Female Reproductive System Endocrine Pathophysiology

Question 1

What is the relative hormonal requirement for ovulation, menstrual cycle proliferation, mucus production, and development of vagina, urethra, and breasts / how is this relevant?

Answer 1

Vagina/urethra/breasts < glandular mucus production < menstrual cycle proliferative phase < ovulation

• > smallest amount is needed to initiate puberty and development of secondary sexual characteristics
• > events of puberty happen in a predictable fashion based on circulating estrogen levels

Question 2

What characterizes the onset of puberty in terms of LH?

Answer 2

Nocturnal rise in LH levels due to pulsatile GnRH release at night -> leads to increased testosterone
-> occurs during REM sleep

Question 3

Why do we think puberty is happening earlier nowadays?

Answer 3

Related to nutrition

-> being a greater mass allows puberty to ensue faster (you’ve met your nutritional requirements)

Question 4

Place the following in the correct order, and define them:

Growth spurt, adrenarche, pubarche, thelarche, menarche

Answer 4

Thelarche - breast bud / breast growth
Pubarche - pubic hair growth
Adrenarche - axillary hair growth (think adrenal glands make hair)
Growth spurt - follow hair growth
Menarche - first menstrual bleed

Question 5

What is the average timespan between thelarche and menarche and who tends to get it earlier? During what Tanner stage does menarche usually occur?

Answer 5

Around 2.5 years, tends to occur earlier in African Americans, with mild obesity

Tanner Stage 3 - Menarche

Question 6

What is the definition of precocious vs delayed puberty in females?

Answer 6

Precocious - Tanner Stage 2 at <8 years

Delay - Tanner Stage 1 at age 13, or no menses by age 16.

Question 7

What is the definition of true precocity and what are the main causes in women?

Answer 7

GnRH dependent or central precocioius puberty (driven by hypothalamus)

1. Idiopathic is primary cause
2. CNS problem can also be the cause - unwanted activation of hypothalamus pulse generator.
   - > this reason is more common in girls

Question 8

What are the most common causes of precocious pseudopuberty in boys and girls? What is this also called?

Answer 8

GnRH-independent puberty (peripheral puberty)

Boys - Testicular tumor (either theca cell or choriocarcinoma secreting hCG)

Girls - Ovarian tumor (i.e. granulosa cell making estrogen)

Question 9

What usually causes hypergonadotropic hypogonadism?

Answer 9

Usually a chromosomal abnormal causing gonadal dysgenesis
-> i.e. Turner syndrome

Gonadotrope levels are high, but gonads are not responding

Question 10

What are some reversile causes of hypogonadotropic hypogonadism?

Answer 10

Physiologic delay in puberty
Weight loss
Hypothyrodism
Prolactinoma

Question 11

What are some causes of irreversible hypogonadotropic hypogonadism?

Answer 11

GnRH deficiency - i.e. Kallmann
Hypopituitarism
Craniopharyngioma / other pituitary tumors
Congenital CNS defects

Question 12

What is the normal range of the menstrual cycle and the average duration of menses? How much blood is lost?

Answer 12

Normal - 21 to 35 days, mean 28 days

Average menses - 3-8 days -> about 30 mL is lost (1 oz)

Question 13

What is the rate of GnRH pulses during follicular and luteal phase?

Answer 13

Follicular phase - quickly to stimulate follicule - every 60 minutes

Luteal phase - slowly to maintain endometrium - 90 minutes

Question 14

What does an activin do? What produces them?

Answer 14

It is produced by the same cells as inhibins (Ovarian stromal cells), except they do the opposite of inhibins -> they STIMULATE gonadotropes to release FSH

Question 15

What marker do primary follicles express, and what stage of Meiosis are they found in? When do they move on?

Answer 15

They express anti-Mullerian hormone -> can be used to track the development of the primary follicles

They are stuck in Prophase I of Meiosis I, they will move on when the corona radiata (inner layer of granulosa cells) stops delivering cAMP thru the zona pellucida (distinct mucopolysaccharide band) during the Graafian follicle stage -> secondary oocyte will arrest at Metaphase II until fertilization.

Question 16

What are the ovarian and endometrial cycles and relative timing?

Answer 16

Ovarian: Starts with follicular phase, then ovulation occurs, then you have the luteal phase (corpus luteum)

Endometrial: Starts with proliferative phase (under influence of estrogens), then enters secretory phase (during luteal phase of ovarian cycle)

Question 17

Defining as day 1 as the first day after menses, when is a dominant follicle selected and how is it selected? What happens to the other follicles?

Answer 17

Selected around day 5-7

Depends on follicle’s intrinsic capacity to synthesis estrogen (highest estrogen to androgen ratio due to most utilization of FSH by granulosa cells)
-> this is based on the number of FSH receptors expressed.

All other follicles become atretic

Question 18

How does estrogen act synergistically with FSH in follicle development?

Answer 18

Estrogen induces LH receptors and induces FSH receptors in granulosa and theca -> helps stimulate and nuture production of testosterone via theca cells to give to granulosa cells.

Question 19

What triggers the LH surge and what affect does this have on the follicle during and after ovulation?

Answer 19

Estradiol reaches a threshold concentration, which leads to LH surge

LH surge causes rupture of follicular wall with ovum release

Granulosa cells become “luteinized” from exposure to so much LH -> become filled with lipid via upregulation of LDL receptor. Also upregulate 3b hydroxysteroid DH to make more progesterone-> primarily progesterone (aromatase is turned off, no estrogen made)

Question 20

What does progesterone do during the luteal phase?

Answer 20

1. Suppresses maturation of other follicles in ipsilateral ovary
2. Thermogenic activity - accounts for the 0.5 degree increase in basal body temp during ovulation

Question 21

What triggers menses?

Answer 21

Overtime, the corpus luteum loses sensitivity to gonadotropins -> stops secretion of estrogen and progresterone.

Can only be saved by hCG

Question 22

What are the two main layers of the endometrium?

Answer 22

1. Basal layer - adjacent to myometrium, remains intact throughout the menstrual cycle. These are basically the stem cells of the uterus.
2. Functional layer - Layer which proliferates from basal layer under influence of estrogen, and will die when spiral arteries become ischemic (mainly due to prostaglandin-mediated constriction)

Question 23

What is characteristic of the secretory / luteal phase in the endometrium (stroma, glands, and arteries)? What is the overall process / change which is occurring in the endometrium?

Answer 23

Mostly under influence of progesterone: Mitotic activity is severely restricted, endometrial glands produce and secrete glycogen-rich vacuoles.

Stroma becomes edematous, enlarged, and corkscrew-shaped.

Spiral arterioles develop and extend nearly to the surface

-> this is the “decidualization” which occurs in preparation for the bb

Question 24

What are the sources of androgens in women?

Answer 24

1. Adrenal cortex - primary source of androgens, mostly DHEA and androstenedione
2. Ovary - a small amount is made, mostly androstenedione

Androstenedione is converted peripherally to testosterone to some degree

Question 25

What are the clinical features of hyperandrogenism in women?

Answer 25

1. Hirsutism 2. Acne 3. Male pattern baldness - central loss of hair with recession of temporal area 4. Android obesity (apple shaped rather than pear-shaped) - increased waist to hip ration (>0.85)

Question 26

What are the two places women never make hair unless it's pathologic?

Answer 26

1. The chest (excluding the breast) | 2. The small of the back

Question 27

How will the ovaries appear in polycystic ovarian syndrome (PCOS)?

Answer 27

Enlarged, bilateral cystic ovaries from unruptured follicular cysts -> cysts are not rupturing due to hormonal imbalance These are secondary follicles which weren't selected for and don't regress.

Question 28

What is the clinical definition of PCOS?

Answer 28

2/3 of the following: 1. Irregular uterine bleeding 2. Hyperandrogenism - either seen clinically or measured 3. Polycystic ovaries

Question 29

What condition is easily confused with PCOS and what causes that condition?

Answer 29

Non-classic Congenital Adrenal Hyperplasia -> Increased androgens due to loss of 21-hydroxylase enzyme. Main distinguishing factor: Non-classic CAH has very high levels of 17-OH-Progesterone (upstream from the block)

Question 30

What is going wrong hormonally in PCOS which accounts for the symptoms?

Answer 30

Hyperinsulinemia / insulin resistance alter the hypothalamic hormonal balance and cause: 1. Increased LH:FSH ratio, which stimulates increased androgen production from theca interna cells --> hirsutism. 2. High circulating androgen levels are converted to estrone via adipose tissue (these women are obese with insulin resistance) -> feedback by estrone decreases FSH levels secreted by anterior pituitary. 3. Since FSH is low, androgens are not rapidly turned into estrogen via granulosa cells -> slowed rate of follicular maturation. This leads to small follicular cysts and anovulation -> infertility.

Question 31

What is the classic presentation of someone with PCOS then?

Answer 31

An obese young woman (adipose tissue required to make estrogen) with infertility, oligomenorrhea, hirsutism/hyperandrogenism, and often insulin resistance (obese)

Question 32

What two conditions are you at increased risk of developing in the future due to PCOS?

Answer 32

1. Type 2 diabetes - insulin resistance 2. Endometrial cancer - due to unopposed circulating estrone and estrogen from anovulatory cycles -> corpus luteum is never made.

Question 33

What "type" of insulin resistance do patients with PCOS have?

Answer 33

"Selective" insulin resistance - > Ovary / liver are sensitive to insulin and will increase androgen synthesis in ovary, and suppress SHBG production by liver (increases free testosterone levels) - > muscle / adipose are reesistant to insulin, causing obesity

Question 34

What is the treatment algorithm for PCOS?

Answer 34

1. Weight reduction 2. OCPs -> prevent endometrial hyperplasia due to unopposed estrogen (provide hormones exogenously) 3. Clomiphene - infertility treatment which blocks estrogen receptor negative feedback in hypothalamus 4. Metformin - to combat insulin resistance 5. Spironolactone / ketoconazole -> block androgen receptor as well as production 6. Statins - for treatment of metabolic syndrome.

Question 35

What is the definition of infertility? When should a consultation be offered?

Answer 35

Failure to conceive after 12 months of regular coital activity in the absence of contraception Should be offered after 1 year, or if older than 35, evaluate at 6 months (little time)

Question 36

What is primary vs secondary infertility?

Answer 36

Primary - no previous pregnancies have occurred Secondary - prior pregnancy has occurred, but not necessarily a live birth

Question 37

How has the rate of infertility been changing since 1950 and why?

Answer 37

It has increased, since marriages are happening later, and contraception is improved. - > As you get older, it becomes harder and harder to conceive - > by age 40, you are about half as fertile as you were at 20.

Question 38

What are the common causes of anovulation in females?

Answer 38

PCOS, obesity, HPO axis abnormalities, premature ovarian failure, hypothyroidism, adrenal dysfunction (high or low)

Question 39

What are tubal / uterine factors which can cause infertility?

Answer 39

Uterine abnormalities -> fibroids / polyps Pelvic inflammatory diseases Endometriosis

Question 40

What are some environmental toxins which can cause infertility?

Answer 40

Smoking (accelerated menopause), marijuana (inhibits GnRH pulsatility), alcohol, caffeine, anesthetic gases

Question 41

What is the clinical definition of menopause? What is the underlying mechanism? What usually precedes it?

Answer 41

No menses for 12 months - > Apoptotic depletion of ovarian follicles (highest levels in the fetus, and number of follicles rapidly decreases until menopause) - > Usually preceded by 4-5 years of abnormal menstrual cycles

Question 42

What is premature ovarian failure? What type of disorder is it?

Answer 42

Menopause before age 40 This is primary ovarian insufficiency -> hypergonadotrophic hypogonadism

Question 43

What is the approximate age of onset of normal menopause, and what marker is specific for it?

Answer 43

Approximately 51 years (can be earlier in smokers) Increased FSH levels are specific (loss of negative feedback on FSH due to decreased estrogen levels)

Question 44

What is the source of estrogen in menopause, and what are the general symptoms to remember?

Answer 44

Peripheral conversion of androgen to estrogen. (LH stimulates the theca cells). These increased androgens can lead to hirsutism. Remember HAVOCS: Hot Flashes Atrophy of -> Vagina Osteoporosis (first three from decreased estrogen) Coronary Artery Disease Sleep Disturbances (from hot flashes and night sweats)

Question 45

What are vasomotor symptoms and what helps them? Are they common?

Answer 45

Vasomotor symptoms = hot flashes. Extremely common, but only 25% of women actually seek treatment. Estrogen therapy reduces them.

Question 46

What is one consequence of vaginal atrophy during menopause which is very distressing?

Answer 46

"Genital Syndrome of Menopause" Dyspareunia (annotate page 600) -> "difficulty + lying with" -> painful sexual intercourse because it's bone dry -> loss of libido

Question 47

What is the treatment for genital syndrome of menopause?

Answer 47

Local estrogen -> safe and effective at any age

Question 48

How do you diagnose osteoporosis in a postmenopausal women? How can this be measured easily? How do you treat?

Answer 48

If they've lost more than 1" from their driver's license reported height, they most likely have vertebral osteoporosis - > Crown to pubis / pubis to floor ratio is about 1 for easier measurement - > Treat with hormone replacement therapy (estrogen), the earlier the better

Question 49

What is the definition of primary amenorrhea? How do you differentiate between hypogonadotropic hypogonadism / gonadal dysgenesis?

Answer 49

Never having had menstruation on their own accord (without OCPs) Hypogonadotropic hypogonadism - FSH will be low / inappropriate normal Gonadal dygenesis - FSH will be high

Question 50

What is the most common cause of primary amenorrhea? Why does it occur in this condition?

Answer 50

Turner syndrome (XO) -> gonadal dysgenesis Occurs because the single cuboidal layer of granulosa cells does not properly form around the egg units -> no protection for the eggs. Thus, the follicles rapidly degrade in utero and become replaced by connective tissue (streak gonads).

Question 51

How does nutrition affect the onset of menarche?

Answer 51

Malnutrition (anorexia / bulimia) -> delay menarche, due to lower fat to lean body weight ratio Moderate obesity -> earlier menarche, due to increased estrogen conversion from adipose tissue

Question 52

What is the question you have to ask yourself when evaluating primary amenorrhea?

Answer 52

Is there normal development of female secondary sexual characteristics. If NO -> hypogonadism, hyper or hypogonadotropic (as explained before) If YES -> Mullerian anomalies, outflow obstruction, androgen insensitivity, or weight/exercise issue

Question 53

What is Mayer-Rokitansky-Kuster-Hauser syndrome also called, and how will the patient present?

Answer 53

Mullerian agenesis Presents as primary amenorrhea in females with fully developed secondary sexual characteristics (ovaries are functional, not derived from Mullerian duct)

Question 54

Why do patients with Mullerian agenesis have primary amenorrhea? How will their gonads look?

Answer 54

Mullerian ducts give rise to fallopian tubes, uterus, and upper vagina. - > uterus and upper vagina + fallopian tubes will be absent - > lower 1/3 of vagina formed via urogenital sinus, will be present as blind vagina.

Question 55

What does the paramesonephric duct become in the male?

Answer 55

Two blind-ended sacs - > prostatic utricle - > appendix of the testis

Question 56

What medical condition causes hematocolpos? What is the clinical presentation

Answer 56

Hematocolpos = condition where vagina fills with blood "blood + vagina" Imperforate hymen -> requires surgical correction Cyclical abdominal pain during periods, with urinary retention, nausea, and diarrhea

Question 57

What genitalia will those with androgen insensitivity have?

Answer 57

They have normal female external genitalia, but blind vagina / absent uterus / upper vagina (Wolffian / mesonephric duct formed in utero) -> testes will be present with normal circulating levels of testosterone for a male, the only difference is end-organ response

Question 58

What is the management for patients with androgen insensitivity syndrome? Will they have hair?

Answer 58

Gonadectomy after puberty with estrogen therapy -> testes will be present as inguinal masses, need to be removed to prevent tumorigenesis (like cryptorchidism) If they have complete androgen insensitivity (there is a spectrum, these patients are viewed as intersex) -> no axillary or pubic hair (requires some testosterone response)

Question 59

What is the first step in the algorithm for secondary amenorrhea (amenorrhea which has started after menarche)? What does a positive test mean?

Answer 59

Progesterone / progestin challenge test - > Withdrawal bleeding 2-7 days after giving progesterone (and levels have dropped) indicates that there is a presence of estrogen, but ovulation and thus formation of corpus luteum has not been occurring - > endometrium stuck in proliferative phase, never reaches secretory phase to turn over Basically, withdrawal bleed = ANOVULATION, where estrogen is present

Question 60

What do you do if there is no withdrawal bleed after the progestin challenge? What are the possible results?

Answer 60

Estrogen + Progesterone challenge If bleeding -> reason for amenorrhea is low estrogen. Check FSH levels to see if gonadal failure or CNS failure. If no bleeding -> uterus / anatomical outflow tract problem

Question 61

What is Asherman syndrome and what typically causes it?

Answer 61

Secondary amenorrhea due to loss of basalis (regenerative layer) of endometrium, with scarring Normally caused by overaggressive dilation and curettage (obestetrical procedure) Refer to pathoma

Question 62

How is the diagnosis of functional hypothalamic amenorrhea made, and is it common?

Answer 62

Low estrogen levels, with no withdrawal bleed from progestin challenge It is one of the most common causes of amenorrhea

Question 63

What are some common causes of functional hypothalamic amenorrhea?

Answer 63

1. Low weight (eating disorders like anorexia / bulimia) -> we said these are causes of anovulation as well 2. Endocrine conditions (hypothyroid, hyperprolactinemia, diabetes) Stress and exercise also contribute -> results in ultimately low GnRH

Question 64

What is the female athletic triad?

Answer 64

1. Disordered eating -> social pressures 2. Menstrual dysfunction -> due to low GnRH from excessive stress / exercise 3. Osteoporosis -> due to low estrogen