Term
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Definition
prevention of pregnancy through action of compounds (sex steroid analogs) on the hypothalamic-pituitary-reproduction axis
primarily, conception (fusion of male and female gametes) is prevented through action of compounds (estrogens and progestins) on the reproductive system
the compounds may be delivered orally, vaginally, transdermally, through implants or injetions |
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Term
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Definition
first half of the menstrual cycle
ends at ovulation
characterized by development of the follicle in the OVARY
refers to maturation of a dominant ovarian follicle in the first half of the menstrual cycle
the developing follicle produces increasing amounts of estrogen |
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Term
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Definition
first half of the menstrual cycle
ends at ovulation
characterized by growth of ENDOMETRIUM
refers to maturation of the endometrium in response to estrogen produced by the follicle
the endometrium is preparing for implantation of a fertailized egg
occurs in parallel with the follicular phase |
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Term
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Definition
second half of the menstrual cycle
begins after ovulation
refers to process in OVARY
begins with formation of corpus luteum (after ovulation)
the corpus luteum produces estrogens and progesterone |
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Term
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Definition
second half of menstrual cycle
begins after ovulation
refers to ENDOMETRIUM process
presence of progesterone (from corpus luteum) causes endometrium to switch to secretory phase
the endometrium has increased blood supply and is ready for implantation of a blastocyst (early embryonic stage; 50-100 cells)
occurs in parallel with luteal phase |
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Term
| hypothalamic pituitary reproduction axis |
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Definition
[image]
1) the hypothalamus secretes gonadotropin releasing hormone (also known as luteinizing hormone releasing hormone) into the hypothalamic pituitary poral system in a pulsatile pattern (peaks and troughs at a frequency of 1-2 peaks per hour)
2) GnRH stimulates cells in the anterior pituitary gland to synthesize and release luteinizing hormone and follicle stimulating hormone
3) LH and FSH promote ovarian and testicular synthesis of estrogens and androgens
4a) estrogen (usually) and testosterone inhibit release of GnRH, LH, and FSH; negative feedback on both the hypothalamus and anterior pitutitary
4b) just before and at ovulation estrogen stimulates LH release; mechanims of LH spike right before ovulation
5) ovaries and testes secrete inhibit, which selectively inhibits FSH secretion (activin promotes FSH secretion) |
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Term
| hypophyseal portal system |
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Definition
[image]
1) neurons in the hypothalamus produce GnRH (among other factors)
2) the nearby capillary bed is fenestrated (GnRH enters the capillaries)
3) GnRH flows through the portal vein toward the second capillary bed
4) GnRH diffuses out of the capillary bed
5) stimulates the anterior pitutitary to produce LH and FSH which then enters the systemic circulation
by contrast, axons originating in the hypothalamus release factors directly into the posterior pitutitary
good general definition of portal venous system: blood flow that has 2 capillary beds
another example of a portal venous system is the hepatic portal system |
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Term
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Definition
[image]
the ovary performs 2 major functions in reproduction: production of a fertilizable ovum and preparation of the endometrium for implantation through sequential secretion of estrogen and progesterone
LH and FSH promote maturation of a follicle and production of estrogen by granulosa cells; immediately before mid-cycle, estrogen has a positive feedback effect on LH and FSH production; ovulation (release of mature ovum from follicle) occurs soon after sharp increase in LH and FSH production; the corpus luteum then produces estrogen and progesteron; the progesterone causes switch of endometrium from proliferative phase to the secretory phase
thecal cells express LH receptor and produce androgen (mainly androstenedione) in response to LH; granulosa cells express FSH receptors and produce aromatse (the enzyme that converts androstenedione to estrogen) |
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Term
| production of estrogen in the ovaries |
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Definition
[image]
production of estrogen in ovaries involves 2 cell types: thecal cells and granulosa cells
LH promotes androgen (androstenedione) synthesis in thecal cells
androgen then diffuses into nearby granulosa cells
the androstenedione can be converted to testosterone
aromatase catalyzes the conversion of androgens to estrogens (androstenedione to estrone; testosterone to estradiol)
FSH increases aromatase activity in granulosa cells, promoting the conversion of androgen to estrogen
receptors for LH and FSH are seven transmembrane spanning GPCRs |
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Term
| characteristics of sex hormone receptors |
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Definition
the receptors for sex hormones (estrogen, testosterone, and progesterone) possess five main characteristics:
1) NUCLEAR LOCALIZATION
the receptors are synthesized by ribosomes (like all proteins) in the cytoplasm
the receptors have nuclear localization signals causing them to be importaed into and reside in the nucleus or translocated to the nucleus after ligand binding
2) HORMONE BINDING
nuclear receptors bind ligands (sex hormones)
the hormone binding domain is a hydrophobic pocket
3) RECEPTOR DIMERIZATION
after hormone binding, the receptors undergo a conformational change and dimerize
4) DNA BINDING
the DNA binding domains of the dimerized nuclear receptors recognize HRE (hormone response elements) in the promoter regions of target genes
5) REGULATION OF TRANSCRIPTION
through recruitment of coactivators or repressors, activated (dimerized) nuclear receptors increase or decrease gene transcription |
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Term
| general domain structure of nuclear receptors |
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Definition
[image]
all nuclear receptors have a common arrangement of domains (A-F) that give the receptor the characteristics described in the previously
particular characteristics (DNA-binding, dimerization, nuclear localization, ligand binding) can be assigned to certain domains (amino acid sequences) as indicated by the horizontal bars in the above figure
the A/B domain can weakly activate gene expression in the absence of hormone
the function of the F domain is unknown |
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Term
| relative binding affinities of endogenous and exogenous estrogens |
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Definition
[image]
the table compares affinities of endogenous and exogenous estrogens (synthetic and natural, steroid and non-steroid) for the estrogen receptor subtypes
the compounds have different affinites for the subtypes
17-beta-estradiol has the highest affinity of the endogenous estrogens (higher number means higher affinity)
estradiol has equal affinity for alpha and beta subtypes
two different estrogen receptor subtypes in the nucleus exist (alpha and beta) encoded by separate genes
the two ER subtypes can homo- or hetero-dimerize
note: a GPCR for estrogens exists (in plasma membrane); this receptor mediates non-genomic effects of estrogen |
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Term
| sex hormone receptor signaling |
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Definition
[image]
the above figure illustrates the general mechanism of action of hormones on cells
a hormone or pro-hormone diffuses across the cell membrane and enters the cytosol
the hormone diffuses into the nucleus and binds the nuclear receptor
the receptor dimerizes
the dimer binds the upstream hormone response element (HRE) and regulates transcription of target genes causing a change in phenotype
[image]
estradiol (E2) binds the estrogen receptor (ER) inducing a conformational change which causes the receptor to dimerize
ligand binding also regulates interaction of the transcription complex with coactivators (CoA) and corepressors (CoR)
the tissue expression of CoA and CoR is important in determining the response to estrogen
CoA increases gene expression
CoR decreases gene expression
expression of genes with estrogen response elements (ERE) are affected by presence of estrogen
the ERE is a DNA sequence that binds to the dimerized estrogen receptor
bottom of figure shows the domain (A-F) organization of the receptor as shown previously |
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Term
| physiologic effects of estrogens |
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Definition
FEMALE SECONDARY SEX CHARACTERISTICS
needed for development of secondary sex characteristics (features that distinguish the sexes other than the reproductive system) in females
secondary sex characteristics include for example, bone structure, location of fat deposits, amount and location of body hair, digit ratio
REPRODUCTIVE SYSTEM DEVELOPMENT
need for normal development of the reproductive system (ovaries, fallopian tubes, vagina, uterus)
MENSTRUAL CYCLE
normally estrogen inhibits production of LH and FSH except right before ovulation when estrogen causes the LH surge
estrogen promotes proliferation of the endometrium
BONE METABOLISM
estrogen is important for maintenance of bone mass
directly regulates bone metabolism through estrogen receptors on osteoclasts and osteoblasts
LIPID METABOLISM
alters serum lipid profile (associated with elevated triglycerides, lower total cholesterol, increased HDL and decreased LDL) |
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Term
| physiologic effects of progestins |
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Definition
MENSTRUAL CYCLE
promote secretory phase of endometrium
the decline of progesterone at end of cycle contributes to onset of menstruation
PREGNANCY
corpus luteum-embryo interaction
progesterone is essential for the maintenance of pregnancy (supports early stages of embryonic development)
produced by corpus luteum in response to human chorionic gonadotropin (hCG) produced by early embryo
the embryo will produce hCG which will stimulate the corpus luteum to produce progesterone to support the pregnancy
CNS EFFECTS
responsible for the slight increase in body temperature at mid-cycle during ovulation
METABOLIC
progesterone (and progestins) can alter insulin secretion and lipid metabolism, and decrease effects of aldosterone (for example, decrease sodium reabsorption in renal tubule) |
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Term
| PARACRINE mechanism of progesterone and estradiol in endometrium |
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Definition
[image]
important epithelial effects of estrogen (proliferation, division of epithelial cells denoted by positive effect on DNA synthesis in the cell nucleus shown above) are mediated primarily by estrogen receptor alpha (ER) in stromal cells in a paracrine manner in the endometrium
effects of progesterone on epithelial cells (decreased proliferation, enahnced differentiation and secretion) are mediated primarily by progesterone receptors (PR) in stromal cells
both estrogen and progesterone are involved in angiogenesis (growth of new blood vessels) in the endometrium
the key point in the above figure is the effects of estrogen and progesterone on the epithelium of the endometrium are indirect (in response to estrogen and progesterone the stromal cells release factors which affect epithelial cell division)
the effects of progesterone are NOT direct on the epithelial cells.
under the epithelial cells are stromal cells
progesterone and estradiol act on the STROMAL CELLS (where receptors are located); this causes the stromal cells to produce growth factors which then have effects on epithelial cells = PARACRINE effect |
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Term
| oral contraceptive classification |
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Definition
COMBINATION
tablets contain an estrogfen and a progestin at one or more ratios
oral contraceptives produced in monophasic (single ratio), biphasic (two ratios), or triphasic (three ratios) course over usually a 21 day period
the series of tablets mimic the natural menstrual cycle (except ovulation is prevented)
tablets contain ethinyl estradiol and a progestin (commonly norethindrone (norethisterone), desogestrel, levonorgestrel, or norgestimate)
PROGESTIN ONLY
no estrogen component
tablets have progestin (no estrogen component)
norethindrone and norgestrel
EMERGENCY CONTRACEPTION
high dose pregestin with or without an estrogen
levonorgestrel +/- ethinyl estradiol |
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Term
| estrogens and progestins commonly used in oral contraceptives |
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Definition
the estrogen component of combined oral contraceptives is usually ethinyl estradiol
mestranol is converted to ethinyl estradiol via demethylation
norgestimate is metabolized to levonorgestrel, and desogrestrel is converted to an active metabolite, ketodesogestrel |
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Term
| mechanism of oral contraceptives |
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Definition
COMBINATION
primarily suppression of ovulation and other mechanisms
combination oral contraceptives act primarily to block ovulation
pulse release of GnRH is suppressed, and thus, rise in FSH and LH is suppressed
development of a dominant follicle and release of an ovum does not occur
estrogen component maintains stability of the endometrium (prevents unwanted bleeding)
the rate of ovulation inhibition is not high enough to completely explain the efficacy in preventing pregnancy
therefore oral contraceptives act through additional (although minor) mechanisms (viscosity of cervical mucus is increased, transport (peristalsis) in fallopian tubes is decreased, and interference with implantation of blastocyst)
PROGESTIN ONLY
cervical environment, altered endometrium
ovulation is blocked by 60-80%
the rate of ovulation inhibition is lower than combination pill
other mechanisms are important (decreeased sperm movement due to more viscous cervical mucus and interference with endometrium implantation (altered endometrium))
EMERGENCY CONTRACEPTION
high dose
thought to interfere with fertilization and implantation
inhibition of ovulation may also occur |
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Term
| effects of COMBINED oral contraceptives |
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Definition
1. cardiovascular
2. cancer
3. endocrine/metabolic
reports of adverse effects appeared from use of high dose oral contraceptives in the 1960-70s
today, overall consensus is that current (low dose) preparations of combined oral contraceptives pose very little or no health risk in women of reproductive age with no additional risk factors (benefits out weight the risks in certain subpopulations)
however, in women with underlying disease or other risk factors, adverse effects of oral contraceptives may be significant
effects (beneficial and adverse) or oral contraceptive use may be classified into one of three categories (cardiovascular, cancer, endocrine/metabolic)
THIS APPLIES ONLY TO THE COMBINED PRODUCTS! |
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Term
| relative risk and incidence of VENOUS THROMBOEMBOLISM |
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Definition
[image]
the above table shows relative and absolute risk of venous thromboembolism in different populations
low-dose oral contraceptive population is slightly higher than young women in general population
note the Leiden mutation has a significant effect on risk in a person taking oral contraceptives
the Leiden mutation (named after the city in the Netherlands where it was discovered) causes a hypercoagulation state (thrombophilia); the mutations cause an amino acid change in factor V that results in less proteolytic cleavage (inactivation) by protein C (the mutant factor V is resistant to inactivation by protein C); the frequency is about 5% in the US (heterozygotes + homozygotes)
[image]
the intrinsic and extrinsic pathways (details not shown) provide activated factor X (Xa) for the common pathway as illustrated above
activated factor V (Va) forms a complex with Xa
the Va-Xa complex catalyzes production of activated thrombin (IIa)
normally, protein C regulates the common pathway through degradation (red arrow) of Va
in patients with Leiden mutation, Va is resistant to the proteolytic activity by protein C, thus resulting in a hypercoagulation state (thrombophilia because of more activated V) |
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Term
| incidence of MYOCARDIAL INFARCTION in reproductive age women |
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Definition
[image]
the above data shows the increased risk of MI in smokers over 35y taking oral contraceptives (nearly 100x greater risk compared to general population
women over 35y who smoke should not use hormonal contraceptives
progestins alone are associated with increased LDL and decreased HDL
estrogen alone is associated with increased HDL and decreased LDL
combined oral contraceptive administration has little or no effect on serum lipid profile (a few studies reported small increase in serum triglycerides)
the effect of OCs on cardiovascular health is thought to be unrelated to serum lipid profile |
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Term
| effects of COMBINED oral contraceptives: CANCER |
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Definition
ENDOMETRIAL - decreased
OVARIAN - decreased
BREAST - none or small increase
combined oral contraceptive use decreases incidence of endometrial cancer by 40-50%
the decrease is attributed to the effects of the progestin component on the endometrium (progestins oppose the proliferative effect of estrogen) which persists for years after stopping use
incidence of ovarian cancer is also reduced
some studies report a small increase in relative risk of breast cancer |
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Term
| steroid receptor binding affinities of progestins |
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Definition
[image]
the above table lists the binding affinities of progestins for different steroid receptors; ideally a progestin would have affinity only for the progesterone receptor
which progestins would most likely alter serum potassium?
gestodene and drospirenone through actions on the mineralocorticoid receptor
aldosterone regulates Na and K
normally aldosterone binds to the mineralocorticoid receptor in the kidney and holds onto Na and secretes K
the progesterone component is antagonizing the effects of aldosterone causing an increase in K (hyperkalemia) |
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Term
| drug interaction between oral contraceptives and antibiotics |
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Definition
coadministration of antibiotics with OCs may decrease the pharmacologic effects of the OCs
possibly because of altered steroid gut metabolism secondary to changes in the intestinal flora
menstrual irregularities (spotting) and pregnancy may occur
an alternate or additional form of birth control may be advisable during concomitant use |
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Term
| regulation of GnRH production |
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Definition
[image]
the above figure illustrates the regulation of the hypothalamic-pituitary-gonadal axis
this figure has information in addition to the previous figures
the secretion of GnRH from the hypothalamus is affected by many factors (indicated by arrows pointing into the hypothalmus)
estrogen and progesterone were previously discussed
neurotransmitters (dopamine, NE, and serotonin), opioids, and coriticotropin releasing hormone (CRH) also modulate GnRH release as indicated by the plus and minus signs
these neurotransmitters and hormones come from endogenous sources and their levels or effects can be altered by drugs, environmental factors (emotional stress, diet, exercise) and disease (depression)
the complex regulation of GnRH by these inputs is the basis for understanding certain etiologies of infertility
FSH and LH are comprised of one alpha and one beta subunit
FSH and LH share the same alpha subunit, but have unique beta subunits |
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Term
| GnRH production and release |
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Definition
[image]
pre-pro GnRH
the non-processed (pre-pro) LHRH (GnRH) peptide sequence
the GnRH gene encodes a precursor protein named pre-pro-GnRH in the neuronal body of the hypothalamus
pre-pro-GnRH is a 92 amino acid protein
the biologically active decapeptide is sandwiched between the 23 aa signal peptide and the GAP sequence (56 aa)
[image]
processing and transport of LHRH (GnRH)
the pre-pro sequence is processed in the cell body of the neuron (the signal peptide is removed and the C-terminal 56 aa peptide is cleaved to release GAP) resulting the active decapeptide
both GnRH and GAP are transported through the axon to the nerve terminal and released (in a pulsatile manner) after depolarization into the portal circulation which goes to the anterior pituitary to stimulate LH and FSH |
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Term
| pulsatile GnRH release is essential to maintain normal LH and FSH |
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Definition
[image]
GnRH is normally released into the portal circulation in a pulsatile fashion (one peak (pulse) every 1-2 hours)
increasing pulsatile frequency of GnRH release causes stimulation of the pituitary to release more LH and FSH
if GnRH is administered continuously (for example intravenously or from a depot preparation) LH and FSH serum levels decline
LH and FSH levels are restored when pulsatile GnRH is returned
generally GnRH administration outside a normal range of amplitude or frequency will cause LH/FSH decline (common types of anovulation are associated with abnormal GnRH release from the hypothalamus) |
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Term
| major etiologic categories of anovulation |
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Definition
there are many different causes of infertility arising from problems in both male and female partners
the pathophysiology of female infertility has many causes and is complex
a major cause of female infertility is anovulation (failure to release a mature ovum)
major etiologic categories of chronic anovulation:
1) FUNCTIONAL HYPOTHALAMIC ANOVULATION
there is no observable anatomic neuroendocrine problem or genetic abnormality in the pateitn but ovulation does not occur
a more subtle, aberrant (and reversible) pathway regulation in the hypothalamic-pituitary-gonadal axis is thought to be the cause
abnormal GnRH secretion in these patients is often associated with excessive exercise, emotional stress, malnutrition or caloric restriction, and depression
2) HYPERPROLACTINEMIA
high serum prolactin can cause anovulation
hyperprolactinemia can be caused by, among others, hypothyroidism, chronic dopamine antagonist (anti-psychotics) use and pituitary tumors
3) ANDROGEN EXCESS (PCOS)
high serum androgens (testosterone and dihydrotestosterone) inhibit ovulation
a very common cause of androgen excess in females is polycycstic ovarian syndrome (PCOS)
PCOS is characterized by infertility, high serum androgen, hirsutism, and multiple follicular cysts in the ovaries
4) PREMATURE OVARIAN FAILURE
defined as early (less than age 40) depletion of ovarian follicles
on average this normally occurs around age 50
there are many causes of premature ovarian failure (autoimmune disease, chronic infection, genetic abnormalities, chemotherapy, radiation)
5) CHRONIC ILLNESS
ex - hepatic or renal failure, acquired immunodeficiency syndrome
chronic disease may cause anovulation through many different mechanisms
note: the first approach to infertility is to treat the underlying cause |
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Term
| pharmacotherapy of anovulation: ovulation stimulants |
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Definition
human choriogonadotropin
choriogonadotropin alfa
follitropins (follitropin alfa, follitropin beta, urofollitropin)
lutropin alfa
menotropins
clomiphene
the above are used for treatment of anovulation (not due to premature ovarian failure) and in assisted reproductive technology procedures
most are purified or recombinant peptides
one is a small molecule (clomiphene) |
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Term
| MOA of ADRs of human choriogonadotropin (hCG) and choriogonadotropin alfa |
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Definition
human choriogonadotropin (hCG):
purified from urine
can replace LH action
rused to induce ovulation
choriogonadotropin alfa:
recombinant hCG
FSH, LH, hCG, and TSH (thyroid stimulating hormone) are peptide hormones comprised of 2 subunits (alpha and beta)
the 4 hormones have the same alpha subunit, but different beta subunites which confers unique activity and specificity
the beta subunit of LH and hCG are very similar
LH and hCG act on the same receptor, thus hCG can be used to replace the action of LH surge
choriogonadotropin alfa is a recombinant form of hCG produced in Chinese hamster ovary (CHO) cells
properties are the same as hCG
ADRs:
ovarian enlargement
ovarian hyperstimulation syndrome
multiple births
adverse effects include uncomplicated enlargement of ovaries (resolves after administration stopped) and more serious ovarian hyperstimulation syndrome (OHSS)
OHSS is characterized by increased vascular permeability causing mild abdominal distention to more serous ascites accumulation or other third space accumulation
hypovolemia (decreased blood volume) and hemoconcentration (increased cell component/concentration of blood) may occur
production of vascular endothelium growth factor (VEGF) and other factors from the ovary are thought to cause increased vascular permeability
exogenous stimulation of the ovaries can cause release of multiple mature ova |
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Term
| MOA and ADRs of follitropins (follitropin alfa, follitropin beta, urofollitropin), lutropin alfa, and menotropins |
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Definition
follitropins (follitropin alfa, follitropin beta, urofollitropin):
recombinant and purified FSH
stimulates follicular development
followed by hCG or choriogonadotropin alfa
follitropin alfa and beta are recombinant forms of FSH differing only in the carbohydrate chain composition
urofollitropin is purified from female urine
they are used in conjunction with hCG or choriogonadotropin alfa to induce follicular development and ovulation
lutropin alfa:
recombinant LH
lutropin alfa is a more recently marketed, recombinant form of LH used to replace LH surge (especially in women with more severe LH deficiency)
menotropins:
partialy purified LH and FSH from urine
menotropins are an extract from femal urine (contains LH, FSH, and other proteins)
ADRs:
ovarian enlargement
ovarian hyperstimulation syndrome
multiple births |
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Term
| MOA and ADRs of clomiphene |
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Definition
estrogen receptor ligand
agonist and antagonist activity
ovulation stimulant
mechanism: blocks negative feedback inhibition
clomiphene is a mixture of cis and trans isomers with estrogen receptor agonist (estrogenic) and antagonist (anti-estrogenic) activity, respectively; the net effect of clomiphene is thought to be anti-estrogenic
the drug is administered daily for 5 dyas
the mechanism is thought to be the estrogen receptor antagonist activity on the hypothalamus and pituitary (relieving negative feedback from endogenous estrogen causing risk in LH and FSH)
7 days after the last dose the body can sense endogenous estrogen causing the LH surge
ADRs:
visual changes
OHSS
ovarian enlargement
vasomotor symtpoms
adverse effects include blurring or other visual symptoms such as spots of flashes (scintillatig scotomata) and ovarian hyperstimulation syndrome (OHSS)
ovarian enlargement and vasomotor hot flashes are common (caused from estrogen withdrawal)
[image]
clomiphene (clomid) administered days 1-5
if treatment is successful, rises in estrogen, LH, FSH, and progesterone should occur as shown in the above graph
intercourse is timed to coincide with expected ovulation |
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Term
| ovulation induction and assisted reproductive technology protocol |
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Definition
[image]
controlled ovarian stimulation is used for preparation for an assisted reproductive technology such as in vitro fertilization or ovulation induction
generally, exogenous hormone preparations are administered in a manner that simulates the natural menstrual cycle
1) follicle development is stimulated with gonadotropin (follitropins) injections that begin about 3 days after menses start
2) when the follicles are ready as assessed by measurement of serum final oocyte (ovum) maturation is induced by an injection of hCG
3) shorthly thereafter, oocytes are retrieved (or not in the protocol for ovulation induction) and fertilized in vitro, the luteal phase is supported with injections of progesterone (the in vitro fertilized eggs (blastocysts) are returned)
4) to prevent a premature luteinizing hormone surge, endogenous gonadotropin secretion is inhibited during the follicular phase with either a GnRH agonist (continuous administration) or a GnRH antagonists (not shown in above figure) |
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