Endocrine and Reproductive Disorders

endocrine system

• a collection of glands that are responsible for making and secreting hormones that control many bodily functions

• hormones are secreted into the circulatory system

• target organs express specific receptors that bind hormones

• binding leads to a cellular response

homeostasis

• main role of the endocrine system is to maintain ______

• accomplished via coordination of hormone signaling pathways that regulate cellular activity in target organs throughout the body

disorders of glucose homeostasis

• type 1 diabetes mellitus

• type 2 diabetes mellitus

disorders of adrenal gland

• Cushing syndrome → excess adrenal hormones

• Addison’s disease → deficiency in adrenal hormones

disorders of thyroid gland

• hyperthyroidism → excess thyroid hormones

• hypothyroidism → deficiency in thyroid hormones

diabetes mellitus

• insulin is required for cells to utilize glucose

• insulin allows uptake of glucose by cells to be used as energy

• without insulin, glucose stays in the bloodstream where it cannot be used by cells

mechanism of insulin secretion

• pancreas produces insulin via beta cells of islets of Langerhans

  • proinsulin is converted to C-peptide and insulin → circulates in the blood

islets of Langerhans

collections of cells throughout pancreas

C-peptide

• part of proinsulin that is cleaved prior to co-secretion with insulin from beta cells

• indicates how much endogenous insulin is present and if beta cells are working

• patient with T₁DM has a pancreas that doesn’t produce insulin → C-peptide level usually < 0.2 nmol/L

type 1 diabetes mellitus (T₁DM)

• insulin-dependent diabetes

• insulin deficiency → autoimmune destruction of beta cells in pancreatic islets → pancreas does not make insulin

• commonly presents in children

type 2 diabetes mellitus (T₂DM)

• non-insulin-dependent diabetes

• dysregulation of insulin release from beta cells (not enough produced)

• insulin resistance in peripheral tissues (skeletal muscle, brain, liver)

• commonly presents in adults

T₁DM: symptoms

• polydipsia

• polyphagia

• enuresis

• blurred vision

• lethargy/fatigue

• abdominal pain

• sudden, unintentional weight loss

T₂DM: symptoms

• polydipsia

• polyphagia

• nocturia

• polyuria

• blurred vision

• lethargy/fatigue

• abdominal pain

• overweight/obesity is a common risk factor but sudden, unintentional weight loss is possible

glutamic acid decarboxylase (GAD) antibodies

• associated with autoimmune disorders and T₁DM

• reliable marker of insulin-dependent diabetes

anti-islet cell antibodies (ICA)

• markers that appear when insulin producing beta cells are damaged

• estimate risk of developing T₁DM

other antibodies

• insulin autoantibodies (IAA)

• insulinoma antigen-2 (IA-2) antibodies

• zinc transpoter 8 (ZnT8) antibodies

diabetes mellitus: diagnosis criteria

• A1C ≥ 6.5%

• fasting plasma glucose ≥ 126 mg/dL

• 2-hour plasma glucose during OGTT ≥ 200 mg/dL

• plasma glucose ≥ 200 mg/dL in a patient with symptoms of hyperglycemia or hyperglycemic crisis

  • in case of hyperglycemic crisis, diagnosis requires confirmatory testing with two abnormal tests that may be obtained at the same time

hemoglobin A1C

• hemoglobin becomes glycated in bloodstream

  • found only in RBCs (have 3-month life span)

• primary lab for monitoring blood glucose control

• average glucose over a 3-month period

• does not give information about glucose variability

• when to check:

  • yearly prior to diagnosis

  • at least every 6 months in patients with diabetes

• goal → may differ for patients based on age and hypoglycemic awareness

  • healthy adult → < 7%

fasting plasma glucose (FPG)

• in an individual without symptoms, can be used for screening and diagnosis (or 2-hour PG)

• measures blood sugar after an overnight fast (8 hours)

• based on two different times

  • normal → ≤ 99 mg/dL

  • pre-diabetes → 100-125 mg/dL

  • diabetes → ≥ 126 mg/dL

oral glucose tolerance test (OGTT)

• not routinely used in general population

• typically done every pregnancy between 24 and 28 weeks gestation

• measures ability of pancreas to respond to a glucose/carbohydrate load

• process:

  • 75 g of glucose in 300 mL water

  • blood sugar is measured at 0, 1, and 2 hours

• results:

  • normal → FPG < 115 mg/dL, 2-hour PG < 140 mg/dL, no value > 200 mg/dL

  • diabetes → 2-hour PG and one other value > 200 mg/dL

  • impaired glucose tolerance → values above upper limits but below diagnostic values

self-monitoring blood glucose (SMGB)

• monitoring parameter aids in management decisions

  • self-monitoring improves metabolic control

  • identifies hypo- and hyperglycemic events

• measures capillary blood glucose

• fasting glucose → represents glucose in blood after fast

  • goal → 80-130 mg/dL

• educate patients on use of glucometer

  • keep monitors at room temperature

  • keep test strips in low humidity environment

continuous glucose monitors

• available brands → Dexcom, Freestyle Libre, Guardians

• choosing between options:

  • compatibility with other devices

  • smartphone use

  • sensor device

  • insurance coverage

• placement:

  • approved locations vary with brand

  • most placed on back of arm or belly

  • “line of sight” requirement with some pumps

• goals:

  • time in range > 70%

  • variability < 35%

• patient education:

  • taking > 500 mg vitamin C per day may interfere with blood glucose readings

  • sensor reads glucose levels in interstitial fluid which may lag behind true blood glucose level (especially when rapidly changing)

  • alerts may be set to notify users of low or high sugars

  • when in doubt, check sugars with fingerstick

urinary glucose

• typically negative upon testing

• glucosuria → high glucose levels in urine

  • common in patients with DM

  • when serum glucose is elevated → spills into urine → osmotic mechanisms → increased urination → risk factor for genital and urinary tract infections

urine ketones

• ketonuria → excretion of abnormally elevated amounts of ketone bodies in urine

  • can be associated with serious complications (ex: DKA)

• may also be present in individuals who have been fasting, strenuously exercising, vomiting repeatedly, or consuming a diet high in fat and low in carbohydrates (blood glucose generally low)

diabetic ketoacidosis (DKA)

• occurs when body does not have enough insulin to allow glucose to enter cells for use as energy (hyperglycemia)

• metabolism of carbohydrates not efficient → body breaks down fat for energy → buildup of acids and ketones

diabetes mellitus: medications

• insulin → NPH, regular

• sulfonylureas → glipizide, glyburide

• biguanides → metformin

• GLP-1, GLP-1/GIP → liraglutide, dulaglutide, semaglutide

• DPP-4 inhibitors → linagliptin, sitagliptin

• TZDs → pioglitazone

• meglitinides → repaglinide

HPA axis

if cortisol is elevated, CRH and ACTH both decrease and vice versa

Cushing syndrome

• results from effects of supraphysiologic glucocorticoid concentrations

• exogenous → long-term use of corticosteroids

• endogenous → overproduction by adrenal gland (often due to tumor)

Cushing syndrome: symptoms

• round, circular face (“moon face”)

• fat accumulation in dorsocervical area (“buffalo hump”)

• hypertension

• osteopenia

• glucose intolerance

• myopathy

• bruising

• depression

dexamethasone suppression test (DST)

• take small dose of cortisol-like drug at 11 PM and have blood drawn for cortisol the next morning

  • normal → very low levels of cortisol (ACTH suppressed)

  • Cushing syndrome → cortisol is readily detected and often elevated

24-hour urine-free cortisol level

urine is collected several times over a 24-hour period and tested for cortisol

midnight plasma control

• measures cortisol in blood

• cortisol is usually suppressed at night

  • in Cushing syndrome, suppression doesn’t occur

Addison’s disease

• primary adrenal insufficiency

• usually involves destruction of all regions of adrenal cortex

• associated with deficiencies in cortisol, aldosterone, and various androgens

  • CRH and ACTH increase in a compensatory manner

• causes:

  • autoimmune dysfunction is responsible for 80-90% of cases in developed countries

  • tuberculosis is primary cause in developing countries

  • lymphomas, sarcomas, AIDS, and other infectious diseases may also contribute

Addison’s disease: symptoms

• weakness

• weight loss

• increases in skin pigmentation

• white patches on skin (vitiligo)

• hypotension

• GI symptoms

• postural dizziness

cosyntropin (ACTH) stimulation test

• assesses how well adrenal glands respond to ACTH

• main medical test to diagnose primary, secondary, or tertiary adrenal insufficiency

• involves a shot into the muscle of ACTH and multiple blood draws at different intervals to assess cortisol levels

• if adrenal insufficiency is present, adrenal glands will not appropriately release cortisol in response to ACTH

adrenal gland disorders: SCHOLAR-MAC

• if not gathered from HPI, ask questions about…

  • fatigue

  • weight loss/weight gain (without change in diet)

  • palpitations

  • anxiety

• timing, when did symptoms start?

  • longer duration before presentation

• medications, including herbals and OTCs

• family history of endocrine disorders

measuring thyroid hormones

• primary screening test and monitoring parameters → TSH

  • TSH is part of feedback loop

  • easy and relatively inexpensive to monitor

• utility in adjustments to thyoid replacement therapy with levothyroxine (synthetic T₄)

  • low TSH → indicates excess circulating thyroid hormones/levothyroxine

  • high TSH → indicates deficiency in circulating thyroid hormones/levothyroxine

total serum T₄

• active thyroid hormone

• standard initial screening (with TSH) for testing thyroid function because it is low cost and results are done quickly

• active thyroid hormone is highly protein-bound so if a drug or medical condition affects the binding of T₄ to protein, the results can be skewed

free T₄

• measures unbound T₄ in serum and is most accurate reflection of thyro-metabolic status

• not affected by protein-binding drugs or interfere with low protein states

total serum T₃

• one is cleaved from T₄ to make T₃

• highly protein-bound, similar to active T₄

• used as an indicator of hyperthyroidism, especially in situations where T₄ is not elevated

hypothyroidism

• clinical and biochemical syndrome resulting from decreased thyroid hormone production

  • hypometabolic state

• labs:

  • TSH concentration above reference range

  • free T₄ and/or T₃ levels below reference range

hypothyroidism: symptoms

• fatigue

• cold intolerance

• hair loss

• dry skin

• weight gain

• sexual dysfunction

• bradycardia

• enlarged thyroid

hyperthyroidism

• clinical and biochemical syndrome resulting from increased thyroid hormone production

  • hypermetabolic state

• labs:

  • low TSH

  • elevated free and total T₄ and T₃ concentrations

hyperthyroidism: symptoms

• excessive sweating/heat intolerance

• hyperactivity

• irritability

• panic attacks

• mood swings

• tachycardia

• palpitations

• insomnia

• irregular menstruation

• abnormal protrusion of eyes

• weight loss

• diarrhea

medications that increase T₄

• amphetamines

• amiodarone

• lithium

medications that decrease T₄

• acute steroid use (glucocorticoids)

• amiodarone

• lithium

• phenobarbital

• carbamazepine

• phenytoin

• antacids

• orlistat

• omeprazole

• cholestyramine

hypothyroidism: medications

• synthetic T₄ → levothyroxine

• synthetic T₃ → liothyronine

• synthetic T₄ + T₃ → liotrix

• dessicated pork thyroid glands → Armour Thyroid, NP Thyroid

hyperthyroidism: medications

• reduce thyroid synthesis:

  • thioamides → methimazole, propylthiouracil

  • iodide, radioactive iodide

  • surgery

• symptom management:

  • beta blockers

thyroid gland disorders: SCHOLAR-MAC

• symptoms:

  • weight loss/gain

  • excessive sweating/cold intolerance

  • hyperactivity/fatigue

• medications:

  • many medications impact thyroid function

  • thyroid function can have an impact on medication metabolism

disorders of male reproductive system

• benign prostatic hyperplasia (BPH)

• male hypogonadism

disorders of female reproductive system

• amenorrhea

• polycystic ovarian syndrome (PCOS)

• endometriosis

male HPA axis

if testosterone increases, then LH and FSH both decrease and vice versa

hormones of male reproductive system

• LH → stimulates testicular Leydig cells to produce testosterone

• FSH → acts on testicular Sertoli cells to stimulate spermatogenesis

• androgens → produced by adrenal gland through stimulation from ACTH

  • DHEA, DHEAS, androstenedione

  • all less potent than testosterone

  • androgens are converted to estrone and estradiol by enzyme, aromatase, in liver and adipose tissue

testosterone

• releases following a circadian pattern

  • highest secretion at 7 AM, lowest at night

• responsible for development of male sexual characteristics

• active in some tissues (CNS, bone, skeletal muscle)

• in other tissues, testosterone is converted to dihydrotestosterone (DHT) by the enzyme 5-alpha reductase

  • more potent androgenic agonist than testosterone

  • can contribute to…

    • BPH at prostate gland

    • alopecia at scalp

benign prostatic hyperplasia (BPH)

• an estimated 80% of older men develop histologic evidence

• approximately half of all patients with microscopic changes develop an enlarged prostate gland

  • those that develop an enlarged prostate may develop symptoms

• about half of all symptomatic patients eventually require treatment

BPH: symptoms

• difficulty with urination → starting flow and taking a long time to relieve self

• nocturia

• urgency

• urge incontinence

• overflow incontinence

• “dribbling”

• untreated BPH may lead to UTI, hematuria, and/or renal failure

BPH: diagnosis

• mostly clinical

• diagnostic tests should be completed to rule out other problems

• PE → digital rectal exam, questionnaires

  • AUA-SI → adopted worldwide as International Prostate Symptom Score

• imaging:

  • ultrasound for post-void residual urine

  • ultrasound of prostate for enlargement and cancer

prostate specific antigen (PSA)

• produced by normal and malignant prostate cells

• prostate cancer, BPH, and prostatitis may all elevate PSA

• may be useful for monitoring progression

• abnormal generally > 4.0 ng/mL

  • may change with age, history, and medication use

International Prostate Symptom Score

• mildly symptomatic → 0-7

• moderately symptomatic → 8-19

• severely symptomatic → 20-35

BPH: SCHOLAR-MAC

• symptoms → obstructive or irritative

  • obstructive → compression/blockage or bladder neck due to hypertrophy of prostate gland, preventing outflow of urine

  • irritative → frequency or urgency, indicates partial obstruction of bladder outlet (detrusor muscle)

    • if not treated, can lead to urinary incontinence

• distinguish BPH from UTI and other conditions

• medications:

  • anticholinergic drugs may cause similar symptoms

    • antihistamines, antipsychotics, tricyclic antidepressants

BPH: medications

• alpha blockers → doxazosin, tamsulosin

• 5-alpha reductase inhibitors → finasteride, dutasteride

• PDE5 inhibitors → tadalafil

male hypogonadism

• body does not produce enough testosterone

• typically associated with complaints of no sexual drive and “problems with performance”

• may impact fetal development, puberty, and adulthood

male hypogonadism: symptoms

• decreased energy

• fatigue

• loss of libido

• impotence

• gynecomastia

• weight gain

• mood instability

• hot flashes

• reduced body hair

• decreased testicular size

• osteoporosis/osteopenia

male hypogonadism: diagnosis

• PE → signs of atrophy in gonads

• ADAM Questionnaire

  • widely used as a screening tool for detecting men at risk of developing androgen deficiency

• no imaging is used in the diagnosis of hypogonadism

male hypogonadism: labs

• total and free testosterone levels:

  • testosterone binds to albumin but is easily released to become active

  • also binds to sex hormone binding globulin (SHBG) which has high affinity and does NOT release easily

    • too much SHBG can decrease free/active testosterone

• LH → secreted from pituitary and induces testosterone production

• prolactin → low prolactin interferes with GnRH production from hypothalamus which decreases testosterone production

male hypogonadism: SCHOLAR-MAC

• ask about morning erection → highest level of testosterone is produced in the morning, trend in lack of morning erections supports low testosterone

• non-sexual related symptoms:

  • fractures (osteoporosis/osteopenia)

  • mood disorder

  • muscle strength → difficult lifting things they would be able to lift at baseline

• medication history:

  • some drugs may cause hypogonadism → corticosteroids, anabolic steroids, opioids

  • some drugs contribute to symptoms → beta blockers, SSRIs, anxiolytics, antihistamines

female HPA axis

• negative feedback → decreased estrogen causes FSH to increase

• positive feedback → increased estrogen stimulates the pituitary gland to produce LH

menstrual cycle: phase 1

• start of menstruation

• new follicle begins to develop under influence of FSH

• initial low estradiol (E2) occurs at end of cycle → increased FSH → increased E2

menstrual cycle: phase 2

• ovulation

• E2 continues to be secreted by follicle

• positive feedback to pituitary causes surge in release of LH around days 11-13 → triggers ovulation

menstrual cycle: luteal phase

• follicle releases egg → triggers follicle to be converted to corpus luteum and produces progesterone to prepare endometrium for fertilization and implantation

• when this doesn’t occur → progesterone production slows → estrogen drops → triggers FSH increase

amenorrhea

• primary amenorrhea → patient is late or never starts menses

• secondary amenorrhea → patient has normal menses and then it becomes irregular or they cease

amenorrhea: symptoms

• primary → no period at age 16 or older

• secondary:

  • woman presents with missed period (typically ≥ 3 months) with negative pregnancy test

  • peri-menopausal woman presents with complaints of hot flashes or painful intercourse

    • decrease in estrogen leads to thinning of vaginal wall and decreasing secretions

    • menopause is diagnosed at 12 months since last period

amenorrhea: SCHOLAR-MAC

• “when was the first day of your last menstrual period?”

• characterization:

  • how heavy is flow

  • how many feminine products used per hour

• duration:

  • how many days of bleeding per cycle

  • how long from start of one period to start of next

  • has patient ever missed a cycle entirely

• when did patient last have intercourse

• all women should track their cycles (ex: apps, calendar)

polycystic ovarian syndrome (PCOS)

• female hormone dysfunction which causes increased production of androgens and testosterone

  • lack of normal ovulation leaves patient with many follicular cysts

• mechanisms act alone or synergistically

  • inappropriate gonadotropin secretion

  • insulin resistance

  • excessive androgen production

• clinical presentation is variable

PCOS: symptoms

• hirsutism → excessive hair production

  • hair tends to be coarser in androgen-dependent areas

• weight gain/central obesity

• deepening of voice

• temporal balding

• abnormal glucose metabolism/insulin resistance

PCOS: diagnosis

• PE → gynecologic exam for abnormalities

• imaging → ultrasound

  • indicated if patient has abdominal pain or if PE shows enlarged ovaries or elicits pain

• labs → FSH, LH, estradiol, progesterone, prolactin, testosterone

Rotterdam criteria

• presence of 2 out of 3 of the following must be present after exclusion of related disorders to confirm diagnosis of PCOS:

  • oligo-ovulation

  • clinical and/or biochemical signs of hyperandrogenism

  • polycystic ovaries → 12 or more ovarian follicles of 2-9 mm diameter or ovarian volume of > 10 mL in follicular phase

PCOS: monitoring

• clinical signs and symptoms at least annually

• weight and blood pressure at every visit

• routine labs:

  • A1C or OGTT at least every 2 years

  • fasting lipid panel

  • hormone monitoring when necessary

hormones in menopause

• FSH and LH very high

• ovaries stop making estradiol → GnRH released from hypothalamus → triggers FSH and LH release from pituitary

hormones in PCOS

• LH is high compared to FSH

  • LH:FSH → 3:1

• patient doesn’t ovulate → LH is released in effort to cause ovulation

PCOS: SCHOLAR-MAC

• ask all questions for amenorrhea

• abnormal hair growth and other symptoms

• family history of PCOS and CVD

endometriosis

• common gynecologic condition that affects females in their reproductive years

• growth of endometrial tissue outside uterus

• pathophysiology and biological mechanisms are multifactorial and not fully understood

• chronic condition that may cause chronic pelvic pain and infertility

endometriosis: symptoms

• clinical presentation and course are variable and unpredictable

  • some patients may even be asymptomatic

• most commonly reported:

  • dysmenorrhea (painful period)

  • infertility

• typical symptoms:

  • pelvic pain

  • dyspareunia (persistent pain in genital area during/after sexual intercourse)

• other possible symptoms:

  • period-related or cyclical GI symptoms (painful BM), menorrhagia (bleeding > 7 days), ovulation pain, chronic fatigue

endometriosis: diagnosis

• PE → pelvic tenderness, enlarged ovaries, pelvic masses/nodules, uterosacral ligaments, or retroverted uterus

  • most significant during menses → complete exam during that time

• imaging:

  • transvaginal ultrasound or MRI may visualize endometrial lesions

  • if imaging studies are normal but endometriosis suspected → laparoscopic surgery visualizes pelvis and endometrial lesions

• lesions vary in size

  • small lesions in ovaries

  • peritoneum to endometriomas → large cysts

endometriosis: diagnosis

• can be challenging and may take several years due to variability of symptoms

• definitive diagnosis → only made by histological exam of lesions removed during surgery

  • rule out all other causes of chronic pelvic pain

• ultrasound, MRI, CT → assess pelvic or adrenal masses

  • lower sensitivity for investigating endometrial lesions (especially during menstruation)

  • imaging helps determine whether there is endometrial tissue in bowel, bladder, or ureter

  • transvaginal ultrasounds can be used to determine if endometrial tissue is infiltrating rectum

endometriosis: SCHOLAR-MAC

• ask all questions that apply to amenorrhea

• symptoms:

  • type of pain, location, frequency

  • cyclic pain vs. acyclic pain

• personal and family medical history