ANS and Endorinology Flashcards
what is the Organization of the sympathetic and parasympathetic systems?
- Sympathetic Nervous System (SNS):
Origin: The sympathetic nervous system originates from the thoracic and lumbar regions of the spinal cord. It is often referred to as the “thoracolumbar division” of the ANS.
Neurotransmitter: The primary neurotransmitter used by the sympathetic nervous system is norepinephrine (also known as noradrenaline).
Ganglia: Sympathetic ganglia are typically located close to the spinal cord and form a chain called the sympathetic chain ganglia (or sympathetic trunk). Pre-ganglionic neurons are short, while post-ganglionic neurons are long.
Response: The SNS is responsible for the “fight or flight” response. It prepares the body for stressful situations by increasing heart rate, dilating airways, shunting blood to muscles, and inhibiting non-essential functions like digestion.
2. Parasympathetic Nervous System (PNS):
Origin: The parasympathetic nervous system originates from the cranial nerves (such as the vagus nerve, CN X) and the sacral region of the spinal cord. It is often referred to as the “craniosacral division” of the ANS.
Neurotransmitter: The primary neurotransmitter used by the parasympathetic nervous system is acetylcholine.
Ganglia: Parasympathetic ganglia are located close to or within target organs. Pre-ganglionic neurons are long, while post-ganglionic neurons are short.
Response: The PNS is responsible for the “rest and digest” response. It promotes relaxation, conservation of energy, and activities such as digestion, salivation, and slowing of the heart rate.
Pre- and postganglionic neuron and their transmitter substances?
preganglionic always have achetylcholin as a neurotransmiter ( Nicotin receptors) ( N1 for sceletal N2 for the others)
post ganglionic neurons of the sympathetic
have norepinephrin ( A, B ANDRNERGIC RECEPTORS)
Preganglionic neurons contact upto 200
postganglionic
Originate from Th1 to L3
post ganglionic neurons of parasympathetic have acetylcholin ( MUSCARINIC RECEPTORS)
Para- and prevertebral sympathetic ganglions?
Paravertebral Ganglia:
In the sympathetic chain ganglia, the pre-ganglionic neurons are relatively short, and the post-ganglionic neurons are relatively long.
Prevertebral Ganglia:
In prevertebral ganglia, the pre-ganglionic neurons are relatively long, and the post-ganglionic neurons are relatively short.
Digestion etc.
Explain adrenal medulla hormones synthesis
Synthesis of Adrenal Medulla Hormones:
Tyrosine Uptake: The synthesis of adrenal medulla hormones begins with the uptake of the amino acid tyrosine from the bloodstream into the adrenal medullary cells.
Conversion to Dopamine: Inside the adrenal medullary cells, tyrosine is converted into dopamine by the enzyme tyrosine hydroxylase.
Conversion to Norepinephrine: Dopamine is then converted into norepinephrine by the enzyme dopamine beta-hydroxylase.
Conversion to Adrenaline: Some of the norepinephrine is further converted into adrenaline (epinephrine) by the enzyme phenylethanolamine-N-methyltransferase (PNMT).
Explain the most common disease with overproduction of catecholamines.
Pheochromocytom: Catecholamine
producing tumor in the adrenal medulla →
hypertension, tachycardia and sweating →
attacks
what are the Cell types that are innervated by autonomic nerves?
many target organs and tissues
Effects of the autonomic nervous system on different organs?
depends on if the autonomic activity is sympathetic or parasympathetic
Know how autonomic nerve activity can be measured?
§ MSNA = muscle sympathetic nerve
activity
§ HRV = Heart rate variability
§ Plasma catecholamine’s and
metabolites
MSNA is quantified by counting the neural bursts identified
in a mean voltage neurogram and expressing them as:
1) bursts / minute (Burst Frequency [BF])
2) bursts / 100 heart beats (Burst Incidence [BI])
Describe important steps in the steroidogenesis
- About 80% of the cholesterol required for steroid hormone formation
comes from LDL (low-density lipoprotein). - LDL ➔taken up via receptor-mediated endocytosis
- The remaining cholesterol is formed In the cell ➔de novo acetyl
coenzyme A (Acetyl CoA)
3β-hydroxysteroid dehydrogenase (3β-HSD)
- Pregnenolon → progesteron
- Dehydroepiandrosteneion (DHEA) → androstenedione
* 17β-hydroxysteroid dehydrogenase (17β-HSD) (oxidation or reduction)
- Estron → Estradiol (or other way around)
- Androstenedion → Testosteron (or other way around)
* 5𝝰-reductase
- Testosteron → dihydrotestosteron (DHT)
* Aromatase
- Androstenedion → Estrone
- Testosteron → Estradiol
* Lack of specific enzymes can lead to over and under production of steroid
hormones
Describe concepts of endocrine, paracrine, autocrine and neurocrine effects.
§ Autocrine signalling → endocrine cell regulates itself
§ Paracrine signalling → endocrine cell regulates cells
nearby
§ Endocrine signalling → all circulating hormones
§ Neurocrine signalling → nervcells produce hormones →
released into blood e.g. nerve cells in hypothalamus
produce oxytocin → released into blood stream
§ Neuroendocrine signalling → Nerves activate hormone
producing cells → released into blood stream
§ E.g. Sympathetic nerves → chromaffin cells in adrenal medulla →
epinephrine released into blood stream
Describe primary endocrine organs and tissues, the hormones they produce and secrete
IGF-1
production by liver and multiple somatic cells
Thyroid follicular cells produce
T3/T4
Ovarian granulosa cells ➔
Estrogens and progestins / Sertoli cells ➔
Spermatogenesis and inhibin
Ovarian theca cells
➔testosterone /Leydig cells ➔ testosterone
Mammary glands,
initates and maintain milk production
Hypothalamic and Posterior
Pituitary Hormones : Arginine vasopressin (AVP) antidiuretic
hormone (ADH) ➔ Acts on the collecting duct
of the kidney to increase water reabsorption
* Oxytocin ➔ Stimulation of smooth-muscle
contraction by the uterus during parturition and
mammary gland during suckling
Define and explain the concepts: Pulsatility, biorhythm and feed-back regulation
Biorythm
§ Circadian rythm (cortisol)
§ Monthly rythm (female sex hormones)
§ Life rythm (growth hormone)
Principles for Feed-back
§ Negative / Positive feedback
§ Long feedback loop
§ Active hormone regulates the hypothalamus
§ Short feedback loop
§ Active hormone regulates pituitary
Explain the hypothalamus-pituitary axis, feedback regulation and differences between adeno-, and neuro pituitary
Hypothalamus: The hypothalamus is a region of the brain that serves as a control center for the autonomic nervous system and plays a vital role in maintaining homeostasis. It produces various neurohormones, such as releasing hormones (e.g., gonadotropin-releasing hormone or GnRH) and inhibiting hormones, which regulate the release of hormones from the anterior pituitary.
Anterior Pituitary (Adenohypophysis): The anterior pituitary is a gland located at the base of the brain, just below the hypothalamus. It is often referred to as the “master gland” because it secretes several important hormones in response to signals from the hypothalamus. These hormones include thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and prolactin (PRL).
Posterior Pituitary (Neurohypophysis): The posterior pituitary is not a true gland but rather an extension of the hypothalamus. It stores and releases two hormones produced by the hypothalamus: oxytocin and vasopressin (antidiuretic hormone, ADH). These hormones are transported down nerve fibers from the hypothalamus to the posterior pituitary, where they are released into the bloodstream.
Feedback Regulation:
The hypothalamus-pituitary axis operates through a feedback system to maintain hormonal balance in the body. This feedback regulation helps to ensure that hormone levels stay within a narrow range.
Negative Feedback: In most cases, hormone release in the hypothalamus-pituitary axis is controlled by negative feedback. When the target endocrine gland releases a hormone that affects a specific physiological process, and the hormone levels reach an optimal range, it sends signals back to the hypothalamus and pituitary to inhibit further hormone production. For example, when thyroid hormone levels are sufficient, they signal the hypothalamus and pituitary to reduce the release of TSH.
Positive Feedback: In some instances, positive feedback is involved. This means that the hormone release stimulates further hormone production. A classic example is the release of oxytocin during childbirth. Oxytocin stimulates uterine contractions, which, in turn, stimulate more oxytocin release, creating a positive feedback loop that helps facilitate labor.
Describe mechanisms for hormone transport and bioavailability
§ Mainly regulated by feed-back loops
§ Low circulating levels pituitary
secretion
§ High circulating levels ¯ pituitary secretion
§ Protein binding free vs bound
§ Only free hormones has an effect and can
exert feed back regulation
§ Local enzymes in the tissue
§ Converts to a more potent form or inactivate
§ Receptor – number and affinity
§ Hormone sensitivity and responsiveness
§ Synergism e.g. estrogen – progesterone –
prolactin – synergism in milk secretion
§ Antagonism e.g. insulin decrease and glucagon
increase glucose
§ Permissiveness e.g. TH on catecholamine’s
Explain differences and similarities between the nervous system and the endocrine system in the regulation of function of target tissues/cells
Autonomic Nervous System (ANS)
- Rapid: seconds
-Specific: innervation to cells / organ
Endocrine System
- Slower: seconds – days
- General / selectiv: via blood / circulation,
receptors in target organ
Autonomic Nervous System (ANS)
- Nerv release hormone (e.g. neuropituitary)
- Nerv stimulates gland to release a hormone
(e.g SA-axis)
Predict the consequences of decreased or increased hormone synthesis example ( decreased ADH)
Homeostatic Imbalance
* Alcohol inhibits ADH release → ↑ urine
output
* ADH deficiency—diabetes insipidus;
↑↑ urine output and intense thirst
* ADH hypersecretion e.g. after
neurosurgery, trauma, or secreted by
cancer cells
* Syndrome of inappropriate ADH
secretion (SIADH)
Explain adrenal cortex hormones synthesis, biological effects and how the production and secretion is regulated
Adrenal cortex – 3 layers
Zona glomerulosa
Zona fasciculate
Zona reticularis
Adrenal cortex produce and
secrete 4 groups of steroid
hormones
Zona glomerulosa
Mineralkortikoider - aldosteron
Zona fasciculata
Glukokortikoider - kortisol
Zona reticularis
Androgener - DHEA och androstenedione
Medulla
Katekolaminer – Adrenalin (noradrenalin)
Explain the most common diseases with over- and underproduction of adrenal cortex hormones and principles for treatment
Regulation of aldosterone
§ Aldosteronism—
hypersecretion due to
adrenal tumors
-Hypertension and edema due to
excessive Na+
- Excretion of K+ leading to abnormal
function of neurons and muscle
Explain the HPA-axis response to stress, the link between the adrenal cortex and adrenal medulla
The glomerulosa zone is
controlled by the reninangiotensin
system and [K+].
The zona fasciculata and zona
reticularis are regulated by the
hypothalamus (CRH)-pituitary
(ACTH).
Despopoulos & Silbernagl,
”Color atlas of physiology”,ed
5, Thieme, 2003
Summary – regulation of
HPA and AS-axes
Adrenal medulla – adrenalin 80% and
noradrenalin 20%
adrena medula regulated by the sympathetic system (SA axis) and not from the HPA axis
Sympathetic activation
§ Stimulation of heart and blood vessels →↑ blood pressure,
cardiac output and peripheral resistance
§ Redistribution of blood → ↑ to muscle and heart
§ Dilatation of brochiolar tree
§ Reduced salivary secretion
§ Demands on metabolic substrates (glucose and fatty acids)
→ sympathetic nerves and epinephrine → liver and adipose
tissue
§ Glucogenolyses (stored glycogen is mobilized)
§ Lipolysis (fat cells converts stored TG to FFA)
§ Maintain body temperature → adjust skin blood flow
how the production and secretion of adrenal medulla hormones is regulated.
The production and secretion of adrenal medulla hormones are tightly regulated by the sympathetic nervous system, which responds to stress and various physiological signals. Here’s how it works:
Sympathetic Nervous System Activation: Stressful situations or stimuli, such as a perceived threat or physical stress, activate the sympathetic nervous system.
Release of Neurotransmitters: The sympathetic nervous system releases neurotransmitters, particularly acetylcholine, at synapses onto the cells of the adrenal medulla. This stimulation triggers the release of adrenaline and noradrenaline.
Hormone Secretion: Upon stimulation by acetylcholine, the adrenal medullary cells release stored adrenaline and noradrenaline directly into the bloodstream.
Feedback Mechanisms: Once the stressor is resolved, negative feedback mechanisms, involving hormones like cortisol and the parasympathetic nervous system, help return the body to a state of homeostasis by reducing the release of adrenaline and noradrenaline.
Chromaffin cells what do they do ?
§ Chromaffin cells secrete epinephrine (80%)
and norepinephrine (20%)
§ Epinephrine stimulates metabolic
activities, bronchial dilation, and blood flow
to skeletal muscles and the heart
§ Norepinephrine: Peripheral
vasoconstriction and blood pressure
§ Pheochromocytom: Catecholamine
producing tumor in the adrenal medulla →
hypertension, tachycardia and sweating →
attacks
β-adrenergic
receptor (AR) what are they and what do they do ?
- β-adrenergic receptor (AR) → adrenalin (noradrenalin)
- Three β-AR subtypes:
- β1-AR – in heart muscle
- β2 -AR – in lung, GI, liver, uterus, smooth muscle, vasculature
- β3-AR – in fat cells and brown fat
α-adrenergic
receptor (AR) types what are they and what do they do ?
- α-adrenergic receptors (AR) → higher affinity for
noradrenalin - Two α –AR subtypes:
- α1-AR – in smooth muscle, heart and liver
- α2 -AR – in thrombocyte, vessels, nerv terminals,
pancreatic islands
Parasympathetic Nervous System – Main effects and how it works
§ Promote nutrition
§ Digestion
§ Recovery
§ Energy saving
§ Slow down the heart rate
§ Reduce force of contraction
§ Constricts bronchioles
§ Bladder emptying
§ Pupil constriction
Craniosacral origin
Preganglionic neurons are long:
§ Cranial nerves: III, VII, IX, X + S2 – S4
Postganglionic neurons:
§ Short
§ Ganglion close to target organ or in the wall of the target
organ
§ No divergens – preganglionic neuron contact 1:1
Cholinergic system:
§ Transmittor: Acethylcholine
§ Receptor: Muscarine and nicotine
Acetylcholin
synthesis
- Choline Uptake: The first step in acetylcholine synthesis involves the uptake of choline, an essential precursor molecule, into the nerve terminal. Choline can be obtained from the diet or synthesized in the body.
- Acetyl Coenzyme A (Acetyl-CoA) Production: Acetyl-CoA is a molecule that provides the acetyl group needed to form acetylcholine. Acetyl-CoA is generated in the mitochondria through various metabolic pathways, including the breakdown of glucose and fatty acids.
- Synthesis of Acetylcholine: The synthesis of acetylcholine occurs within the nerve terminal and involves the following steps:
a. Formation of Acetylcholine (ACh): Acetyl-CoA combines with choline in the presence of the enzyme choline acetyltransferase (ChAT) to form acetylcholine (ACh).
b. Packaging into Vesicles: The newly synthesized acetylcholine is transported into synaptic vesicles in the nerve terminal. This process is energy-dependent and involves the vesicular acetylcholine transporter (VAChT).
- Release of Acetylcholine: When a nerve impulse (action potential) reaches the nerve terminal, it triggers the release of acetylcholine from the synaptic vesicles into the synaptic cleft, which is the small gap between the nerve terminal (presynaptic neuron) and the target cell (postsynaptic neuron, muscle cell, or gland cell).
- Binding to Receptors: Acetylcholine released into the synaptic cleft binds to specific receptors on the surface of the target cell. Depending on the location and type of receptors, this binding can lead to various physiological responses, such as muscle contraction, neuronal excitation, or glandular secretion.
- Termination of Action: To terminate the action of acetylcholine and prevent continuous stimulation, the enzyme acetylcholinesterase (AChE) is present in the synaptic cleft. AChE rapidly breaks down acetylcholine into acetate and choline. The choline is then transported back into the presynaptic neuron, where it can be reused to synthesize new acetylcholine.
Cholinergic Receptors?
§ Muscarin receptors:
* Heart muscle cells, smooth muscle in
gut and muscle vessels and glands
* G protein–coupled receptors
(GPCR)s – linked to G-protein and
acts via different second messengers
§ Nicotin receptors:
* Neuromusclar synaps + , autonomic
ganglion (symp and parasymp)
* Receptors localized in the
cellmembrane – ion channel
ANS activity regulation?
- Hypothalamus is the coordinator of
i. Heart activity
ii. Blood pressure
iii. Body temperature
iv. Water balance
v. Endocrine activity - Limbic structures – emotions
- Cortex
- Brainstem – major control center
i. Heart frequency
ii. Bladder and GI emptying - Spinal cord – regulates reflexes
Sympathetic nervous system → effects on metabolism
lipolysis in adipocytes , gluconeogenesis in liver , insulin release in pancreatic b cells , impaired glucose uptake in skeletal muscles , vasoconstriction in skeletal muscle arteriole
Hormone classes
Water soluble
-Amine hormones (§ Bind to cell-surface receptors ➔ Are classic G protein coupled receptors (GPCRs))
-Peptide hormones § Bind to cell-surface
receptors ➔ Activate a variety of signaltransduction
systems
Fat soluble
-Steroid hormones
-Thyroid hormones
Steroid and thyroid hormones binds to intracellular
receptors that regulates gene transcription
Glucocorticoids – cortisol functions?
§ Metabolic effects
§ Proteolysis, lipolysis, gluconeogenesis—formation of glucose from fats and proteins,
promotes rises in blood glucose, fatty acids, and amino acids (insulin antagonist),
increased hunger
§ Cardiovascular effects (important for life)
§ Permissive effect on α1-receptors →catecholamines can contract vessels
§ CNS
§ Memory, sensory integration, limbic system
§ Bone and Connective tissue
§ Stimulates bone resorption (decomposition), inhibits bone formation, inhibits K+
§ uptake in the intestine, increase K+ from the kidney
§ Immune system
§ Decrease immune function
§ Inhibit inflammation
Mineralkortikoid – aldosteron
Regulates electrolytes (primarly Na+
and K+) in extracellular
Aldosteron
§ Stimulates Na+ reabsorption and
retains water in the kidneys, and
increases K+ secretion →
§ ↑ blood volume and blood
pressure
Mineralcorticoid receptor (MR)
§ Aldosterone and cortisol have similar affinity
for this receptor
§ Aldosterone dissociates/separates less from
the receptor
§ Cortisol has approximately 1000 times
higher concentration than aldosterone and
“occupies” the receptor in many tissues
§ The enzyme 11β-HSD2* inactivates cortisol,
providing a greater opportunity for
aldosterone to bind to the MR receptor
*11b-hydroxysteroid dehydrogenase typ 2
DHEA and androstenedione – zona reticularis
§ Effect of DHEA and androstenedione through peripheral
metabolism to testosterone and DHT or estrogen
§ Adrenal cortex androgens – weaker compared to
testicular/ovarian steroids
§ Fetal
§ Potential impact on development of internal and external genitalia as
well as later secretion patterns of gonadotropins
§ Postnatal
§ Protein anabolic effect
§ Potential impact on male sexual characteristics
§ In women, particularly important during menopause
Explain thyroid hormone synthesis,
Iodide Uptake: The first step in thyroid hormone synthesis is the uptake of iodide ions (I-) from the bloodstream into thyroid follicular cells. This process is facilitated by a protein called the sodium-iodide symporter (NIS), which actively transports iodide into the follicular cells. Iodine is essential for the production of thyroid hormones.
Thyroglobulin Production: Within the thyroid follicular cells, a large glycoprotein known as thyroglobulin (Tg) is synthesized. Thyroglobulin serves as the scaffold for the formation of thyroid hormones.
Iodination of Tyrosine Residues: Iodine is attached to specific tyrosine amino acid residues within the thyroglobulin molecule. This iodination process leads to the formation of two types of iodotyrosines: monoiodotyrosine (MIT) and diiodotyrosine (DIT).
Coupling of MIT and DIT: MIT and DIT molecules combine in a specific way to create the thyroid hormones T4 (thyroxine) and T3 (triiodothyronine). T4 contains four iodine atoms, while T3 contains three. These hormones are stored within the thyroglobulin molecule in the colloid-filled spaces of the thyroid follicles.
Thyroid Hormone Release: When the body requires thyroid hormones, a signal is sent to the thyroid gland to release them into the bloodstream. This is usually stimulated by the secretion of thyroid-stimulating hormone (TSH) from the anterior pituitary gland, which is regulated by the hypothalamus through thyrotropin-releasing hormone (TRH). TSH binds to receptors on the surface of thyroid follicular cells, promoting the release of T4 and T3 by breaking the thyroglobulin molecule.
Conversion of T4 to T3: While T4 is the major thyroid hormone produced by the thyroid gland, it’s relatively inactive compared to T3, which is the biologically active form. Peripheral tissues, particularly the liver and other organs, convert T4 into T3 by removing one iodine atom.
Transport in the Blood: Once released into the bloodstream, T4 and T3 bind to transport proteins such as thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA) to be carried throughout the body. Only a small fraction of thyroid hormones remains unbound and free to enter target cells and exert their biological effects.
Explain thyroid hormone biological effects
Two related compounds
§ T4 (thyroxine); has 2 tyrosine molecules + 4 bound iodine atoms
§ T3 (triiodothyronine); has 2 tyrosines + 3 bound iodine atoms
§ Plays a role in:
§ Maintenance of blood pressure
§ Regulation of tissue growth
§ Development of skeletal and nervous systems
§ Reproductive capabilities
§ Major Metabolic Hormones
§ Permissive Actions – on catecholamine’s by increasing synthesis of β-adrenergic receptors
§ Growth and Development
T3 and T4 kinetics
§ Slow and long lasting
§ >90% of released hormone is T4
§ T4 slowly converted to T3 in blood, liver and kidney
§ T4 quickly converted to T3 in cells
§ T3 ~3 X active than T4
§ 99% of T3 & T4 are bound to thyroxine binding globulin,
transthyretin and albumin
§ T3 lower affinity to transporter proteins than T4
Thyroid hormones increases metabolic rate and heat production
§↑ Mitochondria
§↑ blood flow, heart rate, and cardiac output
§↑ Respiration
§↑ Expression of NA+/K+ ATPase → ↑ neural signaling → muscle tremor (hyperthyroidism)
Explain how thyroid hormone production and secretion
are regulated
Dopamine and Somatostatin decrease T3, T4 production by acting on hypothalamic - pituitary axis
Hypothalamus Sensing Thyroid Hormone Levels:
The hypothalamus, a region in the brain, continuously monitors the concentration of thyroid hormones (T4 and T3) in the bloodstream. When it detects low levels of these hormones, it initiates a response to increase their production.
Thyrotropin-Releasing Hormone (TRH) Release:
In response to low thyroid hormone levels, the hypothalamus releases thyrotropin-releasing hormone (TRH) into the bloodstream. TRH acts as a signal to the anterior pituitary gland.
Anterior Pituitary Response:
The anterior pituitary gland, upon receiving the signal of TRH, responds by releasing thyroid-stimulating hormone (TSH) into the bloodstream. TSH is a crucial regulator of thyroid hormone production.
Stimulation of the Thyroid Gland:
TSH travels through the bloodstream to the thyroid gland. It binds to specific receptors on the surface of thyroid follicular cells.
This binding of TSH stimulates the thyroid follicular cells to take up iodide ions (I-) from the bloodstream and initiate the synthesis of thyroid hormones.
Thyroid Hormone Synthesis:
Inside the thyroid gland, iodide ions are incorporated into thyroglobulin (Tg) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) molecules.
MIT and DIT molecules then couple together to create thyroid hormones, thyroxine (T4), and triiodothyronine (T3).
The newly synthesized T4 and T3 hormones are stored within the colloid-filled spaces of the thyroid follicles, bound to thyroglobulin.
Release of Thyroid Hormones:
When the body requires thyroid hormones to maintain metabolic and physiological functions, a signal is sent to the thyroid gland, often due to fluctuations in TSH levels.
The thyroid gland releases T4 and T3 from thyroglobulin into the bloodstream.
Negative Feedback Loop:
As the concentration of thyroid hormones (T4 and T3) in the bloodstream increases, it exerts negative feedback on the hypothalamus and anterior pituitary.
Elevated thyroid hormone levels inhibit the release of TRH and TSH, respectively. This feedback loop helps maintain thyroid hormone levels within the normal range.
Explain the most common diseases with over- and underproduction of thyroid hormones and
principles for treatment
Hyperthyroidism
* High levels of thyroid hormone
* Graves’ disease
* Toxic adenoma
* Toxic multinodular goitre
Treatments for hyperthyroidism
* Thyreostatics – inhibits the production of T3 and T4
* Only for Graves
* Not during pregnancy, wait 2 years after stopping treatment
* Surgery – remove thyroid gland
* Radioactive iodine – older patients!
hypothyroidism types:
Iodine deficiency ( treatment : food rich in Iodine)
primary( thyroid gland ) : Hasimoto thyroiditis( autoimmune), after treatment for hypertheroidism ( destroyed thyroid gland)
secondary : low TSH ( pituitary affected by a tumor )
tertiary: low TRH
congenital
treatment for all the other types is synthetic Thyroid hormone replacement
Per oral or intavenus
Explain the effects of parathyroid hormon (PTH) and how the production and secretion is
regulated
Effects of Parathyroid Hormone (PTH):
Calcium Regulation: PTH primarily acts to increase blood calcium levels by various mechanisms:
Stimulation of Osteoclasts: PTH stimulates osteoclasts, cells responsible for bone resorption. This process releases calcium from the bones into the bloodstream.
Enhanced Calcium Reabsorption: PTH influences the kidneys to reabsorb more calcium from the urine, preventing its excretion.
Activation of Vitamin D: PTH stimulates the kidneys to convert inactive vitamin D (calcidiol) into its active form (calcitriol). Active vitamin D increases calcium absorption from the intestines.
Phosphorus Regulation: PTH has the opposite effect on phosphorus levels:
PTH reduces the reabsorption of phosphorus in the kidneys, leading to increased phosphorus excretion in the urine.
Regulation of PTH Production and Secretion:
The production and secretion of PTH are tightly regulated by negative feedback mechanisms involving the levels of calcium and phosphorus in the bloodstream:
Low Blood Calcium Levels: When the concentration of calcium in the blood decreases (hypocalcemia), it triggers the parathyroid glands to release more PTH.
Parathyroid Gland Response: Hypocalcemia stimulates the parathyroid glands to synthesize and release PTH.
Parathyroid Gland Response: Hypercalcemia signals the parathyroid glands to decrease the production and secretion of PTH.
Phosphorus Levels: PTH also responds to changes in blood phosphorus levels, but the relationship is inverse. When blood phosphorus levels are high, PTH secretion is decreased.
Explain the structure, synthesis, and effects of vitamin D and how its activity and release is
regulated
Structure of Vitamin D:
Both vitamin D2 and D3 are converted in the body into the biologically active form of vitamin D, known as calcitriol or 1,25-dihydroxyvitamin D3.
Calcitriol is a steroid hormone with a complex structure, consisting of a steroidal nucleus, a side chain, and two hydroxyl groups.
Synthesis of Vitamin D:
Vitamin D synthesis begins when skin is exposed to UV-B sunlight (specifically, UV-B rays with a wavelength of around 290-320 nm).
In the skin, 7-dehydrocholesterol, a precursor molecule, is converted into cholecalciferol (vitamin D3).
Cholecalciferol then enters the bloodstream, where it is transported to the liver.
In the liver, cholecalciferol is converted into 25-hydroxyvitamin D3 (calcidiol), which is the storage form of vitamin D.
Finally, in the kidneys, calcidiol is further converted into the biologically active form, calcitriol (1,25-dihydroxyvitamin D3), under the control of parathyroid hormone (PTH).
Effects of Vitamin D:
Vitamin D, mainly calcitriol, has several effects in the body:
Calcium and Phosphorus Absorption: It enhances the absorption of calcium and phosphorus from the intestines, promoting bone health.
Bone Health: Vitamin D is crucial for maintaining strong and healthy bones. It helps regulate bone remodeling and mineralization.
Immune Function: Vitamin D plays a role in immune system function and may help the body defend against infections.
Cell Growth and Differentiation: It is involved in regulating cell growth and differentiation in various tissues.
Regulation of Vitamin D Activity and Release:
The release and activity of vitamin D are regulated by several factors, primarily the following:
UV Exposure: Sunlight exposure is a major factor in the synthesis of vitamin D. The skin’s ability to produce vitamin D decreases with age and is influenced by factors like latitude, season, and skin pigmentation.
Parathyroid Hormone (PTH): PTH plays a crucial role in regulating the activation of vitamin D in the kidneys. When blood calcium levels are low, PTH stimulates the conversion of calcidiol into calcitriol.
Calcium and Phosphorus Levels: High blood calcium levels can inhibit the production of PTH, reducing the conversion of calcidiol into calcitriol. Elevated phosphorus levels can also have a similar effect.
Dietary Intake: Dietary sources of vitamin D, such as fatty fish, fortified foods, and supplements, can provide an additional source of the vitamin.
Explain the hormonal regulation of bone metabolism
Parathyroid Hormone (PTH):
Source: PTH is produced and released by the parathyroid glands, four small glands located in the neck.
Function: PTH plays a central role in regulating calcium levels in the bloodstream. When blood calcium levels drop (hypocalcemia), PTH is secreted to increase calcium levels.
Effects on Bone Metabolism: PTH stimulates the activity of osteoclasts, which are responsible for bone resorption. This results in the release of calcium from bone into the bloodstream. PTH also increases the reabsorption of calcium in the kidneys and activates vitamin D to enhance calcium absorption from the intestines.
Calcitonin:
Source: Calcitonin is produced by the parafollicular (C) cells of the thyroid gland.
Function: Calcitonin works in opposition to PTH. It helps regulate blood calcium levels by lowering them.
Effects on Bone Metabolism: Calcitonin inhibits osteoclast activity, reducing bone resorption. However, its overall effect on bone metabolism is relatively modest compared to PTH.
Estrogen and Testosterone:
Source: Estrogen is primarily produced by the ovaries, and testosterone is produced by the testes in males.
Function: Estrogen and testosterone have significant effects on bone health. They promote the activity of osteoblasts (cells that build bone) and inhibit osteoclasts (cells that resorb bone).
Effects on Bone Metabolism: These sex hormones help maintain bone density and prevent excessive bone loss. Reduced levels of estrogen in postmenopausal women, for example, can lead to an increased risk of osteoporosis.
Vitamin D:
Source: Vitamin D is synthesized in the skin when exposed to UV-B sunlight and obtained from dietary sources.
Function: Vitamin D is essential for calcium absorption from the intestines. Its active form, calcitriol, is produced in the kidneys under the influence of parathyroid hormone (PTH).
Effects on Bone Metabolism: Adequate vitamin D is necessary to ensure sufficient calcium is absorbed from the diet. A deficiency can lead to poor bone health.
Cortisol (Glucocorticoids):
Source: Cortisol is a steroid hormone produced by the adrenal glands.
Function: While cortisol has many important roles in the body, chronic high levels of cortisol (such as in conditions like Cushing’s syndrome) can lead to decreased bone density.
Effects on Bone Metabolism: Excess cortisol can inhibit bone formation and promote bone resorption.
Thyroid Hormones (T3 and T4):
Source: Thyroid hormones are produced by the thyroid gland.
Function: Thyroid hormones have an impact on bone metabolism, as they influence overall metabolic rate.
Effects on Bone Metabolism: Excessive thyroid hormone levels (hyperthyroidism) can increase bone resorption, leading to bone loss, while hypothyroidism can have the opposite effect.
Know and define osteomalacia and osteoporosis, possible causes and how it can be treated
Osteomalacia:
Definition: Osteomalacia is a condition characterized by the softening and weakening of the bones due to a lack of mineralization, particularly a deficiency in calcium and phosphate. It is more common in adults and can result in bone pain, muscle weakness, and fractures.
Possible Causes:
Vitamin D Deficiency: The most common cause of osteomalacia is insufficient vitamin D, which is necessary for calcium absorption. Inadequate sunlight exposure, dietary deficiencies, or malabsorption disorders can lead to vitamin D deficiency.
Malabsorption Disorders: Certain gastrointestinal conditions (e.g., celiac disease, Crohn’s disease) can interfere with the absorption of vitamin D and other nutrients necessary for bone health.
Treatment:
Treatment primarily involves addressing the underlying cause, such as vitamin D deficiency or malabsorption disorders.
Vitamin D and calcium supplementation may be prescribed to correct deficiencies and promote bone mineralization.
In severe cases, prescription medications that help increase calcium and phosphate levels in the blood may be used.
Physical therapy may also be recommended to manage muscle weakness and improve mobility.
Osteoporosis:
Definition: Osteoporosis is a condition characterized by the loss of bone density and structural integrity, resulting in brittle and fragile bones. It can lead to an increased risk of fractures, particularly in the hip, spine, and wrist.
Possible Causes:
Aging: As people age, bone density naturally decreases.
Hormonal Changes: Postmenopausal women are at a higher risk due to decreased estrogen levels. In men, reduced testosterone levels can contribute.
Nutritional Factors: Inadequate intake of calcium and vitamin D, as well as low dietary protein, can increase the risk.
Lifestyle Factors: Lack of weight-bearing exercise, excessive alcohol consumption, and smoking can all contribute to bone loss.
Medical Conditions: Certain medical conditions, medications (e.g., long-term use of glucocorticoids), and hormonal disorders can predispose individuals to osteoporosis.
Treatment:
Treatment strategies for osteoporosis focus on reducing the risk of fractures and improving bone density.
Lifestyle modifications include regular weight-bearing exercise, a balanced diet rich in calcium and vitamin D, and smoking and alcohol cessation.
Medications such as bisphosphonates, calcitonin, and parathyroid hormone analogs can be prescribed to slow down bone loss and promote bone formation.
In some cases, hormone replacement therapy (HRT) may be considered for postmenopausal women to maintain bone density.
Osteoporosis
* Strategy 1: Inhibiting bone destruction
* Bisphosphonates
* Denosumab
* Estrogen
* Strategy 2: Rebuild bone density (anabolic)
* Romosozumab – inhibits sclerostin
* Teriparatide – PTH analogue
Explain the effects of growth hormone (GH) and insulin like growth factor-1 (IGF-1), their
binding proteins and how the production and secretion is regulated and how they change
during the life cycle
Effects of Growth Hormone (GH):
GH is primarily produced and secreted by the anterior pituitary gland.
Its effects include:
Growth and Development: GH stimulates the growth of bones and cartilage in children and adolescents, contributing to linear growth.
Muscle Growth: GH promotes the growth and development of skeletal muscles.
Metabolism: GH increases the breakdown of fats for energy and reduces the utilization of glucose, helping maintain blood sugar levels.
Cell Growth and Repair: GH stimulates the growth and repair of various tissues, including organs and skin.
IGF-1 Production: GH stimulates the liver to produce IGF-1, which mediates many of GH’s effects.
Effects of Insulin-Like Growth Factor-1 (IGF-1):
IGF-1 is primarily produced in the liver in response to GH, although other tissues can also produce it.
Its effects include:
Bone Growth: IGF-1 stimulates bone growth and mineralization.
Cell Growth and Proliferation: IGF-1 influences the growth and repair of various cells, tissues, and organs.
Muscle Growth: IGF-1 is involved in muscle protein synthesis and growth.
Metabolism: IGF-1 has insulin-like effects and plays a role in regulating glucose and lipid metabolism.
Regulation of GH: IGF-1 provides negative feedback to the hypothalamus and pituitary, reducing GH production when its levels are high.
Binding Proteins for GH and IGF-1:
Both GH and IGF-1 can circulate in the bloodstream bound to specific binding proteins, which can prolong their half-lives and control their actions.
Insulin-like growth factor binding proteins (IGFBPs) are the primary binding proteins for IGF-1, and there are several different types. IGFBPs can either enhance or inhibit IGF-1’s effects depending on their interactions.
Regulation of GH and IGF-1 Production and Secretion:
GH and IGF-1 production and secretion are regulated by several factors:
Hypothalamic Control: The hypothalamus releases growth hormone-releasing hormone (GHRH) to stimulate the anterior pituitary to produce and release GH.
Negative Feedback: GH and IGF-1 provide negative feedback to the hypothalamus and anterior pituitary. Elevated GH and IGF-1 levels reduce GHRH secretion and GH production.
Ghrelin: This hormone, produced by the stomach, can stimulate GH release. Ghrelin levels rise before meals and decline afterward.
Age: GH secretion decreases with age, which is a factor in the reduction of growth velocity during adolescence and growth plate closure.
Stress and Exercise: Stress, intense physical activity, and sleep can influence GH secretion. GH is often released in pulses, with the highest levels occurring during deep sleep.
Changes in GH and IGF-1 Levels During the Life Cycle:
GH and IGF-1 levels are highest during childhood and adolescence when growth and development are most active.
GH secretion decreases in adulthood, and IGF-1 levels also decline with age.
In elderly individuals, lower GH and IGF-1 levels can contribute to reduced muscle mass, bone density, and overall tissue repair.
Adulthood -↓ pulsatile burst, no change in number of pulses
Indirect actions
(growthpromoting)
Direct actions
(metabolic,
anti-insulin)
Metabolic effects
§ Protein synthesis → increase amino acid transport into cells, enhance DNA and RNA
transcription, RNA translation of protein and decrease protein and amino acid catabolism
§ Increase blood glucose → Glycogenolys (glucose production by breakdown of glycogen),
increased gluconeogenesis and insulin production (similar to type 2 diabetes)
§ Decrease glucose uptake in muscle and adipose tissue
§ Lipolysis (break down of fat cells) → increase concentrations of fatty acids
Testosterone and estrogens can stimulate GH production during puberty
insulin stimulates the secretion of IGF1 for postnatal growth.
thyroid hormones have a permissive effect for groth hormone
Explain the most common diseases with over- and underproduction of growth hormones
before and after puberty, and principles for treatment
GH deficiency treatment:
* Recombinant GH
GH overproduction - Acromegaly
* Somatostatin
* GH-receptor antagonist
* Dopamin
* Surgery for the possible tumor
Explain the effects and function of hormones involved in the regulation of glucose
homeostasis
Endocrine pancreas
Exocrine
Secretes bicarbonate ions and digestive enzymes
Endocrine
1. a-cells secrete glucagon and increase glucose release
from the liver
2. b-cells secrete insulin, pro-insulin, C-peptide and amylin –
decrease blood glucose
3. d-cells secrete somatostatin – inhibits secretion of insulin
and glucagon and inhibit GI-tract
4. F-cells secrete pancreatic poly peptide (PP) – inhibits
gastric acid secretion
Glucose homeostasis
§ Glucose the most important energy source
§ Tight regulation under several hormones:
§ GH
§ Cortisol
§ Adrenaline
§ Insulin
§ Glucagon
Regulation of blood glucose
§ Liver together with muscle is the largest storage place for glycogen
§ Liver is a ”buffert-organ” to maintain constant blood sugar
§ Glucagon is important regulator of hepatic glycogen metabolism by
increasing:
1. Glycogenolysis = breakdown of glycogen
2. Gluconeogenesis = new production of glucose from amino acids,
lipids, lactate and simple carbohydrates
3. Lipolysis in liver cells (although small compared with that in
adipose tissue)
4. Ketogenesis = production of ketones
Insulin : glycogen synthesis up , glucogenolysis down
§ Somatostatin: Inhibit glucagon and
insulin and GI-tract
Insulin:
Source: Insulin is produced and secreted by the beta cells of the pancreas.
Function: Insulin is the primary hormone responsible for lowering blood glucose levels. It performs several important functions:
Promotes Glucose Uptake: Insulin facilitates the uptake of glucose by cells, especially muscle and fat cells, by increasing the number of glucose transporters (GLUT4) on the cell surface.
Inhibits Glucose Production: Insulin reduces glucose production in the liver by suppressing gluconeogenesis, the process by which the liver generates glucose from non-carbohydrate sources.
Enhances Glycogen Synthesis: Insulin promotes the storage of excess glucose as glycogen in the liver and muscles.
Stimulates Fat Storage: Insulin encourages the uptake of fatty acids and triglycerides for storage in fat cells, reducing the release of glucose from fat tissue.
Effects: The main effect of insulin is to lower blood glucose levels by facilitating the uptake of glucose into cells and reducing glucose production.
Glucagon:
Source: Glucagon is produced and secreted by the alpha cells of the pancreas.
Function: Glucagon acts in opposition to insulin. It raises blood glucose levels by stimulating several processes:
Promotes Glycogen Breakdown: Glucagon stimulates the breakdown of glycogen in the liver into glucose, a process known as glycogenolysis.
Encourages Gluconeogenesis: Glucagon increases the production of glucose from non-carbohydrate precursors in the liver, mainly amino acids and glycerol.
Reduces Glucose Uptake: Glucagon inhibits the uptake of glucose by cells, particularly muscle and fat cells.
Effects: The primary effect of glucagon is to increase blood glucose levels by releasing stored glucose from the liver and reducing glucose uptake by cells.
Cortisol and Epinephrine:
Cortisol: This steroid hormone, produced by the adrenal glands, can raise blood glucose levels by stimulating gluconeogenesis and inhibiting glucose utilization in peripheral tissues.
Epinephrine (Adrenaline): Released during the “fight or flight” response, epinephrine can quickly raise blood glucose levels by promoting glycogen breakdown and inhibiting insulin secretion.
Growth Hormone:
Source: Growth hormone is produced by the anterior pituitary gland.
Function: Growth hormone has both hyperglycemic (raises blood glucose) and lipolytic (promotes fat breakdown) effects. It can increase blood glucose levels by decreasing glucose uptake by cells and stimulating gluconeogenesis.
define different forms of diabetes mellitus including type 1 diabetes, type 2
diabetes, latent autoimmune diabetes in adults (LADA), gestational diabetes,
pharmacologically induced diabetes.
Classification of diabetes mellitus according to WHO, 1999
§ Type I diabetes (insulin-dependent diabetes mellitus (IDDM)
§ Insulin deficiency ®caused by destruction of the B cells in pancreatic islets
§ autoimmune (autoimmune positive)
§ idiopathic (autoimmune negative)
§ Type 2 diabetes (non insulin-dependent diabetes mellitus (NIDDM)
§ Insulin resistance and impaired insulin secretion
§ Genetic component stronger for type 2 diabetes compared with type 1
§ Other specific types of diabetes (e.g.)
§ Genetics disruption of B cell function
§ Genetic dysfunction of insulin effects
§ Endocrine disease (PCOS, Acromegaly, Cushing)
§ Disease in exocrine pancreas
§ Infection diseases
§ Pharmacological induced diabetes
§ Gestational diabetes
Latent Autoimmune Diabetes in Adults (LADA) is a form of diabetes that shares characteristics with both type 1 diabetes and type 2 diabetes. It is often referred to as a “hybrid” or “type 1.5” diabetes. LADA is typically diagnosed in adults, often between the ages of 30 and 50, and is less common than traditional type 1 or type 2 diabetes.
Key features of LADA include:
Autoimmune Component: Like type 1 diabetes, LADA has an autoimmune component. In LADA, the immune system mistakenly targets and destroys the insulin-producing beta cells of the pancreas, similar to what occurs in classic type 1 diabetes. Autoantibodies associated with type 1 diabetes, such as glutamic acid decarboxylase (GAD) antibodies, are often present in LADA.
the principles for treatment of metabolic syndrome, insulin resistance, type 1 and 2
diabetes and complications
DPP4 inhibitors,Ozempic,GLP-1,Sulfonylurea,Metformin,Metformin,Hybrid closed loop-systems,Beta-cell transplantation,SGLT2 inhibitors
Explain the hormonal regulation, including feed-back system of the ovarian and the menstrual
cycle
- Ovarian Cycle:
The ovarian cycle consists of various stages, including the follicular phase, ovulation, and the luteal phase. These stages are regulated by several key hormones:
Follicle-Stimulating Hormone (FSH): FSH is released by the anterior pituitary gland. It stimulates the growth and development of follicles in the ovaries. Follicles are small sacs containing developing eggs.
Luteinizing Hormone (LH): LH, also released by the anterior pituitary gland, triggers ovulation. It causes the mature follicle to release the egg from the ovary.
Estrogen: Estrogen is produced by the developing ovarian follicles. Its levels increase during the follicular phase, promoting the thickening of the uterine lining.
Progesterone: Progesterone is primarily produced by the corpus luteum, which is the remnant of the follicle after ovulation. It maintains and prepares the uterine lining for implantation and helps suppress further ovulation.
The feedback system in the ovarian cycle involves negative feedback. Rising levels of estrogen and progesterone inhibit the release of FSH and LH, preventing the development of new follicles and further ovulation. This is crucial to prevent multiple eggs from being released simultaneously.
- Menstrual Cycle:
The menstrual cycle refers to the changes that occur in the uterine lining in preparation for potential pregnancy and its subsequent shedding if pregnancy does not occur. Hormones involved in the menstrual cycle include:
Estrogen: As mentioned earlier, estrogen levels increase during the follicular phase of the ovarian cycle. High estrogen levels stimulate the growth of the uterine lining (endometrium).
Progesterone: Following ovulation and during the luteal phase, progesterone is produced. It further thickens and maintains the uterine lining.
The feedback system in the menstrual cycle is closely intertwined with the ovarian cycle. If pregnancy does not occur, the corpus luteum in the ovaries degenerates, causing a drop in progesterone levels. This drop triggers the shedding of the uterine lining, resulting in menstruation. As menstruation occurs, the feedback loop restarts, and the cycle begins anew.
Explain the synthesis of sex steroids, how the steroidogenesis is regulated in the ovaries and
their effects
- Synthesis of Sex Steroids:
Sex steroid synthesis in the ovaries occurs in specialized cells known as ovarian follicles. These follicles contain granulosa cells, which play a crucial role in steroidogenesis. The main sex steroids produced by the ovaries are estrogen and progesterone.
Estrogen Synthesis: Estrogen is primarily produced from the precursor molecule, cholesterol. The process of estrogen synthesis involves the following steps:
a. Cholesterol is transported into the granulosa cells of the developing ovarian follicles.
b. Cholesterol is converted into pregnenolone.
c. Pregnenolone is further converted into various intermediates like testosterone, eventually leading to the formation of estradiol, the most potent form of estrogen.
FSH activates and increases the production of estradiol from testosterone.
Progesterone Synthesis: Progesterone is primarily produced by the corpus luteum, which is the remnant of the ovarian follicle after ovulation. Progesterone is synthesized from cholesterol through a series of enzymatic reactions.
Testosterone: It is produced from cholesterol in theca cells AND granulosa cells because of LH activating the pathway .
- Regulation of Steroidogenesis:
The synthesis of sex steroids in the ovaries is tightly regulated by several hormones and feedback mechanisms:
Follicle-Stimulating Hormone (FSH): FSH, released by the anterior pituitary gland, stimulates the growth and development of ovarian follicles. It also helps in promoting the production of estrogen by granulosa cells.
Luteinizing Hormone (LH): LH, also released by the anterior pituitary gland, triggers ovulation and plays a role in the formation of the corpus luteum. The corpus luteum is responsible for the production of progesterone.
Feedback Mechanisms: There are negative feedback loops involving estrogen and progesterone. High levels of estrogen and progesterone inhibit the release of FSH and LH from the pituitary gland. This feedback system helps regulate the balance of sex steroids and ensures that follicles mature and ovulation occurs at the appropriate times.
- Effects of Sex Steroids:
Sex steroids have various effects on the female reproductive system and other tissues in the body. Some of the key effects include:
Regulation of the Menstrual Cycle: Estrogen and progesterone are essential for regulating the menstrual cycle. They control the growth and shedding of the uterine lining, as well as the maturation and release of eggs.
Development of Secondary Sexual Characteristics: Estrogen is responsible for the development of secondary sexual characteristics in females, such as breast development and widening of the hips.
Maintenance of Pregnancy: Progesterone is crucial for maintaining the uterine lining during pregnancy and preventing further ovulation.
Bone Health: Estrogen plays a role in maintaining bone density and preventing osteoporosis in women.
Mood and Cognitive Function: Sex steroids can influence mood and cognitive function. Fluctuations in estrogen and progesterone levels are associated with mood changes during the menstrual cycle.
Explain the ovarian cycle stages, follicular growth during fetal life, at birth, fertile age and
after menopause
Follicular Growth during Fetal Life:
During fetal life, the ovaries contain all the primary oocytes a female will ever have. These primary oocytes are arrested in prophase I of meiosis and are surrounded by a layer of granulosa cells, forming primordial follicles.
At this stage, the ovaries have the highest number of follicles, usually around 6 to 7 million. However, this number decreases significantly before birth, and by the time of birth, there are only around 1 to 2 million primordial follicles left.
At Birth:
At birth, a female’s ovaries contain approximately 1 to 2 million primordial follicles. These represent her lifetime supply of eggs (oocytes).
The majority of these follicles will undergo atresia (degeneration) over time, and only a fraction will be available for ovulation during her fertile years.
During Fertile Age (Puberty to Menopause):
During the fertile years, typically from puberty to menopause, a monthly cycle of follicular development and ovulation occurs. This cycle can be divided into several stages:
Primordial Follicles: Throughout a woman’s reproductive life, a small number of primordial follicles are periodically activated to enter the growth phase.
Primary Follicles: Some of the activated primordial follicles become primary follicles, characterized by the development of a single layer of granulosa cells around the oocyte.
Secondary Follicles: Further development leads to secondary follicles with multiple layers of granulosa cells, and the oocyte completes its first meiotic division, becoming a secondary oocyte.
Graafian (Mature) Follicle: One of the secondary follicles is selected to become the dominant follicle, while the others undergo atresia. The dominant follicle matures into a Graafian follicle, and the secondary oocyte is arrested in metaphase II of meiosis.
Ovulation: The Graafian follicle ruptures, releasing the mature secondary oocyte, which is then available for fertilization. This is known as ovulation. ( first polar body is created here)
Corpus Luteum Formation: After ovulation, the remaining follicle transforms into the corpus luteum, a temporary endocrine gland that produces hormones like progesterone.
Corpus Luteum Degeneration: If fertilization does not occur, the corpus luteum degenerates, leading to a drop in hormone levels and the start of a new ovarian cycle.
Also in fertilisation there is the second polar body.
After Menopause:
Menopause is the stage in a woman’s life when her ovarian function declines, and she no longer experiences regular menstrual cycles or ovulation.
As a woman approaches menopause, the number of remaining primordial follicles in her ovaries decreases significantly.
Eventually, the ovaries lose their ability to produce viable eggs, and hormonal changes result in the cessation of menstruation and the end of reproductive capability. Decline in inhobin and estradiol , increase in FSH and LH to compensate
Be able to define the general pathology of the following common female reproductive
disorders and their standard treatment strategies:
o Infertility
o Polycystic ovary syndrome (PCOS)
o Premature ovarian failure (POF)
o Endometriosis
o Dysmenorrhea
Infertility:
Pathology: Infertility is defined as the inability to conceive after at least one year of regular, unprotected sexual intercourse. It can result from various causes, including ovulatory disorders, tubal blockages, male factor infertility, or unexplained factors.
Treatment: Treatment depends on the underlying cause. It may include lifestyle changes, medications to induce ovulation, intrauterine insemination (IUI), in vitro fertilization (IVF), or surgical interventions. Counseling and support are also essential.
Polycystic Ovary Syndrome (PCOS):
Pathology: PCOS is a hormonal disorder characterized by the presence of cysts (fluid-filled sacs) on the ovaries and hormonal imbalances. Common features include irregular periods, excess androgen production, and insulin resistance.
Treatment: Treatment aims to manage symptoms and address the underlying hormonal imbalances. It may involve lifestyle modifications (diet and exercise), oral contraceptives to regulate menstrual cycles, anti-androgen medications, and insulin-sensitizing drugs. Fertility treatments may be necessary for women trying to conceive.
Premature Ovarian Failure (POF):
Pathology: POF, also known as premature ovarian insufficiency (POI), occurs when a woman’s ovaries stop functioning before the age of 40. This leads to irregular or absent menstrual cycles and a decrease in fertility. AMH levels decreases earlier than normal .
Treatment: Treatment focuses on managing symptoms and addressing associated health issues. Hormone replacement therapy (HRT) with estrogen and progesterone is often used to alleviate menopausal symptoms. Fertility options like egg donation may be considered for women who want to conceive.
Endometriosis:
Pathology: Endometriosis is a condition where tissue similar to the uterine lining (endometrium) grows outside the uterus, often in the pelvic cavity. This tissue can cause pain, inflammation, and the formation of adhesions.
Treatment: Treatment aims to alleviate pain and manage symptoms. Options include pain medications, hormonal therapies (such as birth control pills or GnRH agonists), and surgery to remove endometrial implants and adhesions. In some cases, a hysterectomy (removal of the uterus) may be considered.
Dysmenorrhea:
Pathology: Dysmenorrhea refers to painful menstruation. It can be classified as primary dysmenorrhea (normal menstruation with painful cramps) or secondary dysmenorrhea (caused by an underlying condition, like endometriosis or fibroids).
Treatment: Treatment for primary dysmenorrhea may include over-the-counter pain relievers, lifestyle changes, and heat therapy. Secondary dysmenorrhea is managed by addressing the underlying condition, such as endometriosis (treated as described above) or fibroids (which may require surgical removal).
what are the common climacteric symptoms, hormonal changes causing climacteric symptoms, and
principles for menopausal hormonal treatment
Common Climacteric Symptoms:
Hot Flashes: Sudden, intense heat and sweating, often accompanied by a rapid heartbeat.
Night Sweats: Hot flashes that occur at night, leading to disrupted sleep.
Vaginal Dryness: A decrease in vaginal lubrication, which can lead to discomfort and pain during intercourse.
Mood Swings: Emotional changes, including irritability, anxiety, and mood swings.
Sleep Disturbances: Insomnia or disrupted sleep patterns.
Inhibin decreases
Irregular Menstrual Cycles: Menstrual periods become irregular and may eventually cease altogether.
Decreased Libido: Reduced sexual desire and changes in sexual function.
Bone Density Loss: An increased risk of osteoporosis due to decreased estrogen levels.
Hormonal Changes Causing Climacteric Symptoms:
The primary hormonal changes during the climacteric period are related to the decline in estrogen and progesterone levels, as well as changes in other hormones:
Estrogen: Estrogen levels gradually decrease, leading to various symptoms, including hot flashes, night sweats, vaginal dryness, and bone density loss.
Progesterone: As ovulation becomes irregular and eventually ceases, progesterone production declines.
Luteinizing Hormone (LH): LH levels increase, often contributing to hot flashes and other symptoms.
Principles for Menopausal Hormonal Treatment:
Hormone Replacement Therapy (HRT) is a common treatment option for managing climacteric symptoms.
Explain the hormonal regulation, including feed-back system of the testis including function of
Sertoli cells, Leydig cells, spermatogenesis and endocrine function of testis
Spermatogenesis:
Spermatogenesis is the process of sperm cell formation. It occurs in the seminiferous tubules of the testes.
Spermatogonia (stem cells) divide and differentiate into spermatocytes, which go through meiosis to form haploid spermatids. Spermatids then undergo further maturation to become mature sperm (spermatozoa).
Sertoli Cells:
Sertoli cells, also known as sustentacular cells, are located within the seminiferous tubules and play a crucial role in spermatogenesis.
They provide physical and nutritional support to developing sperm cells.
Sertoli cells secrete several important factors, including inhibin (which regulates FSH production) and androgen-binding protein (ABP).
Leydig Cells:
Leydig cells, located in the interstitium of the testes, are responsible for producing and secreting testosterone, a key male sex hormone.
Testosterone is crucial for the development of male secondary sexual characteristics (e.g., facial hair, deepening of the voice) and is involved in maintaining male reproductive function.
Endocrine Function of the Testis:
The endocrine function of the testes is centered around the production of testosterone and the regulation of this production through hormonal feedback loops.
Gonadotropin-Releasing Hormone (GnRH):
The hypothalamus releases GnRH, which stimulates the anterior pituitary gland to produce and release two important gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
Luteinizing Hormone (LH):
LH binds to Leydig cells in the testes, promoting the production and secretion of testosterone.
Follicle-Stimulating Hormone (FSH):
FSH stimulates Sertoli cells, which are essential for spermatogenesis.
Sertoli cells, under the influence of FSH, secrete inhibin, which provides negative feedback to the anterior pituitary to regulate FSH secretion. Inhibin inhibits excessive FSH production, helping to maintain the proper balance for spermatogenesis.
Testosterone Feedback:
Testosterone, produced by Leydig cells, has a feedback role in the hypothalamus and anterior pituitary.
When testosterone levels are high, it provides negative feedback to the hypothalamus and anterior pituitary, reducing the release of GnRH and LH. This, in turn, helps to maintain testosterone levels within a normal range.
- Sperm development
- Spermatogonia – stem cells
- Spermatocytes – develop when stem cells divide
- Spermatids – almost mature sperm
- Mature Sperm
- Testis produce 100-200 milj mature sperms per day
- Sertoli cells
- Create blood-testis barrier
- Control the release of mature sperms
- Fagocyte dysfunctional cells
- Supplies spermatocyts and spermatids with nutrients
Effects of leyding cells through testosterone production
Androgenic effects in the body:
§ Development of male genitalia
§ Male pattern hair growth
§ Growth of larynx and vocal cords
§ Sperm production
§ Muscle growth
§ Visceral fat accumulation
§ Increased sexual drive and potens
§ Aggressive behavior
Explain the synthesis of sex steroids, how the steroidogenesis is regulated in the testis and
their effects
Effects of leyding cells through testosterone production
Androgenic effects in the body:
§ Development of male genitalia
§ Male pattern hair growth
§ Growth of larynx and vocal cords
§ Sperm production
§ Muscle growth
§ Visceral fat accumulation
§ Increased sexual drive and potens
§ Aggressive behavior
The synthesis of sex steroids in the testes, which primarily includes testosterone, is a complex process regulated by a series of steps and hormones. The main site of sex steroid synthesis in the testes is the Leydig cells. Here’s an overview of how steroidogenesis is regulated and the effects of sex steroids:
Synthesis of Sex Steroids:
Cholesterol Uptake: The first step in sex steroid synthesis is the uptake of cholesterol by the Leydig cells. Cholesterol is the precursor for all steroid hormones.
Stimulation by Luteinizing Hormone (LH):
Leydig cells are stimulated by luteinizing hormone (LH), which is produced and released by the anterior pituitary gland.
LH binds to receptors on Leydig cells, activating a signaling cascade that triggers the conversion of cholesterol into pregnenolone, an early precursor in steroidogenesis.
Conversion of Pregnenolone to Androgens:
Pregnenolone is converted into androgens, primarily dehydroepiandrosterone (DHEA) and androstenedione. These androgens are then further converted into testosterone.
The enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) is crucial in this process, converting androstenedione into testosterone.
Release of Testosterone:
Testosterone is released into the bloodstream and can affect various target tissues throughout the body. It is also released to the sertoli cells where it is converted to estradiol.
Regulation of Steroidogenesis in the Testis:
The synthesis of sex steroids in the testes is tightly regulated by the hypothalamic-pituitary-gonadal axis.
Hypothalamus: Gonadotropin-releasing hormone (GnRH) is released by the hypothalamus in a pulsatile manner. GnRH stimulates the anterior pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
Anterior Pituitary: LH, in particular, plays a significant role in regulating steroidogenesis. It stimulates Leydig cells to produce and release testosterone.
Feedback Mechanisms:
Negative Feedback: As testosterone levels increase, it provides negative feedback to the hypothalamus and anterior pituitary, reducing the release of GnRH and LH. This helps maintain testosterone levels within a normal range.
Positive Feedback (briefly): In some circumstances, such as during puberty, there can be a positive feedback loop in which increasing levels of testosterone further stimulate LH production.
Know about factors that can affect male fertility
Blockage of
Sperm Transport
. Infections
. Prostate-related
problems
. Absence of vas
deferens
. Vasectomy
. Sperm Antibodies
. Injury or infection in
the epididymis
. Unknown cause
Hormonal
Issues
. Pituitary tumors
. Congenital lack of
LH/FSH
. Andropause (low
testosterone)
Lifestyle
Factors
. This one of the top
causes of male factor
infertility!
. Numerous studies
indicate that poor
diet and lifestyle
(including stress and
sleep patterns) can
negatively affect
sperm production and
maturation.
Other
Issues
. Retrograde and
premature ejaculation
. Failure of ejaculation
. Infrequent
intercourse
. Spinal cord injury
· Prostate surgery
. Damage to nerwes
. Some medicines
Sperm
Production
. Chromosomal or
genetic causes
. Undescended testes
. Infections
. Testicular Torsion /
Injury
. Heat
· Varicocele
. Drugs and chemicals
. Radiation damage
. Unknown causes
Know the pathology behind male infertility disorders and how it can be treated
Spermatogenesis Disorders:
Pathology: Conditions that affect the process of sperm production (spermatogenesis) can lead to a low sperm count (oligospermia) or the absence of sperm in the ejaculate (azoospermia).
Treatment: Treatment depends on the specific cause and may include lifestyle changes, medication, or surgical interventions. For example, hormonal therapy, lifestyle modifications (e.g., weight management and smoking cessation), and varicocele repair may be considered.
Sperm Transport Disorders:
Pathology: Obstructions or abnormalities in the ducts that transport sperm from the testes to the urethra can prevent sperm from reaching the ejaculate.
Treatment: Surgical correction of obstructions (e.g., vasectomy reversal or epididymal repair) may be effective. Assisted reproductive techniques (ART) like in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) can also help overcome transport issues.
Sperm Function Disorders:
Pathology: Sperm must be able to swim (motility) and penetrate the egg for fertilization to occur. Sperm with poor motility or abnormal morphology may not function effectively.
Treatment: Depending on the specific dysfunction, treatment options may include lifestyle changes, antioxidant supplements, or ART methods such as ICSI, where a single sperm is directly injected into an egg.
Hormonal Disorders:
Pathology: Hormonal imbalances, such as low testosterone or high levels of prolactin, can affect sperm production.
Treatment: Hormonal therapy may be used to correct imbalances. In some cases, addressing the underlying cause of the hormonal issue (e.g., medication changes or lifestyle modifications) can help.
Genetic Disorders:
Pathology: Genetic abnormalities, such as chromosomal disorders (e.g., Klinefelter syndrome) or mutations in genes related to spermatogenesis, can result in infertility.
Treatment: Treatment options may be limited for certain genetic disorders. In some cases, assisted reproductive techniques with donor sperm or adoption may be considered.
Infections and Inflammation:
Pathology: Infections and inflammatory conditions of the reproductive tract can interfere with sperm production and transport.
Treatment: Addressing the underlying infection or inflammation with antibiotics or anti-inflammatory medications can help. In some cases, surgical drainage of abscesses may be necessary.
Lifestyle Factors:
Pathology: Lifestyle factors like smoking, excessive alcohol or drug use, obesity, and exposure to environmental toxins can negatively impact sperm quality and fertility.
Treatment: Lifestyle modifications, such as smoking cessation, weight management, and reducing toxin exposure, can improve fertility.
Idiopathic Infertility:
Pathology: In some cases, no specific cause of male infertility can be identified (idiopathic infertility).
Treatment: Treatment for idiopathic infertility may involve empiric therapy, lifestyle changes, and the use of assisted reproductive techniques.
Know common malformations of the genital organs.
Hypospadias: In this condition, the opening of the urethra is located on the underside of the penis rather than at the tip. Surgery is often needed to correct this congenital anomaly.
Epispadias: Epispadias is a rare condition where the urethral opening is on the upper side of the penis. Surgical correction is typically required.
Undescended Testes (Cryptorchidism): This condition occurs when one or both testes do not descend into the scrotum. Surgery or hormonal therapy may be needed to correct this condition.
Micropenis: Micropenis is a condition where the penis is abnormally small. It may be due to hormonal or genetic factors and may be associated with other malformations.
Testicular Torsion: While not a congenital malformation, testicular torsion is a condition where the spermatic cord twists, cutting off blood supply to the testicle. It is a medical emergency and requires immediate surgical intervention.
Female Genital Malformations:
Müllerian Duct Abnormalities: These anomalies involve the development of the female reproductive tract. Common malformations include:
Septate Uterus: A wall (septum) divides the uterus into two separate cavities.
Bicornuate Uterus: The uterus has two distinct cavities, giving it a heart-shaped appearance.
Unicornuate Uterus: The uterus is underdeveloped, with only one half of the normal structure.
Vaginal Agenesis or Aplasia: Some females are born with an underdeveloped or absent vagina. Surgical procedures can be used to create or reconstruct the vaginal canal.
Imperforate Hymen: In this condition, the hymen completely obstructs the vaginal opening, which may require a minor surgical procedure to correct.
Ovarian Malformations: These can include abnormalities in ovarian development or position (e.g., ovarian agenesis or ectopic ovaries).
Cloacal Malformation: In some rare cases, females can be born with a single opening for the urethra, vagina, and anus. Surgical reconstruction is necessary.
Explain the mechanisms that control the normal development of gonads into testes or
ovaries, as well as the hormonal and genetic factors that subsequently determine fetal
development in a male or female direction.
- Genetic Factors:
Sex Chromosomes: The sex chromosomes inherited from the parents play a fundamental role. A human typically has 46 chromosomes arranged as 22 pairs of autosomes and one pair of sex chromosomes. The two sex chromosomes are X and Y.
SRY Gene: The presence or absence of the SRY (Sex-determining Region Y) gene on the Y chromosome is crucial. If the Y chromosome carries the SRY gene, testes will develop; if it lacks SRY, ovaries will develop.
XX or XY Karyotype: In a typical male with an XY karyotype, the SRY gene triggers the differentiation of testes. In a typical female with an XX karyotype, the absence of SRY allows for the development of ovaries.
- Development of Gonadal Primordia:
Bipotential Gonadal Primordia: In early embryonic development, gonadal primordia are bipotential, meaning they can develop into either testes or ovaries.
Presence of Müllerian and Wolffian Ducts: Both male and female reproductive structures, the Müllerian ducts and Wolffian ducts, are initially present but only develop into their respective organs under the influence of hormonal signals.
- Hormonal Regulation:
Testes Development:
If the SRY gene triggers testes development, the developing testes produce two key hormones: anti-Müllerian hormone (AMH) and testosterone.
AMH causes regression of the Müllerian ducts, preventing the development of female reproductive structures (e.g., fallopian tubes, uterus).
Testosterone is responsible for the development of male reproductive structures (e.g., epididymis, vas deferens) and the external genitalia.
Ovaries Development:
In the absence of testes development (due to the absence of SRY), ovaries form, and no AMH or significant testosterone is produced.
Ovaries subsequently produce estrogen, which is essential for the development and maintenance of female reproductive structures and secondary sexual characteristics.
4. Epigenetic and Transcriptional Regulation:
Epigenetic factors, including DNA methylation and histone modifications, are involved in regulating the expression of genes responsible for gonadal development.
Transcription factors and signaling molecules, such as the WNT signaling pathway and homeobox genes, play a role in directing cellular differentiation and the formation of specific structures based on hormonal and genetic cues.
Know the most common sex chromosome disorders.
Sex chromosomal DSD
45,X
47,XXY
Turner syndrome and variants
Klinefelter syndrome and variants
45,X/46,XY and 46,XX/46,XY
· Mixed gonadal dysgenesis
. Chimerism
Know the consequence of deficiency of masculinization of male fetuses and virilization of
female fetuses.
These consequences are associated with disorders of sexual development (DSD) and can vary in severity depending on the specific cause and degree of masculinization or virilization deficiency. Here are some of the potential consequences:
Deficiency of Masculinization in Male Fetuses:
Ambiguous Genitalia: In cases where there is a significant deficiency in masculinization, male fetuses may be born with ambiguous genitalia, making it challenging to determine their biological sex.
Underdeveloped Male Reproductive Organs: The underdevelopment of male reproductive organs, including the penis, scrotum, and testes, can lead to reduced fertility and reproductive difficulties.
Hormonal Imbalances: Masculinization deficiencies can be associated with hormonal imbalances that affect secondary sexual characteristics, such as body hair growth, voice deepening, and muscle development.
Psychosocial Impact: Individuals with underdeveloped or ambiguous genitalia may experience psychosocial challenges, including body image issues and difficulties in gender identity and social interactions.
Virilization of Female Fetuses:
Excess Body Hair (Hirsutism): Female fetuses with virilization deficiencies may develop excess body hair (hirsutism), which can lead to self-esteem and body image concerns.
Deepening of Voice: Virilization can result in a deepening of the female voice, leading to changes in speech patterns.
Clitoral Enlargement: Enlargement of the clitoris, a homologous structure to the male penis, can occur in cases of virilization.
Irregular Menstrual Cycles: Virilization may disrupt normal menstrual cycles and ovulatory function, leading to fertility issues.
Ovotesticular DSD: In some cases of virilization, individuals may have both ovarian and testicular tissue, known as ovotesticular DSD. This can lead to complex medical and surgical considerations.
Explain the hormonal dynamics during fertilization and implantation.
- Ovulation and Fertilization:
Luteinizing Hormone (LH): LH, secreted by the anterior pituitary gland, surges just before ovulation, triggering the release of a mature egg (oocyte) from the ovarian follicle. This surge is essential for fertilization to occur.
Follicle-Stimulating Hormone (FSH): FSH also plays a role in the maturation of eggs in the ovarian follicles.
Estrogen: As the dominant follicle matures, it produces increasing levels of estrogen. Elevated estrogen levels have various effects, including promoting the thickening of the uterine lining (endometrium) and increasing the production of cervical mucus, which facilitates the passage of sperm into the uterus.
Progesterone: After ovulation, the ruptured follicle transforms into the corpus luteum, which produces progesterone. Progesterone helps prepare the endometrium for implantation, making it more receptive to the developing embryo.
- Early Pregnancy and Implantation:
Human Chorionic Gonadotropin (hCG): After fertilization, the embryo begins to produce hCG, which signals to the corpus luteum to continue producing progesterone. This hormone ensures the continued maintenance of the endometrium and prevents menstruation.
Progesterone: Progesterone continues to be produced by the corpus luteum and, later in pregnancy, by the placenta. It supports the thickening of the endometrial lining and prevents it from shedding.
Estrogen: Estrogen levels also increase during early pregnancy. Together with progesterone, it promotes the development of the uterine blood vessels, which provide oxygen and nutrients to the developing embryo.
Implantation Process: As the embryo travels through the fallopian tube and into the uterus, it undergoes a process called implantation. During this phase, it adheres to the endometrial lining, eventually burrowing into it. This process involves a variety of cellular and molecular interactions, but it is also influenced by the hormonal environment of the endometrium.
Cytokines and Growth Factors: Various cytokines and growth factors, such as leukemia inhibitory factor (LIF), are produced by the endometrium and play roles in the regulation of implantation.
- Pregnancy Continuation:
Placental Hormones: As the placenta forms, it takes over the production of hormones. It secretes hCG, which continues to support the corpus luteum during early pregnancy. Eventually, it produces its own hormones, including estrogen, progesterone, and others that are essential for maintaining the pregnancy.
Relaxin: This hormone, produced by the corpus luteum and later by the placenta, helps relax the uterine muscles, preventing contractions that could potentially interfere with implantation and early pregnancy.
Explain hormonal changes during pregnancy
- Human Chorionic Gonadotropin (hCG):
hCG is the first hormone to rise significantly following implantation of the embryo. It is produced by the trophoblast cells of the placenta.
hCG maintains the corpus luteum (a temporary endocrine structure in the ovary) during early pregnancy, which, in turn, sustains the production of progesterone.
hCG is the hormone detected in pregnancy tests and is responsible for many early pregnancy symptoms.
2. Progesterone:
Progesterone is produced by the corpus luteum during the first trimester and then primarily by the placenta.
It maintains the uterine lining and prevents it from shedding, ensuring a stable environment for the developing embryo.
Progesterone also relaxes the uterine muscles to prevent contractions and supports the development of the placenta.
3. Estrogen:
Estrogen levels rise significantly during pregnancy, with the placenta being the primary source of production.
Estrogen promotes the growth of the uterus, increases blood flow to the pelvic area, and stimulates the development of mammary glands.
It plays a role in the development of fetal organs and the regulation of the cervix and uterine muscles.
4. Prolactin:
Prolactin levels rise during pregnancy and continue to increase after childbirth.
Prolactin prepares the breasts for lactation, stimulating milk production.
5. Relaxin:
Relaxin is produced by the corpus luteum and the placenta during pregnancy.
It relaxes the uterine muscles, prevents contractions, and helps prepare the cervix for childbirth.
6. Oxytocin:
While oxytocin levels increase during pregnancy, their major role comes into play during labor and childbirth.
Oxytocin is responsible for uterine contractions during labor and helps facilitate the delivery of the baby.
7. Human Placental Lactogen (hPL):
hPL is produced by the placenta and contributes to metabolic changes in the mother during pregnancy.
It promotes the growth of breast tissue and helps prepare the mother’s metabolism for milk production.
8. Corticotropin-Releasing Hormone (CRH):
CRH levels increase throughout pregnancy, playing a role in the timing of childbirth and fetal development.
9. Thyroid Hormones:
Thyroid hormones increase during pregnancy to support the increased metabolic demands of both the mother and the developing fetus.
Explain the function of the placenta as a metabolic and endocrine organ.
- Endocrine Functions of the Placenta:
hCG Production: The placenta produces human chorionic gonadotropin (hCG), which supports the corpus luteum in the early stages of pregnancy. hCG is the hormone detected in pregnancy tests.
Progesterone Production: The placenta takes over the production of progesterone, a hormone that is vital for maintaining the uterine lining and preventing its shedding. It also helps relax the uterine muscles to prevent contractions.
Estrogen Production: The placenta is a significant source of estrogen production during pregnancy. Estrogen plays a role in the growth of the uterus, the development of mammary glands, and the regulation of cervical and uterine muscles.
Human Placental Lactogen (hPL) Production: hPL, produced by the placenta, affects the mother’s metabolic state and helps prepare her metabolism for milk production.
Corticotropin-Releasing Hormone (CRH) Production: The placenta produces CRH, which plays a role in the timing of childbirth and fetal development.
Parathyroid Hormone-Related Protein (PTHrP) Production: PTHrP, produced by the placenta, regulates calcium transfer to the fetus, ensuring proper bone development.
Vasopressin Production: The placenta synthesizes vasopressin, a hormone that helps regulate water and electrolyte balance in the mother and fetus.
Know about gestational diabetes, gestational hypertension and potential
treatment options.
Gestational Diabetes:
What is Gestational Diabetes?
Gestational diabetes is a type of diabetes that develops during pregnancy. It occurs when the body cannot produce enough insulin to meet the increased needs during pregnancy, resulting in elevated blood sugar levels.
Risk Factors:
Being overweight before pregnancy
A family history of diabetes
Advanced maternal age
Prior history of gestational diabetes
Polycystic ovary syndrome (PCOS)
Diagnosis:
Gestational diabetes is typically diagnosed between the 24th and 28th weeks of pregnancy through a glucose tolerance test.
Potential Complications:
High blood sugar levels can lead to complications for both the mother and the fetus, including increased risk of high birth weight, preterm birth, and cesarean delivery.
Treatment Options:
Diet and Exercise: In many cases, gestational diabetes can be managed through dietary changes and regular exercise.
Blood Sugar Monitoring: Regular monitoring of blood sugar levels is essential to track and manage the condition.
Insulin or Medication: If diet and exercise alone are not sufficient, insulin or other medications may be prescribed.
Fetal Monitoring: Additional fetal monitoring may be necessary to ensure the well-being of the baby.
Delivery Planning: Timing of delivery may be adjusted based on the severity of the condition.
Gestational Hypertension:
What is Gestational Hypertension?
Gestational hypertension, also known as pregnancy-induced hypertension (PIH), is characterized by high blood pressure that develops during pregnancy, typically after the 20th week, and resolves after delivery.
Risk Factors:
First pregnancy
Maternal age under 20 or over 40
Multiple gestations
Obesity
Preexisting high blood pressure or kidney disease
Potential Complications:
Gestational hypertension can lead to preeclampsia, a more severe condition that can harm the mother’s organs and restrict blood flow to the fetus.
Treatment Options:
Regular Monitoring: Blood pressure is regularly monitored during prenatal visits.
Bed Rest: In some cases, rest may be recommended.
Medications: Medications may be prescribed to control high blood pressure if necessary.
Delivery Planning: Depending on the severity, delivery may be induced or scheduled early to prevent complications.
High thyroid hormones
(Low theroid hormones do the opposite)
increase in:
Gluconeogenesis
Glycogenolysis
protein Synthesis
Proteolysis
Lipogenes
Lipolysis
thermogenes
decrease in :
serum cholesterol
What do you know about bone cartilage and IGF1
Bone homeostasis – Dynamic process
§ Osteoblast
§ Osteocytes
§ Osteoclast
§ Chondrocytes → synthesis of cartilage of the
epiphyseal plate
§ IGF-1 → stimulate chondrocyte activity and bone
growth
what is the antagonist to PTH ?
Calcitonin
§ Produced by parafollicular (C) cells of thyroid gland
§ Antagonist to PTH
§ Calcitonin ↑ bone formation (osteosynthesis) and osteoblast
activity and formation and ↓ release of Ca2+ from bone matrix
§ Stimulates Ca2+ uptake and incorporation into bone matrix
§ Minor role in humans
§ Removal of thyroid (and its C cells) does not affect Ca2+
homeostasis
how does menopausal estrogen decline lead to problems with bone density ?
osteoplast become osteoclaasts because we have too much Receptor activator of
nuclear factor kappa-Β
ligand (RANKL) and too little Osteoprotegerin (OPG)
what does calcitonin do?
Calcitonin is a hormone that your thyroid gland makes and releases to help regulate calcium levels in your blood by decreasing it. Calcitonin opposes the actions of the parathyroid hormone, which is a hormone that increases your blood calcium levels
hypocalcemia
But also…
* Vitamin D analogues
* Different variants of calcium
* Calcium balance very difficult
what is sclerostin ?
Inhibition of Bone Formation: Sclerostin’s primary role is to inhibit the activity of osteoblasts, which are the cells responsible for bone formation. It does this by interfering with the Wnt/β-catenin signaling pathway, which is essential for osteoblast function. Inhibition of this pathway by sclerostin leads to a decrease in the formation of new bone tissue.
Regulation of Bone Density: By reducing bone formation, sclerostin acts as a regulator of bone density. Lower levels of sclerostin are associated with increased bone formation and density, while higher levels are associated with reduced bone formation and lower bone density.
Sclerostin Antibodies: Researchers have developed therapeutic antibodies that can target and inhibit sclerostin. These antibodies are used in the treatment of conditions characterized by low bone density, such as osteoporosis. By blocking the activity of sclerostin, these antibodies promote bone formation and increase bone density.
Denosumab?
Mechanism of Action: Denosumab works by inhibiting RANKL, a protein involved in the regulation of bone remodeling. RANKL plays a crucial role in the activation of osteoclasts, cells that break down bone tissue. By binding to and inhibiting RANKL, denosumab reduces the activity of osteoclasts, leading to a decrease in bone resorption (bone breakdown).
What are SERMs drugs?
Selective Estrogen Receptor Modulators (SERMs) are a class of drugs that interact with estrogen receptors in various tissues of the body. SERMs are designed to selectively modulate the activity of these receptors, meaning they can act as agonists (activators) or antagonists (blockers) of estrogen, depending on the tissue and the specific receptor they are targeting.
Osteoporosis treatment?
- Strategy 1: Inhibiting bone destruction
- Bisphosphonates
- Denosumab
- Estrogen
- Strategy 2: Rebuild bone density (anabolic)
- Romosozumab – inhibits sclerostin
- Teriparatide – PTH analogue
Karolinska
Hypercalcemia treatmens?
- What is the hypercalcemia due to?
- Solutions:
- Rehydration
- Calcitonin
- Bisphosphonates (Inhibit osteoclasts)
- Denosumab (RANKL-antibody)
what are the adrenal diseases ?
- Hyperaldosteronism
- Cushing’s disease
- Addison’s disease
what is Hyperaldosteronism (Conn’s syndrome)?
Hyperaldosteronism, often referred to as Conn’s syndrome, is a medical condition characterized by the overproduction of the hormone aldosterone by the adrenal glands. Aldosterone plays a central role in the regulation of sodium and potassium levels in the body and is produced in the outer layer (cortex) of the adrenal glands.
symptoms : Hypertension: Excess aldosterone causes the kidneys to reabsorb more sodium and excrete more potassium, leading to an increase in blood volume and blood pressure. Hypertension is a common and hallmark symptom of Conn’s syndrome.
Low Potassium Levels (Hypokalemia): As the kidneys excrete excessive potassium, individuals with Conn’s syndrome often experience low potassium levels in their blood. This can lead to symptoms like muscle weakness, muscle cramps, and irregular heart rhythms (arrhythmias).
Metabolic Alkalosis: Elevated aldosterone levels can result in an excess of bicarbonate (a base) in the blood, leading to a condition known as metabolic alkalosis. Symptoms may include weakness, fatigue, and muscle twitching.
Increased Urination: Due to the excess sodium reabsorption by the kidneys, individuals with Conn’s syndrome may have increased urinary output, even though their overall blood volume is expanded.
Diagnosis of Conn’s syndrome typically involves blood tests to measure aldosterone and renin levels, as well as imaging studies (e.g., CT or MRI scans) of the adrenal glands to identify any structural abnormalities. If primary hyperaldosteronism is suspected, a confirmatory test called the aldosterone-to-renin ratio (ARR) is often performed.
TREATMENTS:
* Surgery
* Antagonists of MR - Spironolactone
what is Cushing’s disease ?
Cushing’s disease is a specific form of Cushing’s syndrome, a medical condition characterized by the excessive production and release of cortisol, a steroid hormone, by the adrenal glands. Cushing’s disease is primarily caused by a benign pituitary tumor called an adenoma. This adenoma secretes an excess amount of adrenocorticotropic hormone (ACTH), which, in turn, stimulates the adrenal glands to produce and release more cortisol than the body needs.
Key features and characteristics of Cushing’s disease include:
Excess Cortisol: The overproduction of cortisol results in high levels of this hormone in the bloodstream. Cortisol, often referred to as the “stress hormone,” plays a role in various bodily functions, including metabolism, immune response, and the body’s response to stress.
Weight Gain: Individuals with Cushing’s disease typically experience rapid and significant weight gain, particularly in the abdominal area. This can lead to a characteristic “moon face” appearance and the development of a “buffalo hump” of fat on the upper back.
Muscle Weakness: Weakness and muscle atrophy (muscle wasting) can occur in individuals with Cushing’s disease. This can lead to reduced muscle strength and a tendency to bruise easily.
Skin Changes: The skin may become thin and fragile, making it more susceptible to bruising and the development of stretch marks (striae). The skin can also become prone to infections.
Hypertension: High blood pressure is a common symptom in Cushing’s disease, contributing to the risk of cardiovascular issues.
Glucose Intolerance and Diabetes: Elevated cortisol levels can lead to insulin resistance and impair glucose metabolism, increasing the risk of glucose intolerance and diabetes.
Osteoporosis: Excess cortisol can weaken bones and increase the risk of osteoporosis, leading to an increased susceptibility to fractures.
Emotional and Psychological Changes: Mood swings, irritability, and cognitive changes may occur in individuals with Cushing’s disease.
Other Symptoms: Additional symptoms can include menstrual irregularities in women, hirsutism (excessive hair growth), and in some cases, features of virilization in women (developing male-like characteristics), and reduced libido and erectile dysfunction in men.
TREATMENTS:
- Surgery
- Ketoconazole – antifungal treatment – inhibits CYP enzymes like CYP17A1
17a-hydroxylase
what is Addison’s disease?
Addison’s disease, also known as primary adrenal insufficiency or adrenal insufficiency, is a rare and chronic medical condition characterized by the insufficient production of hormones by the adrenal glands. The adrenal glands are small, triangular-shaped organs located on top of each kidney. These glands produce essential hormones, including cortisol and aldosterone, which play crucial roles in regulating various physiological processes in the body.
Key features and characteristics of Addison’s disease include:
Cortisol Deficiency: The primary hormone deficiency in Addison’s disease is cortisol, often referred to as the “stress hormone.” Cortisol is involved in metabolism, immune response, blood sugar regulation, and the body’s response to stress.
Aldosterone Deficiency: In addition to cortisol, aldosterone production may also be impaired. Aldosterone helps regulate sodium and potassium levels and plays a key role in maintaining blood pressure and electrolyte balance.
Symptoms: Common symptoms of Addison’s disease can include fatigue, weakness, weight loss, loss of appetite, nausea, vomiting, diarrhea, and abdominal pain. Affected individuals may also experience low blood pressure, dizziness, and fainting (orthostatic hypotension), as well as hyperpigmentation of the skin, leading to darkening or bronzing.
Adrenal Crisis: In severe cases, when cortisol levels drop significantly, individuals with Addison’s disease can experience an adrenal crisis, a life-threatening condition characterized by extreme weakness, confusion, low blood pressure, dehydration, and electrolyte imbalances. This is a medical emergency that requires immediate treatment with intravenous fluids and replacement of cortisol.
Autoimmune Cause: The most common cause of Addison’s disease is autoimmune adrenalitis, where the body’s immune system mistakenly attacks and damages the adrenal glands. Other potential causes can include infections, hemorrhage, cancer, or certain medications.
Diagnosis: Diagnosis typically involves blood tests to measure cortisol and aldosterone levels, as well as the hormone adrenocorticotropic hormone (ACTH) that stimulates the adrenal glands. Imaging studies (e.g., CT or MRI) may be performed to assess the size and structure of the adrenal glands.
TREATMENTS:
* Cortisone, try to mimic the physiological rhythm
* MR-agonist - fludrocortisone
what are the types of insulin ?
Types of insulin:
rapid acting
short acting
intermediate acting
long acting
treatments for diabetes
b cells transplants behind the eyes,hybrid- closed loop monitored systems
However:
* Insulin is normally produced in pancreas, goes directly to the liver, where it
will act on gluconeogenesis and be heavily metabolized
* Other methods bypass this metabolism à large differences in systemic
insulin concentrations!
* Important consideration, as for instance it can lead to hyperandrogenism
* Liver-targeted insulin not efficient – what comes next?
Metformin
* Works against everything?
* Unclear mechanism
* Complex I – only in vitro
* Decreases intestinal absorption of glucose
* Increases peripheral insulin sensitivity
* Reduces liver gluconeogenesis and glycogenolysis
* AMPK-related?
Sulfonylurea
* Increases secretion of insulin
* Risk for hypoglycemia
GLP-1
increases insulin decreases glucagon ( the incretin effect)
Ozempic
- Decreases appetite
- Increases satiety
DPP4 inhibitors
* DPP4 inactivates GLP-1
* DPP4 inhibition causes GLP-1 accumulation
SGLT2 inhibitors
* ”Miracle drug”
* Decreased risk of heart failure
* Decreased risk of kidney failure
* Even in non-diabetics!
Contraception treatments?
- Barrier-based methods
- Hormonal methods
- Intrauterine methods
- Sterilization
- Cyclic methods
- OR
- Short-term, long-term and permanent
Specificaly:
Cyclic methods
* Temperature (0.1-0.2 degrees increase in temperature after ovulation – only
if regular menstruations!)
* Safe periods (count days, ovulation occurs 12-14 days before the first day of
the menstruation)
* Billings ovulation method – mucus based
* Ovulation tests (measures LH)
Barrier methods
* Condoms – male and female
* Fem cap – in cervix
Sterilization
* In Sweden: >25 yo, written consent.
* Male – vas deferens split bilaterally with local anesthesia
* Female – laparoscopic, in conjunction with sectio, or hysteroscopic
Copper spiral
* Affects the mucus in cervix, uterus and tuba
* Inhibits sperm motility and is toxic for sperm
* Embryotoxicity
* Prevents implantation through endometrial inflammation
Hormonal spiral
* Levonorgestrel-based, leads to thin endometrium
* Cervical mucus becomes hard and impenetrable
* Inhibits sperm motility
* Decreases bleeding
* Very safe!
Usually: progestogens/gestagens
* Progesterone receptor agonists
* Inhibits ovulation – antigonadotropic
* Thickens cervical mucus
* Atrophy of the endometrium
* Pills or implantation
High-dose gestagen
* Every 3 months, injection
* Affects bone density due to estrogen effect
* Contraindicated before 23 yo due to bone growth
Combination therapy – gestagen & estrogen?
* Gestagen:
* Inhibits LH - ovulation inhibition
* Thickens cervical mucus - hinders sperm to penetrate cervix
* Estrogen:
* Increases concentration of progesterone receptors - better bleeding
control
* Inhibits FSH - inhibits follicular development
Thrombosis and contraceptions
* Birth control pills increase the risk of venous thromboembolism (VTE) 2-6
times
* Risk highest 1st year of usage
* BUT, still very low incidence (0.5-3.5/10 000 vs 1-20/10 000)
* 12/10000 pregnant women get VTE.
Endometriosis treatment?
Endometriosis is a disease in which tissue similar to the lining of the uterus grows outside the uterus. It can cause severe pain in the pelvis and make it harder to get pregnant
- Treatment goals: anovulation and amenorrhea.
- Pills, gestagens and sometimes GnRH-analogues.
- If GnRH-analogue – add some estrogen.
Polycystic Ovary Syndrome treatments?
- 2 out of 3: hyperandrogenism, polycystic ovaries, an/oligoovulation
- Metformin?
- Contraceptive pills?
- If overweight, lifestyle changes!
Stimulated ovulation treatment ?
- ”Downregulation” using GnRH agonists, 2 weeks
- FSH stimulation using recombinant FSH
- hCG or GnRH agonists for ovulation
- Progesterone after ovulation
Male infertility causes?
- What cause?
- Hypogonadotropic hypogonadism – give hCG or LH+FSH
- Low sperm count – FSH
- Try to find if any medication is bad – then remove
- Chromosomal?
Insulin resistance what is it ?
Insulin resistance: NO Normal β-cell
function- Compensatory-
hyperinsulinemia-Normoglycemia
INSTEAD:Abnormal β-cell
function-Relative insulin deficiency- Hyperglycemia-Type 2 diabetes
Insulin resistance in peripheral target tissues
§Liver
§ ↓Glycogen synthesis
§Liver
§ ↑Gluconogenesis
§Muscle
§ ↓GLUT4 transloc.
§ ↓Glucose uptake
§ ↓Glycogen synthesis
§ ↓Glucose oxidation
§Adipose tissue
§ ↑Lipogenesis
§ ↑Lipolysis
§ ↑TG
§ ↑FFA
Insulin dependent and insulin independent
glucose uptake
what is metabolic syndrome ?
International Diabetes Federation (IDF) 2005
1. Visceral obesity: Waist ³ 94 cm (men) and waist ³ 80 cm (women)
and at least 2 of the following:
1. High triglycerides: >1,7 mmol/L
2. Low HDL-cholesterol: < 1,03 mmol/L (men) <1,29 mmol/L (women)
3. Blood pressure ³130/85 or medication
4. Fasting plasma glucose ≥5,6 mmol/L or diagnosed type 2 diabetes
what is inhibin ?
So, in both males and females, inhibin acts as a feedback mechanism to help regulate the production of hormones (FSH) that are essential for the reproductive processes of sperm production in males and follicle development in females. It contributes to the overall hormonal balance in the reproductive system.
Androgen receptor (AR) signaling pathway in spermatogenesis
- Sertoli cell proliferation and maturation
- Spermatogonia stem cells self-renewal and
differentiation - Spermatocyte meiosis
- Blood-testis barrier integrity and maintenance
- Sertoli cell - Spermatid adhesion, and sperm
release
Androgen effects on male physiology
Skeletal muscle: ARSàIGF1àMuscle protein synthesis, formation of
myoblasts and utilization of amino acids
* Adipose tissue: ARSà restrain fatty acid (FA) storage by suppressing
lipoprotein lipase (LPL) and acyl coenzyme A synthetase (ACS)
activityàinhibits lipogenesis and accumulation of adipose tissue.
* Cardiovasculature: ARSàstimulate erythropoietin (EPO) and reduce
ferritin and hepcidin levels and increase the activity of red bone marrow
and promote iron incorporation
* Immune system: ARSàthymocyte apoptosis, increase the production
of functional B cells, decrease the pro-inflammatory actions of
macrophages and decrease the secretion of pro-inflammatory
cytokines
* Nervous system: ARSàneuroprotective effects against ROS, enhanced
production of the anti-inflammatory cytokine, metabolized into DHT to
regulate dendritic spine maturation and function
Disorders of sex development (DSD)?
46,XY DSD
Disorders of gonadal
development
Disorders of androgen synthesis
Disorders of androgen
action
Persistent Müllerian
duct syndrome
Unclassified disorders
46,XX DSD
Disorders of gonadal
development
Disorders of androgen excess
Unclassified disorders
Sex chromosomal DSD
45,X
47,XXY
Turner syndrome and variants
Klinefelter syndrome and variants
45,X/46,XY and 46,XX/46,XY
· Mixed gonadal dysgenesis
. Chimerism
Turner syndrome
45 X or 45X/46XX, affecting
about 1/2500-1/5000 girls.
* Shorter stature and infertile
due to early loss of ovarian
function
* Bilateral streak gonads or
hypoplastic ovaries with intact
Müllerian duct structures and
female external genitalia
* The external genitalia, uterus,
and fallopian tubes develop
normally until puberty, at
which time estrogen-induced
maturation fails to occur.
* The ovaries produce very little
estrogen as they are replaced
by fibrous tissue, leading to
amenorrhea 52
Klinefelter syndrome
45 X or 45X/46XX, affecting
about 1/2500-1/5000 girls.
* Shorter stature and infertile
due to early loss of ovarian
function
* Bilateral streak gonads or
hypoplastic ovaries with intact
Müllerian duct structures and
female external genitalia
* The external genitalia, uterus,
and fallopian tubes develop
normally until puberty, at
which time estrogen-induced
maturation fails to occur.
* The ovaries produce very little
estrogen as they are replaced
by fibrous tissue, leading to
amenorrhea 52
Androgen insensitivity syndrome
Mutations in the AR gene cause androgen insensitivity syndrome, inherited in an X-linked
recessive pattern
- 2-5/100,000 who are genetically male
- External sex characteristics of females, but do not
have a uterus, infertile, raised as females and have a
female gender identity - Affected individuals have male internal sex organs
(testes) that are undescended - Sparse or absent hair in the pubic area and under
the arms. - At least similar incidence as CAIS, also called
Reifenstein syndrome - Have genitalia that look typically female,
genitalia that have both male and female
characteristics, or genitalia that look typically
male - May be raised as males or as females and may
have a male or a female gender identity. - Often infertile and tend to experience breast
enlargement at puberty
someone can also have 5α-reductase deficiency and not produce DHT
Mechanism of sex hormones effects
Free (1-2%)+ binding (SHBG, albumin)
* Alter gene expression through ligand-bound receptor binding to
hormone response elements in nucleus
* Production of membrane receptors, enzymes and structural proteins
* Bind to surface membrane receptors to regulate ion channels or
enzyme activity directly, such as that of nitric oxide synthase
how is it decided, Ovary or testis?
Urogenital ridges gives rise to the gonads,
adrenal cortex, kidney, and reproductive tract.
* Genital ridges: cortex and medulla
* Up to 6th week, no phenotypic difference in
male and female
* XX embryo, cortexàovary
* XY embryo, medullaàtestis
* If primordial germ cells fail to reach the
gonadal ridges, the gonads fail to develop
cause + common drug for pre-eclampsia?
decreased uteroplacental blood flow due to defective throphoblast invasion ,
Aspirin
Physiological changes during pregnancy
Increased plasma volume (40%)
Increased cardiac output
Decreased MAP
Increased renal, uterine and cutaneous blood flow
Increased GFR
Increased left ventricle mass (20-40%)
à Mild diastolic dysfunction
gestational diabetes cause ( molecular mechanism?
Etiology of GDM:
Insulin Resistance: During pregnancy, the placenta produces hormones that can lead to insulin resistance in the mother’s body. This means that the mother’s cells become less responsive to insulin, leading to higher blood sugar levels.
Genetic Factors: A family history of diabetes or a genetic predisposition to insulin resistance can increase the risk of developing GDM.
Obesity: Excess body weight, particularly before pregnancy, is a significant risk factor for GDM. Obesity is associated with increased insulin resistance.
Hormonal Changes: Hormones produced by the placenta, such as human placental lactogen (hPL) and cortisol, can interfere with insulin function.
Beta-Cell Dysfunction: Some women may have underlying beta-cell dysfunction, where their pancreas does not produce enough insulin to compensate for increased insulin resistance during pregnancy.
Inflammation: Low-grade inflammation in the body can contribute to insulin resistance and affect glucose metabolism.
Diet and Lifestyle: Poor dietary habits, physical inactivity, and excessive weight gain during pregnancy can exacerbate the risk of GDM.
Molecular Mechanism Involving GLUT Receptors:
Glucose transport into cells is facilitated by glucose transporters, known as GLUT receptors. These receptors play a crucial role in the regulation of blood glucose levels. In the context of GDM, changes in GLUT receptor function and expression can contribute to impaired glucose metabolism. Here’s a simplified overview of the molecular mechanisms involving GLUT receptors in GDM:
GLUT4 Receptors: In non-pregnant individuals, insulin promotes the translocation of GLUT4 receptors to the cell membrane in insulin-sensitive tissues like muscle and fat. This allows these cells to take up glucose efficiently, reducing blood sugar levels.
Insulin Resistance: In GDM, the mother’s cells become less responsive to insulin due to hormonal changes and inflammation. This leads to impaired glucose uptake by cells and elevated blood sugar levels.
GLUT4 Dysregulation: The function and expression of GLUT4 receptors may be altered in GDM. There may be reduced translocation of GLUT4 receptors to the cell membrane, which impairs glucose uptake.
Hormonal Interference: Hormones produced by the placenta, such as hPL,hPGH, hCG, progesterone, estradiol, prolactin, cortisol can interfere with the proper function of GLUT4 receptors and insulin signaling.
the placenta has different ways of taking in glucose like GLUT1 GLUT3 and Simple diffusion
Inflammation: Inflammation can disrupt the normal function of GLUT receptors and insulin signaling pathways, further contributing to insulin resistance.
