Female Reproductive Endocrinology; PCOS Flashcards
1
Q
the menstrual cycle
A
- The menstrual cycle:
- prepares ovaries for ovulation
- Prepares endometrium for implantation of the fertilized ovum.
- Cyclical vaginal bleeding is reflective of changes happening in the uterus and events in the hypothalamus, pituitary and ovary and, therefore, called hypothalamic, pituitary, ovarian (HPO) axis.
- The length of a menstrual cycle is determined by the number of days between the first day of menstrual bleeding of one cycle to the next onset of menses of the next cycle. (28 days is the median) Most cycles are 25-30 days.
2
Q
polymenorrheic, oligomenorrheic, luteal phase, oogenesis
A
- Polymenorrheic-cycles <21 days
- Oligomenorrheic- cycles prolonged >35 days
- Menstrual irregularities are typically at the extremes of reproductive life. ie. menarche and menopause.
- Luteal phase is typically constant (14 days) and so the variability in cycle length comes from the varying lengths of the follicular phase (10-16 days).
- A baby girl is born with more eggs than she will ever use. (up to 450,000)
- Oogenesis begins in utero:
- The primordial germ cells migrate and become oogonia (diploid).
- The germ cells undergo persistent mitosis and generate up to 7 million potential eggs.
- Most undergo atresia and those that haven’t enter the first meiotic division and are transformed from oogonia to primary oocytes.
- The primary oocyte is arrested in Prophase I until the time of ovulation.
- The cells in the ovary are arrested at this phase
3
Q
follicular (proliferative) phase
A
- First day of menses until ovulation. Lower basal body temperatures and the development of the follicle occur in this phase. Here the ovary is the least hormonally active and so serum levels of estradiol and progesterone are lower
4
Q
early follicular phase (recruitment)
A
- Days 1-4 Cohort of follicles recruited from a pool of nonproliferating follicles in response to FSH.
- The only time in the cycle that FSH is dominant
- The hormones progesterone, estrogen and inhibin are all low this stimulates Gonadotropin releasing hormone (GnRH) pulses from the hypothalamus and this stimulates FSH from the pituitary.
- FSH provides the signal for recruitment of a cohort of follicles in the ovary.
- If someone is having pretty regular periods (roughly) that’s a pretty good indicator that the pituitary is functioning properly
- Follicles start at <4mm.
- FSH binds to granulosa cells and triggers a positive feed back system:
- FSH binding>> increases aromatase, (which converts androgens to estradiol)>>estradiol increases FSH receptors>>more estrogen>>granulosa cell proliferation>>more receptors.
- Estrogen level increase causes increased follicular fluid which forms the antrum. (Secondary follicle)
- The granulosa cells in the secondary follicle produce the hormone inhibin.
- Inhibin suppresses pituitary production of FSH. Inhibin increases in parallel with estrogen increase. This changes the LH/ FSH ratio. FSH secretion diminishes but LH is augmented by cycle day 5.
5
Q
midfollicular phase (selection)
A
- Characterized by selection of one dominant follicle from the cohort of growing follicles that were stimulated by FSH.
- *With fraternal twins two follicles become dominant..
- Selection of the dominant follicle is probably (theorized to be) related to the density of FSH receptors and therefore the ability of the follicle to produce estrogen.
6
Q
late follicular phase (dominance)
A
- This phase is characterized by rapid follicular growth. The mid-cycle surge of gonadrotropins results from positive estradiol feedback on the pituitary and hypothalamus. When estradiol concentrations are >300-500pg/ml for 48hrs the LH and FSH surge is initiated.
- This is where you get the switch to the luteal phase
- The LH surge leads oocyte extrusion and resumption of meiosis in the oocyte.
- The associated mid-cyle FSH surge helps detach the oocyte from follicle wall. FSH also aids in conversion of granulosa cells to functional luteal cells by facilitating LH receptor induction.
- Ovulation takes place 36-40hr after the LH surge.
- The oocyte-cumulus complex is extruded from the follicle at a weakened point known as the “Stigma”. This mass is then picked up by fimbriated ends of the fallopian tube. Ciliated cells propel the complex through the ampullary portion of the tube where fertilization generally occurs.
7
Q
luteal phase
A
- Begins on the day of the LH surge and ends at the onset of the next menses.
- The luteal phase is characterized by high concentration of LH receptors on granulosa and theca cells. In response to LH the granulosa cells’ enzymes change from estradiol secretion to progesterone production.
8
Q
early luteal phase
A
- Prior to ovulation the granulosa cells enlarge and accumulate a yellow pigment (lutein). During the 3 days following ovulation LH transformed granulosa cells and theca cells luteinize and become a structure known as the corpus luteum CL. This transient endocrine organ secretes progesterone and its function is to prepare the estrogen primed endometrium for implantation of the fertilized ovum.
9
Q
late luteal phase
A
- The secretory activity and functional lifespan of the CL is dependent on the appropriate LH support (14 days). Unless implantation occurs and HCG from the developing embryo rescues the CL, involution occurs.
- There is a decline in progesterone, estradiol and inhibin. The reduction in estradiol restores the ability of the pituitary to respond to GnRH signals. The GnRH pulse frequency causes a predominance of FSH secretion. The increase in FSH during this phase is key in initiating recruitment of follicles for the ensuing cycle. It appears the demise of the CL aids in the initiation of the next menstrual cycle.
10
Q
uterine/cervical events
A
- Proliferative phase corresponds to follicular phase in ovary
- Uterine Events
- Endometrium Thickens
- Glands and vessels grow in response to estrogen
- Cervical Events
- Estrogen causes changes to cervical mucous
- Thinner
- Clearer
- More elastic (spinnbarkeit)
- Changes facilitate passage of sperm into uterus
- Cervix may feel softer and more open
- Estrogen causes changes to cervical mucous
- Secretory Phase corresponds to luteal phase in ovary
- Uterine Events
- Endometrial glands and blood supply mature
- Prepared to secrete glycogen, which is nutrition for egg
- Progesterone maintains endometrium
- Cervical Events
- Increasing levels of progesterone by CL cause a reduced quantity of thick and tacky cervical mucus.
- Menstruation
- Occurs if fertilization does not occur
- Progesterone and estrogen levels fall
- Uterine events
- Endometrial blood vessels constrict
- Loss of blood supply causes endometrium to be shed
- Menstrual flow is a combination of endometrial tissue and blood
- Cramps are associated with lack of progesterone and presence of prostaglandins secreted in uterus
11
Q
Polycystic ovarian syndrome (PCOS), stein-leventhal syndrome
A
- Stein and Leventhal were the first to recognize the association between polycystic ovaries, hirsutism and amenorrhea.
- These women underwent successful wedge resections of the ovaries and the menstrual cycles normalized and they were able to conceive.
- A primary ovarian defect was thought be the cause of the disease and it was titled polycystic ovarian disease.
- Further biochemical, clinical and endocrinologic studies revealed an array of underlying abnormalities.
- Now it is referred to as polycystic ovarian syndrome (PCOS), but it may occur in women without ovarian cysts.
12
Q
frequency of PCOS
A
- PCOS is the most frequently encountered endocrinopathy in women of reproductive age. Prevalence is 4-12%
13
Q
History of PCOS
A
- Patients with PCOS may present with various clinical features.
- Menstrual abnormalities
- Some women have oligomenorrhea or secondary amenorrhea.
- The menstrual irregularities in PCOS usually manifest around the time of menarche.
- Hyperandrogenism
- Clinically manifests as excess terminal body hair in a male distribution (Upper lip, chin, around the nipples and along the linea alba of the lower abdomen)
- Some have acne or male pattern hair loss
- Occasionally increased muscle mass, deepening of the voice and/or clitoromegaly due to excessive androgens
- Infertility
- A subset of women are infertile
- Most women ovulate intermittently.
- They just don’t ovulate consistently! Can lead to unplanned pregnancies
- Obesity: This is present in nearly half of all women with PCOS
- Diabetes mellitus: 10% of women with PCOS have Type 2 diabetes, 30-40% have impaired glucose tolerance by age 40.
- Its very common to develop impaired fasting glucose when you have PCOS because insulin resistance is the main root underlying problem
- Sleep Apnea: Many women have obstructive sleep apnea syndrome.
- Acanthosis nigricans: Patients with PCOS may have dark, pigmented skin on the skin folds and knuckles or elbows (a skin manifestation of insulin resistance)
- Metabolic syndrome – acanthosis nigricans – indicative of insulin resistance
14
Q
diagnosis of PCOS
A
- This can be diagnosed clinically in a woman with hirsutism, irregular menstrual cycles and characteristic ovarian morphology. (Classic ultrasound findings often include multicystic ovaries (10 or more on each ovary) with the follicle cysts lining the periphery of the ovary)
- The National Institute of Health (NIH) defined 2 minimum criteria for diagnosis in 1990.
- Menstrual irregularities
- Evidence of hyperandrogenism either clinical (hirsutism, acne, male balding) or biochemical (elevated serum androgen level)
- Exclusion of other disorders that can results in menstrual irregularities and hyperandrogenism.
- This is the most important factor
- In 2003 the Rotterdam European Society of Human Reproduction/American Society for Reproductive Medicine (ESHRE/ASRM) sponsored a PCOS Consensus Workshop Group and defined 3 criteria for diagnosis and indicated PCOS maybe present if 2 out of 3 criteria are met:
- Oligoovulation/anovulation
- Clinical or biochemical signs of hyperandrogenism
- Polycystic ovaries
- This can be diagnosed in office without US or lab
15
Q
biochemical abnormalities of PCOS
A
- Testosterone levels may be normal or elevated but usually <200ng/dl.
- If its above 200 youre thinking more tumors or adrenal issues, etc.
- Serum androstenedione and dehydroepiandrosterone sulfate (DHEA-S) are usually normal but may be elevated (typically above 200ug/dl normal is 35-430ug/dl).
- FSH and LH levels are normal to high normal, with a ratio of LH to FSH of 3.0 or more.
- Usually these will be about 1:1 or 2:1 depending on where you are in the cycle
- LH is responsible for the androgen effect in the later portion of the cycle
- Adrenal tumors should be investigated if testosterone is > 150ng/dl. Rule out elevated Cortisol for Cushing’s (run screening ACTH/Cortisol)
- TSH and prolactin are usually normal but are drawn to rule out pituitary or thyroid causes of the clinical symptoms.
- Fasting glucose and insulin level are drawn to evaluate degree of insulin resistance.
