Female Reproductive System Endocrine Pathophysiology Flashcards
What is the relative hormonal requirement for ovulation, menstrual cycle proliferation, mucus production, and development of vagina, urethra, and breasts / how is this relevant?
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
What characterizes the onset of puberty in terms of LH?
Nocturnal rise in LH levels due to pulsatile GnRH release at night -> leads to increased testosterone
-> occurs during REM sleep
Why do we think puberty is happening earlier nowadays?
Related to nutrition
-> being a greater mass allows puberty to ensue faster (you’ve met your nutritional requirements)
Place the following in the correct order, and define them:
Growth spurt, adrenarche, pubarche, thelarche, menarche
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
What is the average timespan between thelarche and menarche and who tends to get it earlier? During what Tanner stage does menarche usually occur?
Around 2.5 years, tends to occur earlier in African Americans, with mild obesity
Tanner Stage 3 - Menarche
What is the definition of precocious vs delayed puberty in females?
Precocious - Tanner Stage 2 at <8 years
Delay - Tanner Stage 1 at age 13, or no menses by age 16.
What is the definition of true precocity and what are the main causes in women?
GnRH dependent or central precocioius puberty (driven by hypothalamus)
- Idiopathic is primary cause
- CNS problem can also be the cause - unwanted activation of hypothalamus pulse generator.
- > this reason is more common in girls
What are the most common causes of precocious pseudopuberty in boys and girls? What is this also called?
GnRH-independent puberty (peripheral puberty)
Boys - Testicular tumor (either theca cell or choriocarcinoma secreting hCG)
Girls - Ovarian tumor (i.e. granulosa cell making estrogen)
What usually causes hypergonadotropic hypogonadism?
Usually a chromosomal abnormal causing gonadal dysgenesis
-> i.e. Turner syndrome
Gonadotrope levels are high, but gonads are not responding
What are some reversile causes of hypogonadotropic hypogonadism?
Physiologic delay in puberty
Weight loss
Hypothyrodism
Prolactinoma
What are some causes of irreversible hypogonadotropic hypogonadism?
GnRH deficiency - i.e. Kallmann
Hypopituitarism
Craniopharyngioma / other pituitary tumors
Congenital CNS defects
What is the normal range of the menstrual cycle and the average duration of menses? How much blood is lost?
Normal - 21 to 35 days, mean 28 days
Average menses - 3-8 days -> about 30 mL is lost (1 oz)
What is the rate of GnRH pulses during follicular and luteal phase?
Follicular phase - quickly to stimulate follicule - every 60 minutes
Luteal phase - slowly to maintain endometrium - 90 minutes
What does an activin do? What produces them?
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
What marker do primary follicles express, and what stage of Meiosis are they found in? When do they move on?
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.
What are the ovarian and endometrial cycles and relative timing?
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)
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?
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
How does estrogen act synergistically with FSH in follicle development?
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.
What triggers the LH surge and what affect does this have on the follicle during and after ovulation?
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)
What does progesterone do during the luteal phase?
- Suppresses maturation of other follicles in ipsilateral ovary
- Thermogenic activity - accounts for the 0.5 degree increase in basal body temp during ovulation
What triggers menses?
Overtime, the corpus luteum loses sensitivity to gonadotropins -> stops secretion of estrogen and progresterone.
Can only be saved by hCG
What are the two main layers of the endometrium?
- Basal layer - adjacent to myometrium, remains intact throughout the menstrual cycle. These are basically the stem cells of the uterus.
- 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)
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?
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
What are the sources of androgens in women?
- Adrenal cortex - primary source of androgens, mostly DHEA and androstenedione
- Ovary - a small amount is made, mostly androstenedione
Androstenedione is converted peripherally to testosterone to some degree
What are the clinical features of hyperandrogenism in women?
- Hirsutism
- Acne
- Male pattern baldness - central loss of hair with recession of temporal area
- Android obesity (apple shaped rather than pear-shaped) - increased waist to hip ration (>0.85)
What are the two places women never make hair unless it’s pathologic?
- The chest (excluding the breast)
2. The small of the back
How will the ovaries appear in polycystic ovarian syndrome (PCOS)?
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.
What is the clinical definition of PCOS?
2/3 of the following:
- Irregular uterine bleeding
- Hyperandrogenism - either seen clinically or measured
- Polycystic ovaries
What condition is easily confused with PCOS and what causes that condition?
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)
What is going wrong hormonally in PCOS which accounts for the symptoms?
Hyperinsulinemia / insulin resistance alter the hypothalamic hormonal balance and cause:
- Increased LH:FSH ratio, which stimulates increased androgen production from theca interna cells –> hirsutism.
- 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.
- 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.
What is the classic presentation of someone with PCOS then?
An obese young woman (adipose tissue required to make estrogen) with infertility, oligomenorrhea, hirsutism/hyperandrogenism, and often insulin resistance (obese)
What two conditions are you at increased risk of developing in the future due to PCOS?
- Type 2 diabetes - insulin resistance
- Endometrial cancer - due to unopposed circulating estrone and estrogen from anovulatory cycles -> corpus luteum is never made.
What “type” of insulin resistance do patients with PCOS have?
“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
What is the treatment algorithm for PCOS?
- Weight reduction
- OCPs -> prevent endometrial hyperplasia due to unopposed estrogen (provide hormones exogenously)
- Clomiphene - infertility treatment which blocks estrogen receptor negative feedback in hypothalamus
- Metformin - to combat insulin resistance
- Spironolactone / ketoconazole -> block androgen receptor as well as production
- Statins - for treatment of metabolic syndrome.
What is the definition of infertility? When should a consultation be offered?
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)
What is primary vs secondary infertility?
Primary - no previous pregnancies have occurred
Secondary - prior pregnancy has occurred, but not necessarily a live birth
How has the rate of infertility been changing since 1950 and why?
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.
What are the common causes of anovulation in females?
PCOS, obesity, HPO axis abnormalities, premature ovarian failure, hypothyroidism, adrenal dysfunction (high or low)
What are tubal / uterine factors which can cause infertility?
Uterine abnormalities -> fibroids / polyps
Pelvic inflammatory diseases
Endometriosis
What are some environmental toxins which can cause infertility?
Smoking (accelerated menopause), marijuana (inhibits GnRH pulsatility), alcohol, caffeine, anesthetic gases
What is the clinical definition of menopause? What is the underlying mechanism? What usually precedes it?
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
What is premature ovarian failure? What type of disorder is it?
Menopause before age 40
This is primary ovarian insufficiency -> hypergonadotrophic hypogonadism
What is the approximate age of onset of normal menopause, and what marker is specific for it?
Approximately 51 years (can be earlier in smokers)
Increased FSH levels are specific (loss of negative feedback on FSH due to decreased estrogen levels)
What is the source of estrogen in menopause, and what are the general symptoms to remember?
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)
What are vasomotor symptoms and what helps them? Are they common?
Vasomotor symptoms = hot flashes.
Extremely common, but only 25% of women actually seek treatment.
Estrogen therapy reduces them.
What is one consequence of vaginal atrophy during menopause which is very distressing?
“Genital Syndrome of Menopause”
Dyspareunia (annotate page 600) -> “difficulty + lying with” -> painful sexual intercourse because it’s bone dry
-> loss of libido
What is the treatment for genital syndrome of menopause?
Local estrogen -> safe and effective at any age
How do you diagnose osteoporosis in a postmenopausal women? How can this be measured easily? How do you treat?
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
What is the definition of primary amenorrhea? How do you differentiate between hypogonadotropic hypogonadism / gonadal dysgenesis?
Never having had menstruation on their own accord (without OCPs)
Hypogonadotropic hypogonadism - FSH will be low / inappropriate normal
Gonadal dygenesis - FSH will be high
What is the most common cause of primary amenorrhea? Why does it occur in this condition?
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).
How does nutrition affect the onset of menarche?
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
What is the question you have to ask yourself when evaluating primary amenorrhea?
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
What is Mayer-Rokitansky-Kuster-Hauser syndrome also called, and how will the patient present?
Mullerian agenesis
Presents as primary amenorrhea in females with fully developed secondary sexual characteristics (ovaries are functional, not derived from Mullerian duct)
Why do patients with Mullerian agenesis have primary amenorrhea? How will their gonads look?
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.
What does the paramesonephric duct become in the male?
Two blind-ended sacs
- > prostatic utricle
- > appendix of the testis
What medical condition causes hematocolpos? What is the clinical presentation
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
What genitalia will those with androgen insensitivity have?
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
What is the management for patients with androgen insensitivity syndrome? Will they have hair?
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)
What is the first step in the algorithm for secondary amenorrhea (amenorrhea which has started after menarche)? What does a positive test mean?
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
What do you do if there is no withdrawal bleed after the progestin challenge? What are the possible results?
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
What is Asherman syndrome and what typically causes it?
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
How is the diagnosis of functional hypothalamic amenorrhea made, and is it common?
Low estrogen levels, with no withdrawal bleed from progestin challenge
It is one of the most common causes of amenorrhea
What are some common causes of functional hypothalamic amenorrhea?
- Low weight (eating disorders like anorexia / bulimia) -> we said these are causes of anovulation as well
- Endocrine conditions (hypothyroid, hyperprolactinemia, diabetes)
Stress and exercise also contribute
-> results in ultimately low GnRH
What is the female athletic triad?
- Disordered eating -> social pressures
- Menstrual dysfunction -> due to low GnRH from excessive stress / exercise
- Osteoporosis -> due to low estrogen
