Puberty, Disorders of Development, & Menstrual Disorders Flashcards
A major characteristic of follicular growth and estradiol secretion is explained by the 2 cell theory of ovarian follicular development. What is the 2 cell theory?
LH stimulates the theca cells to produce androgens
FSH stimulates the granulosa cells to convert those androgens to estrogens
Hormone changes during the luteal phase
LH and FSH are significantly suppresed through negative feedback effect of elevated circulating estradiol and progesterone
If conception does not occur, progesterone and estradiol level decline near the end of the luteal phase as a result of corpus luteal regression
FSH will then rise which initiates new follicular growth for the next cycle
______ appears to enhance the hypothalamic release of GnRH and induce the midcycle LH surge
Estradiol
[during early follicular development, estradiol levels are low; approx 1 wk before ovulation, estradiol levels begin to increase; during the luteal phase, estradiol rises to a maximum 5-7 days after ovulation and returns to baseline before menstruation]
Describe changes in secretion of progestins during the ovarian cycle
During follicular development, the ovary secretes only a small amount of progesterone
Prior to ovulation, the unruptured luteinizing graafian follicle begins to produce increasing amounts of progesterone
Secretion of progesterone by the corpus luteum reaches a maximum 5-7 days after ovulation and returns to baseline before menstruation
At about 8-10 weeks of fetal development, oocytes become surrounded by precursor granulosa cells. This oocyte-granulosa cell complex is called a ____
Primordial follicle
In the ADULT ovary, a graafian follicle forms. The innermost 3-4 layers of multiplying granulosa cells become cuboidal and adherent to the ovum; this is known as the _____
Cumulus oophorus
After ovulation, the granulosa cells of the ruptured follicle undergo luteinization. The luteinized granulosa cells, theca cells, capillaries, and CT form the corpus luteum. The corpus luteum produces copious amounts of _____ and some estradiol
Progesterone
What histologic portion of the endometrium contains spiral arteries and undergoes cyclic changes during the menstrual cycle and is sloughed off at menstruation?
Functionalis
[the basalis layer contains basal arteries, remains relatively unchanged during each cycle, and produces stem cells for renewal of functionalis layer]
During which phase of the uterine cycle is endometrial lining at its maximal thickness?
Secretory phse
Why is an intact coagulation pathway important in regulating menstruation?
Menstruation disrupts blood vessels, but with normal hemostasis, the injured vessels are rapidly repaired
Restoration of these blood vessels requires successful interaction of platelets and clotting factors
[certain medications and clotting disorders are associated heavy bleeding]
The median age of menarche is _____. Menarche usually occurs within 2-3 years after ______ at tanner stage IV, rarely before tanner stage III.
12.43; thelarche
Define primary amenorrhea
No menstruation by 13 y/o without secondary sexual development OR by the age of 15 with secondary sexual characteristics
Length of normal menstrual cycle in adults
21-35 days
[in first few years after menarche may be 21-45 days]
Normal vs. excessive menstrual flow
Normal mean blood loss per menstrual period is 30 cc — most report changing a pad 3-6x/day
Excess is >80cc — often associated with anemia [changing a pad q1-2 hrs is considered excessive especially if bleeding is lasting >7 days]
Onset of puberty is determined primarily by what 3 factors?
Genetic factors (including race)
Geographic location
Nutritional status (obese children have earlier puberty, malnourished later, mean weight of 106 lbs required to start menarche)
The female infant acquires the lifetime peak number of oocytes of 6-7 million by midgestation (16-20 wks). The HPO axis is _____ between the ages of 4-10 y/o.
Suppressed
[low levels of gonadotropins and sex steroids during prepubertal period are due to both negative feedback by low levels of estradiol as well as intrinsic CNS inhibition of GnRH secretion]
Between ages of 8-11 there is an increase in which 3 hormones responsible for axillary and pubic hair development?
DHEA, DHEA-S, and androstenedione
Describe onset of puberty around age 11
Around age 11, there is a gradual loss of sensitivity to the negative feedback of sex steroids + intrinsic loss of CNS inhibition of hypothalamic GnRH release
Sleep-associated increases in GnRH occur and gradually shift into adult type secretory patterns
The increase in GnRH promotes ovarian follicular maturation and sex steroid production, which leads to the deveopment of secondary sex characteristics
By mid to late puberty, the positive-feedback mechanism of estradiol on LH release from the anterior pituitary gland is complete and ovulatory cycles are established
Stages of normal pubertal development
- Thelarche (first physical sign of puberty, requires estrogen)
- Pubarche/adrenarche (requires androgens)
- Peak height velocity (occurs about 1 yr before onset of menses)
- Menarche (requires pulsatile GnRH from hypothalamus, FSH and LH, estrogen and progesterone, and normal outflow tract)
- Mature sexual hair and breasts
Tanner staging of breast development
Stage 1: preadolescent; elevation of papilla only
Stage 2: breast bud stage; elevation of breast and papillla as a small mound with enlargement of the areolar region
Stage 3: Further enlargement of breast and areola without separation of their contours
Stage 4: projection of areola and papilla to form a secondary mound above the level of the breast
Stage 5: mature stage; projection of papilla only, resulting from recession of the areola to the general contour of the breast
Tanner staging of pubic hair
Stage 1: Preadolescent; absence of pubic hair
Stage 2: Sparse hair along the labia; hair downy with slight pigment
Stage 3: Hair spreads sparsely over junction of pubes; hair is darker and coarser
Stage 4: adult-type hair; there is no spread to the medial surface of the thighs
Stage 5: adult-type hair with spread to the medial thighs assuming an inverted triangle pattern
Define precocious puberty
Development of any sign of secondary sex characteristics prior to an age 2.5 standard deviations earlier than the expected age of pubertal onset (in North America — 8 y/o for girls, 9 y/o for boys)
75% of cases of precocious puberty are idiopathic. Why is it important to do a thorough evaluation?
To eliminate a serious disease and to arrest potential osseous maturation that can affect normal growth patterns (can lead to premature fusion of the long bones epiphysis)
What is heterosexual precocious puberty and what are 3 potential causes?
Development of secondary sexual characteristics opposite those of anticipated phenotypic sex
Causes include virilizing neoplasms, congenital adrenal hyperplasia, and exposure to endogenous androgens
Define isosexual precocious puberty and its primary cause
Premature sexual maturation that is appropriate for the phenotype of the affected individual
Cause is typically constitutional and organic brain disease (tumors, trauma, infectious process)
One potential cause of heterosexual precocity is a virilizing neoplasm. These are very rare in childhood and typically originate in the ovaries (Sertoli-Leydig cell) or adrenals. How are these diagnosed and treated?
Diagnosed by PE and radiology
Treated with surgical removal
One potential cause of heterosexual precocity is congenital adrenal hyperplasia, most commonly resulting from a defect of the adrenal enxyme 21-hydroxylase leading to excess androgen production. What is the difference between classical vs. non classical congenital adrenal hyperplasia?
Classical — most severe forms can cause birth of female w/ ambiguous genitalia; if untreated, progressive virilization and short adult status will result
Nonclassical — late-onset, can cause premature pubarche and an adult disorder resembling PCOS
True isosexual precocity arises from premature activation of the normal process of pubertal development involving the HPO axis. What is pseudoisosexual precocity?
Increased estrogen levels and sexual characteristic maturation WITHOUT activation of the HPO axis (i.e., estrogen producing tumors)
75% of true isosexual precocious puberty is constitutional or idiopathic. How is it diagnosed and treated?
Diagnose with administration of exogenous GnRH and see a resultant rise in LH levels consistent with older girls who are undergoing normal puberty
Tx with GnRH agonist — this will suppress pituitary release of FSH/LH, resulting in decline of gonadotrophins to prepubertal levels and arrest of gonadal sex steroid secretion
[note: 10% of cases are caused by CNS disorder and are dx by MRI of the head]
Cause of pseudoisosexual precocity involving somatic mutation during embryogenesis which causes them to function independent of their normal stimulating hormones; associated with multiple cystic bone defects, cafe au lait spots, and adrenal hypercortisolism
McCune-Albright syndrome
Cause of pseudoisosexual precocity associated with a sex cord tumor that secretes estrogen; associated with GI polyposis and mucocutaneous pigmentation
Peutz-Jeghers syndrome
When is puberty considered delayed?
Secondary sexual characteristics have not appeared by age 13
Thelarche has not occurred by 14
No menarche by 15-16
No menarche 5 years after onset of thelarche
Causes of delayed puberty
Hypergonadotropic hypogonadism (Turner syndrome)
Hypogonadotropic Hypogonadism (Constitutional delay, Kallman syndrome, anorexia/extreme exercise, pituitary tumors/disorders, hyperprolactinemia, drug use)
Anatomic causes (mullerian agenesis, imperforate hymen, transverse vaginal septum)
Define secondary amenorrhea
Patient with prior menses has absent menses for 6+ months
Primary amenorrhea with absence of secondary sexual characteristics as well as diagnostic findings of FSH and LH <5 IU/L indicates hypogonadotropic hypogonadism. what is the most common cause of this type of delayed puberty?
Constitutional (physiologic) delay
Cause of hypogonadotropic hypogonadism characterized by absence of migration of GnRH neurons into the hypothalamus as well as anosmia
Kallman syndrome
Describe workup for pt who presents with primary amenorrhea in whom secondary sex characteristics are ABSENT
Measure FSH and LH levels
If FSH and LH < 5 IU/L, it is hypogonadotropic hypogonadism which can be due to many causes including hypothalamic or pituitary lesions, anorexia, hyperprolactinemia, Kallman syndrome, or most commonly constitutional (physiologic) delay
If FSH > 20 IU/L and LH >40 IU/L, it is hypergonadotropic hypogonadism. Next step is a karyotype analysis. If karyotype is 46, XX it is premature ovarian failure. If karyotype is 45,XO, it is Turners syndrome
Most common form of female gonadal dysgenesis, characterized by absent secondary sexual characteristics, webbed neck, shield chest, short stature, streak ovaries, and coarctation of aorta
Turner’s syndrome
Describe workup for pt who presents with primary amenorrhea in whom secondary sex characteristics are PRESENT
First perform uterine ultrasound.
If uterus is absent or abnormal, do a karyotype analysis. 46,XY = androgen insensitivity syndrome. 46,XX = mullarian agenesis.
If uterus is present or normal, check for outflow obstruction. If there is no outflow obstruction, evaluate for secondary amenorrhea. If there is an outflow obstruction, evaluate for imperforate hymen vs. transverse vaginal septum
Condition in which there are male levels of testosterone in a female, as well as testes in the abdominal wall secreting normal amounts of antimullerian hormone — thus there is no uterus formation but external genitalia appear female w/ absent or sparse pubic hair, as well as breast development with smaller than normal areola/nipples
Androgen insensitivity syndrome (46,XY)
Tx for androgen insensitivity syndrome
Gonadectomy after puberty to avoid neoplasm (gonadoblastomas and dysgerminomas)
Can create neovagina by surgical and nonsurgical methods; consider HRT
Most common cause of primary amenorrhea in women with normal breast development
Mullerian agenesis (Meyer-Rokitansky-Kuster-Hauser) [46,XX]
[failure of mullerian ducts to fuse distally, so uterus is absent but may have unilateral or bilateral rudimentary uterine tissue, tubes, and ovaries; normal female testosterone levels; renal anomalies are common so check IVP]
Outflow obstruction suspected in adolescents who present complaining of monthly dysmenorrhea without vaginal bleeding, vaginal bulge, and midline cystic mass
Imperforate hymen
[confirm with US, showing normal uterus and hematocolpos]
Tx with hymenectomy
Condition that presents similar to imperforate hymen but will not have vaginal bulge; usually dx by MRI and corrected with surgery
Transverse vaginal septum
The first step in the workup of a pt who presents with secondary amenorrhea and a negative pregnancy test is to check a TSH and prolactin level. What is the next step if both of these are normal?
Progesterone challenge test
If there is withdrawal bleeding, it is normogonadotropic hypogonadism (causes include PCOS, nonclassic CAH, Cushings, Sertoli-leydig tumor, exogenous androgens)
If there is no withdrawal bleeding, proceed with estrogen/progesterone challenge test. If there is withdrawal bleeding, check FSH/LH, if elevated it is hypergonadotropic hypogonadism; if FSH/LH low then do MRI to check for pituitary adenoma. If there is no withdrawal bleeding, it is likely an outflow obstruction
First step in workup of pt with secondary amenorrhea
Pregnancy test
Leading cause of female anovulatory infertility, associated with insulin resistance and increased circulating testosterone
PCOS
Tx for PCOS
Weight loss
OCPs — suppresses FSH and LH, estrogen stimulates SHBG
Clomiphene citrate — can induce ovulation
Ovarian diathermy/laser tx
Spironolactone and/or electrolysis
Insulin-sensitizing agents - metformin
The first step in the workup of a pt who presents with secondary amenorrhea and a negative pregnancy test is to check a TSH and prolactin level. What is the next step if the prolactin is normal but the TSH is abnormal?
Treat thyroid disease
[note: mild hypothyroidism is more often associated with hypermenorrhea or oligomenorrhea; tx should restore menses w/i a few months]
The first step in the workup of a pt who presents with secondary amenorrhea and a negative pregnancy test is to check a TSH and prolactin level. What is the next step if TSH is normal but prolactin is abnormal?
If prolactin is <100, consider other causes
If prolactin is >100, perform MRI to evaluate for prolactinoma. If MRI is negative, consider other causes — ectopic prolactin production (bronchogenic carcinoma, ovarian dermoid cyst, RCC, gonadoblastoma), breastfeeding and stimulation, excessive exercise, severe head trauma, hypothyroid, liver or renal failure, meds (OCPs, antipsychotics, antidepressants, antihypertensives, H2 blockers, opiates, cocaine)
PE considerations in pts presenting with hyperandrogenism
Degree of hirsutism, acne, and alopecia should be documented
Acanthosis nigricans — sign of insulin resistance
Bimanual exam assessing for ovarian enlargement
What labs should you do on someone who presents with apparent hyperandrogenism?
17-hydroxyprogesterone level to exclude 21 hydroxylase deficiency CAH
24 hr free urinary cortisol or overnight dexamethasone suppression test — will rule out cushing syndrome
Prolactin and TSH to exclude hyperprolactinemia +/- thyroid dysfunction
Glucose, lipid levels
Testosterone and DHEA-S — high testosterone suspect ovarian androgen producing tumor; DHEA-S suspect adrenal androgen producing tumor
Abnormally frequent menses at intervals <21 days
Polymenorrhea
Excess and/or prolonged bleeding (>80mL and >7days) occurring at normal intervals
Menorrhagia
Irregular episodes of uterine bleeding
Metrorrhagia
Heavy and irregular uterine bleeding
Menometrorrhagia
Define intermenstrual bleeding
Scant bleeding at ovulation for 1-2 days
Menstrual cycles occurring >35 days but less than 6 months
Oligomenorrhea
PALM-COEIN classification system for abnormal bleeding in reproductive age women
PALM: Structural Causes Polyp Adenomyosis Leiomyoma (or other myoma) Malignancy and Hyperplasia
COEIN: Nonstructural Causes Coagulopathy Ovulatory Dysfunction Endometrial Iatrogenic (IUD, hormones) Not yet classified
Medical history considerations in pt that presents with abnormal uterine bleeding
Age of menarche and menopause Menstrual bleeding patterns Severity of bleeding Pain Medical conditions Surgical hx Medications Signs/symptoms of bleeding d/o
PE considerations in pt that presents with DUB
General exam
Pelvic exam — external, speculum with pap if needed, bimanual
Lab and other diagnostic tests to consider in pts that present with DUB
Pregnancy test CBC Targeted screening for bleeding d/o (VonW, PT, PTT) TSH Chlamydia
Consider transvaginal US, saline infusion sonohysterography, MRI, hysteroscopy, endometrial biopsy
Treatment for AUB in which there is massive bleeding
Hospitalization and transfusions if hemodynamically unstable
25 mg IV conjugated estrogens, then hormonal tx (combo therapy, Mirena)
Treatment for AUB in which there is moderate bleeding
Combination OCPs
Mirena
Treatments to consider for AUB in which bleeding is unresponsive to conservative therapy
D and C, polypectomy, myomectomy, endometrial ablation, hysterectomy
