Reproduction 4: Female Repro (Continued) Flashcards
what is primary amenorrhea?
absence of menses in a phenotypic female by age 17
What are some common causes of primary amenorrhea?
disorders of sexual differentiation
What are some disorders of sexual differentiation that can result in primary amenorrhea?
Turner’s Syndrome: no ovaries
Complete androgen resistance (testicular feminization): no ovaries
Hormonal disorders in ovaries, adrenals, thyroid, pituitary/adrenal/hypothalamic axis
What is secondary amenorrhea?
cessation of menstruation for longer than 6 months
What are the main causes of secondary amenorrhea?
pregnancy, lactation, menopause
What are some less common causes of secondary amenorrhea?
prolactinoma
panhypopituitarism
What is the problem with a prolactinoma?
excess prolactin inhibits GnRH
What is oligomenorrhea?
infrequent periods (cycle length >35 days)
What is the most common cause of oligomenorrhea?
Changes due to functional abnormalities in CNS mechanisms that regulate GnRH release, including stress and illness
What are some other causes of oligomenorrhea?
changes in body fat composition (very low levels)
Intense exercise, extreme weight loss, anorexia nervosa – no consistent changes in plasma gonadotropins or ovarian steroids
What is dysmenorrhea?
painful menses
What are some causes of dysmenorrhea?
prostaglandin released during menses can cause uterine contractions which may be severe enough to cause ischemia and pain
What is a social result of dysmenorrhea?
single most common cause of female work/school absenteeism
What is prostaglandin synthesis promoted by?
E2, followed by progesterone
How do you treat dysmenorrhea?
prostaglandin synthesis inhibitors, oral contraceptions
What is premenstrual syndrome and premenstrual dysphoric disorder?
physical and behavioral symptoms that interfere with normal life, 30% women with normal cycles
What are the symptoms of PMS?
abdominal bloating, extreme sense of fatigue, breast tenderness, labile mood, irritability, depression, tension
What is a treatment of PMS and what has been shown not to work?
linked to cycle, but no clear link to progesterone - progesterone replacement therapy doesn’t work
vitamin supplement also doesn’t work
SSRI first line treatment if socioeconomic dysfunction present
What is hirsutism?
inappropriate hair growth in androgen sensitive areas (beard area, back, etc.)
What are some causes of hirsutism?
excessive androgen intake
excessive androgen production by adrenals (adrenal hyperplasia, cushing’s)
idiopathic increases in sensitivity to androgens
What is virilization?
includes hirsutism and more pronounced evidenc eof androgen stimulation, such as deepening voice, clitoral hypertrophy, temporal balding, male pattern skeletal development
What is the cause of virilization?
excessive androgen production
What is polycystic ovarian syndrome (PCOS)?
accumulation of preantral follicles that become cysts
What is a root cause of PCOS?
insulin resistance and obesity –> causes of and caused by PCOS
High insulin stimulates androgen production (causing infertility) and increased conversion to estrogens (weight gain)
What is a consequence of PCOS on the ovaries?
follicle development impaired, ovulation is not complete, and the follicles degenerate into cysts. ovaries can double (or more) in size
What is PCOS a leading cause of?
infertility
What are some symptoms of PCOS?
sleep apnea (consistent with obesity), oligomenorrhea, obesity, acne, decreased HDL and increased triglycerides, hirsutism
What is the treatment for PCOS?
weight loss, smoking cessation, Metformin
Metformin alone is often sufficient to restore fertility
Clomiphene also effective
What are the three types of estrogen?
E1 - estrone
E2 - 17-beta-estradiol
E3 - estriol
What are the general features of estrone (E1)?
produced in higher amounts after menopause, lower affinity for estrogen receptor
What are the general features of estradiol (E2)?
primary circulating hormone during reproductive years, higher binding affinity for estrogen receptors
What are the general features of estriol (E3)?
produced by the placenta - only high during pregnancy
also converted from estrone in the liver
weak binding to estrogen receptors
How are estrogens transported in the blood?
38% bound to SHBG
60% bound to albumin
1-2% free
How are estrogens processed by the target tissues?
high conversion in target tissues by aromatase - high local concentrations
What are some diseases associated with a loss of estrogen (menopause)?
alzheimers, stroke, cardiovascular disease, osteoporosis, ovarian cancer, breast cancer, uterine cancer
What kind of receptor are estrogen receptors (ERs)?
nuclear steroid hormone receptors
What are the two kinds of estrogen receptors, and what are their general features?
ER-alpha: mediate most reproductive effects of estrogen (knock out mice are infertile)
ER-beta: mediates non-reproductive effects (mood, cardioprotection, neuroprotection). ER-beta knock out mice are subfertile
Which ER does E2 bind?
both, with equal affinity
Which receptor has a higher affinity for plant-derived estrogens (e.g. from soy)?
ER-beta
What are selective estrogen receptor modulators (SERMs)?
synthetic compounds specifically designed to target ERs
What do SERMs do?
can bind both ERalpha and ER beta and have tissue specific actions
ex: tamoxifen, clomiphene
What does tamoxifen do?
Tamoxifen is an antagonist in the breast and uterus, but an agonist in bone and the brain
What does clomiphene do?
originally designed to treat oligomenorrhea
selective for ER alpha, very low binding to ER beta
antagonist for ERalpha, specific for hypothalamus (blocks negative feedback)
induces ovulation
What are the progesterone receptors, and what increases their expression?
PR A and B
nuclear steroid hormone receptor family
E2 upregulates
How is progesterone (P4) transported?
mostly bound to albumin, very low affinity for SHBG
What are the actions of progesterone?
prepares endometrium for implantation of embryo (proliferation, synthesis of enzymes that lyse zona pellucida)
inhibits myometrium contractions (maintains pregnancy)
stimulates mammary gland development (preparation for lactation)
antagonizes actions of estrogen (important consideration in hormone replacement therapy)
What are the hormonal changes in menopause?
depletion of ovarian follicles results in decreased E2 and P4 production, and decreased inhibins
the loss of negative feedback increases FSH and LH (FSH>LH)
What are women in menopause at increased risk for, and why?
osteoporosis: E2 stimules OPG (protective for bone)
Cardiovascular disease: E2 protects against cardiac hypertrophy and reduces cholesterol
Vascular flushing (hot flashes): increased gonadotropins results in increased core body temp, reflex vasodilation
dementia: E2 is neuroprotective
vaginal atrophy and dryness: decreased E2induced cellular proliferation and decreased secretion of cervical mucous
What quadruples between ages 20 and 40?
infertility
What increases with maternal age?
pregnancy complications
What is the site of fertilization, and how many sperm reach this area?
ampulla of oviduct, 50-100 million sperm out of 150-600 million deposited in the vagina reach this area
what helps the sperm reach the ampulla of the oviduct?
vaginal secretions become more alkaline and less viscous
uterine and cervical contractions propel sperm forward
prostaglandin in seminal plasma induces muscle contractility
vaginal secretions prevent semen from coagulating and forming a plug
What is the first step in the fertilization process?
gamete transport
How does the oocyte reach the ampulla?
only one oocyte released from ovary into the peritoneal cavity, cumulus cells help the fimbriae capture the oocyte and direct it towards the oviduct
Where do the first stages of embryonic development occur?
stays about 3 days in the ampulla of oviduct where the start of blastocyst formation occurs - the first few cell divisions
What does the egg enter the uterine cavity as?
a morula (days 3-4)
What is the second step of fertilization?
sperm penetration of oocyte
What is the final step in sperm maturation?
capacitation
What is capacitation?
allows sperm to penetrate the zona pellucida surrounding oocyte
involves removal of protective protein coat
Name and describe the mechanism that allows sperm to breach the zona pellucida
the acrosomal reaction: the sperm binds to ZP3 (glycoprotein) receptors which stimulates increased calcium in the sperm resulting in a release of hydrolytic enzymes
these sperm can then bind ZP2 receptors and the sperm and oocyte membranes can fuse
What prevents multiple sperm from entering an oocyte?
the cortical reaction
describe the cortical reaction
Ca mediated release of cortical granules, these enzymes will prevent ZP3 and ZP2 binding and lead to “hardening” of zona pellucida
Ca release also leads to meiosis II and extrusion of polar body
What does the cortical reaction prevent?
polyspermy - triploid cells not viable
What is “hatching” of the embryo during implantation?
dissolution of the zona pellucida by trophoblast cells
discuss the differentiation of the blastocyst at implantation
trophoblast differentiates into cytotrophoblast and syncytiotrophoblast
What does the cytotrophoblast do?
initially the feeder for continually dividing cells
What does the syncytiotrophoblast do?
adhesion, invasion, endocrine
What do embryos express that facilitates adhesion?
syncytiotrophoblasts secrete adhesive surface proteins (integrins and cadherins)
What is the bridging molecules between the embryo and endometrium?
Osteopontin: E2-dependent secreted by uterine glands
How do stromal cells facilitate adhesion?
Stromal cells form decidua and secrete nutrients. Will later become a barrier and endocrine organ
What is the physical result of embryo invasion?
embryo completely burrows into superficial layers of the endometrium (most invasive of all mammals)
What prevents the trophoblast from penetrating the endometrium to deeply?
balance between decidual cells (defense - inhibitors of MMP, IGF-BP) and trophoblast migration (offense - MMP and IGF2 secretion)
What are lacunae?
fluid filled spaces in the syncytium that make contact with the maternal blood vessels
What forms the chorionic villus?
cytotrophoblasts proliferate and invade the syncytiotrophoblast
describe a mature villus
fetal tissue protruding into maternal blood - the brush border of the syncytiotrophoblast faces maternal blood
Vascular remodeling is essential or fetal life. describe these vascular changes
conversion of high resistance, low capacity to low resistance, high volume vessels
Spiral arteries increase in diameter as the muscular and elastic properties are lost
What is preeclampsia-eclampsia?
relative placental ischemia leads to oxidative stress and endothelial damage. The damaged epithelial cells will increase vasoconstrictors and decrease vasodilators, which will worsen placental hypoperfusion.
Breach of endothelial cell barrier between platelets and basement membrane leads to capillary leak resulting in edema and proteinuria
What is the leading cause of maternal death in developed countries?
preeclampsia-eclampsia
What are the hallmark symptoms of preeclampsia-eclampsia?
hypertension
proteinuria
edema
