis, becomes coarse and curly
• Boys experience a more pronounced growth spurt that begins later than in girls
• Boys' testes and penis enlarge, which is a primary sexual characteristic
• Boys: Increased sweat and sebum production can lead to acne
• Boys develop broader shoulders and narrower hips, resulting in a typical male body shape
• Girls: (driven by estrogen): Breast development marks the first sign of puberty
• Girls' hips widen as the pelvis broadens for potential childbirth
• Girls: Pubic hair appears on the mons pubis that darkens and curls over time
• Girls experience axillary (underarm) hair growth after pubic hair
• Girls: Menstruation begins around ages 12-13
• Girls develop increased fat deposition for a curvier figure
• Girls exhibit growth spurts that occurs earlier than in boys and ends sooner
• Girls exhibit Increased sweat and sebum production, which can lead to acne
• Girls have a softer voice with some deepening, but less than in boys

Key Hormones in the Pubertal Growth Spurt

• GH made in anterior pituitary stimulates liver/tissues to produce insulin-like Growth Factor 1 (IGF-1)
• GH and IGF-1 together enable long bone growth (epiphyseal plates), muscle development and organ growth
• Estrogen in girls stimulates GH secretion and enhances epiphyseal plate activity early in puberty
• Testosterone in boys can convert to estrogen via aromatase in growth plates, then epiphyseal plate closure
• Thyroid hormones are needed for normal GH secretion and bone development, regulating metabolism so cells have enough energy for growth
• Thyroid hormones potentiate effects of GH and IGF-1
• Testosterone in boys increases muscle mass and bone density. Testosterone stimulates secretion of GH, which then boosts IGF-1, and therefore growth
• In both, estrogen causes epiphyseal closure, ending growth

Timing of Growth Spurts

• GH stimulates IGF-1 production and bone growth while IGF-1 directs cartilage and bone growth
• Girls start puberty around ages 9-11 while boys start later around ages 11-13
• Peak height velocity is around age 11-12 in girls and around age 13-14 in boys
• Girls also growth spurts typically and for a shorter time (2-3 years), whereas boys grow for longer (up to 4 years)
• In boys, this testosterone converts to estrogen
• In girls, the growth spurt occurs is earlier but the epiphyseal closure which triggers estrogen is sooner

Height and Skeletal Differences

• Estrogen leads to early growth plates fusion
• Skeletal differences between the sexes is girls have greater amounts of fat mass and boys have more bone length and muscle mass
• Girls: have peak height velocity of around 8.3 cm per year and Boys around 9.5 cm per year
• Epipyseal closure occurs earlier in girls (estrogen induced) and later in boys (testoterone converted to estrogen)
• Wider pelves with shorter limbs is present in girls and broader shoulder s with longer limbs are present in boys
• Further, girls have less prominent skull and jaw growth while more more prominent brow and jawline is present in boys
• Estrogen encourages fat deposition, whereas testosterone promotes muscle growht and lean body mass
• This means broader hips for childbirth with less change in the shoulders in girls while the hips remain narrow for boys and the shoulders widen significantly

Brain Size Growth Postnatally

• The brain increase in size through
• Glial cell proliferation, especially astrocytes and oligodendrocytes
• Myelination of neutrons for faster signal transmission
• Synaptogenesis for new synaptic connections
• Dendritic growth and increased complexity
• Compared before birth, myelination continues into early adulthood
• Different brain regions myelinate at different times
• Specifically, Sensory and motor areas first (early childhood) and then prefrontal cortex last (into mid-20s)

Synaptic Pruning and Functional Maturation

• There is overproduction of synapses in infancy and early childhood
• Followed by pruning to eliminate weak or unused connections
• The 'use it or lose it' principle means experience shapes brain architecture
• All this optimizes efficiency and specialization of brain networks
• Cognitive functions (language, reasoning, emotional regulation) develop but critical periods exist where the brain is more sensitive to specific stimuli

Other Tissues Postnatal Growth Patterns

• Muscle increases in fiber size due to Testosterone in puberty
• Bones lengthen at epiphyseal plates until they close in late adolescence
• Fat/Adipose tissue increases in size and number during infancy through adolescence
• Liver and kidneys grow proportionally with body mass but there is increased collagen with physical activity,
• Neural tissue grows by network development, myelination, and synaptic refinement; brain is experience-dependent
• Other tissues like muscle and bone grow through cell enlargement, hypertrophy, and mechanical stimuli

Relative Order of Brain Development

• Brain regions mature from basic survival functions to higher-order thinking
• Brainstem controls basic life functions, such as heart rate, breathing, and matures at birth.
• Cerebellum controls balance, coordination, and motor control
• It grows rapidly during infancy
• The primary sensory cortex processes touch, vision, and hearing, and matures during infancy
• Parietal lobes control spatial awareness, math, reading, and undergo middle to late childhood
• Temportal lobes oversee language, memory, hearing, and undergo early to middle childood
• Lastly, prefrontal cortex controls planning, decision-making, and impulse control, during adolescence to mid 20s

Relation to Changes in Abilities by Age

• Infancy means reflexes can give way to coodrinated motor skills and rapid sensory processing
• Myelination boosts motor and sensory speed
• Middle childhood can have enhanced logical thinking, attention span, and problem-solving
• Middle childhood exhibit improved spatial reasoning, and multi-step instruction usage
• Adolescence bring about the development of executive function

Sensitive Periods

• A sensitive period is a limited phase in early life when neural circuits are more response
• These have starting and end points where same input has less impact
• This implies skills may be partially recovered with intensive therapy, but typically not to full potential

Examples of Sensitive Period Effects

• Vision in early infancy (0-6 months) means visual exposure prevents impaired acuity(eg, blindness/lazy eye)
• Language in early childhood/infancy (0-7 years) means speech and social interaction and prevent issues such as impaired acquistion(eg, grammar/pronunciation)
• Emotional bonding in early childhood/infancy(1-2 years) means consisten caregiving and affection to prevent issues such as attachment/emotional dysregulation
• Motor skills in early childhood/infancy (0-5 years) means movement, touch, and prevent issues such as delayed coordination
• Lastly, musical perception in middle childhood(0-10 or 12 years) means music exposure and prevent issues such as less pitch/rhythm later with
• In contrast, lack of it prevents this, leading to prunign that creates cognitive delays/poor emotional regulation.

Effects of Lack of Stimulation

• Developed or miswired circuits where, in particular, the window closes
• There are long-term deficits, creating issues such as less sensitivity
• EArly, enriched stimulation is essential for future neurodevelopment
• All sensitive periods act as a window of opportunity for brain development

Barker and Mismatch Hypotheses

• The Barker Hypothesis suggests early famine leads to biological shifts in offspring, which are linked to high disease risk later in life due to wealth later.
• That is, low nutrition signals biological shifts to optimize growth with little nutrition
• LBW babies commonly have fewer nephron, altered development, and changes in the metabolism and fat

Mismatch Hypothesis

• Mismatch Hypothesis builds on Barkers ideas

Understanding Long Lifespans

• The maximum capacity of a human to live is typically between 120 years
• Today increased sanitation and antibiotic has led to reduced mortality risk leading to an overall life expectancy increase
• Most of this change is people living after 65, however certain chronic diseases such as Alzheimer's, etc., are more common

Factors That Influence Life Expectancy

• There are global disparities
• Generally, rich people tend to live healthier (positive correlation with income levels)
• More negative influence such as environment tend to affect mortality

9 Hallmarks of Aging

• Genomic instability is due to accumulation of DNA damage + environmental insults
• Telomere attrition occurs to protective caps, leading to eventually cell senescence.
• Epigenetic alterations change with expression over time + alter cell function + identity
• Loss of proteostasis from impaired ability leads to protein aggregation + dysfunction
• Deregulated nutrient sensing affects the insulin/IGF-1, mTOR pathways and leads to reduced resistance
• Mito dysfunction from ROS is often from cells being less efficient leading to less energy
• Cell senescene from increased cell inflammation leads to damaged tissues
• Integraative markers 8+9 include: stem cell + intercellular alteration, which both contribute to tissue damage+dysfunction

Molecular

• DNA damage from oxidation and the shorter telomere that limit division
• Then comes epigentetic alteration
• Then comes oxidation stress where toxins lead to damaged cellular components
• Following lastly by decrease in repair mechansisms

Cellular Level

• Cells become damaged, dividing less and secreting factors
• Mitocontrial dysfunction is where less ATP and more ROS and more fatigue come from
• Impaired autophagy leads to less recycling for what damaged
• Stem cell exhaustion comes about

The 6 Lifestyle Interventions

• The goal of lifestyle intervention is to increase benefits + maintain healthiness
• The goal of many supplements that are advertised is to increase mitochondrial function in the body and more
• They should then activate SIRT!1 which can perform DNA repair
• To summarize, there are three main pathways the body tries to fix in these interventions - mTOR, sirtuins, AMPK

Top 6 Potential Solutions

• Caloric Restriction is the most commonly advertised/known intervention
• Rapamycin is an mTOR inhibation that promotes the breaking down and recycling of material
• Metformin is a anti inflammation with high longevity, and acts as insulin/IGF-1. Need more human data.

Booster

Mitochondria + aging cells can be fixed via the prior mechanisms - but requires more human data + studies

• Lastly for senolytic telomerase activations can delay cell growth that slows down the signs of aging

Scepticism in Organisms

• Even in animal studies, it may not be a 1;1 translation, you cannot expose humans to harm
• There are biological, genetic + lifespan differences, including lack of natural data + human testing due to practical limits
• A treatment may create side effects in humans or in the lab is not how it should be done

Value of Studies

• Overall however, they are useful to know of common and efficient data and test and conserved throughout species and provide insight to the mechanisms
• Bottom Line: there must be a standard for testing and testing