Clin: Puberty Disorders - Moulton Flashcards
what 6 hormones are produced by the anterior pituitary gland?
FSH, LH, TSH, prolactin, GH, ACTH
what 2 neuro-hormones are produced by the posterior pituitary?
vasopressin and oxytocin
the FOLLICULAR phase of the ovarian cycle begins with what?
the onset of menstruation and culminates in the preovulatory surge of LH
the LUTEAL phase of the ovarian cycle begins with what?
the onset of preovulatoy LH surge and ends with the first day of menses
decreasing levels of estradiol and progesterone from the regressing corpus luteum of the preceding cycle initiate what?
an increase in FSH by a negative feedback mechanism, which stimulates follicular growth and estradiol secretion
what does LH stimulate?
theca cells
- produce androgens (androstenedione and testosterone)
what does FSH stimulate?
granulosa cells
- convert androgens into estrogens (E1 and E2)
during the luteal phase, LH and FSH are significantly suppressed through negative feedback effect of what?
elevated circulating estradiol and progesterone
if conception does NOT occur during the luteal phase, what happens?
progesterone and estradiol levels decline as a result of corpus luteal regression
after corpus luteal regression, levels of what will rise, initiating new follicular growth for the next cycle?
FSH
what are the 5 peptides of the hypothalamus that have an affect on the reproductive cycle?
GnR, TRH, SRIF, CRF, PIF (prolactin release-inhibiting factor)
which peptide is responsible for the release of LH and FSH?
gonadotropin-releasing hormone
- acts on anterior pituitary to stimulate release of LH/FSH
what are the levels of estrogen during early follicular development?
LOW
- approx 1 week before ovulation, estradiol levels begin to increase
when do estrogen levels reach their maximum?
1 day before the midcycle LH peak
- after peak and before ovulation, there is marked and precipitous fall
- during luteal phase, estradiol rises to a maxim 5-7 days after ovulation and returns to baseline before menstruation
when does secretion of progesterone by the corpus luteum reach a maximum?
5-7 days after ovulation
- returns to baseline before menstruation
- disruption and disitegration of the endometrial glands and stroma, leukocyte infiltration and RBC extravasion
- sloughing of the functionalis layer and compression of the basalis layer
menstrual phase
endometrial growth secondary to estrogenic stimulation
- increase in length of the spiral arteries and numerous mitoses can be seen in the tissues
proliferative phase
following ovulation, progesterone secretion by the corpus luteum stimulates the glandular cells to secrete mucus, glycogen and other substance
- grands become tortuous and lumens are dilated, filled with these substances
- stroma becomes edematous
- mitoses are rare
- spiral arteries continue to extend into superficial layer of the endometrium and become convoluted
- endometrial lining reaches it’s maximal thickness
secretory phase
what happens if conception does not occur by day 23?
the corpus luteum begins to regress, secretion of progesterone and estradiol declines, and the endometrium undergoes involution
1 day prior to the onset of menstruation, marked constriction of the spiral arteries occurs resulting in what?
ischemia of the endometrium, leukocyte infiltration and RBC extravasion
- results in necrosis that causes sloughing of the endometrium -> menstruation
why is an intact coagulation pathway important in regulating menstruation?
restoration of blood vessels requires successful interaction of platelets and clotting factors
- meds like warfarin, aspirin, and clopidogrel can impair the coagulation system and be associated with heavy bleeding
what is the median age of menarche?
- 43 years
- 10% of females menstruate at 11.11 years
- 90% are menstruating by 13.75
menarche occurs how long after thelarche?
within 2-3 years after thelarche
- at Tanner stage IV
- rare before Tanner stage III
what is primary amenorrhea?
no menstruation by 13 without secondary sexual development
- OR by the age of 15 WITH secondary sex characteristics
what was the range of most normal cycles during the first gynecologic year?
21-45 days
- by third year, 80% of menstrual cycles are 21-35 days long
what is the mean cycle interval during the first gynecologic year?
32.2 days
what was the menstrual flow length during the first gynecologic year?
7 days or less
what is the mean blood loss per menstrual period?
30cc
blood loss greater than 80cc is associated with what?
anemia
- changing pas q 1-2 hours is considered excessive, especially if bleeding is lasting > 7 days
what is the mean age of puberty?
12.4 (between 11-16 years)
onset of puberty determined by:
- genetic factors
- geographic location (metropolitan areas, near sea level began puberty earlier)
- nutritional status (obese children have earlier onset, malnourished had later onset)
female infant acquires the lifetime pear number of oocytes by when?
16-20 weeks gestation
- 6-7 million oocytes!
what is termed the gonadostat?
the HPA regulating gonadotropin release
what causes low levels of gonadotropins and sex steroid during the prepubertal period?
- gonadostat sensitivity to negative feedback of low circulating estradiol
- intrinsic CNS inhibition of hypothalamic gonadotropin-releasing hormone (GnRH) secretion
between the ages of 8-11, there is an increase in what?
serum concentrations of DHEA, DHEA-S and androstenedione
what are the initial endocrine changes associated with puberty?
adrenal androgen production and differentiation by the zona reticularis of the adrenal cortex
what causes growth of axillary and pubic hair? (adrenarche, pubarche)
rise in adrenal androgens
around 11 years old, there is a gradual loss of sensitivity of what?
gonadostat to the negative feedback of sex steroids
- in combination with intrinsic loss of CNS inhibition of hypothalamic GnRH release
increase in GnRH promotes what?
ovarian follicular maturation and sex steroid production, which leads to the development of secondary sex characteristics
first physical sign of puberty
- unilateral development in first 6 months in not uncommon
- required estrogen
thelarche (breast development)
pubic har/axillary hair development
- required androgens
pubarche/adrenarche
onset of menses
- required pulsatile GnRH from the hypothalamus, FSH, and LH from the pituitary, estrogen and progesterone from the ovaries, normal outflow tract
menarche
when does maximal growth or peak height velocity happen?
about 1 year before onset of menses
- 2 years earlier in girls that boys
thelarche, adrenarche, and menarche for white, black, and hispanic girls
white: 10.3, 10.5, 12.7
black: 9.5, 9.5, 12.3
hispanic: 9.8, 10.3, 12.5
preadolescent, elevation of papilla only
Tanner stage 1
breast bug stage, elevation of breast and papilla as a small mound with enlargement of the areolar region
Tanner stage 2
further enlargement of breast and areola without separation of their contours
Tanner stage 3
projections of areola and papilla to form secondary mound above the level of the breast
Tanner stage 4
mature stage, projection of papilla only, resulting from recession of the areola to the general contour of the breast
Tanner stage 5
preadolescent, absence of pubic hair
Tanner stage 1
sparse hair along the labia, hair downy with slight picment
Tanner stage 2
hair spreads sparsely over the junction of the pubes, hair is darker and coarses
Tanner stage 3
adult-type hair, there is no spread to the medial surface of the thigh
Tanner stage 4
adult-type hair with spread to the medial thighs assuming an inverted triangle pattern
Tanner stage 5
development of any sign of secondary sexual characteristics prior to an age 2.5 standard deviations earlier than the expected age of pubertal onset
precocious puberty
- 8 years old for girls (5x more likely in girls)
- 9 years old for boys
NOTE: do a thorough evaluation to eliminate serious disease, and arrest potential osseous maturation that can affect normal growth patterns (can lead to premature fusion of long bones of the epiphyses)
what are the two major subgroups of precocious puberty?
- heterosexual: develop opposite sex characteristics
2. isosexual: premature sexual maturation that is appropriate for the phenotype
can be caused by viralizing neoplasms, congenital adrenal hyperplasia, or exposure to exogenous androgens
- androgen secreting neoplasms (usually in ovaries)
- congenital adrenal hyperplasia (CAD)
heterosexual precocity
congenital adrenal hyperplasia most commonly results from a defect in what enzyme?
adrenal enzyme 21-hydroxylase
- leads to excessive androgen production
- classical: most severe form can cause birth of female w/ ambiguous genitalia
- nonclassical: can cause premature pubarche and an adult disorder resembling PCOS
results in development of the full complement of secondary sexual characteristics and increased levels of sex steroids
complete isosexual precocious puberty
true isosexual precocity
arises from premature activation of the normal process of pubertal development involving the hypothalamic-pituitary-ovarian axis
pseudoisosexual precocity
exposure of estrogens independent of the H-P-O axis
- estrogen producing tumors
how do you diagnose true isosexual precocious puberty?
administration of exogenous GnRH and see a resultant rise in LH levels consistent with older girls who are undergoing normal puberty
what is the tx of true isosexual precocious puberty?
GnRH agonist (leuprolide acetate) - suppresses pituitary release of FSH and LH, resulting in the decline of gonadotropins to prepubertal levels and arrest of gonadal sex steroid secretion
ovarian tumor, exogenous estrogenic compound use, McCune-ALbright syndrome and Peutz-Jeghers syndrome
- increased estrogen levels that cause sexual characteristic maturation WITHOUT activation of H-P-O axis
pseudoisosexual precocity
somatic mutation during embryogenesis which causes them to function independent of their normal stimulating hormones
McCune-Albright syndrome (Polyostotic fibrous dysplasia)
associated with a sex cord tumor that secretes estrogen
- gastrointestinal polyposis and mucocutaneous pigmentation
Peutz-Jeghers syndrome
when is puberty considered delayed?
- secondary sexual characteristics have not appeared by age of 13
- if thelarche has not occurred by 14
- no menarche by age 15-16
- when menses has not begun 5 years after onset of thelarche
- gonadal dysgenesis (Turner syndrome)
hypergonadotropic hypogonadism (FSH > 30mIU/mL)
- constitutional (physiologic delay)
- Kallmann syndrome
- anorexia/extreme exercise
- pituitary tumors
hypogonadotropic hypogonadism (FSH + LH < 10mIU/mL)
no spontaneous uterine bleeding by age 13, without secondary sexual characteristics
- no menstruation by 15 years with secondary sex development
primary amenorrhea
patient with prior menses has absent menses for 6 months or more
secondary amenorrhea
what are the diagnostic findings of primary amenorrhea with ABSENCE of secondary sex characteristics?
FSH, LH < 5 IU/L
- hypogonadotropic hypogonadism
- MRI
mutation of KAL gene on x chromosome that prevents the migration of GnRH neurons into the hypothalamus
- patients will often have anosmia (lose sense of smell) or hyposmia
Kallmann syndrome
most common form of female gonadal dysgenesis (1 in 250 births)
- majority show no signs of secondary sex characteristics
- mosaicism: 25%
- webbing of neck
- broad flat chest
- short stature
- streaked ovaries
- coarctation of aorta
Turners syndrome, 45 XO
46 XY
- male levels of testosterone
- defect in androgen receptor
- testes in abdominal wall: secrete normal amounts of antimullerian hormones (so no uterus forms)
- external female genitalia
- breast development with smaller than normal areola/nipples (caused by estrogen secretion in testes and conversion of androgens to estrogen in the liver)
androgen insensitivity syndrome (AIS)
- tx: gonadectomy after puberty to avoid neoplasm (gonadoblastoma and dysgerminomas)
primary amenorrhea, breast development, levels of testosterone consistent with females and karyotype 46XX
- mullerian defects that cause obstruction of vaginal canal
- imperforate hymen or transverse septum
- absence of normal uterus: failure of the mullerian ducts to fuse distally and to form the upper genital tract (will have a vaginal dimple)
mullerian dysgenesis or agenesis
15% of primary amenorrhea, 46XX
- normal secondary development and external female genitalia
- normal FEMALE range testosterone
- absent uterus and upper vagina
- normal ovaries
- renal anomalies are common
- most common cause primary amenorrhea in women with normal breast development
Mayter-Rokitanksky-Kuster-Hauser syndrome
mullerian agenesis
normal uterus on US
- imperforate hymen
- suspect in adolescents if they present complaining of monthly dysmenorrhea without vaginal bleeding
- vaginal bulge and midline cystic mass
outflow tract obstruction
- tx: hymenectomy
these patients present with similar sx to outflow tract obstruction, but will NOT have vaginal bulge
transverse vaginal septum
diagnostic evaluation of pt with secondary amenorrhea d/t:
- thyroid disease
- normal prolactin
- abnormal TSH
diagnostic evaluation of pt with secondary amenorrhea d/t:
- mild hypothyroidism
more often associated with hypermenorrhea or oligomenorrhea (NOT amenorrhea)
- tx should restore menses, may take several months
what is the tx for microadenomas (<10mm) found on MRI
- typically are slow growing and rarely malignant
can be monitored with repeat prolactin measurements and imaging
- tx should focus on management of infertility, glactorrhea, and breast discomfort
- consideration for dopamine agonist
what is the tx for macroadenoma (>10mm)
may be treated with dopamine agonist
- transphenoidal resection or craniotomy
secondary amenorrhea
- normal TSH and prolactin -> progesterone challenge test (PCT)
- if PCT positive?
- if PCT negative?
if positive: positive bleeding (normogonadotropic -> PCOS most common)
in negative: no withdrawal bleeding (indicates inadequate estrogenization or an outflow tract abnormality)
what is performed after a progesterone challenge test?
estrogen/progesterone challenge test
what does a negative estrogen/progesterone challenge test indicate?
outflow tract obstruction
what does a positive estrogen/progesterone challenge test indicate?
abnormality with the hypothalamic-pituitary axis or ovaries
- if FSH/LH is elevated = ovarian abnormality
- if FSH/LH normal or low = pituitary or hypothalamic abnormality -> ORDER MRI
what does it indicated if an MRI shows no tumor after positive estrogen/progesterone challenge test and normal/low FSH/LH?
hypothalamic cause of amenorrhea
- *leading cause of female anovulatory infertility**
- 60-70% of patients have insulin sensitivity
- elevated insulin and androgen levels reduce the hepatic production of sex hormone binding globulins(SHBG)
PCOS
- anovulation
- y=hyperandrogenism
- hirsuitism
- acne
- menstrual dysfunction
- hyperinsulinemia
- LH hypersecretion
- elevated testosterone
- obesity, sleep disorders, acanthosis nicrigans, lipid abnormalities
what are the 3 criteria for diagnosing PCOS (need 2/3)?
- oligomenorrhea or amenorrhea
- biochemical or clinical signs of hyperandrogenism (LH to FSH 2:1)
- US revealing multiple small cysts beneath the cortex of the ovary
what are the tx for PCOS?
- weight loss
- oral contraceptives (suppress gonadotropins FSH/LH, estrogen also stimulates the sex hormone binding globulin)
- clomiphene citrate (can induce ovulation)
- ovarian diathermy/laser tx
- spironolactone and/or electrolysis (competes for testoterone-binding sites)
- insulin sensitizing agents (metformin)
excess terminal hair in a male pattern distribution
- represents exposure to hair follicles to androgen excess
0 can be familial, not always pathological
- Ferrima-Galloway scale
hirsutism
masculinization of a female associated with marked increase in circulating testosterone
- enlargement of the clitoris, temporal balding, deepening of the voice, decreased breast size, loss of female body fat distribution, and hirsutism
- usually results from excessive male hormone production or exogenous hormone use
virilization
polymenorrhagia
abnormally frequent menses at intervals <21 days
menorrhadia (hypermenorrhea)
excessive or prolonged bleeding (>80mL and > 7 days)
- occurs at normal intervals
metrorrhagia
irregular episodes of uterine bleeding
menometrorrhagia
heavy and irregular uterine bleeding
intermenstrual bleeding
scant bleeding at ovulation for 1 or 2 days
oligomenorrhea
menstrual cycles occurring >35 days but less than 6 months
abnormal uterine bleeding that cannot be attributed to:
- meds
- blood dyscrasias (thrombocytopenia, leukemia, autoimmune)
- systemic disease
- trauma
- organic conditions (pregnancy, fibroids, polyps)
- usually caused by aberrations in the HPO axis
- most often occurs around years of menarche (11-14) or perimenopause (45-50)
dysfunctional uterine bleeding (DUB)
what are the structural causes of abnormal bleeding? (PALM)
polyps
adenomyosis
leiomyoma
malignancy and hyperplasia
what are the nonstructural cause of abnormal bleeding? (COEIN)
coagulopathy (associated with heavy flow)
ovulatory dysfunction (unpredictable menses w/variable flow)
endometrial (infection)
iatrogenic (exogenous hormones)
not yet classified (arteriovenous malformations)
what is the workup for abnormal uterine bleeding (AUB)?
- pregnancy test
- CBC
- targeted screening for vWF, PT/PTT
- TSH
- chlamydia trachomatic
what is the tx for AUB if massive bleeding?
hospitalization and transfusion if unstable
- 25mg IV conjugated estrogens then normal treatment (combination hormonal therapy, mirena)
what is the tx for AUB if moderate bleeding?
combination OCP’s, Mirena
wht is the tx for AUB if unresponsive to conservative therapy?
D&C, polypectomy, myomectomy, endometrial ablation, hysterectomy
