EXAM FOUR STUDY GUIDE.docx

**[EXAM FOUR STUDY GUIDE]** **[Week 11 Musculoskeletal ]** **[Types of fractures ]** **Colles fracture** -- wrist fracture usually due to fall with OUTSTRETCHED hand, distal radius and ulnar just above the wrist **Reverse Colles fracture** -- fall on flexed hand landing on wrist area, surgery or...

**[EXAM FOUR STUDY GUIDE]** **[Week 11 Musculoskeletal ]** **[Types of fractures ]** **Colles fracture** -- wrist fracture usually due to fall with OUTSTRETCHED hand, distal radius and ulnar just above the wrist **Reverse Colles fracture** -- fall on flexed hand landing on wrist area, surgery or splint for four weeks **Snuff Box Fracture** -- Outstretched hand, extreme dorsiflexion load on scaphoid bone, MRI for detection, thumb splint **Non-Displaced Fracture** -- Thumb splint followed by cast immobilization, re-image several weeks later **Displaced fractures** -- Surgical fixation to prevent injury to scaphoids tenuous blood supply **Stress fractures** -- result of multiple microfractures caused by repeated pressure on a bone, radiographs will often be negative, easily dx with MRI or bone scan **Secondary signs of fractures** -- Joint effusion, periosteal reaction or callus formation **Radial head fracture** -- most common fracture of the elbow in an adult, caused by extra synovial fat that's adjacent to elbow and has been lifted away. May be hard to see fracture but presence of fat density posteriorly strongly correlates with a radial head In children will see the same signs -- called a Supracondylar fracture **Hills Sachs Deformity** -- Very commonly seen with anterior shoulder dislocations **Spiral fracture** -- When extends to joint space there will be clinical implications **Pathologic fracture** -- abnomality of density in bone and around it, geographic lytic lesion of the humerus **Pediatric Fractures:** Pediatric bones have an epiphyseal "growth plate: Salter Harris classification: 1. Thru the growth plate -- good prognosis 2. thru the growth plate and metaphysis -- good prognosis, most common 3. thru the growth plate and epiphysis, premature GP fusion, osteoarthritis 4. thru the growth plate, epiphysis and metaphysis -- same as 3 5. Crush injury of growth plate, very poor prognosis, possible vascular injury **INCOMPLETE FRACTURES:** Occur in soft bones, seen mainly in pediatric population Involve a portion of the cortex **Toris or Buckle --** Bulging, partial compression of the cortex-- any long bone, mainly the wrist, buckling of boney cortex and periostrum without true fracture lines Immobilize, pain control **Greenstick** -- only a portion of the cortex, doctor may need to break completely break to set it correctly. Long term immobilization, pain control **Supracondylar fracture** -- posterior fat pad sign, most common elbow fracture in a child, anterior humeral line should normally intersect the middle of capitellum, but with this kind of fracture it's displaced anteriorly. Slipped fat pad IMMEDIATE Ortho consultation, neurovascular supply to the arm is in danger **Apophyseal Avulsion Fracture:** Apophis turn off by muscle after repeated use. Anterior superior iliac crest -- happens in swimmers and runners. Tibial tubercle -- Osgood Schlatter -- happens in jumpers and runners **Toddlers fracture:** Spiral fracture of distal tibia, when child pivots forcefully on one leg, NOT a sign of child abuse **[Secondary signs of fracture on x-ray]** Secondary signs of a fracture on an X-ray can include signs of healing, such as: Periosteal reaction: Linear elevation and calcification of the periosteum around the fracture site Soft callus: Early new bone that appears fluffy around the fracture site Hard callus: Well-defined new bone with a dense edge that\'s almost as dense as the cortex Other signs of a fracture on an X-ray include: Discontinuity of the cortical and trabecular bone Step off in cortical and trabecular bone Displacement of osseous fragments Abnormal fat pad or elevation of fat pad Impaction lines or sclerotic band **[Characteristics of Parkinson\'s]** Progressive neurodegenerative disease that affects movements due to damage of dopaminergic neurons. Will see shakiness, stiffness, slowed movements, and balance issues Substantia Nigra and Striatum Basal Ganglia -- the communication between these gets broken Substantia Nigra are dopaminergic neurons: Direct pathway leads to increased movement, Indirect pathway acts to reduce and finetune movement In Parkinsons, the direct pathway is shut down due to accumulation of Lewy Bodies Lewy bodies involve a protein called alpha synuclein, accumulation of this interferes with signaling, leads to neuronal death 80% neuronal degeneration causes bradykinesia, rigidity, dementia in later progression Parkinsons tremors are resting, NOT intentional Some causes of Parkinsons could be: Pesticide and chemical exposures, inhalation of heavy metals, concussions. More common in males **[Cause of chorea]** Involuntary abrupt irregular movement of body from one part to another, Huntingtons and Wilsons disease, drugs -neuroleptics and domaiminergic, Toxic -- ETOH, CO, thyrotoicoisis, Immunologic -- SLE, Post- Strep, Pregnancy, and Vascular -- Caudate damage **[Differentiate myoclonus, dystonia, and tremors]** **Dystonia:** Hyperkinetic. Sustained muscle contraction leading to repetitive twitching movements or abnormal postures May be focal -- blepharospasm, spasmotic, dysphonia, torticollis, writers Or segmental or generalized Causes: Idiopathic primary -- torsion dystonia, autosomal dominant *Secondary* -- Wilsons, Huntington's, Parkinsons, anoxia, stroke, drug induced **Myoclonus:** Sudden lightning like movement produced by abrupt and brief muscle contraction. Hiccups, Jerks, Epileptic. Management includes clonazepam and valproate "Depakote" **TICS:** Abrupt, stereotyped, coordinated movements of vocalizations, can be voluntarily suppressed. Suppression causes anxiety, the tics relieve the anxiety. Tourette's is an example. Manage with dopamine agonist, Clonidine, SSRIs for OCD **Tremor:** Resting is Parkinsons Postural -- Essential tremor -- most common Action -- Jerk like movements, cerebellar outflow lesion **[Pathway of movement control]** The pathway of movement control is a multisynaptic central nervous system (CNS) pathway that extends from the cerebral motor cortex to neuromuscular junctions. This pathway is also known as the pyramidal tract or corticospinal tract Movement disorders: Hyperkinetic -- tremor, chorea,dystonia, myoclonus, Tics, stereotypies Hypokinetic -- Parkinsonism, can also have hyperkinetic movements Tremor: Resting is Parkinsons Postural -- Essential tremor -- most common Action -- Jerk like movements, cerebellar outflow lesion **Chorea** -involuntary abrupt irregular movement of body from one part to another, Huntingtons and Wilsons disease, drugs -neuroleptics and domaiminergic, Toxic -- ETOH, CO, thyrotoicoisis, Immunologic -- SLE, Post- Strep, Pregnancy, and Vascular -- Caudate damage **Dystonia:** Hyperkinetic. Sustained muscle contraction leading to repetitive twitching movements or abnormal postures May be focal -- blepharospasm, spasmotic, dysphonia, torticollis, writers Or segmental or generalized Causes: Idiopathic primary -- torsion dystonia, autosomal dominant Secondary -- Wilsons, Huntington's, Parkinsons, anoxia, stroke, drug induced **[Patho of Wilson's disease]** Autosomal recessive disorder of copper metabolism Results in excessive serum copper, copper deposition in liver, kidneys, cornea, and CNS -- particularly the basal ganglia Free copper in iris = Kayser-Fleischer -- golden brown green Clinical features: Hyperkinetic movement, tremor, parkinsonism, dysathria, cognitive -- personality and mood disorders Diagnosis: Increased serum copper, decreased ceruloplasmin, increased 24 hour urine copper is the most sensitive screen, liver biopsy Management: Chelation, penicillamine -- be careful of kidney damange, trientine with zinc, zinc Clinical presentation of Wilson disease: ABCD A: Asterixis B: Basal ganglia degeneration symptoms (parkinsonism) C: Cirrhosis Corneal deposits (Kayser-Fleischer ring) D: Dementia **[What is Brown-Sequard syndrome?]** Hemisection of the cord, caused by trauma, rarely cord compression or partial transverse myelitis Signs and symptoms: Ipsilateral weakness, joint position sense loss, contralateral pain and temperature loss Bowel bladder dysfunction is rare **[Complications of Salter-Harris Type III fracture]** Pediatric bones have an epiphyseal "growth plate: Salter Harris classification: 1. Thru the growth plate -- good prognosis 2. thru the growth plate and metaphysis -- good prognosis, most common 3. thru the growth plate and epiphysis, premature GP fusion, osteoarthritis 4. thru the growth plate, epiphysis and metaphysis -- same as 3 5. Crush injury of growth plate, very poor prognosis, possible vascular injury **[Patho of Multiple Sclerosis, ALS, and Myasthenia Gravis]** **MS: White Matter Lesions**: Inflammatory lesions in the white matter of the brain. - **Multiple Lesions**: Plaques form in various locations. ALS: The exact pathogenic mechanism of ALS is unknown. There appear to be both molecular and genetic pathways that combine to cause UMN and LMN apoptosis. Reduced uptake of glutamate from the synaptic cleft causes glutamate excitotoxicity Mediated by poorly functioning excitatory amino acid transporter 2 (EAAT2) on astrocyte cellmembranes Ca2+-dependent enzymatic pathways are activated, inducing neurodegeneration Abnormal translation ensues Intracellular neuronal aggregates form Mutations in the SOD1 gene is pathogenic: Causes dysfunction of the mitochondria Increases free radical → cellular oxidative stress Further accumulation of intracellular aggregates Axonal transport becomes defective Microglial activation: Abnormal secretion of proinflammatory cytokines Cytokines further contribute to neurotoxicity MG: There are 2 main clinical forms of MG: Ocular myasthenia: weakness is limited to the eyelids and extraocular muscles and is characterized by ptosis and oculomotor paresis. Generalized myasthenia: Weakness not only occurs in the ocular muscles but also affects the bulbar, limb, and respiratory muscles. Weakness can be proximal, distal, symmetric, or asymmetric.In addition, rarer forms of MG exist that primarily affect the pediatric population:Neonatal MGs:A rare condition that occurs when mothers with MG have children who are born with the disorder.Transplacental passage of maternal antibodies that attack the neuromuscular junctionImmediate treatment can resolve the condition within 2 months after birth.Congenital myasthenic syndrome:A rare, hereditary form of myasthenia that is present from birth.This syndrome may be the result of rare mutations that affect neuromuscular transmission. Presence of antibodies against either AChR, MuSK, or LRP4 is referred to as seropositive MG: AChR-positive MG: Presents primarily with proximal limb muscle weakness Facial, bulbar, and respiratory weakness may also be present. Present in about 80% of MG cases Present in 30%--40% of ocular MG 20% chance of remission 3 subtypes of AChR antibodies: Binding antibodies: activate complement → loss of AChRs (the most common type) Modulating antibodies: causes antigenic modulation → receptor endocytosis (Modulating antibodies will be found in 73% of patients with thymoma and MG.) Blocking antibodies: act as a competitive antagonist at the AChR (Fewer than 1% of patients have only blocking antibodies, without detectable binding or modulating antibodies.) MuSK-positive MG: Presents primarily with facial, bulbar, and respiratory weakness No or relatively mild limb weakness Common in younger female patients Present in 30%--40% of MG cases in which AChR antibody is absent Less chance of remission Absence of AChR, MuSK, or LRP4 antibodies in the presence of clinical signs/symptoms is referred to as seronegative MG (15% of cases). Classification based on symptom severity:\[4,6\] Class I: ocular MG Class II: generalized MG with mild weakness Class III: generalized MG with moderate weakness Class IV: generalized MG with severe weakness Class V: generalized MG requiring intubation because of respiratory muscle weakness Pathogenesis AChR antibodies (produced in the thymus): Are IgG1 and IgG3 subtypes and divalent Antibodies are typically polyclonal within an individual patient. Antibodies target AChRs on the postsynaptic membrane: Block ACh binding Cause AChR cross-linking, which leads to internalization and destruction of the AChR Antibodies activate the classical complement pathway, which in turn activates the membrane attack complex (MAC). The reaction is classified as type 2 hypersensitivity reaction (i.e., it causes cytotoxic injury). MAC causes a calcium influx that damages the postsynaptic membrane, which in turn damages the AChRs. MuSK antibodies: Mostly IgG4 subtype The pathogenesis is not exactly delineated. Effects on neuromuscular junction: Damage to the AChRs leads to decreased binding of acetylcholine, which in turn impairs signal transduction at the neuromuscular junction. Decreased response causes failure of muscle contraction, which causes skeletal muscle weakness and fatigue. **[Clinical manifestations of ALS]** Affected individuals report:Limb weakness Cramping in the early morning Gait instability Falling Fatigue when walking Stiffness of the affected limb(s)Incoordination of the affected limb(s) Pain: Commonly due to muscle spasticity or decreased mobility Traumatic injury from falls is also a common source of pain. Average time between onset of symptoms and diagnosis is roughly 1 year. During the usual natural course of the disease, more muscle groups are affected with time, starting with an asymmetrical distribution of weakness, later becoming symmetrical. Speech difficulties (e.g., dysarthria) Dysphagia and sialorrhea due to progressive weakening of the muscles of mastication and swallowing Exaggeration of the motor expressions of emotion Excessive forced yawning Pseudobulbar affect (e.g., episodes of uncontrollable laughter or crying) Frontotemporal dementia (frontal lobe dysfunction): Early behavioral abnormalities and personality changes Weight loss (predictor of poor outcome) Poor executive functioning Constipation due to immobility Extrapyramidal symptoms and parkinsonism before or after motor neuron manifestations Pearl: Weakness is followed by muscle atrophy as the disease progresses. Asymmetrical weakness (earliest sign) can be attributed to either one. Spasticity (occurs in wasted muscles) Slowed rapid alternating movements Spastic gait Spontaneous clonus Hyperreflexia Muscle atrophy Fasciculations (good specificity) Proximal arm and leg weakness Poor heel and/or toe walking Poor rise from chair Foot drop Waddling gait Hyporeflexia **[Treatment of MG]** *Indications for hospitalization:* Significant bulbar symptoms (refer to speech and language therapy), Low vital capacity (regular assessment required), Respiratory symptoms ,Progressive deterioration *Conditions typically safe for outpatient management:* Ocular MG, Mild-to-moderate limb weakness , Mild bulbar symptoms Pharmacotherapy Acetylcholinesterase inhibitors are first line Useful for mild and moderate forms of MG Increase the amount of acetylcholine available by preventing its breakdown The most commonly used drug is pyridostigmine, an oral AChE inhibitor. Oral glucocorticoids Indicated if symptoms persist despite pyridostigmine therapy for a few weeks Additional nonsurgical therapies: *Plasmapheresis or therapeutic plasma exchange:* Removes AChR or MuSK antibodies from the circulation Plasmapheresis is considered only in an emergency such as dysphagia or respiratory failure, as it is associated with adverse effects and is expensive. *Thymectomy:* Research suggests that in patients who undergo thymectomy when indicated, remission and decreased drug dependency are observed. Indications: Patients with thymoma Patients without thymoma who meet both of the following criteria: Positive anti-AChR antibody \< 50--65 years of age with generalized MG Thymectomy is not recommended in patients with MuSK antibodies. Thymectomy is an elective procedure and should be performed when the patient is stable enough to undergo a procedure that could limit respiratory function postoperatively (due to mechanical factors and pain).\[8\] Management of myasthenic crisis: An exacerbation of MG symptoms that puts a patient at risk for neuromuscular respiratory failure Can be precipitated by: Infection Surgery Pregnancy/delivery Some medications Intubation/mechanical ventilation may be performed electively prior to the development of emergent situations. Rapid therapies include plasmapheresis and IVIG. Immunosuppressive drugs are started at a moderate to high dose **[Causes of bone loss in women]** Osteopenia is precursor for osteoporosis Causes: decreased estrogen, diseases, diet, lifestyle, medications such as glucocorticoids, age, white women of European dissent, low body weight, family history Adolescence is a critical time to accumulate bone for peak mass Factors that may interfere with bone mass accrual include: pregnancy during adolescence, eating disorders, poor calcium intake Presents with vertebral compression factors: Colles fracture, tooth loss, head of femur fracture Women over 65 or under with one or more risk factors should be screened Screening for secondary osteoporosis -- primary hyperparathyroidism or secondary hyperparathyroidism with chronic renal failure Hyperthyroidism Multiple myloma Biochemical markers occur in response to repair, fatigue, damage, and microfracutures in the bone = serum C telopeptide CTX and Urinary NTX Also test for alkaline phosphatase and osteocalcin Bone turnover markers for borderline patients Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to the rise of fracture Decreased bone density Bone remodeling - equilibrium between formation by osteoblasts and resorption by osteoclasts Peak bone mass is achieved at thirty years Bone loss occurs in 0.3-.5% per year around the 4th to 5th decade Loss is accelerated with menopause *VITAMIN D DEFICIENCY:* Diet and sun exposure provide a substrate for hydroxylation in the liver Renal enzyme alpha hydroxylase performs a second hydrolylation step to give the active molecule the enzyme stimulated by PTH and lower calcium **[Ottawa ankle rules]** Ankle rules -- pain at mid malleolus or along distal 6cm of posterior/medial tibia, pain at lateral malleolus or along distal 6cm of posterior fibula **[When to order an MRI for fractures]** A doctor may order an MRI for a fracture if an X-ray doesn\'t show anything obvious, or if the X-ray shows abnormal findings. MRIs are better for soft tissue injuries, like torn ligaments or damaged tendons, and can help visualize damaged tissue and other secondary injuries. MRIs can also be used to diagnose stress fractures, which are tiny cracks in bones that can\'t always be seen on an X-ray.  Here are some other reasons a doctor might order an MRI for a fracture: - If a leg fracture has been treated with casting and rest but doesn\'t seem to be getting better - If hip pain persists even though an X-ray doesn\'t show a fracture - If there are clinical symptoms, even if radiographs are negative **[Understand EMG nerve conduction testing]** Electromyography (EMG) and nerve conduction studies (NCS) are diagnostic tests that are often performed together to assess nerve and muscle function and help detect diseases that damage them: Measures electrical activity in muscles when they are at rest and when they contract. During an EMG, a neurologist or technologist may insert a needle electrode directly into a muscle to record its electrical activity. The doctor may also ask the patient to perform simple tasks while the needle is in place. This portion of the test can be uncomfortable, but the pain is usually brief and not continuous **[Physical exam techniques to assess carpal tunnel]** Associated with compression of median nerve. Heavily associated with overuse. Predispositions include obesity, female, short stature, history of fractures Physical findings -- numbness in radial 3 and ½ digits, heaviness in hands, decreased grip strength, thenar muscles wasting Pain in volar aspect of the hand on the palmer side Electric shock sensation at night TInels sign -- tingling by tapping over media nerve Compression test -- full compression of carpal tunnel in effort to mimic the syndrome EMG studies **[Evaluating Paget's Disease]** Prevalent in the UK, Australia, South Africa, USA Chaotic osteoclast function with increased bone remodeling both formation and resorption New bone formed is structurally weaker Hypervascularity Etiology is unclear Hat size with increase One or more bones ASYMETRICALY -- pevis, lumbar, skull, femur 90% asymptomatic Bowed lower extremities Front and occipital enlarged skull Increase fracture risk of femur, tibia, radius Impingement syndroms -- inner ear, hearing loss, vertigo 1gf1 will be elevated Uncommon manifestations -- increased CHF output from vascular shunts, osteosarcoma, hypercalcemia during immobilization Paget's hip -- increased thickening cortex, prominent traberculae Pagets can cause pain, deformities, disabilities Does NOT spread to other bones after those initially affected Cotton wool skull appearance Alk Phosphate increase is a HALLMARK sign, can be over 500 Plain films can show phases: 1 -- osteoporosis from osteolytic activity 2- mixed phase with sclerosis and osteolytic activity 3-sclerosis with corticol thickening Teatment: bisphosphonates, alendronate, risendronate **[Ankle sprain management]** **ANKLE SPRAIN:** Most common ankle injury Caused by inversion/supination stress. Plantar flexed and inverted foot causes stretch of the lateral collateral ligaments Most common injured ligament is the ANTERIOR TALOFIBULAR ATF Discomfort is due to swelling, ends in first 1-2 hours after sprain Decreased ROM, swelling, warm, may be visible ankle deformity and bruising Ottawa ankle rules to determine if X-ray is needed: Foot rules -- pain midfoot and at base of 5^th^ metatarsal, pain midfoot and navicular bone, inability to bear weight for 4 steps Ankle rules -- pain at mid malleolus or along distal 6cm of posterior/medial tibia, pain at lateral malleolus or along distal 6cm of posterior fibula Inability to bear weight immediately and for 4 consecutive steps in the ER Treatment -- Comfort, PRICE -- Protection, Rest, Ice, Elevation, air or gel cast, acupuncture, NSAIDS Sprains are often accompanied by tibiofibular interosseous membrane strain Can occur with posterior fibular head malfunction Myofascial release -- restricted leg fascial rotation related to leg, ankle pain, gait abnormality, and other issues -- don't do for acute sprain, fracture or DVT **[What is radiculopathy?]** Radiculopathy, also known as a pinched nerve, is a condition that occurs when one or more nerves in the spinal column are damaged or pinched, causing them to malfunction. The pinched nerve can occur in the cervical (neck), thoracic (mid-back), or lumbar (lower back) areas of the spine. Symptoms vary by location but often include: Pain, Weakness, Numbness, Altered sensation, and Difficulty controlling muscles **[Week 12 Reproductive:]** **[Breast cancer risk factors]** Common postmenopause Arise from mammary duct epithelium or lobular glands Other less common areas -- mucinous, tublar, medullary, papillary, angiosarcoma Tissue from biopsy is tested for hormone receptors, estrogen and progesterone, growth promoting protein HER2 Tumor stage -- most important prognostic indicator: Tumor size, lymph node involvement, is metastatic disease present Most common location for breast cancer is the upper quadrant Risk factrs include: increased estrogen exposure with early menses, late menopause, nulliparity, obesity, PCOS **[Understand the normal menstrual cycle]** Menarche: 1st menstrual period Menses: the time of menstruation Perimenopause: interval (months to years) of menstrual irregularities leading up to the total cessation of cycles Menopause: cessation of menses for 12 months or more Phases The menstrual cycle is divided into 2 components: ovarian cycle and endometrial cycle: Average adult menstrual cycle is 28--35 days. "Normal" cycle length is defined as 24--38 days. "Regular" cycles are when variation in cycle length is ≤ 7‒9 days. Intervals in cycles usually remain consistent until perimenopause, when follicular phases become shorter and more frequent. *Ovarian cycle phases:* **Follicular phase:** Represents the time during which the follicle and its oocyte develop, leading up to ovulation Spans from menses onset (day 1) to the day before the surge of luteinizing hormone (LH), leading to ovulation Length: 14 to 21 days (may be shorter, especially in perimenopause) **Luteal phase:** The time after ovulation when the ovary produces hormones to support a potential pregnancy and maintain a healthy endometrium. Spans from the day of LH surge until the onset of the next menses Length: 14 days **Endometrial cycle phases:** Desquamation: shedding of the endometrial lining (menses) Proliferative phase: endometrial proliferation with straight, tubular glands Secretory phase: maturation of the spiral arteries and endometrial glands, preparing the endometrium for potential pregnancy **[Understand hormones related to menstrual cycle, pregnancy, and menopause]** The menstrual cycle is regulated by the hypothalamic-pituitary-ovarian axis. Hypothalamus: Releases gonadotropin-releasing hormone (GnRH) → stimulates gonadotropes of the anterior pituitary Secreted from the preoptic neurons of the hypothalamus in a pulsatile fashion Regulated by biologic rhythms (and to a lesser extent by other physiologic factors, such as stress) Anterior pituitary: Stimulated by GnRH → releases follicle-stimulating hormone (FSH) and luteinizing hormone (LH) FSH and LH → stimulate the ovaries FSH: Stimulates follicular development and egg maturation Stimulates the granulosa cells within the ovary to produce estradiol LH: Stimulates theca cells within the ovary to produce testosterone (most of which is converted to estradiol in the granulosa cells) A surge of LH midcycle triggers ovulation. Stimulated by GnRH → releases follicle-stimulating hormone (FSH) and luteinizing hormone (LH) FSH and LH → stimulate the ovaries FSH: Stimulates follicular development and egg maturation Stimulates the granulosa cells within the ovary to produce estradiol LH: Stimulates theca cells within the ovary to produce testosterone (most of which is converted to estradiol in the granulosa cells) A surge of LH midcycle triggers ovulation. Ovaries: Estrogens: Estradiol is the most notable. Secreted by the granulosa cells of ovarian follicles → stimulated by FSH Stimulates the endometrium to grow/develop Makes the developing follicles more sensitive to FSH Feedback/regulation: Negative feedback inhibition: During most of the menstrual cycle, estrogens inhibit further secretions of FSH, LH, and GnRH. Positive feedback: For a short time midcycle, estradiol stimulates FSH and LH secretion from the pituitary → results in ↑ estrogen production in the ovaries and causes the surge of LH, which triggers ovulation Progestins: Progesterone is the most notable. Secreted by the theca-lutein and granulosa lutein cells in the corpus luteum (stimulated by LH) after ovulation Uterine effects:↓ Endometrial growth Stabilizes and causes maturation of the endometrium → prepares the endometrium for implantation ↑ Endometrial secretions (↑ secretion thickness) Progestin withdrawal at the end of the luteal/secretory phases triggers menstrual bleeding. Breast effects: ↑ Lobular development Inhibition of milk production ↑ Body temperature → can be used to track ovulation Required for the development of the placenta during pregnancy Activins: Secreted by the granulosa cells of ovarian follicles (stimulated by FSH) Provides positive feedback to gonadotropes → stimulates secretion of LH, especially midcycle Inhibins: Secreted by the granulosa cells of ovarian follicles (stimulated by FSH) Provides negative feedback to gonadotropes → selectively inhibits further FSH secretion **PREGNANCY:** The major analyte used to establish pregnancy is β-hCG. β-hCG is a hormone produced early by the developing embryo. The presence of β-hCG indicates pregnancy. Human chorionic gonadotropin (hCG) Produced almost exclusively in the placenta, hCG levels rise rapidly during the first trimester and may contribute to nausea and vomiting. Human placental lactogen (hPL) Also known as human chorionic somatomammotropin, hPL is produced by the placenta and helps nourish the fetus and stimulate milk glands. - Estrogen Helps develop the baby\'s organs and placenta, and may cause nausea. Estrogen levels can also cause changes to your appearance, such as darkening nipples, a faint line of hair from the lower abdomen to the pubic area, and larger breasts. - Progesterone Increases blood flow to the womb, and may cause heartburn, vomiting, reflux, gas, and constipation. Progesterone levels can also cause mood swings. - Oxytocin Created toward the end of pregnancy, oxytocin eases pain during labor, encourages the cervix to open, and plays a role in milk production and bonding. - Relaxin Produced by the ovaries and the placenta, relaxin loosens and relaxes muscles, joints, and ligaments to help your body stretch and prepare for deliver **MENOPAUSE:** Anti-Müllerian hormone (AMH) ↓ Secreted by premature follicles Marker of ovarian reserve Begins to decrease 5 years prior to last menstrual period May lead to increased risk for twin pregnancies Inhibin B ↓ Inhibits FSH secretion May begin to ↓ around age 35 (earliest measurable marker) → ↑ FSH LH and FSH ↑ Inhibin B has an inhibitory effect on LH and FSH, so during menopause their levels increase. Testosterone ↓ Primary source of production shifts from ovaries to adrenals. Hypoplasia of adrenal cortex leads to a 25% decrease in testosterone. **[Review the Hypothalamic-pituitary-ovarian (HPO) axis ]** The hypothalamic-pituitary-ovarian (HPO) axis is a complex system that regulates female reproduction and the menstrual cycle through a network of communication between the hypothalamus, pituitary gland, and ovaries. The HPO axis uses hormones and neurotransmitters to create a dynamic equilibrium between the hypothalamic-pituitary unit and the gonads. This system uses both positive and negative feedback loops to regulate the production of hormones such as gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicular stimulating hormone (FSH), estrogen, and progesterone. The end goal of the HPO axis is to signal ovulatio **[Defining puberty and expected changes ]** Puberty is the time period from the 1st appearance of secondary sexual characteristics until achieving complete sexual development. Puberty involves a complex series of physical, psychosocial, and cognitive changes. Range: 8--13 years in girls 8--12 years in boys Hormonal control in the initiation of puberty A critical event in puberty is an increase in the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus in the hypothalamus. Kisspeptin neurons in the arcuate nucleus release neurokinin B and dynorphin. Neurokinin B and dynorphin cause the pulsatile secretion of GnRH. GnRH causes the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. Both LH and FSH affect the Leydig and Sertoli cells in the testes and the theca and granulosa cells of the ovary. Zona reticularis of the adrenal glands secretes androgens such as DHEA, resulting in the characteristics of adrenarche. Zona reticularis functions separately from the hypothalamic-pituitary-gonadal axis. Hormonal changes in girls: LH acts on the theca cells of the ovary to convert cholesterol into androgens. Granulosa cell converts the androgens to estradiol under the control of FSH signaling. Estradiol acts on various organs until the completion of puberty. Hormonal changes in boys: LH acts on Leydig cells convert cholesteral into terstosterone Steroid-producing cells in the interstitial tissue of the testis. They are under the regulation of pituitary hormones; luteinizing hormone; or interstitial cell-stimulating hormone. Testosterone is the major androgen (androgens) produced. **to convert cholesterol into testosterone.P** Puberty can be divided into 4 different consecutive stages, namely, thelarche, pubarche, growth spurt, and menarche. **Thelarche** Breast development with formation of the breast bud and proliferation of the duct and gland epithelium 1st sign of puberty in girls Participating hormones: estrogen, estradiol, prolactin Onset: 7--14 years of age **Pubarche** Growth of pubic and armpit hair Participating hormones: testosterone, 5α-dihydrotestosterone Onset: 8--15 years of age **Growth spurt** Onset: On average, 2 years earlier in girls than boys Approximately 1 year after the 1st indicators of puberty 3--10 cm of growth per year Participating hormones: Release of sex steroids leads to the production of growth hormones. Leads to production of insulin-like growth factor-1 in the liver **Menarche** 1st menstrual bleeding Due to estrogen withdrawal without preceding ovulation Onset: Between 9 and 16 years of age Approximately 1 year after a growth spurt Normally occurs later than other signs of puberty. **[Identifying precocious puberty or delayed puberty ]** **Precocious puberty is** diagnosed in the outpatient clinic, often prompted by parental observation. Parents note early pubertal changes (body odor, new hair growth, oily skin, changes in voice and behavior). Patients present for evaluation because they are abnormally short in stature. Precocious puberty can be a difficult subject for patients and parents to discuss. Physician tact and knowledge of culturally appropriate practices are essential. History Focused history looking for possible causes of PP: CNS: infection, perinatal asphyxia, head trauma, neoplasms and radiation, personality changes, headaches, visual field defects Exposure to endocrine disruptors: cosmetic, dietary products, or medications that may contain estrogens or androgens Family history: Strong family history in males may indicate familial male-limited PP. Clinical features in central precocious puberty Secondary sex characteristics are isosexual. Early development of breast buds in girls and of testicles (volume ≥ 4 mL) in boys. Puberty occurs with a normal sequence: Girls: thelarche (breast buds) → pubarche (pubic hair) → menarche Boys: growth of testes and thinning of scrotum → pigmentation of scrotum and growth of penis → pubarche Major growth restriction (\< 5th percentile of height as adults) occurs in 30% of girls and a larger proportion of boys: Height, weight, and osseous maturation are advanced, while mental development is normal for chronological age. 3 main patterns of pubertal progression: Rapid physical and osseous maturation with loss of linear growth (most common, especially in girls \< 6 years old) Slowly progressive osseous maturation with preserved linear growth (commonly seen in girls \> 6) Transient CPP (rarest form) Precocious is pathologic All girls less than 6yrs old who have thelarche or pubarche need evaluation Girls less than 8 with both should be evaluated Under 6 it will be a CNS issue -- headaches, neuro defects, seizures Two types: Gonadotropin Dependent: early activation of HPO axis, development is isosexual, 90% idiopathic, can be associated with CNS lesions, irradiation, trauma Gonadotropin Independent: Not reliant on FSH or LH, excess secretion of sex steroids from ovaries. Can happen if young girl is ingesting mom's birth control pills. The most common cause is autonomously functioning ovarian cysts. Sometimes ovarian tumors -- granulosa cell -- intertola leydis -rare McUne Albright Syndrome -- alpha subunit mutation of g protein or GNAS1 gene. Will have café au lait spots, polyosotic fibrous dysplasia of the bone Will see gigantism, cushing syndrome, thyrotoxosis, adrenal hyperplasia Sequence of pubertal development may be abnormal bleeding before thelarche. X Ray of left hand to get bone age, stimulation tests (GnRh test), for gonadotropin depending. If + need MRI, TSH Free T4 to rule out hypothyrodisim For Gonadatropin independent -test estradoil and testosterone, HcG, DHEAS and PM cortisol and 170HP, do an abdominal pelvic ultrasound [DELAYED PUBERTY:] Inactive hypothalamic pituitary ovarian axis "HPO" -- Hypo Hypo, GnRH deficiency Ovarian insufficiency, ovarian failure, turner syndrome Hyper Hypo = ovarian failure Can be the first sign of an occult metabolism problem -- IBS or hypothyroidism Kallman Syndrome can cause Hypothalamic/Pituitary tumors Test FSH, Estradiol, LH, Prolactin **[Know Tanner Stages]** Females: Prepubertal -- Tanner 1 Pubic hair -- villus hair only Breasts -- Evelation of papilla only Adrenarche and ovarian growth 8-11.5 years -- Tanner 2 Pubic hair -- sparse along the labia Breasts -- Buds are palpable -- first sign of puberty in females, areale are inlarged. Clitoral enlargement, labial pigmentation, growth of uterus 11.5-13 years -- Tanner 3 Pubic Hair -- coarse and curly Breast tissue -- grows with no contour or separation Axilliary hair, acne 12-15 -- Tanner 4 Pubic Hair -- adult hair that doesn't spread to thigh Breasts -- enlargement and areole form secondary mound on breast Menarche and development of menses Over 15 years old -- Tanner 5 Pubic hair -- adult hair reaching the thigh Breasts -- adult breast contours present, only papilla is raised Adult geniltalia Males: Prebubertal -- Tanner 1 Pubic Hair -- villus only Genitalia -- testes \500 no** **Stage 2: CD4 and T 200-499** **Stage 3: AIDS -- CD4 and T \