Lecture 3 - Repro Endo Disease 2023-2b-lecture - Tagged.pdf

Reproductive and Endocrine Disease Shuo Xiao, PhD Office: EOHSI, 406 Tel: 848-445-3729 Email: [email protected] The whole picture of the Reproductive and Endocrine System • Lecture 1: Male and female reproductive diseases • Lecture 2: Diseases in pituitary, thyroid, and parathyroid • Lecture 3:...

Reproductive and Endocrine Disease Shuo Xiao, PhD Office: EOHSI, 406 Tel: 848-445-3729 Email: [email protected] The whole picture of the Reproductive and Endocrine System • Lecture 1: Male and female reproductive diseases • Lecture 2: Diseases in pituitary, thyroid, and parathyroid • Lecture 3: Diseases in adrenal gland, pancreas, and others https://anatomy-medicine.com/endocrine-system/ Pituitary physiology (Sella turcica) • • • Lima bean-sized gland that extends downward from the brain. Pituitary is actually two different tissues that merged during fetal development: the anterior and posterior pituitary. The anterior pituitary is the true endocrine gland. The posterior pituitary stores and release two neurohormones (oxytocin and vasopressin/anti-diuretic hormone, ADH) produced in the hypothalamus. Pituitary physiology Neuro hormones • • • • • Oxytocin ADH • TRH: Thyrotropin-releasing hormone PIF: Prolactin inhibiting factor CRH: Corticotropin-releasing hormone GHRH: Growth hormone-releasing hormone GHIH (somatostatin): Growth hormoneinhibiting hormone GnRH: Gonadotropin-releasing hormone Trophic hormones • • • • • • TSH: Thyroid stimulating hormone (Thyrotrophs) PRL: Prolactin (Lactotrophs) ACTH: Adrenocorticotropic hormone (Corticotrophs) GH: Growth hormone (Somatotrophs) FSH: Follicle-stimulating hormone (Gonadotrophs) LH: luteinizing hormone (Gonadotrophs) Trophic: feeding/ nourishing Pituitary histology • Histologically, pituitary consists of a colorful array of cells containing blue staining / basophilic cytoplasm (blue arrow, thyrotrophs, gonadotrophs, and corticotrophs), eosinophilic / acidophilic cytoplasm (red arrow, somatotrophs and lactrophs), or non-staining / chromophobic cytoplasm (yellow arrow, immature). Feedback loop is the primary pathway regulating pituitary hormone secretion Exogenous hormone has the same negative feedback effect Q1: High FSH is commonly seen in postmenopausal women, why? Q2: If the adrenal cortex atrophy occurs due to tuberculosis (TB), what happens to the hypothalamus and pituitary? CRH: Corticotropin-releasing hormone ACTH: Adrenocorticotropic hormone Pituitary diseases • Pituitary disorder is the insufficient or excessive production of pituitary hormones. It is primarily caused by a pituitary adenoma but not carcinoma. • Pituitary adenoma-induced pituitary diseases:  Hyperpituitarism: most common;  Hypopituitarism: tumor, surgery, radiation, inflammation;  Local mass effects: vision loss as it is close to optic nerves (headache, fatigue, vomiting). https://www.ohsu.edu/brain-institute/understanding-pituitary-disorders Pituitary adenoma - Pathogenesis • It is usually caused by mutations in cancer genes. Somatic mutation is common, germline mutation is rare; • G-protein mutations are most common; • Activating mutations of ubiquitin-specific protease 8 (USP8) accounts for 30-60% of corticotroph adenoma; • Germline mutation of cell cycle related genes (MEN1, CDKN1B) causes about 5% of pituitary adenomas. DOI: Pituitary adenoma - classification • Pituitary adenoma is common in 35-60 years, in >10% of the population but most are clinically silent; • Classified based on the hormoneproducing cells, can be functional or nonfunctional, is usually associated with one type of pituitary cells / hormone; • Classified as microadenoma (<1cm) or macroadenoma (>1cm). Nonfunctional pituitary adenoma is usually detected when it grows to the large size. Pituitary adenoma – Lactotroph adenoma • Also termed prolactinoma, the most common hyperfunctioning pituitary adenoma (30-50%); • It causes hyperprolactinemia which suppresses the functions of gonads in both males and females (mechanism); • Microadenoma is sufficient to cause hyperprolactinemia and induce symptoms, including galactorrhea, amenorrhea, lost of sexual desire, irregular period, anovulation, and infertility … • Hyperprolactinemia is more apparent in young women, so diagnosed at an early stage; in contrast, hyperprolactinemia is subtle in men and older women, causing a late diagnosis. Pituitary adenoma – Somatotroph adenoma • The 2nd most common pituitary adenoma (10%); develop slowly over decades, so late diagnosis when detected; • Gigantism, also termed pediatric acromegaly, occurs when a child or adolescent has high levels of GH; • Acromegaly occurs in adults by affecting body’s bones and soft tissues to grow in irregular ways; • GH excess is also associated with diabetes as GH induces peripheral insulin resistance. It also heightens the risks of gonadal dysfunction, muscle weakness, hypertension, arthritis, heart failure, GI cancers. Pituitary adenoma – Corticotroph adenoma • • • • • • • Cortisol is a stress hormone. There is an extra cortisol secretion during stress, which increases: Heart rate Blood pressure Blood glucose Respiration rate Muscle tension Decrease digestion and reproduction • Account for 5% of pituitary adenoma, hypersecretion of ACTH results in hypercortisolism which causes multiple symptoms that together as Cushing’s syndrome (can be caused by adrenal tumor too); • Cushing’s syndrome peaks in 25-50 years, more common in female > male (7:3), diagnosed by classic symptoms, high blood levels of cortisol, and MRI/CT scan, treated by radiation or surgery, usually good prognosis. Other pituitary diseases • Gonadotroph adenoma (usually clinically silent or non-functioning until large enough to cause mass effects); • Thyrotroph adenoma is rare but can cause hyperthyroidism; • Non-functioning pituitary adenomas account for 25-30% all pituitary tumors (clinically silent until large enough to cause mass effects); • Pituitary carcinoma is extremely rare; • Hypopituitarism is usually caused from pituitary lesions (surgery or radiation, inflammation, but failed delivery of hypothalamus hormones is possible). The clinical symptoms depend on specific hormones o FYI: postpartum ischemic necrosis of the anterior pituitary (Sheehan syndrome) is a common clinical necrosis of the anterior pituitary (insufficient increase of the portal venous system when the anterior pituitary enlarges during pregnancy, leading to ischemic injury) • Posterior pituitary diseases: under or over production of antidiuretic hormone (ADH) o ADH deficiency causes diabetes insipidus, featured by excessive urination (polyuria, 1-3 vs 20 quarts a day) due to an inability of the kidney to resorb water from the urine; drinking water can compensate but can be life-threatening due to dehydration; o ADH excess causes excessive renal water resorption (the syndrome of inappropriate ADH, ISADH). SIADH causes nausea, vomiting, headache, confusion, weakness, and fatigue. Pituitary adenoma – Diagnosis of endocrine pathology is complex Pituitary disease – Exogenous hormone treatment • Signs of hyperpituitarism can be the result of medical treatment of an exogenous hormone or agonist; • Exogenous hormone exhibits the same negative feedback effect (Cortisol case for treating poison ivy and severe allergies, how about FSH/LH?); • It is important to note that if the pituitary remains suppressed by the exogenous hormone (e.g., cortisol) and the target organ (e.g., adrenal cortex) is deprived of trophic hormone (e.g., ACTH) for a long period of time, both pituitary and target organ shrink (atrophy) and become unfunctional (long time and hard to reverse back); • When medical treatment is complete, the dosage needs to be tapered off gradually to allow the pituitary and adrenal gland back to normal functions. Pituitary physiology Oxytocin Vasopressin Anti-diuretic hormone (ADH) Thyroid physiology • • • • A butterfly shaped gland that lies across the trachea at the base of the throat, below the larynx; Consists of two types of cells: C cells that secretes calcitonin to regulate calcium and follicular cells that secrete thyroid hormones (triiodothyronine/T3 and thyroxine/T4); Thyroid hormones are not essential for life but are crucial for normal growth, development, and metabolism; In children, thyroid hormones regulate GH secretion. Thyroid physiology • TRH and TSH regulate thyroid hormone secretion; • Thyroid hormones are amines derived from the amino acid tyrosine and are the only hormones use iodine; • Thyroid hormones are synthesized in thyroid follicles that consist of a single layer of follicular epithelial cells and enclosed sticky glycoprotein mixture of colloid; • The follicular cells make a glycoprotein called thyroglobulin and enzymes such as thyroid peroxidase; they also uptake iodine using the sodium-iodide symporter (NIS); • Thyroglobulin, thyroid peroxidase, and iodine transport to the colloid to synthesize and release thyroid Hormones (right figure); • T3/4 are lipophilic and bind to thyroidbinding globulin (TBG) • Most in the blood are T4 but T3 is more active Thyroid physiology • Thyroid hormones almost regulate all organ systems, including liver, fat, heart, muscle, and bone … • By binding to its intranuclear receptor (TRα/β), thyroid hormones activate the genes for increasing the metabolic rate and thermogenesis. The increased metabolic rate involves increased oxygen and energy consumption. RXR: retinoic X receptors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433956/ Thyroid diseases - Hyperthyroidism • Thyroid diseases are associated with hyperthyroidism, hypothyroidism, or mass lesions; • Hyperthyroidism (also called thyrotoxicosis): Marty Feldman, English comedian (1934-82) Exophthalmos o Goiter: an overall enlargement of the thyroid (not a sign to determine hyperthyroidism); o Increased oxygen consumption and metabolism, leading to increased internal heat and related soft, warm and sweaty skin and intolerance to heat; o Increased muscle catabolism, muscle weakness, so increased appetite but weight loss; o In nervous system, there are hyperexcitable reflexes and psychological disturbances, causing irritability and insomnia to psychosis; o Rapid heartbeat and increased contraction because thyroid hormones activate b adrenergic receptors in the heart. Older adults with existing heart disease can develop congestive heart failure. Thyroid diseases – Graves’s disease • What are the expected lab results? • The most common cause of hyperthyroidism (80%); • Peaks in 20-40 years, women (2% in the US) > men (7:1); • Caused by an autoantibody, thyroid-stimulating immunoglobulin (TSI) that mimics the action of TSH; • Enlarged gland, crowded, enlarged follicular epithelial cells, scalloped colloid edge due to the absorption of the colloid; • Infiltration of lymphocytes, mostly T cells, and fibrosis. Thyroid diseases - Hypothyroidism (most common) • Insufficient iodine diet is still affecting 2 billion people worldwide. Children and lactating women are the most vulnerable (WHO); • Maternal hypothyroidism can lead to severe fetal metal disability. Thyroid diseases – Autoimmune hypothyroidism • Hashimoto thyroiditis is the most common cause of hypothyroidism in areas without iodine issue; • Peaks in 45-65 years, women > men (10-20:1); • The progressive depletion of thyroid epithelial cells and infiltration of lymphocytes and fibrosis due to an immune response against thyroid antigens; • The antithyroid antibody can be anti-thyroglobulin or anti-thyroid peroxidase antibodies; • Can be the genetic or environmental reason (40% in monozygotic twins and 50% asymptomatic siblings) Thyroid diseases – Autoimmune hypothyroidism • The thyroid is usually diffusely and symmetrically enlarged. Microscopic examination reveals widespread infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing lymphocytes, plasma cells, and macrophages with welldeveloped germinal centers. • Follicles are atrophic with epithelial cells having abundant eosinophilic and granular cytoplasm, termed Hürthle or oxyphil cells Thyroid diseases – Autoimmune hypothyroidism • The subacute granulomatous thyroiditis is much less common than Hashimoto disease; • Present in 30-50 years women > men; the onset is often acute; • Caused by a viral infection or an inflammation triggered by the viral infection (e.g., upper respiratory infection) • It is not like the Hashimoto thyroiditis that is selfperpetuating, the process spontaneously remits within 6-8 weeks. Thyroid diseases – Thyroid tumor • The majority of thyroid tumors are benign adenoma but can be aggressive carcinoma (<1%); • Thyroid carcinoma is always a concern in patients who have thyroid nodules. Several clinical criteria provide a clue of thyroid carcinoma: solitary nodules in patients <30 years, in males, a history of radiation, hormonally inactive nodules that do not take up radioactive iodine; • Thyroid adenomas are typically discrete, solitary masses derived from follicular epithelial cells; most of them are non-functional but some cause hyperthyroidism (toxic adenoma); • Non-functional thyroid adenomas have a variety of genetic mutations (RAS, PTEN); the toxic adenomas usually have somatic mutation of TSHR or Gs α protein. Thyroid diseases – Thyroid tumor • Thyroid adenoma is typically a solitary, spherical lesion next to the nonneoplastic thyroid; • Neoplastic cells are within a well-defined, intact capsule; • Under microscopic examination, the cells are arranged in uniform follicles that contain colloid and show little variation in cell size, shape, or nuclear morphology; mitotic figures are rare; • A careful evaluation of the integrity of the capsule is critical in distinguishing thyroid adenoma from carcinoma, which demonstrates capsular and/or vascular invasion; • Thyroid adenomas (nontoxic) are usually painless nodules and found during routine physical examination; large masses can cause difficult swallowing; toxic adenomas take up radioactive iodine (cold (nontoxic) / warm / hot (toxic) nodules; cold has 10-20% malignancy). Thyroid diseases – Thyroid tumor Carcinoma is always a concern in patients who have thyroid nodules. • Women > men in early and mid adults and equal in children and elder people; • Well differentiated, and most are derived from follicular epithelium except the medullar carcinoma • Four subtypes based on their distinct molecular pathogenesis: papillary (>85%), follicular (5-15%); anaplastic (<5%), and medullary (5%); Papillary Activation of the MAPK signaling • Translocation of RET or NTRK • Point mutation of BRAF • Oncogenic mutation of RAS Radiation is a risk factor, children experienced Chernobyl nuclear disaster in 1986 Follicular Activation of the PI3K/AKT signaling Is related to dietary iodine but the • Oncogenic mutation of RAS • Gain of function mutation of PIK3CA mechanism is unknown or loss of function mutation in PTEN • Translocation of PAX8 and PPARG Anaplastic De novo or more commonly by the progression of the papillary or follicular type • Mutation of RAS or PI3K as in the follicular type • Loss function of mutation of P53 Highly aggressive, grow rapidly, , almost 100% mortality rate < 1 year, mean age of 65 Medullary Arise from parafollicular C cells • Germline mutation of RET Different from the above three Thyroid diseases – Thyroid tumor • RET: Ret Proto-Oncogene • PTC: papillary thyroid carcinoma • RAS: a family of oncogenes (KRAS, HRAS, NRAS) • BRAF: B-Raf Proto-Oncogene, Serine/Threonine Kinase • PI3K: Phosphoinositide 3-kinase • MEK: Mitogen-activated protein kinase kinase • ERK: Mitogen-activated protein kinase • PDK1: Pyruvate Dehydrogenase Kinase 1 • Akt: Protein kinase B • PAX8: Paired Box 8 • PPARG: Peroxisome Proliferator Activated Receptor Gamma Thyroid physiology – C cells and calcitonin • Calcitonin is a peptide hormone produced from the C cells of the thyroid. • It decrease Ca2+ absorption in the bone and kidney (PTH and calcitriol?); • Only play a minor role in calcium balance in adults (removal of thyroid or thyroid tumor with hyper calcitonin secretion in adults doesn’t affects calcium balance), but it is important in children when the net bone deposition is needed and in women during pregnancy and lactation when they need more calcium supply; The whole picture of the Reproductive and Endocrine System • Lecture 1: Male and female reproductive diseases • Lecture 2: Diseases in pituitary, thyroid, and parathyroid • Lecture 3: Diseases in adrenal gland, pancreas, and others https://anatomy-medicine.com/endocrine-system/ Parathyroid physiology Parathyroid disease – Hyper- or hypo-parathyroidism • Hyperparathyroidism is a common endocrine disorder and a primary cause of hypercalcemia; women > men (4:1) • Caused by parathyroid adenoma (80-90%, usually in a single gland), hyperplasia (5-10%, multi-glands), or carcinoma (1%); Hyperparathyroidism • Associated with two genetic aberrations, cyclin D1 rearrangement (40%) and MEN1 mutation (35%); NIDDK • Hypoparathyroidism is rare, primarily caused by thyroid or neck surgery (most common), congenital absence, autoimmune hypoparathyroidism (AIRE gene mutation) • Symptoms: neuromuscular irritability (tingling lips/fingers/toes, muscle spasms, facial grimacing, tetany, cardiac arrhythmias) Chromosome 11 MEN1: Multiple endocrine neoplasia The whole picture of the Reproductive and Endocrine System • Lecture 1: Male and female reproductive diseases • Lecture 2: Diseases in pituitary, thyroid, and parathyroid • Lecture 3: Diseases in adrenal gland, pancreas, and others https://anatomy-medicine.com/endocrine-system/