Graves’ Disease: Pathogenesis and Clinical Findings B & T lymphocyte mediated autoimmunity attack TSH receptor -> Continuous stimulation of thyrotropin receptor by circulating autoantibodies -> Increased iodination of thyroglobulin, Thyroid gland hyperplasia Note: B & T lymphocytes also attack other thyroid antigens (thyroglobulin, thyroid peroxidase, Na-I Symporter) but is believed to play little role in the etiology Signs/Symptoms: - Pretibial myxedema - Fat pad: proptosis - Muscle: diplopia - Conjunctiva: conjunctivitis - Decr TSH - Goiter -> Hoarseness, Dysphagia, Thyroid gland bruit #GravesDisease #pathophysiology #endocin #endocrinology #symptoms #signs #diagnosis

Primary Hyperthyroidism - Pathogenesis and Clinical Findings Note: Although rare, gestational diseases can lead to thyrotoxicosis due to excess secretion of hCG, which is structurally similar to TSH. Secondary hyperthyroidism due to excess TSH production by the pituitary can also occur. Signs/Symptoms: - Diarrhea - Nervousness - Hyperkinesia - Hyperreflexia - Tremor - Poor attention - Incr weight loss - Heat intolerance - Incr appetite - Incr sweating - Proptosis - Diplopia - Lid retraction - Conjunctivitis - Tachycardia - Palpitations - Bruit over thyroid - Decr exercise tolerance - Pretibial myxedema #Primary #Hyperthyroidism #endocrinology #pathophysiology

Menstrual Cycle Physiology: the Uterine Cycle The endometrium has receptors for ovarian hormones! Changes in structure and secretory capacity of the endometrium occur in response to hormonal changes in the ovarian cycle. Note: The drop in progesterone concentration that triggers menses is the physiologic basis of the progesterone withdrawal challenge (used to test if a woman is hypo-estrogenized). If a woman is making estrogen (i.e. if ovaries/follicles are functioning), endometrium will be built up, so a short course of progesterone (10-14 days) will induce menses within 3 days once the progesterone is stopped. If woman is hypo-estrogenized (i.e. ovarian failure, menopause) -> no endometrium -> no menses upon termination of progesterone. Note: The drop in progesterone concentration that triggers menses is the physiologic basis of the progesterone withdrawal challenge (used to test if a woman is hypo-estrogenized). If a woman is making estrogen (i.e. if ovaries/follicles are functioning), endometrium will be built up, so a short course of progesterone (10-14 days) will induce menses within 3 days once the progesterone is stopped. If woman is hypo-estrogenized (i.e. ovarian failure, menopause) -> no endometrium -> no menses upon termination of progesterone. • The days of high blood progesterone concentration leads to: Death of the outer endometrium tissue, Hemorrhaging of blood vessels in endometrium; washes dead tissues out through vagina -> Menses (shedding of endometrium) • Estrogen secreted during the follicular phase stimulates endometrial growth: Endometrial cells enlarge and divide, Blood vessel networks in the endometrium expand, # of progesterone receptors incr -> Readies endometrium for implantation • Progesterone from the corpus luteum stimulates endometrial secretion of: Nutrient-rich mucus, Incr glycogen content -> Provides a suitable, nutritious substrate for the (possibly fertilized) ovum #MenstrualCycle #OvarianCycle #pathophysiology #UterineCycle #endocrinology

Menstrual Cycle Physiology: Ovarian Cycle – Luteal Phase Explained • The LH surge can be thought of as only providing enough "battery power" for the corpus luteum to run and make progesterone for 14 days, which is why the luteal phase is a fixed length. • The timing and function of estrogen and progesterone during the ovarian cycle are also important to the uterine cycle (see Uterine Cycle slide) Besides ovulation, the Day 14 surge in LH also stimulates a process called "luteinization": the maturation of the ruptured follicle's granulosa cells into the corpus luteum -> Corpus luteum begins to secrete a large amount of progesterone and a smaller amount of estrogen -> The combination of high progesterone and estrogen negatively feed back on hypothalamus and anterior pituitary -> Decreased Production of GnRH, FSH, and LH • Decreased FSH means no new follicles grow in the ovary in this phase • Decreased LH means less stimulation for continued corpus luteum growth => • If implantation does occur, HCG (human chorionic gonadotropin) maintains the corpus luteum so progesterone (and therefore endometrium) will be maintained • If no implantation of embryo, corpus luteum degenerates after 14 days, allowing GnRH/FSH/LH to restart the Ovarian Cycle #MenstrualCycle #OvarianCycle #pathophysiology #LutealPhase #endocrinology

Menstrual Cycle Physiology: Ovarian Cycle – Ovulation Explained Around Day 14, estrogen exerts sudden +++ positive feedback on the anterior pituitary (switch from negative to positive feedback poorly understood) -> surge in LH production and release LH causes: • Increased fluid production within the follicle • Enzymatic degradation of ovarian + follicle walls • Protrusion of follicle against ovary wall • Compression of oocyte towards one side of follicle => Ultimately, these forces release the oocyte into the uterine / fallopian tube (the oocyte is actually released about 36 hours after LH surges, even though it is commonly depicted as shown in the graph for clarity) #MenstrualCycle #OvarianCycle #pathophysiology #Ovulation #endocrinology

Menstrual Cycle Physiology: Correlating the Ovarian and Uterine Cycles Note: Some charts show different relative levels of the gonadotropins (LH and FSH) to estrogen and progesterone, but the key is to compare the relative levels of estrogen with progesterone, and to observe how they change compared to the gonadotropins. Ovarian Cycle 1. Follicular phase (around 10-14 days long) • Starts at puberty (unclear mechanisms), 6-20 follicles re-activated per month. • One follicle outpaces the others, continues to develop into the mature follicle (others degenerate). • The process also involves hormones released by theca and granulosa cells (activin and inhibin) that affect follicle development as well. See also "Follicular Phase Explained" slide. 2. Ovulation • Release of secondary oocyte around day 14 (can vary) • Triggered mostly by LH surge. See also "Ovulation Explained" slide. 3. Luteal phase (always 14 days long) • Follows release of oocyte • Transformation of granulosa and theca cells of the follicle into the corpus luteum, which secretes progesterone and a bit of estrogen to negatively feed back on the anterior pituitary and inhibit the growth of new follicles. • Corpus luteum degenerates in 14 days if no fertilization (thus, luteal phase is always 14 days long). See also "Luteal Phase Explained" slide. Uterine Cycle: 1. Menses (menstrual bleeding) • Occurs during the first part of the follicular phase of the ovarian cycle due to the sharp decline in progesterone 2. Proliferative phase • Before and up to ovulation, the endometrium adds new cell layers, especially due to estrogen • During late proliferative phase: estrogen makes cervical mucous thinner, more abundant, and stringier, which allows it to be penetrated by sperm. 3. Secretory phase • Corpus luteum hormones, mostly progesterone, limit endometrial growth while endometrial secretions. • After ovulation, progesterone causes mucus to become thick and tacky, less likely to be penetrated by sperm. #UterineCycle #MenstrualCycle #OvarianCycle #pathophysiology #comparison #endocrinology

Menstrual Cycle Physiology: Ovarian Cycle – Follicular Phase Explained Early Follicular Phase (Days 0-5) • Granulosa cells secrete activin, a hormone that 1) Incr FSH production by pituitary, 2) Incr FSH receptors on granulosa cells, and 3) Decr theca cell androgen production. • This effect limits conversion to estrogen, preventing estrogen from negatively feeding back on anterior pituitary which would reduce FSH production. • Resulting high FSH level stimulates follicle growth. • By Day 5, the dominant follicle (the one most responsive to FSH) will be selected to continue growing (mechanism for this "selection" unclear, but this follicle is also the first to switch from activin to inhibin, and that inhibin decr the FSH such that other follicles are not as stimulated). Late Follicular Phase (Days 5-14) • Granulosa cells of dominant follicle switch to secreting inhibin instead of activin. Inhibin 1) Decr FSH production by pituitary, and 2) helps LH Incr theca cell production of androgens (leading to Incr conversion to estrogen) • The Incr in estrogen during this time: 1. Incr FSH receptors on the follicle 2. Negatively feeds back on pituitary to reduce, not stop, FSH production (dominant follicle still grows because of greater number of FSH receptors) 3. Incr number of LH receptors on granulosa cells of the follicle, preparing for ovulation Note: 1) Inhibin and activin are named for their effect on the anterior pituitary's FSH production. 2) Timely balance in steroid secretion between theca and granulosa cells is key to normal follicle growth. Disruption of this balance can lead to menstrual cycle disorders. I.e. early estrogen secretion -> inhibits FSH secretion too early -> lack of follicle growth (this is one mechanism behind Polycystic Ovarian Syndrome, PCOS). #MenstrualCycle #OvarianCycle #pathophysiology #FollicularPhase #endocrinology

Menstrual Cycle Physiology: The Hypothalamic-Pituitary-Ovarian Axis Estrogen, when released: • Negatively feeds back on the hypothalamus and anterior pituitary to Decreased FSH production • Positively feeds back on the hypothalamus and anterior pituitary to Increased LH production Note: the hormones of the menstrual cycle vary in terms of when and how much they are secreted, according to the various phases of the cycle. This flow-chart is simply meant to capture the main players and their functions in the menstrual cycle, in as much detail as a medical student needs to know. #MenstrualCycle #pathophysiology #HPOA #HypothalamicPituitary #endocrinology #feedback

Menstrual Cycle Physiology: Ovarian Cycle – Brief Overview LH and FSH are required for follicular development and continued growth until ovulation • Follicular Phase - Selection of dominant follicle - FSH from pituitary stimulates granulosa cells - LH from pituitary Incr androgens from theca cells • Ovulation - Release of dominant follicle • Luteal Phase - Ripening of corpus luteum Corpus luteum forms following ovulation -> LH supports corpus luteum function until natural atrophy or pregnancy occur -> Progesterone produced -> Inhibit FSH/LH release from pituitary -> Atrophy of corpus luteum if embryo does not implant #MenstrualCycle #OvarianCycle #pathophysiology #menstruation #endocrinology

Pituitary Mass Effects - Pathogenesis and Clinical Findings • Pituitary turnors are almost always a benign adenoma. Pituitary adenomas are very common - approximately 1 in 6 individuals. These are usually asymptomatic and are found incidentally. Symptomatic pituitary adenomas that require treatment are much less common and affect approximately I in 1000 individuals. • For pituitary masses of all sizes, it is important to determine whether the pituitary tumor is secreting (70%) or non-secreting (30%) as secreting tumors can be targeted with medication. The most common secreting tumors secrete prolactin (most common), growth hormone, and ACTH. • Typically (but not always) the anterior hormones will be lost in the following order; GH, LH, FSH, TSH, ACTH, PRL. This order (with the exception of prolactin) is the order of least-essential to most essential hormones needed for survival. A good mnemonic to remember the order the hormones are is, "Go Look For The Adenoma Please". Signs / Symptoms / Complications: • Hyperprolactinemia • Diabetes insipidus • Loss of pituitary hormones • Headaches • Nausea and vomiting • Hypothalamic dysfunction • Bitemporal hemianopsia • Hydrocephalus • Diplopia • Post-nasal drip • Meningitis #Pituitary #MassEffects #Macroadenoma #SideEffects #endocrinology #mnemonic #GLFTAP #pathophysiology