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Repro Week 2 > LM 13.3: Hirtuism, Virilization and PCOS > Flashcards

LM 13.3: Hirtuism, Virilization and PCOS Flashcards

1
Q

what are the 5 types of androgens?

A
  1. testosterone
  2. dehydroepiandrosterone sulfate (DHEAS)
  3. dehydroepiandrosterone
  4. androstenedione
  5. androstenedione

androstenedione and androstenediol have both androgenic and estrogenic activity

testosterone and dihydrotesterone (DHT) are the only androgens with direct androgenic activity; DHEAS, DHEA and androstenedione are all precursors of testosterone

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2
Q

what is sex hormone binding globulin?

A

80% of testosterone is bound to sex hormone binding globulin (SHBG), 19% is bound to albumin, and 1% circulates freely

the androgenicity depends on unbound fraction due to high affinity of SHBG to the bound androgens. SHBG levels are influenced by various factors

estrogen, thyroid hormones and pregnancy increases the level of SHBG whereas androgens, synthetic progestins, glucocorticoids, growth hormones, insulin, obesity and hypothroidism decreases SHBG levels

DHEAS, DHEA and androstenedione are entirely bound to albumin which has low affinity to these hormones.

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3
Q

what stimulates androgen secretion?

A

adrenal androgen increases in response to ACTH, however androgens do not influence the ACTH secretion

LH stimulates the ovaries to secrete androgens, however there is no feedback regulation that controls androgen secretion in women

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4
Q

what is the pathway for androgen production in the adrenals and ovaries?

A

?

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5
Q

what is androgen induced virilization?

A

it is responsible for forming male external genitalia in the fetus and secondary sexual characteristics in males

their absence or the absence of androgen receptors result in a female phenotype, even in the presence of a 46 XY karyotype –> an example of this is androgen insensitivity syndrome

androgen excess can affect different tissues and organs, causing variable clinical features such as acne, hirsutism, virilization, and reproductive dysfunction

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6
Q

what does androgen do in the body?

A
  1. increases sebum production in pilosebaceous units
  2. prolongs the growth phase of hair
  3. promotes hair conversion from velds to terminal hair
  4. forms the male external genitalia in the fetus and secondary sexual characteristics in males

acne vulgaris can be aggravated or initiated by increased androgen levels as the excess sebum production and shedding of hyperkeratinized epithelium may occlude the hair follicle

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7
Q

what does androgen excess do in females?

A
  1. acne
  2. hirsutism
  3. virilization
  4. reproductive dysfunction
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8
Q

what hair on the body is terminal hair?

A
  1. eyebrows
  2. eyelashes
  3. scalp
  4. pubic hair
  5. axillary hair

hair of the pubis, axilla, sternum, and facial areas are responsive to androgen, and vellus hair, eyelashes, eyebrows are androgen insensitive

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9
Q

why do men have hair where they do in comparison to women?

A

axillary and pubic areas are sensitive to low levels of androgen, whereas hair on face, chest, upper abdomen, and back requires higher levels of androgen and is therefore more characteristic of the pattern typically seen in men

vellus hair, eyelashes, eyebrows are androgen insensitive

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10
Q

how does androgen effect hair growth on the scalp?

A

androgen excess leads to increase hair growth in most androgen sensitive sites except in the scalp region, where hair loss occurs because androgen causes scalp hair to spend less time in the anagen phase (growth phase

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11
Q

what is hirsutism?

A

androgen dependent excessive male pattern of hair growth

most often idiopathic or the consequence of androgen excess associated with polycystic ovary syndrome

rarely it may result from adrenal androgen overproduction as occur in nonclassic congenital adrenal hyperplasia

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12
Q

what are the causes of hirsutism?

A

functional androgen excess disorders

  1. PCOS
  2. idiopathic hirsutism

specific identifiable disorders
1. non-classic congenital adrenal hyperplasia

  1. thyroid dysfunction
  2. hyperprolactinemia

4 hyperandrogism

  1. virilising ovarian or adrenal tumor
  2. hyperthecosis
  3. Cushing’s disease
  4. acromegaly
  5. danazol, testosterone, anabolic steroids, androgenic prostogens
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13
Q

what is virilization?

A

a condition in which androgen levels are sufficiently high to cause additional signs and symptoms, such as deepening of the voice, breast atrophy, increased muscle bulk, clitoromegaly, and increased libido

may be due to benign hyperplasia of ovarian theca and stroma cells

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14
Q

how can you evaluate for what is causing hirtuism?

A

assess age at onset and rate of progression of hair growth and associated symptoms and signs

depending on the cause the onset of hirsutism may be seen in the second or third decades of life

  1. hair growth is usually slow and progressive, however a sudden development and rapid progression suggest the possibility of androgen-secreting neoplasm, in which case virilization may also be present
  2. irregular cycles from the time of menarche is more likely to be ovarian etiology
  3. associated symptoms such as galactorrhea should prompt evaluation for hyperprolactinemia and possibly hypothyroidism.
  4. hypertension, striae, easy bruising, centripetal weight gain, and weakness suggests Cushing’s syndrome
  5. use of medications such a phenytoin, minoxidil, and cyclosporine may be associated with androgen independent excess hair growth (hypertrichosis)
  6. family history of infertility and/ or hirsutism may indicate disorders such as nonclassic congenital adrenal hyperplasia
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15
Q

what do you look for during a PE of someone with suspected hirtuism?

A
  1. measure height, weight and BMI

30+ BMI usually associated with hirsutism probably due to increased peripheral conversion of androgen precursor to testosterone

  1. acanthuses nigricans
  2. skins tags
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16
Q

what are the distinguishing clinical clues for PCOS?

A
  1. irregular menses
  2. normal to mildly elevated androgen levels
  3. polycystic ovaries on ultrasonography
  4. central obesity
  5. infertility
  6. insulin resistance
  7. acanthuses nigerians
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17
Q

what are the distinguishing clinical clues for hyperandrogenemia?

A
  1. normal menses
  2. normal ovaries on US
  3. elevated androgen levels
  4. no other explainable cause
18
Q

what are the distinguishing clinical clues for idiopathic hirsutism?

A
  1. normal menses, androgen levels and ovaries on US

2. no other explainable cause

19
Q

what are the distinguishing clinical clues for andrenal hyperplasia?

A
  1. family history of congenital adrenal hyperplasia
  2. high risk ethic group: Ashkenazi Jews, hispanic, Slavs

classic form: ambiguous genitalia at birth

non classic: late onset form, menstrual dysfunction, oligoanovulation, infertility

20
Q

what are the distinguishing clinical clues for androgen-secreting tumors?

A
  1. rapid onset of hirsutism
  2. progression of hirsutism despite treatment
  3. virilization
  4. palpable abdominal or pelvic mass
21
Q

what does total, free testosterone levels tell you?

A

total testosterone level of >12 nmol/L usually indicates virilizing tumor

hyperinsulinemia and/or androgen excess decreases hepatic production of SHBG, resulting in levels of total testosterone within high normal range, whereas the unbound hormone is elevated more substantially

22
Q

what does elevated serum DHEAS levels tell you?

A

serum DHEAS is elevated in patients with adrenal tumor

23
Q

what does elevated LH:FSH ratio tell you?

A

PCOS

24
Q

what is the dexamethasone suppression test?

A

an overnight 1 mg dexamethasone androgen suppression test , with measurement of 8:00 A.M serum cortisol helps diagnose Cushing’ s syndrome

but a 24 hour urine free cortisol levels in those with clinical evidence of Cushing’s syndrome – this is more specific than the dexamethasone suppression test

25
Q

what is the most common cause of non classic congenital adrenal hyperplasia?

A

21-hydroxylase deficiency

because of enzyme defect the adrenals cannot secrete glucocorticoids, hence no negative feedback inhibition of ACTH

elevated ACTH results in adrenal hyperplasia and accumulation of steroid precursors which are subsequently converted to androgens

serum levels of 17 hydroxyprogesterone is a screening test

synthetic ACTH (corticotrophin) stimulation test is a diagnostic test for nonclassic congenital adrenal hyperplasia

26
Q

what imaging do you do in PCOS and suspected tumor patients?

A
  1. US
  2. CT
  3. MRI
27
Q

how do you treat hirsutism?

A

MEDICAL THERAPY
1. combined oral contraceptives

  1. anti androgens: cyproterone acetate, spironolactone
  2. GnRH agonists
  3. 5-alpha-reductase inhibitor: finasteride
  4. eflornithine hydrochloride is a topical antimetabolite cream, slows hair growth

the primary goal in treating hirsutism is to lower androgen levels, however medical therapy will not eliminate hair already present and also require 6 to 12 months before clinical improvement is apparen

medical therapy is directed at interrupting one or more steps in the pathway of androgen synthesis and action. It includes combined oral contraceptives, antiandrogenic agents, GnRH agonists, and 5 alpha reductase inhibitor which blocks the conversion of testosterone to dihydrotestosterone

28
Q

what is the first line treatment for hirtuism in women who are not seeking fertility?

A

combined oral contraceptives

antiandrogen monotherapy is not recommended as initial therapy due to teratogenic potential

when hirsutism persists after 6 months of monotherapy with COCs antiandrogens are added –> cyproterone acetate –> however, this isn’t available in the US because it has side effects like interfering with external genitalia development in male fetuses so spironolactone is the primary antiandrogen used in the US

29
Q

what is the MOA of cyproterone acetate?

A

it’s an anti androgen

acts mainly by competitive inhibition of the binding of testosterone and DHT to the androgen receptor

30
Q

what is the MOA of finasteride?

A

5 alpha reductase inhibitor

used to treat male alopecia but also modernly effective for hirsutism

however there is a risk for male fetus teratogenicity and effective contraception must be used

31
Q

what is depilation vs. epilation?

A

depilation = hair removal above skin surface –> shaving

epilation = removal of the entire hair shaft and root –> plucking, waxing, threading, electrolysis, laster

32
Q

A 27 year old female presents for evaluation of excess facial hair. She attained menarche at the age of 13 years, her menses are always irregular. Physical examination shows hair on her upper lip, chin, chest and back. What is the mechanism of excess hair growth?

A

excess androgen transforms villous hair to terminal hair

33
Q

what are the characteristics of PCOS?

A
  1. oligo or anovulation
  2. signs of excess androgen
  3. multiple small ovarian cysts
  4. higher rates of dyslipidemia and insulin resistance
  5. increased risk of infertility, metabolic syndrome, DM, CVD, endometrial carcinoma

PCOS is a diagnosis of exclusion

34
Q

what is the diagnostic criteria for PCOS?

A
  1. clinical and/ or biochemical hyperandrogenism
  2. oligo/ anovulation
  3. polycystic ovarie

need 2/3 writer

35
Q

what is the pathogenesis of PCOS?

A

unknown

a genetic basis that is both multifactorial and polygenic is suspected, as there is a well documented aggregation of the syndrome within families

36
Q

what is the pathophysiology of PCOS?

A
  1. altered GnRH pulsatility leads to preferential production of LH compared to FSH –> LH: FSH ratio rise above 2:1 in approximately 60% of patients

LH stimulates ovarian androgen production, while low FSH prevents adequate stimulation of aromatase activity within the granulosa cells, decreasing androgen conversion to potent estrogen (estradiol)

increased intrafollicular androgen results in follicular atresia, contributes to abnormal lipid profile, hirsutism and acne

  1. then, in the periphery, Elevated serum androgens are converted to estrogens (estrone) primarily in the stromal cells of the adipose tissue; hence this conversion is augmented in obese patients –> unopposed estrogen results in endometrial hyperplasia
  2. patients with PCOS also have decreased production of sex- hormone binding globulin and hence more unbound androgens available to bind the receptors
  3. insulin resistance due to genetic abnormalities and/ or increased adipose tissue contributes to follicular atresia and development of acanthosis nigricans in the skin – lack of follicular development results in anovulation and subsequent oligo or amenorrhea
  4. precise mechanism leading to anovulation is unclear – altered GnRH pulsatility and inappropriate gonadotropin secretion have been implicated in menstrual irregularity

anovulation may result from insulin resistance, as substantial number of patients will resume ovulatory cycles when treated with Metformin, an insulin sensitizer; the large antral follicle with increased intraovarian androgens may contribute to anovulation

37
Q

what are the symptoms of PCOS?

A
  1. amenorrhea
  2. oligomenorrhea
  3. unpredictable heavy menstrual bleeding
  4. hirsutism
  5. acne
  6. androgenic alopecia
  7. increased muscle mass
  8. boive depending
  9. clitoromegaly
  10. acanthosis nigerians

the problem is that irregular cycles and acne are frequent in unaffected adolescents, the diagnosis of PCOS is delayed until after age 18

38
Q

why does PCOS cause acne?

A

testosterone is converted to dihydrotestosterone within the sebaceous glands

they act on the androgen receptors in the pilosebaceous unit and increase sebum production that eventually leads to inflammation and comedone formation

39
Q

what are the metabolic abnormalities seen with PCOS?

A
  1. impaired glucose tolerance
  2. DM
  3. dyslipidemia
  4. metabolic syndrome = insuline resistance, obesity, atherogenic dyslipidemia and HTN
40
Q

is PCOS associated with a risk of cancer?

A

endometrial cancer is increased threefold due to long term chronic anovulation

41
Q

how do you diagnose PCOS?

A

it’s a diagnosis of exclusion! so other conditions with similar presenting symptoms should be excluded first

once they’re diagnosed, periodic screening for dyslipidemia, DM and metabolic syndrome is really important

diagnose with transvaginal ultrasound but with adolescents diagnose with trans abdominal ultrasound –> sonographic criteria for polycystic ovaries include >/= 12 small cysts (2 to 9 mm in diameter) or an increased ovarian volume (>10mL) or both

42
Q

how do you treat PCOS?

A
  1. first line treatment for menstrual irregularities is combined oral contraceptive pills which can induce regular menstrual cycles, lower androgen levels and thing the endometrium – they also suppress gonadotropin release which decreases ovarian androgen production

estrogen component increases sex hormone binding globulin and lowers free androgen levels

the progestin component antagonizes the endometrial proliferative effect of unopposed estrogen, reducing the risk of endometrial hyperplasia

  1. if they’re not a candidate for COC, progesterone withdrawal is recommended every 1-3 months
  2. those desiring pregnancy ovulation induction with clomiphene citrate is the the first line treatment
  3. metformin, a category B drug decreases androgen levels in both lean and obese women with PCOS, leading to increased rates of spontaneous ovulation
  4. diet and exercise for obese women is important, as even a modest weight loss, 5% of body weight can restore normal ovulatory cycles in some women

Repro Week 2 (21 decks)

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