ENDOCRINE PHYSIOLOGY AND PATHOPHYSIOLOGY

1. ENDOCRINE PHYSIOLOGY AND PATHOPHYSIOLOGY Barb Bancroft, RN, MSN, PNP www.barbbancroft.com bbancr9271@aol.com

2. General Anatomy • Limbic system (Temporal lobe) • Hypothalamus—the “big cheese” • Pituitary gland—anterior and posterior lobes—”the Master Gland” TARGET GLANDS • Thyroid gland • Parathyroid glands (4) • Adrenal glands—cortex and medulla • Endocrine portion of the pancreas—Islets of Langerhans (Insulin, Glucagon) • Endocrine portion of the kidney—erythropoietin (EPO) • Ovaries and testicles Your NEWEST ENDOCRINE ORGAN? • BELLY FAT (visceral obesity)

3. Let’s start at the top… • Hypothalamus is the link between the brain (temporal lobe/limbic system) and the “master gland”—the pituitary gland • The hypothalamus sends messages to the anterior and posterior pituitary gland which in turn send their message to target organs • Once the target organ receives the message and performs the appropriate action, it sends a message BACK to the pituitary and hypothalamus to… • TURN OFF the message…this is known as “negative feedback”

4. Analogy…start at the top…the BIG CHEESE • Chief Nursing Officer, Director of Nursing, Dean of the Nursing School (the hypothalamus)--Sends her MEMO via EMAIL to

5. Analogy…the “Middle woMan” • The MEMO can be either “DO something” or “STOP doing something… • This memo goes to the: • Heads of the Departments, Nursing Supervisors (the pituitary gland)—relay the message to

6. Analogy…the “worker bee” • Floor Nurses, student nurses (the TARGET ORGANS)—that do all of the work • “Ok, OK, OK…I’ll get it done…”

7. Enough already! • When you have performed the required work, you (the target organ) send a message back to TURN OFF the messages from the “higher ups” • This is known as NEGATIVE feedback

8. Who are the memos/messengers? • Releasing factors/hormones (DO IT!) or inhibiting factors/hormones (STOP DOING IT) from the hypothalamus via a capillary network to the… • The anterior pituitary gland which in turn releases either a stimulating or inhibiting hormone which in turn interacts with a receptor on the target organ to perform a certain task • The hypothalamus sends a direct message via neuronal axons to the posterior pituitary to release hormones that interact with target tissues

9. Example: • The Hypothalamus sends thyrotropin (an affinity for) releasing hormone (TRH) to… • The anterior pituitary which in turn sends thyroid stimulating hormone (TSH) to • The thyroid. The thyroid releases thyroxine (T4) and tri-iodothyronine (T3) • Once enough T4 and T3 are released to boost metabolism…the message returns to the pituitary and hypothalamus to TURN OFF • NEGATIVE FEEDBACK TRH - Hypothalamus + TSH - negative (off) • Pituitary -- + • Thyroid T3, T4

10. What if something goes wrong?… • Let’s start at the bottom with the TARGET ORGAN, thyroid…hypthyroidism • Decreased T3, T4 feeds back to the pituitary gland and hypothalamus…pump out more TRH and TSH to stimulate a thyroid …as the thyroid continues to “die” and T3, T4 are not being produced, the TRH and TSH continue to rise…

11. Too much or too little…hyper- or hypo- • If the problem is in the TARGET organ—it’s a PRIMARY disorder—PRIMARY HYPOTHYROIDISM (Hashimoto’s thyroiditis is an example) • If the problem is in the pituitary —it’s a SECONDARY disorder—SECONDARY HYPOTHYROIDISM (removal of pituitary/radiation) • If the problem is with the hypothalamus —it’s a TERTIARY disorder—TERTIARY or CENTRAL HYPOTHYROIDISM (Pituitary and hypothalamic dysfunction may also be referred to as CENTRAL dysfunction)

12. So, to diagnose thyroid problems… • If it’s primary hypothyroidism, the thyroid will not be able to produce thyroid hormones…decreased circulating T₃, T₄ • This feeds back to the pituitary gland and says…I NEED A LITTLE HELP…so the pituitary ramps up the production of TSH and the hypothalamus ramps up the production of TRH • TSH and thyroid measurements will show decreased thyroid hormones and an increased TSH

13. So, to diagnose thyroid problems… • If the problem is in the pituitary, ie. Secondary hypothyroidism… • The pituitary will NOT be able to produce TSH to stimulate the thyroid…so… • Thyroid hormones will be low or non-existent AND TSH will be low since the pituitary gland is NOT WORKING.

14. Let’s prepare an egg in the ovary for ovulation…eggs live in follicles, follicles produce estrogen • The Hypothalamus releases gonadotropin releasing hormone (GnRH)…message to the • The Anterior pituitary gland to release follicle stimulating hormone (FSH) • FSH stimulates the target organ, the ovary, to prepare a follicle/ egg/estrogen • Egg prepared? Estrogen released? Job done. • Feedback to turn off the system

15. SO then, what is PRIMARY ovarian failure—menopause!! • Over the years the ovaries have a preprogrammed dropout of eggs /estrogen/and follicles--less and less estrogen, the negative feedback to the pituitary gland says…Something is wrong, I need MORE estrogen • The pituitary RAMPS up it’s production of FSH…thinking that will help…more FSH, more FSH • FSH is a diagnostic marker of menopause…more later

16. Historical highlight • An Italian medical student, Bruno Lunenfeld, in the early 1960s had an epiphany. At the time, he recognized that during menopause women’s urine was likely to contain high levels of the hormones that stimulate ovulation. Of course, finding a regular source for of such urine presented a problem. At a conference in Italy, however, Lunenfeld met the nephew of Pope Pius and discussed his idea. The nephew of the Pope responded …how about using the urine of postmenopausal nuns? • Buckets of urine were collected from nuns in convents in Italy…the fertility drug? Clomid (clomiphene)

17. Let’s get back to the original concept: Secondary or tertiary ovarian failure? • Hypopituitarism—something has destroyed the pituitary gland and FSH can no longer be produced (low or no FSH, low or no estrogen) • Causes? Pituitary adenoma, other pituitary tumors and cysts, sarcoidosis, Sheehan’s necrosis (hemorrhage during delivery shuts off blood supply to anterior pituitary) • Hypothalamic dysfunction—Prader-Willi Syndrome, Kallman’s syndrome

18. Prader-Willi* Syndrome • *First described in 1956 by Andrea Prader  (1919–2001) and Heinrich Willi (1900–1971) • A rare genetic hypothalamic disorder characterized by a chronic feeling of hunger that can lead to excessive eating and life-threatening obesity; incomplete sexual maturity • Used to be the “fat lady in the circus”…120 pounds by age 6; 350 pounds by age 12 • With the recent benefits of early diagnosis and ongoing interventions, the obesity rate among children with PWS has decreased to be similar to the typical population.

19. So many examples…we’ve talked about two… • HPT—Hypothalamic-anterior Pituitary-Thyroid-axis • HPO—Hypothalamic-anterior Pituitary-Ovarian (gonadal)-axis BUT THERE ARE OTHERS: • HPA—Hypothalamic- anterior Pituitary-Adrenal axis • HPT—Hypothalamic-anterior Pituitary-Testicular (gonadal)-axis • HPB—Hypothalamic – anterior Pituitary-Breast AND MORE: • Hypothalamus – posterior pituitary –target organ kidney, breast, uterus

20. The Hypothalamus (under the thalamus) • The hypothalamus is, millimeter for millimeter, the most powerful subdivision in the brain. • It weighs about 4 grams, is the size of an almond, and constitutes no more than 1 percent of total brain volume • But it packs a powerful punch • The critical link between the cerebral cortex, the limbic system, and the hormonal output of the “master gland”, the pituitary

21. The hypothalamus • Contains numerous clumps of neurons (nuclei) regulating appetite and satiety, thirst (osmoreceptors), growth and reproduction, sex drive and sexual orientation, temperature regulation, sleep, 24-hour biological clock

22. Who runs the entire show? • The suprachiasmatic nucleus (SCN) of the hypothalamus coordinates all of the activities of the hypothalamus (appetite and satiety, thirst, temperature, sexual function, hormonal production, emotions, and blood pressure) • The SCN also regulates the activity of the pineal gland and the secretion of melatonin—the sleep/wake cycle

23. How does our “biological clock” work? • Light hits the retina and specialized cells send the message to the SCN • The SCN sends the message to the pineal gland which in turn influences the secretion of melatonin – sleep/wake cycle • Quite a few genes are involved with your biological clock • One is cleverly called the CLOCK gene and is not working properly in patients with bipolar disease • Lithium resets the biological clock • Stops the manic phase and helps the patient re-synchronize to a 24-hour day

24. Other nuclei of the hypothalamus… the appetite and satiety center • Appetite center and norepinephrine—Prednisone, Remeron (mirtazapine), • Satiety center and serotonin (fenphen); atypical antipsychotics block a specific serotonin receptor, which in turn stimulates appetite and weight gain (especially Clozapine and olanzapine)

25. Inhibiting and Releasing Hormones (Factors) from the hypothalamus • Most of the activities of the hypothalamus are carried out by inhibiting or releasing hormones • Thyrotropin Releasing Hormone (TRH)—TSH (pituitary)—thyroid gland • Gonadotropin Releasing Hormone (GnRH)—FSH, LH (pituitary)—ovaries and testicles • Corticotropin Releasing Hormone (CRH)—ACTH (pituitary)—adrenal cortex • Somatropin –GH (pituitary)—lots of tissues • Prolactin Inhibiting Factor (PIF) and Prolactin Releasing Factor (PRF)—milk-producing glands of the female breast

26. Examples of inhibiting and releasing factors from the hypothalamus: • Prolactin-releasing (promote lactation) hormone (PRH) stimulates the secretion of prolactin (PRL) from the anterior pituitary gland (WHEN NECESSARY—lactating mom’s would be a good reason to release prolactin releasing hormone)

27. However, the USUAL message is to INHIBIT the release of prolactin from the pituitary • Prolactin-inhibiting factor (PIF) from the hypothalamus inhibits the secretion of prolactin from the anterior pituitary (THANK GOODNESS) • Who would want to lactate on any given day WITHOUT a baby to lactate for? • Wet nurses—

28. Wet nurse • A woman can only act as a wet-nurse if she is lactating. It was once believed that a wet-nurse must have recently undergone childbirth. This is not necessarily true, as regular breast suckling can elicit lactation via a neural reflex of prolactin production and secretion. Some adoptive mothers have been able to establish lactation using a breast pump so that they could feed an adopted infant. • There is no medical reason why women should not lactate indefinitely (some 3rd world countries breast feed children up to the age of five) or feed more than one child simultaneously (known as 'tandem feeding')... some women could theoretically be able to feed up to five babies.

29. Examples of inhibiting and releasing factors from the hypothalamus: • Gonadotropin-releasing hormone (GnRH) – stimulates the pituitary to release LH and FSH (follicle stimulating hormone) to stimulate the gonads; triggers hormonal secretion from the ovaries and testicles and jump starts puberty in kids

30. Girls –fat tissue and puberty • Girls—fat = early puberty • Aromatase in fat tissue converts testosterone to estradiol and triggers early puberty • Leptin (from adipocytes) sends a signal to the hypothalamus to produce GnRH and says…she’s READY! • OPPOSITE problem--Female Athlete Triad—thin (no adipose tissue) with disordered eating, amenorrhea /oligomenorrhea, and osteopenia/porosis

31. Puberty…in girls… • When does puberty start? • Breast development (thelarche) at 10 in Caucasians and before 9 in African-Americans • Pubic hair one year later • Menarche two years after breast development • 27% of AA girls have breasts at 7; 7% Caucasian girls • Precocious puberty is under 8 in C girls and under in AA girls • B & B Supergrow? • Diet? Fat, Fat tissue? • Environmental estrogens? PCBs, PBBs, DDE, phthalates, BPA

32. Boys, fat tissue, and delayed puberty • Boys – fat = delayed puberty • Aromatase in fat tissue converts testosterone to estradiol and delays their development

33. Synthetic GnRH drugs • We make synthetic drugs that mimic the functions of GnRH – • Leuprolide(Lupron, Eligard); nafarelin (Synarel), goserelin (Zoladex), buserelin (Suprefact/Suprecor) • We can use these drugs to boost fertility OR we can use these drugs to DOWNREGULATE the function of the ovaries and testicles

34. Endometriosis of the small bowel • Use of GnRF drugs to “downregulate” the gonadal secretion of estrogen • after 10 days of administering these drugs hypogonadism develops via downregulationof receptors • When used to “downregulate” endometriosis symptoms, the symptoms will get WORSE initially, due to the “flare effect” (increase in LH and FSH)

35. The GnRH agonists—other uses • Also used for hormonally-stimulated cancers such as prostate cancer to downregulate testosterone to reduce hormonal stimulation of the prostate (hormonal castration)— • causes gynecomastia in men (the old days we used DES—diethylstilbesterol to change the hormonal environment in men)… • Downregulate hormonal stimulation in breast cancer patients (as above) • Used to delaying puberty in precocious puberty cases • shrink uterine fibroids

36. Central precocious puberty • Histrelin acetate (Supprelin LA)—first and only implant for the treatment of children with central precocious puberty • Steady flow of GnRH actually turns OFF the system

37. Congenital deficiency of GnRH • Kallman’s syndrome • Anosmia • amenorrhea

38. Examples of inhibiting and releasing factors from the hypothalamus: • Growth hormone-releasing factor somatotropin—stimulates the release of growth hormone from the anterior pituitary (released at night) • KIDS GROW AT NIGHT—growing pains

39. Examples of inhibiting and releasing factors from the hypothalamus: • Corticotropin-releasing hormone (CRH)—stimulates the release of ACTH (adrenocorticotrophic hormone) from the pituitary which in turn triggers cortisol release from the adrenal gland • Hypothalamic—pituitary—adrenal axis

40. Let’s move on to the the Pituitary gland • Pituitary comes from the Latin pituita, meaning “phelgm,”, also related to the Greek ptuō, meaning “I spit.” The Greek word, obviously, is vividly imitative and is the forerunner of the expletives “Ptooey!” and “Phooey!” • The Greeks and Romans believed that the brain secreted a mucoid substance that was discharged through the nose (ie, “snot”) • …this notion was finally nixed in the 17th century but the name pituitary stuck

41. You actually have two separate pituitary glands—the anterior and the posterior pituitary* • The posterior pituitary gland is a direct extension of the hypothalamus via the infundibulum (pituitary stalk—actually infundibulum means “funnel”) and therefore is part of the nervous system • Neurons in the hypothalamus make and store hormones secreted by the posterior pituitary • Oxytocin and ADH (antidiuretic hormone, aka arginine vasopressin, AVP) • *lower forms of animals have a middle pituitary

42. The anterior pituitary • The anterior pituitary is an embryologic outpouching of the posterior pharynx / roof of the mouth (Rathke’s pouch) (GI tract)—backs up through the craniopharyngeal canal and “sticks” itself to the posterior pituitary • the anterior pituitary gland is NOT part of the nervous system, it’s actually part of the GI tract • Craniopharyngioma

43. Anterior pituitary • To release hormones from the anterior pituitary, the hypothalamus has to send it’s releasing or inhibiting hormones via the capillary system (hypophyseal portal system)—connects the capillary system of the hypothalamus with the capillary system of the pituitary • This capillary network is vulnerable to sudden loss of blood-- • Sheehan’s necrosis of the anterior pituitary gland—infarction of the anterior pituitary during labor and delivery (sudden loss of blood via a hemorrhaging episode in the mom)

44. Anatomic location of the pituitary gland • The entire pituitary gland sits beneath the optic chiasm in a small bone called the sellaturcica (turkish saddle) • If the pituitary enlarges (macroadenoma, for example), it will push up against the optic chiasm and cause a visual loss known as bitemporalhemianopsia or “TUNNEL VISION” • Prolactinoma in a graduate NP student at UVA (visual fields)

45. Bitemporal hemianopsia

46. Hormones of the anterior pituitary released in response to hypothalamic factors • GH (Growth Hormone) (somatotropin) • FSH (Follicle Stimulating Hormone) (GnRH) • LH (Luteinizing Hormone)(GnRH) • TSH (Thyroid Stimulating Hormone)(TRH) • ACTH (Adrenocorticotropic Hormone)(CRH) • PRL (Prolactin)(PIF)

47. Hormones of the posterior pituitary • Oxytocin • ADH (Anti-diuretic Hormone) also known as Arginine Vasopressin (AVP)

48. Hormone of the posterior pituitary—Oxytocin • The first peptide ever to be replicated outside the body was oxytocin (1953). It’s released from the posterior pituitary gland during childbirth to bind with receptors in the uterus, where it stimulates uterine contractions to help “expel” the baby • Synthetic oxytocin, as we all know, is Pitocin • HISTORICAL HIGHLIGHT: As early as 1902, people knew there was something in crude extracts of farm animal pituitary glands that could be used by obstetricians to aid women who had been in labor for a prolonged period

49. Oxytocin • Milk let-down response from the mammary glands for breast feeding • Uterine contractions during orgasm

50. What else does oxytocin do? • The “Tend to and be a friend to” hormone—bonding hormone; trusting; higher levels in women • Helps us to read other’s minds • Cuddly, touchy-feely, earth-momma hormone; calming effect • Estrogen enhances oxytocin