Puberty, Disorders of Development, & Menstrual Disorders

Question 1

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?

Answer 1

LH stimulates the theca cells to produce androgens

FSH stimulates the granulosa cells to convert those androgens to estrogens

Question 2

Hormone changes during the luteal phase

Answer 2

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

Question 3

______ appears to enhance the hypothalamic release of GnRH and induce the midcycle LH surge

Answer 3

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]

Question 4

Describe changes in secretion of progestins during the ovarian cycle

Answer 4

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

Question 5

At about 8-10 weeks of fetal development, oocytes become surrounded by precursor granulosa cells. This oocyte-granulosa cell complex is called a ____

Answer 5

Primordial follicle

Question 6

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 _____

Answer 6

Cumulus oophorus

Question 7

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

Answer 7

Progesterone

Question 8

What histologic portion of the endometrium contains spiral arteries and undergoes cyclic changes during the menstrual cycle and is sloughed off at menstruation?

Answer 8

Functionalis

[the basalis layer contains basal arteries, remains relatively unchanged during each cycle, and produces stem cells for renewal of functionalis layer]

Question 9

During which phase of the uterine cycle is endometrial lining at its maximal thickness?

Answer 9

Secretory phse

Question 10

Why is an intact coagulation pathway important in regulating menstruation?

Answer 10

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]

Question 11

The median age of menarche is _____. Menarche usually occurs within 2-3 years after ______ at tanner stage IV, rarely before tanner stage III.

Answer 11

12.43; thelarche

Question 12

Define primary amenorrhea

Answer 12

No menstruation by 13 y/o without secondary sexual development OR by the age of 15 with secondary sexual characteristics

Question 13

Length of normal menstrual cycle in adults

Answer 13

21-35 days

[in first few years after menarche may be 21-45 days]

Question 14

Normal vs. excessive menstrual flow

Answer 14

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]

Question 15

Onset of puberty is determined primarily by what 3 factors?

Answer 15

Genetic factors (including race)

Geographic location

Nutritional status (obese children have earlier puberty, malnourished later, mean weight of 106 lbs required to start menarche)

Question 16

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.

Answer 16

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]

Question 17

Between ages of 8-11 there is an increase in which 3 hormones responsible for axillary and pubic hair development?

Answer 17

DHEA, DHEA-S, and androstenedione

Question 18

Describe onset of puberty around age 11

Answer 18

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

Question 19

Stages of normal pubertal development

Answer 19

1. Thelarche (first physical sign of puberty, requires estrogen)
2. Pubarche/adrenarche (requires androgens)
3. Peak height velocity (occurs about 1 yr before onset of menses)
4. Menarche (requires pulsatile GnRH from hypothalamus, FSH and LH, estrogen and progesterone, and normal outflow tract)
5. Mature sexual hair and breasts

Question 20

Tanner staging of breast development

Answer 20

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

Question 21

Tanner staging of pubic hair

Answer 21

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

Question 22

Define precocious puberty

Answer 22

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)

Question 23

75% of cases of precocious puberty are idiopathic. Why is it important to do a thorough evaluation?

Answer 23

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)

Question 24

What is heterosexual precocious puberty and what are 3 potential causes?

Answer 24

Development of secondary sexual characteristics opposite those of anticipated phenotypic sex

Causes include virilizing neoplasms, congenital adrenal hyperplasia, and exposure to endogenous androgens

Question 25

Define isosexual precocious puberty and its primary cause

Answer 25

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)

Question 26

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?

Answer 26

Diagnosed by PE and radiology Treated with surgical removal

Question 27

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?

Answer 27

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

Question 28

True isosexual precocity arises from premature activation of the normal process of pubertal development involving the HPO axis. What is pseudoisosexual precocity?

Answer 28

Increased estrogen levels and sexual characteristic maturation WITHOUT activation of the HPO axis (i.e., estrogen producing tumors)

Question 29

75% of true isosexual precocious puberty is constitutional or idiopathic. How is it diagnosed and treated?

Answer 29

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]

Question 30

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

Answer 30

McCune-Albright syndrome

Question 31

Cause of pseudoisosexual precocity associated with a sex cord tumor that secretes estrogen; associated with GI polyposis and mucocutaneous pigmentation

Answer 31

Peutz-Jeghers syndrome

Question 32

When is puberty considered delayed?

Answer 32

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

Question 33

Causes of delayed puberty

Answer 33

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)

Question 34

Define secondary amenorrhea

Answer 34

Patient with prior menses has absent menses for 6+ months

Question 35

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?

Answer 35

Constitutional (physiologic) delay

Question 36

Cause of hypogonadotropic hypogonadism characterized by absence of migration of GnRH neurons into the hypothalamus as well as anosmia

Answer 36

Kallman syndrome

Question 37

Describe workup for pt who presents with primary amenorrhea in whom secondary sex characteristics are ABSENT

Answer 37

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

Question 38

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

Answer 38

Turner’s syndrome

Question 39

Describe workup for pt who presents with primary amenorrhea in whom secondary sex characteristics are PRESENT

Answer 39

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

Question 40

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

Answer 40

Androgen insensitivity syndrome (46,XY)

Question 41

Tx for androgen insensitivity syndrome

Answer 41

Gonadectomy after puberty to avoid neoplasm (gonadoblastomas and dysgerminomas) Can create neovagina by surgical and nonsurgical methods; consider HRT

Question 42

Most common cause of primary amenorrhea in women with normal breast development

Answer 42

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]

Question 43

Outflow obstruction suspected in adolescents who present complaining of monthly dysmenorrhea without vaginal bleeding, vaginal bulge, and midline cystic mass

Answer 43

Imperforate hymen [confirm with US, showing normal uterus and hematocolpos] Tx with hymenectomy

Question 44

Condition that presents similar to imperforate hymen but will not have vaginal bulge; usually dx by MRI and corrected with surgery

Answer 44

Transverse vaginal septum

Question 45

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?

Answer 45

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

Question 46

First step in workup of pt with secondary amenorrhea

Answer 46

Pregnancy test

Question 47

Leading cause of female anovulatory infertility, associated with insulin resistance and increased circulating testosterone

Answer 47

PCOS

Question 48

Tx for PCOS

Answer 48

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

Question 49

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?

Answer 49

Treat thyroid disease [note: mild hypothyroidism is more often associated with hypermenorrhea or oligomenorrhea; tx should restore menses w/i a few months]

Question 50

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?

Answer 50

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)

Question 51

PE considerations in pts presenting with hyperandrogenism

Answer 51

Degree of hirsutism, acne, and alopecia should be documented Acanthosis nigricans — sign of insulin resistance Bimanual exam assessing for ovarian enlargement

Question 52

What labs should you do on someone who presents with apparent hyperandrogenism?

Answer 52

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

Question 53

Abnormally frequent menses at intervals <21 days

Answer 53

Polymenorrhea

Question 54

Excess and/or prolonged bleeding (>80mL and >7days) occurring at normal intervals

Answer 54

Menorrhagia

Question 55

Irregular episodes of uterine bleeding

Answer 55

Metrorrhagia

Question 56

Heavy and irregular uterine bleeding

Answer 56

Menometrorrhagia

Question 57

Define intermenstrual bleeding

Answer 57

Scant bleeding at ovulation for 1-2 days

Question 58

Menstrual cycles occurring >35 days but less than 6 months

Answer 58

Oligomenorrhea

Question 59

PALM-COEIN classification system for abnormal bleeding in reproductive age women

Answer 59

``` 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 ```

Question 60

Medical history considerations in pt that presents with abnormal uterine bleeding

Answer 60

``` Age of menarche and menopause Menstrual bleeding patterns Severity of bleeding Pain Medical conditions Surgical hx Medications Signs/symptoms of bleeding d/o ```

Question 61

PE considerations in pt that presents with DUB

Answer 61

General exam | Pelvic exam — external, speculum with pap if needed, bimanual

Question 62

Lab and other diagnostic tests to consider in pts that present with DUB

Answer 62

``` Pregnancy test CBC Targeted screening for bleeding d/o (VonW, PT, PTT) TSH Chlamydia ``` Consider transvaginal US, saline infusion sonohysterography, MRI, hysteroscopy, endometrial biopsy

Question 63

Treatment for AUB in which there is massive bleeding

Answer 63

Hospitalization and transfusions if hemodynamically unstable 25 mg IV conjugated estrogens, then hormonal tx (combo therapy, Mirena)

Question 64

Treatment for AUB in which there is moderate bleeding

Answer 64

Combination OCPs Mirena

Question 65

Treatments to consider for AUB in which bleeding is unresponsive to conservative therapy

Answer 65

D and C, polypectomy, myomectomy, endometrial ablation, hysterectomy