Repro Physio Flashcards
Delayed puberty
absence or incomplete development of secondary sexual characteristics by an age at which 95% of chldren of that sex and cultrure have initiated sexual maturation
boys - 14, girls - 12
hypothalamic, pituitary, thyroid, genetic, autoimmune
Medical reason for period on BC?
Why do women menstruate? To shed the endometrial lining so that it doesn’t become hyperplastic, atypical, and go on to cancer. Do you know how many times a year when you’re not on any kind of birth control or any kind of hormones you need to shed the lining? 4 times a year – about every 3 months to make sure that it doesn’t become hyperplastic and atypical. What do birth control pills, combined hormonal contraceptives, do to the endometrium? They suppress the endometrium and make it really thin. So why do we need to shed that? We don’t! There’s no reason to do that. Now people are starting to know a little bit about that because we have pills that you take continuously for 3 months. Patients calculate how much they save without pads and tampons. Patients can take these pills every day, every month for the whole year. It doesn’t matter because the endometrium is suppressed. The bleeding isn’t a woman’s period – it’s a withdrawal bleed and there’s no reason to have it.
how do you calculate EDC
mark from last period and add 2 weeks
40 weeks (+/- 2w) Expected date of confinement (EDC)-280 days from the beginning of last menstrual period, 266 from the ovulation.
HT timing and CVD risk
Does estrogen cause a decrease in heart disease? Does it not? Well, it depends on when you went into menopause and when you started estrogen.
- If you begin your estrogen right at the time of menopause or within the first nine years, then guess what? You lower your risk of heart disease. However, if you wait, and you wait 10 to 19 years after menopause, you’re actually going to increase your risk of heart disease.
- If you wait 20 more years and then start estrogen, you’re going to really increase your risk of heart disease. So, timing is critical.
- You need to begin your treatment, if you’re going to do it, within the first nine years. I say within the first five years.
basal breast molecular subtype
triple negative - really hard to treat
postpartum psychiatric disorders
- Postpartum Blues (40-80%)
- Postpartum Depression (4-9%)
- Postpartum Psychosis (.1-.2%)
- Postpartum psychosis is rare—1 in 1000 deliveries and usually occur in people who have had some signs including previous depression, previous postpartum depression, family history, insufficient support system. All these can be a factor and we really need to pay attention to this.
Depo (DMPA)
It is an intramuscular injection that is given either IM or subQ. Although subQ is not taking up so much in this country. You can start it within 5 days of your period or any time if you are relatively sure a patient isn’t pregnant. And you give every 11-13 weeks although the CDC says you can extend that up to 15 weeks for Depo. It’s a 3 month acting birth control.
Something people don’t think about so much: one of the only birth control methods that leaves no evidence. For teenagers, that can be something critical. People can find a pill pack, they can find a patch, they might feel a ring, people might feel the strings of an IUD, people can see an implant. A Depo injection is something no one needs to know. It’s something that adolescents think about.
- Effective for 3 months
- Ideal Use = 0.3% failure rate¹
- Typical Use = 6% failure rate¹
- 26-53% continuation at 1 year
effects of increased estrogen during pregnancy
Increased:
Hepatic protein synthesis, heart rate, stroke volume, cardiac output, uterine blood flow, blood volume, coagulation factors, renal perfusion, creatinine clearance
Causes:
Peripheral vasodilation
Physiologic anemia
benefits of breast feeding
immunity - protects fetus from infection
decreases fetal allergies
optimal mix for vital organs
ideal “formula”
•Breastfeeding protects the fetus from infection not 100% of the time, but very often. Because of breast milk, there are maternal Abs which are important for decreasing infection in newborns. Additionally, the American academy of pediatrics recommends breastfeeding for at least 6 weeks because of the decrease in fetal allergies—not guaranteed, but overall there is a decrease.
how the onset of puberty starts theory
“gonadostat” (hypothalamus) becomes 6-15x more sensitive to negative feedback in child than in adult
in childhood - much more sensitive so a little E will keep hypothalamus quiet
there is a change in sensitive that allows the same amt of E make GnRH pulsitile
pulsitile GnRH acts on the AP to secrete pulsitile FSH and LH
large nocturnal LH pulses begin during REM sleep
Estrogen causes development of secondary sex characteristics
ethinyl estradiol
As I said, most pills are low-dose. In the US, ethinyl estradiol is the estrogen that is in every pill. There’s a few exceptions to that (that mestranol – the contaminant that I just talked about).
secondary amenorrhea
absence of meses after menses has begun (usually >3 months)
sign there may be another illness
prostaglandins in labor
- Prostaglandins are incredibly important
- At the beginning stages of labor, they start to help soften and open the cervix and get mom ready for contractions to occur.
- Prostaglandins will have a big role in softening the cervix (they also play a small role in contractions). We will now insert them in women who haven’t gone into labor yet or if we want to induce labor—we give them right into the cervix which will start the ripening process.
formation of the corpus luteum
reorganization o f the follicle
theca-lutein, granulosa-lutein cells, fibroblasts, endothelial cells, immune cells
secretes progesterone, estrogen usuall 14 day
without hCG, involutes (luteolysis)
contraindications for hormnal contraception
There are some contraindications. They’re listed here:
- Smoking if you’re over the age of 35 – it increases your risk of MIs
- If you have a personal thrombotic history – not good to take estrogenic-containing products
- If you have diabetes with vascular complications
- If you have migraines with neurologic symptoms
- If you’re over 35 with ANY migraines
- If you have hypertension
- Any coronary artery disease
- Or if you have unexplained vaginal bleeding – we need to figure out what that’s about before we possibly stimulate a cancer with our hormones
eugonadotropic pirmary amenorrhea
FSH 5-20 - normal HPO axis - anatomic, ovulatory dysfunction
primary amenorrhea
no meses by age 13-14 in the absence of secondary sex characteristics
no menses by age 15-16 regardless of devlopment
no menses 5 years after breast development
SPRMs
There is a new pill called Ella (brand name) – Ulipristal Acetate. Also within 5 days. It is a selective progestin receptor modulator. It’s a partial agonist and antagonist that works on the progesterone receptor. This you need a prescription for. This can disrupt an existing pregnancy. It’s similar to Mifepristone. Mifepristone is the medication abortion pill – similar mechanism of action.
when is the 2nd meiotic division of the egg?
after the fertilization of the egg by sperm
mammary gland structure
10-100 alveoli/lobule
20-40 lobuli / lobe
Each lobe drained by a lactiferous duct
15-20 ducts / breast
Ducts drain to sinuses to nipple
enzymes needed for estrogen synthesis in pregnancy?
- placenta doesn’t have 17-hydroxylase or 17,20 desmolase à it cannot make the conversion from progesterone to estrogen.
- That is why we need the fetus to be able to function and help us continue the conversion.
- It is the fetal adrenal gland and liver that contribute.
How to measure progesterone to check for ovulation
should be taken d 21 or calculated 7d after ovulation
<2 - anovulation
>3 - ovulation
>15 - pregnancy
adrenarche
activation of the adrenal medulla for the production of adrenal androgens
clinical development of pubic and axillary hair
begins at about age 6 in boys and girls
unrelated to pubertal maturation of the neuroendocrine-gonadotropin-gonadal axis
clinical manifestations of both usually become apparent at the same time
biochemical features of PCOS
increased LH/FSH ratio
increased T
increased AMH (made by follicles recruited in the follicular phase –> used to screen in the future?)
normal cortisol, prolactin
OGTT - see what glucose tolerance is
NO hyperglycemia - just insulin resistance (can progress)
alveolar stimulation in breast milk
•You can see the blood vessels and the milk duct with lots of lobules that feed into the duct and go into the nipple. Around the lobules are blood vessels and myoepithelial cells. Myoepithelial cells are stimulated by oxytocin. In the lumen, it is filled with milk. The alveolar cells will get stimulated by prolactin which will make the milk. Oxytocin will cause contraction of the lobule, which will spill the milk down into the duct.
•
Usually we recommend a year of breast feeding, you can have pumps at home, 6 months, 6 weeks, 3 years. Once the baby has teeth, it is more challenging, but it depends on the individual. You can keep this going for a long time.
mechanism of polycystic ovary disease
- Polycystic ovaries result when increased local androgens and decreased FSH prevent the development of a dominant follicle.
- The increased local androgens can be the result of a genetic defect in ovarian steroidogenesis and/or the result of increased circulating insulin (insulin resistance).
- The elevated local ovarian androgens “stunt” the ability of the follicle to grow beyond 2-10 mm .
- This leads to the accumulation of 20-100 subcapsular “cysts” which give the ovary its characteristic “polycystic” appearance.
- The ovary’s estradiol output is sufficient to exert low-level positive feedback on LH and negative feedback on FSH, resulting in an increased LH and decreased FSH
- Increased LH levels then stimulate the ovarian stroma to increase its production of testosterone and androstenedione, perpetuating the unfavorable conditions for follicular development and keeping the woman in an anovulatory state. .
- When released into the general circulation, these elevated androgens cause hirsutism, or the increased coarseness and pigmentation in hair on the face, chest, and abdomen.
This is a patient with polycystic ovary disease—instead of having one, big dominant follicle she has many small ones.
We don’t know where the problem is with this disease.
- Could be a problem in the ovary—it’s not picking one dominant follicle
- Could be a problem with the message—LH or FSH is different and is causing multiple follicles instead of one dominant one
- In PCO we have chronic anovulation, and high LH
- There is so much LH telling the theca cells to overproduce testosterone
- All of these follicles are trying to be the dominant ones and are working hard
- Testosterone increases insulin (plus there’s a high insulin bc of the insulin resistance)àinsulin drives the theca cell to make even more testosterone
- There is so much testosterone that the granulosa cell can’t keep up with the aromatase needed to make estradiol so we get a build up of testosterone, high androgens, hirsutism and acne and often hair loss
inhibin
inhibits FSH
LH, theca cells
thelarche
appearance of breast tissue
what hcg subunit do we use for pregnancy test?
beta subunit
•Alpha unit: Identical to TSH, FSH, LH
Encoded by a single gene on chromosome
•Beta unit: Unique, encoded by several genes on chromosome 19
process of IVF
stimulation (make superovulate)
retrieval (take eggs out)
fertilization (surround egg w sperm or stick one in)
transfer (1 if know it’s normal or 2)
give progesteron or HCG in luteal phase
mechanism of progesterone synthesis in pregnancy
•
- On the top is progesterone synthesis.
- The mom is supplying the cholesterol. The cholesterol from the mother goes to the placenta and the placenta is going to be able to make progesterone.
That progesterone is going to be exposed to both the fetus and mom
HPG in the follicular phase
treatment of hyperprolactinemia
dopamine agonist (bromocriptine, cabergoline)
kallman’s syndrome
hypogonadotropic hypogonadism
males more effected
anosmia - aplasia - failed migration of GnRH neurons from the olfactory placode to the medial basal hypothalamus
deficiency of GnRH = clinical feature
low FSH, low estradiol
precocious puberty
premature sexual development which occurs at an age more than 2.5 SD below the mean age of puberty
defined as the onset of pubertal development in girls before age 8, boys before age 9
What is the fetal substrate for mineralocorticoids and glucocorticoids?
progesterone
Ospemifene (Osphena)
non estrogen option for vulvovaginal atrophy
SERM - E agonist in some parts (vagina), E antagonist in others (breasts, bone)
gonadotropin-independent precocious puberty
independent of GnRH and gonadotropin
caused by excess secretion of sex hormones (estrogens or androgens) derived from either the gonads or adrenal glands
GnRH, FSH, LH still really low but have E and T
i,e, McCune-Albrigh, polyostotic fibrous dysplasia = triad of periopheral precocious puberty, cafe au lait skin pigmentation and fibrous dysplasia of bone
(autonomous g protein activation - always on, continued stim of endocrine function
pubarche
appearace of pubic hair
functions of estrogen in puberty
breast enlargement
maturation of vaginal mucosa
growth acceleration
advancement of skeletal maturation
complete epiphyseal fusion
placenta sulfatase deficiency
•Unable to hydrolyse DHEAS
•Low estriol levels
- Post Dates
- Failure of cervical dilation or effacement
- Occurs in 1:2,000 – 1:6,000 newborns
- The babies are fine and grow normally—the only difference is that we see lower levels of estriol, the pregnancies tend to go post dates (sulfatase is probably involved in determining when pregnancy is over), and normal L&D doesn’t take place as well so the patients often need to be induced.
HPG in luteal phase
what COC has highest and lowest estrogen content?
nuva ring - lowest
patch
pill - highest
how does estrogen formation happen?
in ovary
theca cells: make androgens under direction of LH, send to granulosa cells
granulosa cells aromatize to estrogens under FSH
DMPA non contraeptive benefits
- Improvement of fibroid symptoms
- ** Reduction in frequency of epileptic seizures
- ** Reduction in sickle crises
- Reduction in symptoms of endometriosis
- No known drug interactions
HPG in midcycle
prolactin after labor
- This is days and months postpartum [no box].
- If a woman doesn’t breast feed, prolactin levels will fall on their own.
- If a baby is sucking, the sucking will stimulate prolactin, which is important for milk production.
- Milk will continue to be produced because of the sucking.
- Prolactin inhibits the menstrual cycle (inhibits GnRH, FSH, estrogen), so a woman is not getting her period, but NOT adequate birth control because when someone is no longer breastfeeding, they will ovulate before getting 1st period and you don’t know when that ovulation will happen.
Additionally, after months of breast feeding, we only need a little bit of prolactin to make milk, so the overall prolactin level will start to decrease and menstruation returns even though the sucking process is increasing these huge surges of prolactin
mammary gland
Myoepithelial cells are stimulated by oxytocin
Alveolar cells are stimulated by prolactin
how do you test pelvic factor of infertility?
hysterosalpingogram
laparoscopy
what estrogen increases the most through pregnancy?
estriol - 100x
what cells secrete hCG?
synctiotrophoblasts
•aintains corpus luteum steroidogenesis until the placenta assumes this role (7-10.4 weeks)
see it even at the 4 cell stage
•
- This is broken down into alpha hCG and beta hCG
- Alpha HCG continues to rise
- Beta HCG peaks early and then drops like the picture from above (Figure A)
- We use this one.
estrogen component of hormonal contraception
for side effects! very small amount to stop breakthrough bleeding etc
suppresses FSH, LH to suporess ovulation and endometiral changes at the cellular level
androgen insensitivty sundrome
absent androgen receptors
male genotype, fenal phenotyle
high T levels
female pattern with no uterus
T= elevated
actions of progesterone
breast development
endometrial gland maturation
maintain uterus/inhibits lactation during preg
contributes to insulin resistance
increases body temp and minute ventilation
ovulation predictor kits
test urine
ovulate 10-12 days after LH peak
sperm day of surge and day after (may be on way up or down)
growth hormone in puberty
pulsatile release from anterior pituitary
more than 70% of total daily gh secretion occurs at night - first few waves
peak can be 100x low levels
How long protected on placebo pill?
7 days
Types of Progestin only contraceptive?
We’re going to talk a little bit about the progestin-only contraceptives. Again, progestin being the workhorse, we’re not going to talk about estrogen-only contraceptives because they do not exist.
Here we have some options:
- Progestin only pills (POP)
- Injectables
- Implants
- IUS (intrauterine systems) – the same as IUD except they decided to change it up because of the progestin
•
mechanism of estriol synthesis in pregnany
- Estriol synthesis
- Cholesterol will go to the placenta, which will start in it’s progesterone synthesis by making pregnenolone.
- This is what confuses Nachtigall: The fetal adrenal gland is going to take over and make DHEA-S and the liver will convert it to a 16-hydroxy DHEA-S. Then, the placenta will get the sulfate with sulfatase and form estriol.
where is progesterone converted to estrogen in pregnancy?
- placenta doesn’t have 17-hydroxylase or 17,20 desmolase à it cannot make the conversion from progesterone to estrogen.
- That is why we need the fetus to be able to function and help us continue the conversion.
- It is the fetal adrenal gland and liver that contribute.
mirena mechanism of action
Mirena – the levonorgestrel IUS – has about 20 micrograms per day of levonorgestrel.
This suppresses the endometrium, thickens that cervical mucus – that’s the take home message of these progestrin-only methods.
Does not reliably suppress ovulation. We know this because we’ve done ultrasound of women with the Mirena in place and about 50% of them have follicles. 50% of them don’t which means that their ovaries are suppressed. But 50% are still making follicles which means that it’s not suppressed so that means that prevention of ovulation is not a mechanism of action.
It has an incredibly good success rate. The failure rate is very very low. It also has been used many times to help reduce heavy menstrual bleeding. It can reduce it to up to 90% and really has no long-term effects on fertility.
luteal placental shift
- hCG from the embryo is causing the corpus luteum to make progesterone. The corpus luteum is supplying the progesterone in the beginning part of pregnancy which is keeping the endometrium in a healthy state for the embryo to progress.
- However, that will wear off around 8 weeks. At this point, the placenta is getting started and formed. The placental will start to be functional at 7.5 weeks.
- There is a period of time between 7.5 weeks and 10 weeks, 4 days where the corpus luteum and the placenta are working together and one is taking over for the other (placenta is taking over for the corpus luteum).
stages of secondary sex characteristics in puberty
- breast
- pubarche
- growth spurt
- menarche
hCG release
•The major hormone of pregnancy is hCG—human chorionic gonadotropin. That is made very early on by the embryo.
•
•You see the increase over the 1st 10 weeks of pregnancy, then a plateau, then a decrease over time.
•
In addition, we see other key hormones like estrogens where Estriol is the predominant hormone and progesterone is the major hormone made by the placenta. There is also some prolactin, which has a big increase in pregnancy, but not from the placenta. This is actually maternal prolactin.
hypothalamic amenorrhea
decreased hypothalamic GnRH secretion
hypogonadotropic hypogonadism
low fsh, estradiol
normal MRI
decreased pulses –> absent midcycle surges in LH –> absence of normal follicular development –> anovulation –> low serum estradiol concentrations
low body fat (under 17%), stress, genetic, systemic disease, hypothyroid
acanthosis nigricans
a physical characteristic of insulin resistance
what is the best way to biopsy breast for initial bx?
core needle biopsy - get more info!
FNA - can’t distinguish in situ from invasive
surgical - usually not necessary
secretory/luteal phase hormone profile
estrogen and progesterone
both made by corpus luteum, both have ffect!
hormones in 3 days after delivery
•Within 3 days of delivery, estrogen and progesterone levels are right at the level of the beginning of a period. From 1000 to 30 pg/mL. That is a huge drop (see orange and blue bars). Prolactin shoots sky high and estrogen and progesterone go way down. If you give someone estrogen, you will inhibit the ability to make prolactin.
Prolactin neg feedback and suppress estrogen and progesterone
•
•What about that change? Hormones really affect behavior and mood. While not everyone is affected by the changes in the cycle, when progesterone and estrogen start to fall, some women become very moody, but don’t have that sensation 3 days later. Now, that sensation is multiplied by 20 because the levels have a huge drop.
•
granulosa cell stimulation
FSH
take androgens from theca cells and aromatize to make estrogens
myoepithelial cell stimulation
•You can see the blood vessels and the milk duct with lots of lobules that feed into the duct and go into the nipple. Around the lobules are blood vessels and myoepithelial cells. Myoepithelial cells are stimulated by oxytocin. In the lumen, it is filled with milk. The alveolar cells will get stimulated by prolactin which will make the milk. Oxytocin will cause contraction of the lobule, which will spill the milk down into the duct.
•
Usually we recommend a year of breast feeding, you can have pumps at home, 6 months, 6 weeks, 3 years. Once the baby has teeth, it is more challenging, but it depends on the individual. You can keep this going for a long time.
secretion of GnRH
pulsitile secretion
pulse generator is in the hypothalamus
profertility when it’s pusitile
antifertility (pharmacologic) endo or exo - suppresses pituitary
hypothyroidism mechanism of amenorrhea
TRH causes prolactin secretion
if hypothyroid - high TRH will turn on prolactin which will inhibit GnRH (inhibits FSH and LH and leads to low estrogen)
irregular periods
if correct hypothyroid - restore cycles
proliferative/follicular phase
GnRH –> AP makes FSH –> FSH tells ovaries to have follicles grow and make estradiol –> estradiol stimulates endometrial proliferation in uterus
asherman’s syndrome
outflow obstruction
responsible for 7% of secondary amenorrhea
endometrial lining scarred by surgery or infection
for pregnancy related hemorrhage, abortion, utermine surgery, endometritis due to TB or schistisome
bands of scarring - E is normal but no build up of lining
mucus ferning
rise in estrogen increases production and causes thinning of cervical mucus which allows sperm to penetrate the cervic more easily
the ability of cervical mucus to stretch is referred to as spinnbarkeit
3 types of estrogent in pregnancy?
•estradiol, estriol, and estrone
activan
activates FSH
FSH/granulosa cells/activates aromatase
kisspeptin
encoded by KISS 1
gatekeeper of puberty
modulates GnRH secretion, feedback?
ductal v lobular carcinoma
lobular - has more open space, can be bigger before we see it!
LH surge
when estrogen peaks it’s the only time there is a reversal to POSITIVE feedback causing LH surge
may be rate of rise of estrogen
ovulation about 10-12 hours after LH surge
When in menstrual cycle does body temperature rise?
luteal phase
if doesn’t rise - not ovulating
theca cell stimulation
stimuated by LH
take cholesterol and make androgens - send to granulosa cells
dominant follicle
- has the highest concentration of FSH receptors
- has the highest level of aromatase activity
- has the greatest estradiol production
one follcle per month devlops to maturity and ovulation
prolactin and amenorrhea
inhibits pulsatile GnRH!
ihibits FSH and LH - no ovulation
low estrogen production!!
high prolactin = low FSH, LH, estradiol
see it in:
hypothyroid
pregnancy
lactation
breast stimulation
gonadotrophs
anterior pituitary cells
GnRH binds to G protein linked GnRH receptors on the surface of gonadotrophs
make FSH, LH
neural responses to baby crying
•This happens through the brain. When the baby sucks, you get a message through spinal cord. This increases prolactin, and increases milk. There is also an increase in oxytocin and increase in excretion that way.
•
- In the beginning, the mom can respond to a baby cry. What’s been shown that any baby can cause milk coming out of nipples (milk let down). Because the mother is anticipating the feeding.
- Within 3-4 days, mom can unknowingly differentiate her baby’s cry from other babies cry.
- But, there are lots of mistakes so in the beginning of breast feeding, many women will have breasts that leak.
- Over time, this response becomes fine-tuned so the basal prolactin level is only slightly above normal
- When sucking occurs, prolactin increases, oxytocin is there and milk is excreted.
prolactin release controls
inhibited by dopamine
stimulated by TRH
prolactin inhibits GnRH!
levels rise during pregnancy!!
pathophysiology of hot flushes
Why do people get hot flushes? We think it has something to do with the hypothalamic thermoregulatory zone [specifically the anterior hypothalamic nucleus] and the sensation of where temperature is. As this zone diminishes or decreases, the sweating threshold definitely lowers, and so the same temperature will feel hot.
-/-
This graphic demonstrates that in symptomatic women the thermoneutral zone is narrower. The sweating threshold deceases and the shivering threshold increases. It demonstrates how small core body temperature elevations can trigger hot flashes more easily within the narrow thermoneutral zone.
Freedman and colleagues suggested that elevated norepinephrine in the brain narrows the thermoregulatory threshold zone in symptomatic postmenopausal women.
